WO2021175199A1

WO2021175199A1 - Aromatic heterocyclic compound and application thereof in drug

Info

Publication number: WO2021175199A1
Application number: PCT/CN2021/078555
Authority: WO
Inventors: 杜锋田; 王海波; 张强; 张涛
Original assignee: 上海喆邺生物科技有限公司
Priority date: 2020-03-02
Filing date: 2021-03-01
Publication date: 2021-09-10
Also published as: CN114901663A

Abstract

The present invention provides an aromatic heterocyclic compound, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof as a protein inhibitor, and further provides methods related to the preparation and use of the compound, a pharmaceutical composition comprising the compound, and a relevant method for treating a cancer. The aromatic heterocyclic compound disclosed by the present invention has selective and significant inhibitory activities on proteins, and has broad application prospects in the field of tumor treatments.

Description

一类芳香杂环类化合物及其在药物中的应用A class of aromatic heterocyclic compounds and their application in medicine

技术领域Technical field

本发明涉及一种芳香杂环类化合物，及其制备方法，及该芳香杂环化合物在疾病治疗中的应用。The invention relates to an aromatic heterocyclic compound, a preparation method thereof, and the application of the aromatic heterocyclic compound in disease treatment.

背景技术Background technique

具有芳香杂环结构的小分子化合物，在生命体内起到了重要的生理作用，例如，维生素B2(核黄素)等等。具有氨基取代基的芳香杂环或者芳香环(例如苯环)，构成芳香胺结构，该结构片段在药物分子中普遍存在，除了可以作为有效的分子结构连接片段，也可以作为与药物靶点蛋白相互作用的药效基团，发挥分子药理学作用，例如，以下上市药物，或者处于临床阶段的候选药物分子结构中，均含有芳香胺(苯胺)结构，具有广泛的药理作用。Small molecular compounds with aromatic heterocyclic structure play an important physiological role in the living body, for example, vitamin B2 (riboflavin) and so on. Aromatic heterocycles or aromatic rings (such as benzene rings) with amino substituents constitute an aromatic amine structure. This structural fragment is ubiquitous in drug molecules. In addition to being an effective molecular structure linking fragment, it can also be used as a drug target protein The interacting pharmacophore groups exert molecular pharmacological effects. For example, the molecular structures of the following listed drugs or candidate drugs in the clinical stage all contain aromatic amine (aniline) structures, which have a wide range of pharmacological effects.

RAS蛋白是一种三磷酸鸟苷(Guanosine triphosphate，GTP)结合蛋白，包括有活性的GTP结合构象和无活性的GDP结合构象，两种构象在一定条件下可以相互转化，构成RAS循环，调控多条下游信号通路的激活，RAS被称为细胞信号网络传递中的“分子开关”。临床数据显示，RAS是人类肿瘤中发生突变率最高的基因，所有肿瘤中，约20-30％有RAS突变，大约98％的胰腺癌，52％的结肠癌,43％的多发性骨髓瘤，及32％的肺腺癌中存在RAS基因突变。RAS最常见的突变方式是点突变，其中以第12位密码子突变最常见。KRAS-G12C突变占KRAS突变的约10-20％，在非小细胞肺癌中占14％。The RAS protein is a guanosine triphosphate (GTP) binding protein, which includes an active GTP binding conformation and an inactive GDP binding conformation. The two conformations can be transformed into each other under certain conditions, forming the RAS cycle and regulating multiple The activation of a downstream signaling pathway, RAS is called the "molecular switch" in the transmission of cell signaling networks. Clinical data shows that RAS is the gene with the highest mutation rate in human tumors. About 20-30% of all tumors have RAS mutations, about 98% of pancreatic cancer, 52% of colon cancer, and 43% of multiple myeloma. And 32% of lung adenocarcinomas have RAS gene mutations. The most common mutation mode of RAS is point mutation, among which the mutation at codon 12 is the most common. KRAS-G12C mutations account for about 10-20% of KRAS mutations, and 14% of non-small cell lung cancers.

寻找靶向RAS的药物非常困难。在近年来KRAS-G12C的成药性被发现后，KRAS-G12C抑制剂成为当前药物研发热点领域之一。目前进展较快的在研KRAS-G12C抑制剂主要包括AMG510和MRTX849。It is very difficult to find drugs that target RAS. After the discovery of KRAS-G12C as a drug in recent years, KRAS-G12C inhibitors have become one of the current hot areas of drug research and development. KRAS-G12C inhibitors that are currently undergoing rapid progress mainly include AMG510 and MRTX849.

本发明设计具有通式(AI)，(I)结构的化合物，发现具有此类含芳香胺结构的化合物表现出优异效果。The present invention designs compounds with general formulas (AI) and (I), and finds that compounds with such aromatic amine-containing structures exhibit excellent effects.

发明内容Summary of the invention

本发明提供一种式(AI)化合物，其立体异构体，互变异构体或药学上可接受的盐，The present invention provides a compound of formula (AI), its stereoisomer, tautomer or pharmaceutically acceptable salt,

其中，J为氮原子，或者CH；Among them, J is a nitrogen atom, or CH;

环B为芳基，杂芳基；Ring B is aryl, heteroaryl;

C为以下基团：C is the following group:

其中，“3”位碳原子与环A连接，“7”位碳原子与环B连接；Wherein, the carbon atom at position "3" is connected to ring A, and the carbon atom at position "7" is connected to ring B;

U为氮原子或者CR ^U，其中R ^U为氢或者氘； U is a nitrogen atom or CR ^U , where R ^U is hydrogen or deuterium;

M为氧原子，或者硫原子；M is an oxygen atom or a sulfur atom;

X为氮原子或者CR ¹，Y为氮原子或者CR ²，Z为氮原子或者CR ³； X is a nitrogen atom or CR ¹ , Y is a nitrogen atom or CR ² , and Z is a nitrogen atom or CR ³ ;

R ^a，R ^b各自独立地选自氢，氘，卤素； R ^a and R ^b are each independently selected from hydrogen, deuterium, and halogen;

R ¹，R ²，R ³，R ^d，R ^e各自独立地选自氢，氘，卤素，烷基，氘代烷基，卤代烷基，环烷基，氘代环烷基，羟基，氨基，砜基，磺酰胺基，碳酰胺基，烯基，炔基； ^{^{^{R 1, R 2, R 3}}} , R d, R e are each independently selected from hydrogen, deuterium, halo, alkyl, deuterated alkyl, haloalkyl, cycloalkyl, deuterated cycloalkyl group, a hydroxyl group, an amino group, Sulfone, sulfonamide, carbonamide, alkenyl, alkynyl;

环A为5至12元含氮杂环基，为以下结构：Ring A is a 5- to 12-membered nitrogen-containing heterocyclic group and has the following structure:

R ^15a，R ^15b，R ^17a，R ^17b，R ^17c，R ^17d，R ^17e，R ^17f，R ^17g，R ^17h各自独立地选自氢，氘，卤素，烷基，氘代烷基，烯基烷基，炔基烷基，氘代烯基烷基，氘代炔基烷基； R ^15a , R ^15b , R ^17a , R ^17b , R ^17c , R ^17d , R ^17e , R ^17f , R ^17g , R ^17h are each independently selected from hydrogen, deuterium, halogen, alkyl, deuterated alkyl, and alkenyl Alkyl, alkynyl alkyl, deuterated alkenyl alkyl, deuterated alkynyl alkyl;

或者R ^15a，R ^15b与其连接的氮原子共同组成含氮杂环基团； Or R ^15a , R ^15b and the nitrogen atom to which they are connected together form a nitrogen-containing heterocyclic group;

Q为-C(O)-，-C(S)-，-S(O)-，-S(O) ₂-； Q is -C(O)-, -C(S)-, -S(O)-, -S(O) ₂ -;

L为炔基，烯基，卤代烷基。L is alkynyl, alkenyl, haloalkyl.

本发明提供一种式(I)化合物，其立体异构体，互变异构体或药学上可接受的盐，The present invention provides a compound of formula (I), its stereoisomer, tautomer or pharmaceutically acceptable salt,

其中，环B为芳基，杂芳基；Wherein, ring B is aryl, heteroaryl;

C为以下基团：C is the following group:

M为氧原子，或者硫原子；M is an oxygen atom or a sulfur atom;

环A为5至7元含氮杂环基，为以下结构：Ring A is a 5- to 7-membered nitrogen-containing heterocyclic group and has the following structure:

R ^15a，R ^15b，R ^17a，R ^17b，R ^17c，R ^17d，R ^17e，R ^17f，R ^17g，R ^17h各自独立地选自氢，氘，卤素，烷基，氘代烷基，烯基烷基，炔基烷基，氘代烯基烷基，氘代炔基烷基，且R ^15a，R ^15b不同时为氢； R ^15a , R ^15b , R ^17a , R ^17b , R ^17c , R ^17d , R ^17e , R ^17f , R ^17g , R ^17h are each independently selected from hydrogen, deuterium, halogen, alkyl, deuterated alkyl, and alkenyl Alkyl, alkynyl alkyl, deuterated alkenyl alkyl, deuterated alkynyl alkyl, and R ^15a and R ^{15b are} not hydrogen at the same time;

L为炔基，烯基，卤代烷基；L is alkynyl, alkenyl, haloalkyl;

以下结构片段：The following structure fragment:

选自以下基团：

Selected from the following groups:

环A选自以下基团：Ring A is selected from the following groups:

选自以下基团：

Selected from the following groups:

选自以下基团：

Selected from the following groups:

且，不包括以下的化合物：And, the following compounds are not included:

其中，环B为芳基，杂芳基；Wherein, ring B is aryl, heteroaryl;

环C为以下基团：Ring C is the following group:

M为氧原子，或者硫原子；M is an oxygen atom or a sulfur atom;

R ^d，R ^e各自独立地选自氢，氘，卤素，烷基，氘代烷基，羟基，氨基，砜基，磺酰胺基，碳酰胺基，烯基，炔基； R ^d, R ^e are each independently selected from hydrogen, deuterium, halo, alkyl, deuterated alkyl group, a hydroxyl group, an amino group, a sulfone group, a sulfonamide group, carbonamide group, alkenyl group, alkynyl group;

R ^15a，R ^15b，R ^17a，R ^17b，R ^17c，R ^17d，R ^17e，R ^17f，R ^17g，R ^17h各自独立地选自氢，氘，卤素，烷基，氘代烷基，且，R ^15a，R ^15b不同时为氢； R ^15a , R ^15b , R ^17a , R ^17b , R ^17c , R ^17d , R ^17e , R ^17f , R ^17g , R ^17h are each independently selected from hydrogen, deuterium, halogen, alkyl, deuterated alkyl, and, R ^15a and R ^{15b are} not hydrogen at the same time;

L为炔基，烯基，卤代烷基；L is alkynyl, alkenyl, haloalkyl;

以下结构片段：The following structure fragment:

优选以下基团：

The following groups are preferred:

环A优选自以下基团：Ring A is preferably selected from the following groups:

优选以下基团：

The following groups are preferred:

优选以下基团：

The following groups are preferred:

本发明提供下列化合物，其立体异构体，互变异构体或药学上可接受的盐，The present invention provides the following compounds, their stereoisomers, tautomers or pharmaceutically acceptable salts,

本发明提供一种式(II)化合物，其立体异构体，互变异构体或药学上可接受的盐，The present invention provides a compound of formula (II), its stereoisomer, tautomer or pharmaceutically acceptable salt,

其中，X为氮原子或者CR ⁴，Y为氮原子或者CR ⁵， Where X is a nitrogen atom or CR ⁴ , and Y is a nitrogen atom or CR ⁵ ,

R ¹，R ^2a，R ^2b，R ^2c，R ^2d，R ^2e，R ^2f，R ^2g，R ^3a，R ^3b，R ^3c，R ⁴，R ⁵，R ¹²，R ¹³，R ¹⁴，R ^15a，R ^15b各自独立地选自氢，氘，烷基，氘代烷基，卤代烷基，烯基烷基，炔基烷基，氘代烯基烷基，氘代炔基烷基，且，R ^15a，R ^15b不同时为氢； R ¹ , R ^2a , R ^2b , R ^2c , R ^2d , R ^2e , R ^2f , R ^2g , R ^3a , R ^3b , R ^3c , R ⁴ , R ⁵ , R ¹² , R ¹³ , R ¹⁴ , R ^15a , R ^15b are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkenylalkyl, alkynylalkyl, deuterated alkenylalkyl, deuterated alkynylalkyl, and R ^15a , R ^{15b are} not hydrogen at the same time;

R ^6a，R ^6b，R ^6c，R ^6d，R ^6e，R ^6f，R ^6g，R ^6h各自独立地选自氢，氘，甲基，三氘甲基； R ^6a , R ^6b , R ^6c , R ^6d , R ^6e , R ^6f , R ^6g , and R ^6h are each independently selected from hydrogen, deuterium, methyl, and tri-deuterium methyl;

R ⁷为氢，氟，氯； R ⁷ is hydrogen, fluorine, chlorine;

R ⁸，R ⁹，R ¹⁰，R ¹¹各自独立地选自氢，氘，氟； R ⁸ , R ⁹ , R ¹⁰ , and R ¹¹ are each independently selected from hydrogen, deuterium, and fluorine;

结构片段

Structure fragment

选自以下结构：Selected from the following structures:

结构片段

Structure fragment

选自以下结构：Selected from the following structures:

结构片段

Structure fragment

选自以下结构：Selected from the following structures:

结构片段

Structure fragment

选自以下结构：Selected from the following structures:

本发明提供一种式(II-1)化合物，其立体异构体，互变异构体或药学上可接受的盐，The present invention provides a compound of formula (II-1), its stereoisomer, tautomer or pharmaceutically acceptable salt,

R ¹，R ^2a，R ^2b，R ^2c，R ^2d，R ^2e，R ^2f，R ^2g，R ^3a，R ^3b，R ^3c，R ⁴，R ⁵，R ¹²，R ¹³，R ¹⁴，R ^15a，R ^15b各自独立地选自氢，氘，烷基，氘代烷基； R ¹ , R ^2a , R ^2b , R ^2c , R ^2d , R ^2e , R ^2f , R ^2g , R ^3a , R ^3b , R ^3c , R ⁴ , R ⁵ , R ¹² , R ¹³ , R ¹⁴ , R ^15a , R ^15b are each independently selected from hydrogen, deuterium, alkyl, and deuterated alkyl;

R ⁶为氢，氘，甲基，三氘甲基； R ⁶ is hydrogen, deuterium, methyl, tri-deuterium methyl;

R ⁷为氟，氯； R ⁷ is fluorine, chlorine;

结构片段

Structure fragment

优选以下结构：The following structure is preferred:

其中，结构片段

Among them, the structure fragment

优选以下结构：The following structure is preferred:

结构片段

Structure fragment

优选以下结构：The following structure is preferred:

结构片段

Structure fragment

优选以下结构：The following structure is preferred:

本发明提供下列化合物，其立体异构体，互变异构体，稳定同位素衍生物，药学上可接受的盐，The present invention provides the following compounds, their stereoisomers, tautomers, stable isotope derivatives, pharmaceutically acceptable salts,

本发明提供一种式(III)化合物，其立体异构体，互变异构体或药学上可接受的盐，The present invention provides a compound of formula (III), its stereoisomer, tautomer or pharmaceutically acceptable salt,

R ¹，R ^2a，R ^2b，R ^2c，R ^2d，R ^2e，R ^2f，R ^2g，R ⁴，R ⁵，R ¹²，R ¹³，R ¹⁴，R ^15a，R ^15b各自独立地选自氢，氘，烷基，氘代烷基，烯基烷基，炔基烷基，氘代烯基烷基，氘代炔基烷基，且，R ^15a，R ^15b不同时为氢； R ¹ , R ^2a , R ^2b , R ^2c , R ^2d , R ^2e , R ^2f , R ^2g , R ⁴ , R ⁵ , R ¹² , R ¹³ , R ¹⁴ , R ^15a and R ^15b are each independently selected from hydrogen , Deuterium, alkyl, deuterated alkyl, alkenyl alkyl, alkynyl alkyl, deuterated alkenyl alkyl, deuterated alkynyl alkyl, and R ^15a and R ^{15b are} not hydrogen at the same time;

R ⁷为氟，氯； R ⁷ is fluorine, chlorine;

结构片段

Structure fragment

选自以下结构：Selected from the following structures:

结构片段

Structure fragment

选自以下结构：Selected from the following structures:

结构片段

Structure fragment

选自以下结构：Selected from the following structures:

本发明提供一种式(III-1)化合物，其立体异构体，互变异构体或药学上可接受的盐，The present invention provides a compound of formula (III-1), its stereoisomer, tautomer or pharmaceutically acceptable salt,

R ¹，R ^2a，R ^2b，R ^2c，R ^2d，R ^2e，R ^2f，R ^2g，R ⁴，R ⁵，R ¹²，R ¹³，R ¹⁴，R ^15a，R ^15b各自独立地选自氢，氘，烷基，氘代烷基； R ¹ , R ^2a , R ^2b , R ^2c , R ^2d , R ^2e , R ^2f , R ^2g , R ⁴ , R ⁵ , R ¹² , R ¹³ , R ¹⁴ , R ^15a and R ^15b are each independently selected from hydrogen , Deuterium, alkyl, deuterated alkyl;

R ⁷为氟，氯； R ⁷ is fluorine, chlorine;

结构片段

Structure fragment

优选以下结构：The following structure is preferred:

结构片段

Structure fragment

优选以下结构：The following structure is preferred:

结构片段

Structure fragment

优选以下结构：The following structure is preferred:

结构片段

Structure fragment

优选以下结构：The following structure is preferred:

本发明提供一种式(IV)化合物，其立体异构体，互变异构体或药学上可接受的盐，The present invention provides a compound of formula (IV), its stereoisomer, tautomer or pharmaceutically acceptable salt,

R ⁷为氟，氯； R ⁷ is fluorine, chlorine;

结构片段

Structure fragment

选自以下结构：Selected from the following structures:

结构片段

Structure fragment

选自以下结构：Selected from the following structures:

结构片段

Structure fragment

选自以下结构：Selected from the following structures:

本发明提供一种式(IV-1)化合物，其立体异构体，互变异构体或药学上可接受的盐，The present invention provides a compound of formula (IV-1), its stereoisomer, tautomer or pharmaceutically acceptable salt,

R ⁷为氟，氯； R ⁷ is fluorine, chlorine;

结构片段

Structure fragment

优选以下结构：The following structure is preferred:

结构片段

Structure fragment

优选以下结构：The following structure is preferred:

结构片段

Structure fragment

优选以下结构：The following structure is preferred:

结构片段

Structure fragment

优选以下结构：The following structure is preferred:

本发明提供一种式(V)化合物，其立体异构体，互变异构体或药学上可接受的盐，The present invention provides a compound of formula (V), its stereoisomer, tautomer or pharmaceutically acceptable salt,

R ¹，R ^2a，R ^2b，R ^2c，R ^2d，R ^2e，R ^2f，R ^2g，R ⁴，R ⁵，R ¹²，R ¹³，R ¹⁴，R ^15a，R ^15b，R ^15c各自独立地选自氢，氘，烷基，氘代烷基，烯基烷基，炔基烷基，氘代烯基烷基，氘代炔基烷基，且，R ^15a，R ^15b不同时为氢； R ¹ , R ^2a , R ^2b , R ^2c , R ^2d , R ^2e , R ^2f , R ^2g , R ⁴ , R ⁵ , R ¹² , R ¹³ , R ¹⁴ , R ^15a , R ^15b , R ^15c are each independently Selected from hydrogen, deuterium, alkyl, deuterated alkyl, alkenyl alkyl, alkynyl alkyl, deuterated alkenyl alkyl, deuterated alkynyl alkyl, and R ^15a and R ^{15b are} not hydrogen at the same time;

R ⁷为氟，氯； R ⁷ is fluorine, chlorine;

R ⁸，R ⁹，R ¹⁰，R ¹¹为氢，氘，氟； R ⁸ , R ⁹ , R ¹⁰ , and R ¹¹ are hydrogen, deuterium, fluorine;

结构片段

Structure fragment

选自以下结构：Selected from the following structures:

结构片段

Structure fragment

选自以下结构：Selected from the following structures:

结构片段

Structure fragment

选自以下结构：Selected from the following structures:

本发明提供一种式(V-1)化合物，其立体异构体，互变异构体或药学上可接受的盐，The present invention provides a compound of formula (V-1), its stereoisomer, tautomer or pharmaceutically acceptable salt,

R ¹，R ^2a，R ^2b，R ^2c，R ^2d，R ^2e，R ^2f，R ^2g，R ⁴，R ⁵，R ¹²，R ¹³，R ¹⁴，R ^15a，R ^15b，R ^15c各自独立地选自氢，氘，烷基，氘代烷基； R ¹ , R ^2a , R ^2b , R ^2c , R ^2d , R ^2e , R ^2f , R ^2g , R ⁴ , R ⁵ , R ¹² , R ¹³ , R ¹⁴ , R ^15a , R ^15b , R ^15c are each independently Selected from hydrogen, deuterium, alkyl, deuterated alkyl;

R ⁷为氟，氯； R ⁷ is fluorine, chlorine;

结构片段

Structure fragment

优选以下结构：The following structure is preferred:

结构片段

Structure fragment

优选以下结构：The following structure is preferred:

结构片段

Structure fragment

优选以下结构：The following structure is preferred:

结构片段

Structure fragment

优选以下结构：The following structure is preferred:

本发明提供一种式(VI)化合物，其立体异构体，互变异构体或药学上可接受的盐，The present invention provides a compound of formula (VI), its stereoisomer, tautomer or pharmaceutically acceptable salt,

其中，环E的1位氮原子与环F的1′位的碳原子连接构成的轴手性立体构型为光学纯；Among them, the axial chiral configuration formed by connecting the nitrogen atom at position 1 of ring E and the carbon atom at position 1′ of ring F is optically pure;

X为氮原子或者CR ⁴，Y为氮原子或者CR ⁵， X is a nitrogen atom or CR ⁴ , Y is a nitrogen atom or CR ⁵ ,

R ¹，R ^2a，R ^2b，R ^2c，R ^2d，R ^2e，R ^2f，R ^2g，R ⁴，R ⁵，R ¹²，R ¹³，R ¹⁴，R ^15a，R ^15b为氢，氘，烷基，氘代烷基，烯基烷基，炔基烷基，氘代烯基烷基，氘代炔基烷基，且R ^15a，R ^15b不同时为氢； R ¹ , R ^2a , R ^2b , R ^2c , R ^2d , R ^2e , R ^2f , R ^2g , R ⁴ , R ⁵ , R ¹² , R ¹³ , R ¹⁴ , R ^15a , R ^15b are hydrogen, deuterium, alkane R ^15a and R ^{15b are} not hydrogen at the same time;

R ^6a，R ^6b，R ^6c，R ^6d，R ^6e，R ^6f，R ^6g，R ^6h各自独立地选自氢，氘，甲基，三氘代甲基； R ^6a , R ^6b , R ^6c , R ^6d , R ^6e , R ^6f , R ^6g and R ^6h are each independently selected from hydrogen, deuterium, methyl, and tri-deuterated methyl;

R ⁷为氢，氟，氯； R ⁷ is hydrogen, fluorine, chlorine;

R ¹⁷为氢，烷基，氘代烷基，甲基，乙基，丙基，环丙基，氘代甲基，氘代乙基，氘代丙基，氘代环丙基。 R ¹⁷ is hydrogen, alkyl, deuterated alkyl, methyl, ethyl, propyl, cyclopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated cyclopropyl.

本发明提供一种式(IIIM)化合物，其轴手性立体构型为R构型，其互变异构体或药学上可接受的盐，The present invention provides a compound of formula (IIIM) whose axial chiral configuration is R configuration, its tautomers or pharmaceutically acceptable salts,

其中，R ¹，R ^2a，R ^2b，R ^2c，R ^2d，R ^2e，R ^2f，R ^2g，R ¹²，R ¹³，R ¹⁴，R ^15a，R ^15b各自独立地选自氢，氘，烷基，氘代烷基，烯基烷基，炔基烷基，氘代烯基烷基，氘代炔基烷基，且R ^15a，R ^15b不同时为氢； Wherein, R ¹ , R ^2a , R ^2b , R ^2c , R ^2d , R ^2e , R ^2f , R ^2g , R ¹² , R ¹³ , R ¹⁴ , R ^15a , R ^15b are each independently selected from hydrogen, deuterium, and alkane R ^15a and R ^{15b are} not hydrogen at the same time;

R ^6a，R ^6b，R ^6c，R ^6d，R ^6e，R ^6f，R ^6g，R ^6h各自独立地选自氢，氘，甲基，三氘代甲基； R ^6a , R ^6b , R ^6c , R ^6d , R ^6e , R ^6f , R ^6g , R ^6h are each independently selected from hydrogen, deuterium, methyl, and tri-deuterated methyl;

R ⁷为氢，氟，氯； R ⁷ is hydrogen, fluorine, chlorine;

R ¹⁷为氢，氘，甲基，乙基，氘代甲基，氘代乙基； R ¹⁷ is hydrogen, deuterium, methyl, ethyl, deuterated methyl, deuterated ethyl;

结构片段

Structure fragment

选自以下结构：Selected from the following structures:

结构片段

Structure fragment

选自以下结构：Selected from the following structures:

结构片段

Structure fragment

选自以下结构：Selected from the following structures:

本发明提供下列化合物，其轴手性立体构型为R构型，互变异构体，稳定同位素衍生物，药学上可接受的盐，The present invention provides the following compounds whose axial chiral configuration is R configuration, tautomers, stable isotope derivatives, and pharmaceutically acceptable salts,

本发明提供一种药物组合物，其包括治疗有效剂量的本发明中任一项所述化合物或其立体异构体，互变异构体或药学上可接受的盐及可药用的载体。The present invention provides a pharmaceutical composition, which comprises a therapeutically effective dose of the compound or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier.

本发明中任意一项所述的化合物或其可药用的盐或根据本发明所述的药物组合物，在制备用于预防和/或治疗与KRAS突变介导的癌症有关的疾病的药物中的用途，该用途包括可单独使用本发明中任意一项所述的化合物或其可药用的盐或根据本发明所述的药物组合物，或者与包括免疫疗法在内的其他治疗方法联合使用，预防和/或治疗与KRAS突变介导的癌症疾病。The compound according to any one of the present invention or its pharmaceutically acceptable salt or the pharmaceutical composition according to the present invention is used in the preparation of a medicine for the prevention and/or treatment of cancer-related diseases mediated by KRAS mutations The use includes the use of the compound described in any one of the present invention or its pharmaceutically acceptable salt or the pharmaceutical composition according to the present invention alone, or in combination with other treatment methods including immunotherapy , Prevention and/or treatment of cancer diseases mediated by KRAS mutations.

本发明中任意一项所述的化合物或其可药用的盐或根据本发明所述的药物组合物，在制备用于预防和/或治疗与KRAS G12C突变介导的癌症有关的疾病的药物中的用途，该用途包括可单独使用本发明中任意一项所述的化合物或其可药用的盐或根据本发明所述的药物组合物，或者与包括免疫疗法在内的其他治疗方法联合使用，预防和/或治疗与KRAS G12C突变介导的癌症疾病。The compound according to any one of the present invention or its pharmaceutically acceptable salt or the pharmaceutical composition according to the present invention is used in the preparation of drugs for preventing and/or treating cancer-related diseases mediated by KRAS G12C mutation The use includes the use of the compound described in any one of the present invention or its pharmaceutically acceptable salt or the pharmaceutical composition according to the present invention alone, or in combination with other treatment methods including immunotherapy Use, prevent and/or treat cancer diseases mediated by KRAS G12C mutations.

本发明中的用途，其中所述与KRAS功能有关的各种癌症疾病为肝癌，食管癌，胃癌，肾细胞癌，肉瘤，胆管癌，结肠癌，***癌，卵巢癌，乳腺癌，血液学癌症，胰腺癌，MYH相关息肉癌，结直肠癌，肺癌，子宫癌，间皮瘤，***，膀胱癌。The use in the present invention, wherein the various cancer diseases related to KRAS function are liver cancer, esophageal cancer, gastric cancer, renal cell carcinoma, sarcoma, cholangiocarcinoma, colon cancer, prostate cancer, ovarian cancer, breast cancer, hematological cancer , Pancreatic cancer, MYH-related polyp cancer, colorectal cancer, lung cancer, uterine cancer, mesothelioma, cervical cancer, bladder cancer.

附图说明Description of the drawings

图1：显示中间体3M的单晶衍射结果。Figure 1: Shows the single crystal diffraction results of intermediate 3M.

发明详述Detailed description of the invention

本说明书所使用的所有技术和科学术语均具有本领域普通技术人员通常所理解的含义。All technical and scientific terms used in this specification have meanings commonly understood by those of ordinary skill in the art.

术语“氢”在本文中是指-H。The term "hydrogen" refers herein to -H.

术语“氘”在本文中是指-D。The term "deuterium" refers herein to -D.

术语“卤素”在本文中是指-F，-Cl，-Br和-I。The term "halogen" refers herein to -F, -Cl, -Br and -I.

术语“氟”在本文中是指-F。The term "fluorine" refers herein to -F.

术语“氯”在本文中是指-Cl。The term "chlorine" refers herein to -Cl.

术语“溴”在本文中是指-Br。The term "bromine" refers herein to -Br.

术语“碘”在本文中是指-I。The term "iodine" refers to -I herein.

术语“氰基”在本文中是指-CN。The term "cyano" refers herein to -CN.

术语“氨基”在本文中是指-NH ₂。 The term "amino" refers herein to -NH ₂ .

术语“羟基”在本文中是指-OH。The term "hydroxyl" refers herein to -OH.

术语“烷基”在本文中是指具有1至10个碳原子的饱和脂肪族烃基，该术语包括直链和支链烃基。烷基的非限制性实例包括甲基，乙基，正丙基，异丙基，正丁基，异丁基，仲丁基，叔丁基，正戊基，新戊基，正己基等。本文所述烷基可以任选地被一个或多个下列取代基所取代：氘，氟，氯，溴，碘，氰基，硝基，羟基，羧基，氨基，烷基，烷氧基，酰基，酰氧基，氧代，酰胺基，酯基，胺基，环烷基，环烯基，杂环烷基，烯基，烯氧基，炔基，环烷氧基，杂环烷基氧基，芳氧基，杂芳氧基，芳基或杂芳基。The term "alkyl" herein refers to a saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms, and the term includes straight chain and branched chain hydrocarbon groups. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl and the like. The alkyl groups described herein may be optionally substituted with one or more of the following substituents: deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, carboxy, amino, alkyl, alkoxy, acyl , Acyloxy, oxo, amide, ester, amino, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkenyloxy, alkynyl, cycloalkoxy, heterocycloalkyloxy Group, aryloxy group, heteroaryloxy group, aryl group or heteroaryl group.

术语“芳基”在本文中是指6至10元全碳单环或稠合多环(即共享相邻碳原子对的环)基团，具有共轭的π电子体系的多环(即带有相邻碳原子对的环)基团。芳基可以在产生稳定结构的任意碳原子上与所定义的化学结构共价连接。本文所述芳基可以任选地被一个或多个下列取代基所取代：氘，氟，氯，溴，碘，氰基，硝基，羟基，羧基，氨基，烷基，烷氧基，酰基，酰胺基，酯基，胺基，磺酰基，亚磺酰基，环烷基，环烯基，杂环烷基，烯基，炔基和环烷氧基。The term "aryl" as used herein refers to a 6 to 10-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group, a polycyclic group with a conjugated π-electron system (i.e., with A ring) group with adjacent pairs of carbon atoms. The aryl group can be covalently attached to the defined chemical structure on any carbon atom that results in a stable structure. The aryl groups described herein may be optionally substituted with one or more of the following substituents: deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, carboxy, amino, alkyl, alkoxy, acyl , Amido, ester, amino, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkynyl and cycloalkoxy.

术语“杂芳基”在本文中是指由5至10个原子所组成的并且含有至少一个选自N，O或S等杂原子的芳香族基团。该术语可以具有单个环(非限制性实例包括呋喃，噻吩，咪唑，吡唑，吡啶，吡嗪，恶唑，噻唑等)或多个稠环(非限制性实例包括苯并噻吩，苯并呋喃，吲哚，异吲哚等)，其中稠环可以是或者可以不是包含杂原子的芳香族基团，假定连接点是通过芳族杂芳基基团的原子。本文所述杂芳基可以任选地被一个或多个下列取代基所取代：氘，氟，氯，溴，碘，氰基，硝基，羟基，氨基，烷基，烷氧基，酰基，酰氧基，酰胺基，酯基，胺基，磺酰基，亚磺酰基，环烷基，环烯基，杂环烷基，烯基，炔基和环烷氧基。The term "heteroaryl" herein refers to an aromatic group consisting of 5 to 10 atoms and containing at least one heteroatom selected from N, O or S. The term may have a single ring (non-limiting examples include furan, thiophene, imidazole, pyrazole, pyridine, pyrazine, oxazole, thiazole, etc.) or multiple condensed rings (non-limiting examples include benzothiophene, benzofuran , Indole, isoindole, etc.), where the fused ring may or may not be an aromatic group containing heteroatoms, assuming that the point of attachment is through an atom of the aromatic heteroaryl group. The heteroaryl groups described herein may be optionally substituted with one or more of the following substituents: deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, amino, alkyl, alkoxy, acyl, Acyloxy, amido, ester, amino, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkynyl and cycloalkoxy.

烯基，是一种含有碳碳双键的不饱和烃基。术语“烯基”在本文中是指分子中含有碳碳双键的烷基基团，其中所述烷基如前文中定义。本文所述烯基可以任选地被一个或多个下列取代基所取代：氘，氟，氯，溴，碘，氰基，硝基，羟基，羧基，氨基，烷基，烷氧基，酰基，酰胺基，酯基，胺基，磺酰基，亚磺酰基，环烷基，环烯基，杂环烷基，环烷氧基，巯基，烷基巯基，氘代烷基巯基，砜基，亚砜基，氨基，硅基，膦酰基，氘代烷基，杂环烷基，芳基，杂芳基，炔基，烯基，芳基烷基，酯基。烯基非限制性实例包括乙烯基，丙烯基，烯丙基，异丙烯基，丁烯基，异丁烯基等。Alkenyl is an unsaturated hydrocarbon group containing carbon-carbon double bonds. The term "alkenyl" herein refers to an alkyl group containing a carbon-carbon double bond in the molecule, wherein the alkyl group is as defined above. The alkenyl groups described herein may be optionally substituted with one or more of the following substituents: deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, carboxy, amino, alkyl, alkoxy, acyl , Amide group, ester group, amine group, sulfonyl group, sulfinyl group, cycloalkyl group, cycloalkenyl group, heterocycloalkyl group, cycloalkoxy group, mercapto group, alkyl mercapto group, deuterated alkyl mercapto group, sulfone group, Sulfoxide, amino, silyl, phosphono, deuterated alkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, alkenyl, arylalkyl, ester group. Non-limiting examples of alkenyl groups include vinyl, propenyl, allyl, isopropenyl, butenyl, isobutenyl, and the like.

炔基，是一种含有碳碳三键的不饱和烃基。术语“炔基”在本文中是指分子中含有碳碳三键的烷基基团，其中所述烷基如前文中定义。炔基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自氘，氟，氯，溴，碘，氰基，硝基，羟基，羧基，氨基，烷基，烷氧基，酰基，酰胺基，酯基，胺基，磺酰基，亚磺酰基，环烷基，环烯基，杂环烷基，环烷氧基，巯基，烷基巯基，氘代烷基巯基，砜基，亚砜基，氨基，硅基，膦酰基，氘代烷基，杂环烷基，芳基，杂芳基，炔基，烯基，芳基烷基，酯基。炔基非限制性实例包括乙炔基，1-丙炔基，2-丙炔基，1-，2-或3-丁炔基等。Alkynyl is an unsaturated hydrocarbon group containing carbon-carbon triple bonds. The term "alkynyl" herein refers to an alkyl group containing a carbon-carbon triple bond in the molecule, wherein the alkyl group is as defined above. The alkynyl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl , Carboxy, amino, alkyl, alkoxy, acyl, amide, ester, amino, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, cycloalkoxy, mercapto, Alkyl mercapto, deuterated alkyl mercapto, sulfone, sulfoxide, amino, silyl, phosphono, deuterated alkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, alkenyl, aryl Alkyl, ester group. Non-limiting examples of alkynyl groups include ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like.

术语“杂环基”是指取代的或未取代的饱和或者不饱和且至少含有1至5个选自N，O或S杂原子的芳香环，非芳香环。芳香环，非芳香环可以是3至10元的单环，4至20元的螺环，并环或桥环，杂环基环中选择性取代的N，S可被氧化成各种氧化态。优选3至12元杂环。非限制性实施例包括氧杂环丙烷基，氧杂环丁基，氧杂环戊基，氧杂环己基，氧杂环己基，氧杂环辛基，氮杂环丙烷基，氮杂环丁基，氮杂环戊基，氮杂环己基，氮杂环丙烯基，1,3-二氧环戊基，1,4-二氧环戊基，1,3-二氧环戊基，1,3-二氧环己基，1,3-二硫环己基，氮杂环庚烯基，吗啉基，哌嗪基，吡啶基，呋喃基，噻吩基，吡咯基，吡喃基，N-烷基吡咯基，嘧啶基，吡嗪基，哒嗪基，咪唑基，哌啶基，硫代吗啉基，二氢吡喃，噻二唑基，噁唑基，噁二唑基，吡唑基，1,4-二氧杂环己二烯基等。The term "heterocyclic group" refers to a substituted or unsubstituted saturated or unsaturated aromatic ring containing at least 1 to 5 heteroatoms selected from N, O or S, but not an aromatic ring. Aromatic ring, non-aromatic ring can be 3 to 10 membered monocyclic ring, 4 to 20 membered spiro ring, and ring or bridged ring, heterocyclic ring group selectively substituted N, S can be oxidized to various oxidation states . It is preferably a 3- to 12-membered heterocyclic ring. Non-limiting examples include oxetanyl, oxetanyl, oxetanyl, oxetanyl, oxanyl, oxetanyl, aziridinyl, azetidine Group, azacyclopentyl, azacyclohexyl, azacyclopropenyl, 1,3-dioxolpentyl, 1,4-dioxolpentyl, 1,3-dioxolpentyl, 1 ,3-dioxyl, 1,3-dithiocyclohexyl, azepanyl, morpholinyl, piperazinyl, pyridyl, furyl, thienyl, pyrrolyl, pyranyl, N- Alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, thiomorpholinyl, dihydropyran, thiadiazolyl, oxazolyl, oxadiazolyl, pyrazole Group, 1,4-dioxanyl, etc.

术语“卤代烷基”是指前述定义“烷基”被卤素取代得到的烷基。其中卤素包括。氟，氯，溴，碘等。The term "haloalkyl" refers to an alkyl group in which "alkyl" as defined above is substituted by halogen. Among them, halogen includes. Fluorine, chlorine, bromine, iodine, etc.

术语“烯基烷基”是指前述定义“烷基”被前述定义“烯基”取代得到的烷基。The term "alkenylalkyl" refers to an alkyl group obtained by substituting the aforementioned definition "alkyl" with the aforementioned definition "alkenyl".

术语“炔基烷基”是指前述定义“烷基”被前述定义“炔基”取代得到的烷基。The term "alkynylalkyl" refers to an alkyl group obtained by substituting the aforementioned definition "alkyl" with the aforementioned definition "alkynyl".

术语“含氮杂环基”指含有氮原子的环系，该环系可以“骈合”芳香和非芳香环系，或者通过“螺碳原子”链接其他环系，其中氢原子可以被氘。卤素，烷基取代，例如以下结构：The term "nitrogen-containing heterocyclic group" refers to a ring system containing a nitrogen atom. The ring system can "pure" aromatic and non-aromatic ring systems, or link other ring systems through "spiro carbon atoms", in which hydrogen atoms can be deuterated. Halogen, alkyl substitution, such as the following structure:

等等。

and many more.

术语“酰胺”(或“酰胺基”)包括C-酰胺基团和N-酰胺基团，即分别是-C(O)NR ^AR ^B和-NR ^AC(O)R ^B基团。R ^A和R ^B独立地是如本文定义的氢或者经取代的或未经取代的烷基，烯基，炔基，环烷基，芳基，芳烷基，杂环基烷基或杂环基。酰胺基因此包括但不限于氨基甲酰基(-C(O)NH ₂)和甲酰胺基团(-NHC(O)H)。在一些实施方式中，酰胺是-NR ^AC(O)-(C _1-5烷基)，该基团被称为“羰基氨基”，在另一些实施方式中，酰胺是-NHC(O)-烷基，该基团被称为“烷酰基氨基”。 The term "amide" (or "amido") includes C- and N- amide group amide groups, i.e. is -C (O) NR ^A R ^B, and -NR ^A C (O) R ^B groups. R ^A and R ^B are independently as defined herein is hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl base. Amide groups thus include, without limitation, a carbamoyl group (-C (O) NH ₂₎ and formamide groups (-NHC (O) H). In some embodiments, the amide is -NR ^A C(O)-(C _1-5 alkyl), and this group is referred to as "carbonylamino", in other embodiments, the amide is -NHC(O) -Alkyl, this group is called "alkanoylamino".

术语“磺酰胺”包括S-磺酰胺基团和N-磺酰胺基团，即分别是-SO ₂NR ^CR ^D和-NR ^CSO ₂R ^D基团。R ^C和R ^D独立地是如本文定义的氢或者经取代的或未经取代的烷基，烯基，炔基，环烷基，芳基，芳烷基，杂环基烷基或杂环基。磺酰胺基团因此包括但不限于磺酰基(-SO ₂NH ₂)。在本文的一些实施方式中，磺酰胺是-NHSO ₂-烷基，其被称为“烷基磺酰基氨基”。 The term "sulfonamide" includes S-sulfonamide groups and N-sulfonamide groups, that is, -SO ₂ NR ^C R ^D and -NR ^C SO ₂ R ^D groups, respectively. R ^C and R ^{D are} independently hydrogen as defined herein or substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclic base. Sulfonamide groups therefore include, but are not limited to, sulfonyl (-SO ₂ NH ₂ ). In some embodiments herein, a sulfonamide -NHSO ₂ - alkyl, which is referred to as "alkylsulfonylamino."

本发明还包括同位素标记的本发明化合物，即与上述所公开的结构相同，但该结构中一个或多个原子被与其具有相同质子数但不同中子数的原子所替代。结合本发明化合物的同位素实施例包括氢、碳、氮、氧、硫、氟、氯、碘的同位素，分别如 ²H、 ³H、 ¹³C、 ¹⁴C、 ¹⁵N、 ¹⁸O、 ¹⁷O、 ³⁵S、 ¹⁸F、 ³⁶Cl和 ¹³¹I等。本发明的化合物，其立体异构体、互变异构体或医药上可接受的盐，以及含有上述同位素和/或其他原子同位素的所述以上形式的化合物，均在本发明范围内。某些同位素标记的本发明化合物，如被 ³H或 ¹⁴C所标记的那些化合物可以用于药物组织分布试验中，因此，这些 ³H或 ¹⁴C同位素由于其容易制备和检测是特别优选的。 The present invention also includes isotopically labeled compounds of the present invention, which have the same structure as disclosed above, but one or more atoms in the structure are replaced by atoms having the same number of protons but different numbers of neutrons. Examples of isotopes that combine the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, and iodine, such as ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³⁵ S, ¹⁸ F, ³⁶ Cl and ¹³¹ I, etc. The compounds of the present invention, their stereoisomers, tautomers or pharmaceutically acceptable salts, and compounds in the above forms containing the above-mentioned isotopes and/or other atomic isotopes are all within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as ^{those labeled with 3} H or ¹⁴ C, can be used in drug tissue distribution tests. Therefore, these ³ H or ¹⁴ C isotopes are particularly preferred due to their ease of preparation and detection.

被较重的同位素如 ²H， ¹⁸O所替代的某些本发明化合物由于具有更好的代谢稳定性而具有某些治疗优势，如可以增加体内半衰期和较少剂量等综合性能，因此， ²H， ¹⁸O在某些情况下也是优选的。 Some of the compounds of the present invention replaced by heavier isotopes such as ² H, ¹⁸ O have certain therapeutic advantages due to their better metabolic stability, such as increased in vivo half-life and lower doses. Therefore, ² H, ¹⁸ O is also preferable in some cases.

具体实施方式Detailed ways

下面用实施例来进一步说明本发明，但本发明并不受其限制。贯穿本申请，本文提及本发明的化合物和方法的多个实施例。本发明不限于这些实施例，以下实施例只是提供实践本发明的方法，并不以任何方式限制本发明的范畴。The following examples are used to further illustrate the present invention, but the present invention is not limited thereto. Throughout this application, various embodiments of the compounds and methods of the invention are mentioned herein. The present invention is not limited to these embodiments. The following embodiments only provide methods for practicing the present invention, and do not limit the scope of the present invention in any way.

本发明提供的化合物可以通过本领域公知的标准合成方法来制备，本说明书提供了制备本发明化合物的一般方法。起始原料通常可通过商业化获得，或者通过本领域技术人员所熟知的方法进行制备。The compounds provided by the present invention can be prepared by standard synthetic methods known in the art, and this specification provides general methods for preparing the compounds of the present invention. The starting materials are usually commercially available or prepared by methods well known to those skilled in the art.

流程1如下：Process 1 is as follows:

首先，以SM-1为起始原料，与SM2进行亲核取代反应得到M1，然后与SM-3进行进行反应得到M2，经过保护基脱除得到M3，然后进行进一步反应得到化合物II-1。Firstly, using SM-1 as the starting material, undergo a nucleophilic substitution reaction with SM2 to obtain M1, then react with SM-3 to obtain M2, and remove the protective group to obtain M3, and then proceed to further react to obtain compound II-1.

下文通过实施例与制备进一步解释并列举本发明化合物及相应的制备方法。应了解，尽管具体实施例中给出了典型或优选的反应条件，但是本领域技术人员也可以使用其它反应条件。最佳反应条件可随所用的特定反应底物或溶剂而发生改变，但所述条件可由所属领域的技术人员通过常规优化而确定。The following examples and preparations are used to further explain and list the compounds of the present invention and the corresponding preparation methods. It should be understood that although typical or preferred reaction conditions are given in the specific examples, those skilled in the art can also use other reaction conditions. The optimal reaction conditions can vary with the specific reaction substrate or solvent used, but the conditions can be determined by those skilled in the art through routine optimization.

中间体制备Intermediate preparation

中间体1：Intermediate 1:

第一步first step

于2000ml的单口瓶中加入2,6-二氯-5-氟烟酸(61.0g)，二氯甲烷(600ml)和N,N-二甲基甲酰胺(1ml)，降温至0℃，滴加草酰氯(36.9ml)的二氯甲烷(30ml)溶液，滴毕后逐渐升至室温搅拌16小时。减压浓缩至干，降温至0℃，加入1,4-二氧六环(600ml)，再滴加氨水(120ml)，滴毕后于0℃继续搅拌1小时。减压浓缩至干，浓缩物用乙酸乙酯和正己烷打浆，静置，过滤，滤饼用正己烷洗涤，干燥。滤液浓缩后，经硅胶柱层析纯化，共得白色固体38g。Add 2,6-dichloro-5-fluoronicotinic acid (61.0g), dichloromethane (600ml) and N,N-dimethylformamide (1ml) into a 2000ml single-neck bottle. Add a solution of oxalyl chloride (36.9ml) in dichloromethane (30ml), gradually warm to room temperature and stir for 16 hours after dripping. Concentrate under reduced pressure to dryness, lower the temperature to 0°C, add 1,4-dioxane (600ml), and then add ammonia water (120ml) dropwise, and continue stirring at 0°C for 1 hour after the completion of the drop. It was concentrated to dryness under reduced pressure, the concentrate was slurried with ethyl acetate and n-hexane, allowed to stand, filtered, and the filter cake was washed with n-hexane and dried. After the filtrate was concentrated, it was purified by silica gel column chromatography to obtain a total of 38 g of white solid.

第二步Second step

0℃，滴加草酰氯(18.5ml)的二氯甲烷(20ml)溶液，滴毕后升温至75℃搅拌1小时。减压浓缩至干，降温至0℃，加入四氢呋喃(300ml)，滴加2-异丙基-4-甲基吡啶-3-胺(28.7g)的四氢呋喃(150ml)溶液，保持0℃继续搅拌1小时。将反应液倒入饱和氯化铵水溶液，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩至有固体析出，冷却至0℃，保持15分钟，过滤，滤饼用乙酸乙酯和石油醚洗涤，干燥；滤液再经硅胶柱层析纯化，共获得白色固体51g。At 0°C, a solution of oxalyl chloride (18.5ml) in dichloromethane (20ml) was added dropwise, and after the dropping, the temperature was raised to 75°C and stirred for 1 hour. Concentrate to dryness under reduced pressure, lower the temperature to 0°C, add tetrahydrofuran (300ml), add dropwise a solution of 2-isopropyl-4-methylpyridin-3-amine (28.7g) in tetrahydrofuran (150ml), keep at 0°C and continue stirring 1 hour. The reaction solution was poured into saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure until a solid precipitated, cooled to 0°C, and kept for 15 minutes. After filtration, the filter cake was washed with ethyl acetate and petroleum ether, and dried; the filtrate was purified by silica gel column chromatography to obtain a total of 51 g of white solid.

第三步third step

于1000ml的单口瓶中加入2,6-二氯-5-氟-N-((2-异丙基-4-甲基吡啶-3-基)氨甲酰)烟酰胺(51.0g)和四氢呋喃(500ml)，降温至0℃，滴加双(三甲基硅基)氨基钾(278ml)，滴毕，逐渐升至室温搅拌1小时。将反应液倒入饱和氯化铵水溶液，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩至有固体析出，冷却至0℃，保持30分钟，过滤，滤饼用乙酸乙酯和石油醚洗涤，干燥；滤液浓缩，硅胶柱层析纯化，共获得浅黄色固体38g。Add 2,6-dichloro-5-fluoro-N-((2-isopropyl-4-methylpyridin-3-yl)carbamoyl)nicotinamide (51.0g) and tetrahydrofuran to a 1000ml single-mouth bottle (500ml), the temperature was lowered to 0°C, potassium bis(trimethylsilyl)amide (278ml) was added dropwise, after the dropping, the temperature was gradually raised to room temperature and stirred for 1 hour. The reaction solution was poured into saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure until a solid precipitated, cooled to 0°C, and kept for 30 minutes. After filtration, the filter cake was washed with ethyl acetate and petroleum ether and dried; the filtrate was concentrated and purified by silica gel column chromatography to obtain 38 g of light yellow solid.

第四步the fourth step

于500ml的单口瓶中加入上一步产物(24.0g)，乙腈(240ml)和N,N-二异丙基乙胺(68.2ml)，降温至0℃，滴加三氯氧磷(38.5ml)，滴毕，升温至80℃，搅拌2小时。减压浓缩至干，甲苯共沸两次，向残余物中加入乙腈(240ml)，降温至0℃，加入N,N-二异丙基乙胺(68.2ml)，再分批加入(S)-4-N-叔丁氧羰基-2-甲基哌嗪(20.7g)，加毕后于室温搅拌1小时。缓慢倒入饱和碳酸氢钠水溶液淬灭反应，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩至有固体析出，冷却至0℃，保持15分钟，过滤，滤饼用乙酸乙酯：石油醚洗涤，干燥；滤液浓缩，硅胶柱层析纯化，共获得黄色固体18g。 ¹H NMR(400MHz,DMSO-d ₆):δ8.50(d,J＝4.9Hz,1H),8.38(d,J＝8.5Hz,1H),7.30(d,J＝4.8Hz,1H),4.84(s,1H),4.27-4.10(m,1H),4.03-3.88(m,1H),3.88-3.76(m,1H),3.75-3.58(m,2H),3.38-3.24(m,1H),2.70-2.56(m,1H),1.96(s,3H),1.45(s,9H),1.36-1.29(m,3H),1.07(d,J＝6.7Hz,3H),1.04-0.97(m,3H)；MS:m/z 531.2,[M+H] ⁺。 Add the product of the previous step (24.0g), acetonitrile (240ml) and N,N-diisopropylethylamine (68.2ml) into a 500ml single-necked flask, reduce the temperature to 0℃, and add phosphorus oxychloride (38.5ml) dropwise , After dripping, heat up to 80°C and stir for 2 hours. Concentrate to dryness under reduced pressure, azeotrope twice with toluene, add acetonitrile (240ml) to the residue, cool to 0°C, add N,N-diisopropylethylamine (68.2ml), and add (S) in batches -4-N-tert-butoxycarbonyl-2-methylpiperazine (20.7g), after the addition, stirred at room temperature for 1 hour. Slowly pour into saturated sodium bicarbonate aqueous solution to quench the reaction, extract with ethyl acetate, combine the organic layers, wash with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure until a solid precipitates, cool to 0°C, keep for 15 minutes After filtering, the filter cake was washed with ethyl acetate: petroleum ether and dried; the filtrate was concentrated and purified by silica gel column chromatography to obtain a total of 18 g of yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ): δ8.50(d,J=4.9Hz,1H), 8.38(d,J=8.5Hz,1H), 7.30(d,J=4.8Hz,1H), 4.84 (s, 1H), 4.27-4.10 (m, 1H), 4.03-3.88 (m, 1H), 3.88-3.76 (m, 1H), 3.75-3.58 (m, 2H), 3.38-3.24 (m, 1H) ), 2.70-2.56(m,1H),1.96(s,3H),1.45(s,9H),1.36-1.29(m,3H),1.07(d,J=6.7Hz,3H),1.04-0.97( m, 3H); MS: m/z 531.2, [M+H] ⁺ .

中间体2：Intermediate 2:

于50ml的单口瓶中加入7-氯-6-氟-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮(2.0g)，乙腈(20ml)和N,N-二异丙基乙胺(5.8ml)，降温至0℃，滴加三氯氧磷(3.2ml)，滴毕，升温至80℃，搅拌2小时。减压浓缩至干，甲苯共沸两次，向残余物中加入乙腈(20ml)，降温至0℃，加入N,N-二异丙基乙胺(5.8ml)，再分批加入(3S,5S)-3,5-二甲基-1-哌嗪羧酸叔丁酯(1.3g)，加毕，逐渐升至室温搅拌1小时。缓慢倒入饱和碳酸氢钠水溶液淬灭反应，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩后经硅胶柱层析纯化，得黄色固体2g。 ¹H NMR(400MHz,DMSO-d ₆):δ8.50(dd,J＝4.8,1.7Hz,1H),8.45(dd,J＝8.6,6.4Hz,1H),7.28(d,J＝4.8Hz,1H),4.43-4.27(m,2H),3.74(br s,2H),3.48(br s,2H),2.70-2.55(m,1H),1.94(d,J＝4.4Hz,3H),1.45(s,9H),1.30-1.21(m,6H),1.08-1.04(m,3H),1.02(t,J＝6.4Hz,3H)；MS:m/z 545.3,[M+H] ⁺。 Add 7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H ,3H)-diketone (2.0g), acetonitrile (20ml) and N,N-diisopropylethylamine (5.8ml), reduce the temperature to 0℃, add phosphorus oxychloride (3.2ml) dropwise, The temperature was raised to 80°C and stirred for 2 hours. Concentrate to dryness under reduced pressure, azeotrope twice with toluene, add acetonitrile (20ml) to the residue, lower the temperature to 0°C, add N,N-diisopropylethylamine (5.8ml), and add (3S, 5S) tert-butyl-3,5-dimethyl-1-piperazinecarboxylate (1.3g), after the addition, gradually rise to room temperature and stir for 1 hour. Slowly poured into saturated sodium bicarbonate aqueous solution to quench the reaction, extracted with ethyl acetate, combined the organic layers, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by silica gel column chromatography to obtain 2 g of yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ): δ8.50(dd,J=4.8,1.7Hz,1H), 8.45(dd,J=8.6,6.4Hz,1H), 7.28(d,J=4.8Hz ,1H),4.43-4.27(m,2H),3.74(br s,2H),3.48(br s,2H),2.70-2.55(m,1H),1.94(d,J=4.4Hz,3H), 1.45(s,9H),1.30-1.21(m,6H),1.08-1.04(m,3H),1.02(t,J=6.4Hz,3H); MS: m/z 545.3,[M+H] ⁺ .

中间体3：Intermediate 3:

第一步first step

于2000ml的单口瓶中加入2,5,6-三氯烟酸(50.0g)和四氢呋喃(500ml)，分批加入N,N’-羰基二咪唑(39.4g)，加毕，逐渐升温至50℃搅拌2小时。冷却至室温，加入甲苯(100ml)，减压蒸馏，出去二分之一的溶剂，再降温至0℃，滴加氨水(60ml)，滴毕，保持0℃继续搅拌1小时。加水，分液，水相用乙酸乙酯萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得白色固体36g。 ¹H NMR(400MHz,CDCl ₃):δ8.36(s,1H),6.76(br s,1H),6.47(br s,1H)。 Add 2,5,6-trichloronicotinic acid (50.0g) and tetrahydrofuran (500ml) into a 2000ml single-neck bottle, add N,N'-carbonyldiimidazole (39.4g) in batches, and gradually increase the temperature to 50 Stir at °C for 2 hours. Cool to room temperature, add toluene (100ml), distill under reduced pressure to remove one-half of the solvent, then lower the temperature to 0°C, add ammonia water (60ml) dropwise, and keep at 0°C and continue stirring for 1 hour. Water was added for liquid separation, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 36 g of white solid. ¹ H NMR (400MHz, CDCl ₃ ): δ 8.36 (s, 1H), 6.76 (br s, 1H), 6.47 (br s, 1H).

第二步Second step

于500ml的单口瓶中加入2,5,6-三氯烟酰胺(15.4g)和四氢呋喃(150ml)，降温至0℃，滴加草酰氯(7.0ml)的二氯甲烷(7ml)溶液，滴毕，升温至75℃搅拌2小时。将反应液浓缩至干，降温至0℃，加入四氢呋喃(150ml)，滴加2-异丙基-4-甲基吡啶-3-胺(10.8g)的四氢呋喃(70ml)溶液，滴毕保持0℃继续搅拌1小时。将反应液倒入饱和氯化铵水溶液，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得白色固体12g。 ¹H NMR(400MHz,DMSO-d ₆):δ11.34(s,1H),9.58(br s,1H),8.68(s,1H),8.34(d,J＝4.8Hz,1H),7.16(d,J＝4.8Hz,1H),3.33-3.23(m,1H),2.22(s,3H),1.17(d,J＝6.6Hz,6H)。 Add 2,5,6-trichloronicotinamide (15.4g) and tetrahydrofuran (150ml) into a 500ml single-neck bottle, cool to 0℃, add dropwise a solution of oxalyl chloride (7.0ml) in dichloromethane (7ml), dropwise After that, the temperature was raised to 75°C and stirred for 2 hours. The reaction solution was concentrated to dryness, the temperature was lowered to 0°C, tetrahydrofuran (150ml) was added, and a solution of 2-isopropyl-4-methylpyridin-3-amine (10.8g) in tetrahydrofuran (70ml) was added dropwise. Stirring was continued for 1 hour at °C. The reaction solution was poured into saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 12 g of white solid. ¹ H NMR (400MHz, DMSO-d ₆ ): δ 11.34 (s, 1H), 9.58 (br s, 1H), 8.68 (s, 1H), 8.34 (d, J = 4.8 Hz, 1H), 7.16 ( d, J=4.8 Hz, 1H), 3.33-3.23 (m, 1H), 2.22 (s, 3H), 1.17 (d, J=6.6 Hz, 6H).

第三步third step

于500ml的单口瓶中加入上步产物(12.0g)和四氢呋喃(150ml)，降温至0℃，滴加双(三甲基硅基)氨基钾(74.8ml)，滴毕，于室温搅拌1小时。将反应液倒入饱和氯化铵水溶液，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得浅黄色固体9.6g。Add the product of the previous step (12.0g) and tetrahydrofuran (150ml) to a 500ml single-necked flask, cool to 0°C, add potassium bis(trimethylsilyl)amide (74.8ml) dropwise, and stir at room temperature for 1 hour . The reaction solution was poured into saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 9.6 g of light yellow solid.

第四步the fourth step

于500ml的单口瓶中加入上步产物(26.0g)，乙腈(250ml)和N,N-二异丙基乙胺(16.4g)，降温至0℃，滴加三氯氧磷(11.9ml)，滴毕，升温至80℃搅拌2小时。减压浓缩至干，甲苯共沸两次，向残余物中加入乙腈(250ml)，降温至0℃，加入N,N-二异丙基乙胺(16.4g)，再分批加入(S)-4-N-叔丁氧羰基-2-甲基哌嗪(15.0g)，加毕后于室温搅拌1小时。缓慢倒入饱和碳酸氢钠水溶液淬灭反应，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体23.5g。 ¹H NMR(400MHz,DMSO-d ₆):δ8.55-8.43(m,2H),7.26(d,J＝4.9Hz,1H),4.88(br s,1H),4.26-4.09(m,1H),4.02-3.88(m,1H),3.88-3.77(m,1H),3.77-3.61(m,1H),3.33-2.92(m,2H),2.72-2.55(m, 1H),1.98-1.90(m,3H),1.45(s,9H),1.36-1.28(m,3H),1.06(d,J＝6.7Hz,3H),1.01(d,J＝6.6Hz,3H)；MS:m/z 547.2,[M+H] ⁺。 Add the product of the previous step (26.0g), acetonitrile (250ml) and N,N-diisopropylethylamine (16.4g) to a 500ml single-necked flask, reduce the temperature to 0℃, and add phosphorus oxychloride (11.9ml) dropwise , After dripping, heat up to 80°C and stir for 2 hours. Concentrate to dryness under reduced pressure, azeotrope with toluene twice, add acetonitrile (250ml) to the residue, cool to 0°C, add N,N-diisopropylethylamine (16.4g), and add (S) in batches -4-N-tert-butoxycarbonyl-2-methylpiperazine (15.0g), after the addition, stirred at room temperature for 1 hour. Slowly poured into saturated sodium bicarbonate aqueous solution to quench the reaction, extracted with ethyl acetate, combined the organic layers, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 23.5 g of yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ): δ8.55-8.43 (m, 2H), 7.26 (d, J = 4.9Hz, 1H), 4.88 (br s, 1H), 4.26-4.09 (m, 1H) ),4.02-3.88(m,1H),3.88-3.77(m,1H),3.77-3.61(m,1H),3.33-2.92(m,2H),2.72-2.55(m,1H),1.98-1.90 (m,3H),1.45(s,9H),1.36-1.28(m,3H),1.06(d,J=6.7Hz,3H),1.01(d,J=6.6Hz,3H); MS: m/ z 547.2, [M+H] ⁺ .

中间体4：Intermediate 4:

于100ml的单口瓶中加入6,7-二氯-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮(3.0g)，乙腈(30ml)和N,N-二异丙基乙胺(8.1ml)，降温至0℃，滴加三氯氧磷(4.6ml)，滴毕，升温至80℃，搅拌2小时。减压浓缩至干，甲苯共沸两次，向残余物中加入乙腈(30ml)，降温至0℃，加入N,N-二异丙基乙胺(5.8ml)，再分批加入(3S,5S)-3,5-二甲基-1-哌嗪羧酸叔丁酯(1.8g)，加毕，于室温搅拌1小时。缓慢倒入饱和碳酸氢钠水溶液淬灭反应，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体2.2g。 ¹H NMR(400MHz,DMSO-d ₆):δ8.53(d,J＝7.2Hz,1H),8.50(dd,J＝4.8,1.6Hz,1H),7.28(d,J＝4.8Hz,1H),4.47-4.31(m,2H),3.73(br s,2H),3.52(br s,2H),2.71-2.54(m,1H),1.95(d,J＝7.3Hz,3H),1.45(s,9H),1.31-1.24(m,6H),1.08-0.99(m,6H)；MS:m/z 561.2,[M+H] ⁺。 Add 6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H, 3H)-diketone (3.0g), acetonitrile (30ml) and N,N-diisopropylethylamine (8.1ml), lower the temperature to 0°C, add phosphorus oxychloride (4.6ml) dropwise, drop it and increase the temperature Bring to 80°C and stir for 2 hours. Concentrate to dryness under reduced pressure, azeotrope twice with toluene, add acetonitrile (30ml) to the residue, lower the temperature to 0°C, add N,N-diisopropylethylamine (5.8ml), and add (3S, 5S) tert-butyl-3,5-dimethyl-1-piperazinecarboxylate (1.8g), after the addition, stir at room temperature for 1 hour. Slowly poured into saturated sodium bicarbonate aqueous solution to quench the reaction, extracted with ethyl acetate, combined the organic layers, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 2.2 g of yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ): δ8.53(d,J=7.2Hz,1H), 8.50(dd,J=4.8,1.6Hz,1H), 7.28(d,J=4.8Hz,1H ), 4.47-4.31(m,2H),3.73(br s,2H),3.52(br s,2H),2.71-2.54(m,1H),1.95(d,J=7.3Hz,3H),1.45( s, 9H), 1.31-1.24 (m, 6H), 1.08-0.99 (m, 6H); MS: m/z 561.2, [M+H] ⁺ .

中间体5：Intermediate 5:

第一步first step

于250ml的单口瓶中加入2,6-二氯-5-氟烟酰胺(1.2g)和四氢呋喃(40ml)，降温至0℃，滴加草酰氯(860mg)，滴毕后升温至70℃搅拌1小时。减压浓缩至干，降温至0℃，加入四氢呋喃(40ml)，滴加2-异丙基-4-(甲基-d3)吡啶-3-胺(783mg)的四氢呋喃(10ml)溶液，5分钟后滴加三乙胺(580mg)，加完继续搅拌30分钟。将反应液倒入饱和氯化铵水溶液，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得类白色固体1.45g。 ¹H NMR(400MHz,CDCl ₃):δ10.38(s,1H),9.79(s,1H),8.45(d,J＝4.9Hz,1H),7.85(d,J＝7.0Hz,1H),7.07(d,J＝4.9Hz,1H),3.33-3.19(m,1H),1.25(d,J＝6.8Hz,6H).MS:m/z 388.1,[M+H] ⁺。 Add 2,6-dichloro-5-fluoronicotinic acid amide (1.2g) and tetrahydrofuran (40ml) into a 250ml single-neck bottle, cool to 0°C, add oxalyl chloride (860mg) dropwise, and then heat up to 70°C and stir. 1 hour. Concentrate under reduced pressure to dryness, lower the temperature to 0°C, add tetrahydrofuran (40ml), add dropwise a solution of 2-isopropyl-4-(methyl-d3)pyridin-3-amine (783mg) in tetrahydrofuran (10ml) for 5 minutes After that, triethylamine (580mg) was added dropwise, and after the addition, stirring was continued for 30 minutes. The reaction solution was poured into saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 1.45 g of off-white solid. ¹ H NMR (400MHz, CDCl ₃ ): δ10.38 (s, 1H), 9.79 (s, 1H), 8.45 (d, J = 4.9 Hz, 1H), 7.85 (d, J = 7.0 Hz, 1H), 7.07 (d, J=4.9 Hz, 1H), 3.33-3.19 (m, 1H), 1.25 (d, J=6.8 Hz, 6H). MS: m/z 388.1, [M+H] ⁺ .

第二步Second step

于250ml的单口瓶中加入上步产物(1.45g)和四氢呋喃(20ml)，降温至0℃，滴加双(三甲基硅基)氨基钾(8.3ml)，滴毕，逐渐升至室温搅拌1小时。将反应液倒入饱和氯化铵水溶液，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得类白色固体1.15g。 ¹H NMR(400MHz,CDCl ₃):δ8.64(d,J＝4.9Hz,1H),8.28(d,J＝6.6Hz,1H),7.19(d,J＝4.9Hz,1H),6.64(br s,1H),2.80-2.65(m,1H),1.24(d,J＝6.7Hz,3H),1.15(d,J＝6.7Hz,3H).MS:m/z 352.1,[M+H] ⁺。 Add the product of the previous step (1.45g) and tetrahydrofuran (20ml) to a 250ml single-necked flask, cool to 0℃, add potassium bis(trimethylsilyl)amide (8.3ml) dropwise, and gradually raise to room temperature and stir. 1 hour. The reaction solution was poured into saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 1.15 g of off-white solid. ¹ H NMR (400MHz, CDCl ₃ ): δ8.64 (d, J = 4.9 Hz, 1H), 8.28 (d, J = 6.6 Hz, 1H), 7.19 (d, J = 4.9 Hz, 1H), 6.64 ( br s, 1H), 2.80-2.65 (m, 1H), 1.24 (d, J = 6.7 Hz, 3H), 1.15 (d, J = 6.7 Hz, 3H). MS: m/z 352.1, [M+H ] ⁺ .

第三步third step

于250ml的单口瓶中加入上一步产物(1.1g)，乙腈(20ml)和N,N-二异丙基乙胺(1.0g)，降温至0℃，滴加三氯氧磷(970mg)，滴加再滴加2滴N-甲基吗啉，室温搅拌1小时。减压浓缩至干，甲苯共沸两次，向残余物中加入乙腈(20ml)，降温至0℃，加入N,N-二异丙基乙胺(1.0g)，再加入(S)-4-N-叔丁氧羰基-2-甲基哌嗪(632mg)，加毕后于室温搅拌1小时。缓慢倒入饱和碳酸氢钠水溶液淬灭反应，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩硅胶柱层析纯化，获得黄色固体1.2g。MS:m/z 534.2,[M+H] ⁺。 Add the product of the previous step (1.1g), acetonitrile (20ml) and N,N-diisopropylethylamine (1.0g) into a 250ml single-necked flask, reduce the temperature to 0°C, and add phosphorus oxychloride (970mg) dropwise. Add 2 drops of N-methylmorpholine again, and stir at room temperature for 1 hour. Concentrate to dryness under reduced pressure, azeotrope toluene twice, add acetonitrile (20ml) to the residue, cool to 0℃, add N,N-diisopropylethylamine (1.0g), and then add (S)-4 -N-tert-Butoxycarbonyl-2-methylpiperazine (632 mg), stir at room temperature for 1 hour after addition. Slowly poured into saturated sodium bicarbonate aqueous solution to quench the reaction, extracted with ethyl acetate, combined the organic layers, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by silica gel column chromatography to obtain 1.2 g of yellow solid. MS: m/z 534.2, [M+H] ⁺ .

中间体6：Intermediate 6:

第一步first step

向250ml烧瓶中加入干燥的四氢呋喃(100ml)和草酰氯(3.0g)，搅拌下分批加入2,5,6-三氯烟酰胺(4.6g)，室温搅拌10分钟后于75℃搅拌1小时。将反应液减压浓缩至干，加入干燥的四氢呋喃(50ml)，2,4-二异丙基-3-氨基吡啶(3.0g)，滴加三乙胺(2.1g)，加完后搅拌20分钟。加入水淬灭反应，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得白色固体6.8g。MS:m/z 429.1, [M+H] ⁺。 Add dry tetrahydrofuran (100ml) and oxalyl chloride (3.0g) to a 250ml flask, add 2,5,6-trichloronicotinamide (4.6g) in batches with stirring, stir at room temperature for 10 minutes and then at 75°C for 1 hour . Concentrate the reaction solution under reduced pressure to dryness, add dry tetrahydrofuran (50ml), 2,4-diisopropyl-3-aminopyridine (3.0g), add triethylamine (2.1g) dropwise, and stir after adding 20 minute. Water was added to quench the reaction, extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 6.8 g of white solid. MS: m/z 429.1, [M+H] ⁺ .

第二步Second step

在250ml单口瓶中，加入上步产物(6.7g)和干燥的四氢呋喃(50ml)，冰浴下，缓慢滴加1M的双(三甲基硅基)氨基钾(39ml)，加完后于室温搅拌40分钟。将反应液倒入100ml饱和氯化铵水溶液中，乙酸乙酯萃取，合并有机层，饱和氯化钠洗涤，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得类白色固体4.58g。MS:m/z 393.1,[M+H] ⁺。 Add the product of the previous step (6.7g) and dry tetrahydrofuran (50ml) to a 250ml single-necked flask. Under ice bath, slowly add 1M potassium bis(trimethylsilyl)amide (39ml) dropwise. Stir for 40 minutes. The reaction solution was poured into 100 ml of saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic layers were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain an off-white solid 4.58g. MS: m/z 393.1, [M+H] ⁺ .

第三步third step

在100ml单口瓶中，加入上步产物(2.0g)，乙腈(30ml)，N,N-二异丙基乙胺(4.5ml)和(S)-3-甲基哌嗪-1-羧酸叔丁酯(1.1g)，滴加三氯氧磷(0.94ml)，加完后继续搅拌1小时。向反应液中加入饱和碳酸钠溶液淬灭反应，乙酸乙酯萃取，合并有机层，饱和氯化钠洗涤，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体1.7g。MS:m/z 575.2,[M+H] ⁺。 In a 100ml single-necked flask, add the product from the previous step (2.0g), acetonitrile (30ml), N,N-diisopropylethylamine (4.5ml) and (S)-3-methylpiperazine-1-carboxylic acid Tert-butyl ester (1.1g), phosphorus oxychloride (0.94ml) was added dropwise, and stirring was continued for 1 hour after the addition. The reaction was quenched by adding saturated sodium carbonate solution, extracted with ethyl acetate, combined the organic layers, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain a yellow solid 1.7 g. MS: m/z 575.2, [M+H] ⁺ .

中间体7：Intermediate 7:

于烧瓶中依次加入3-氨基-2-氯-吡啶-4-羧酸甲酯(9.2g)，异丙烯基硼酸频那醇酯(11.9g，)，碳酸钾(7.6g)、pdCl ₂(dppf)(5.5g)，1,4-二氧六环(85ml)，水(17ml)，加完后氮气充分置换，置于105℃油浴中搅拌回流反应3小时。将反应液垫硅藻土过滤，向滤液加入300ml水，乙酸乙酯萃取3次，合并乙酸乙酯层，饱和食盐水洗2次，无水硫酸钠干燥，过滤，减压浓缩后经硅胶柱层析纯化，得橙黄色固体9.3g。MS:m/z 193,[M+H] ⁺。 Add 3-amino-2-chloro-pyridine-4-carboxylic acid methyl ester (9.2g), isopropenyl boronic acid pinacol ester (11.9g,), potassium carbonate (7.6g), pdCl ₂ ( dppf) (5.5g), 1,4-dioxane (85ml), water (17ml), after the addition, nitrogen is fully replaced, placed in a 105°C oil bath with stirring and refluxing for 3 hours. The reaction solution was filtered through Celite, 300ml of water was added to the filtrate, and the mixture was extracted three times with ethyl acetate. The ethyl acetate layers were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and passed through a silica gel column. Analyze and purify to obtain 9.3 g of orange-yellow solid. MS: m/z 193, [M+H] ⁺ .

于烧瓶中加入3-氨基-2-异丙烯基-吡啶-4-羧酸甲酯(9.3g)，5％钯碳(1.86g)，四氢呋喃(120ml)，加完后氢气充分置换，氢气球氛围下常温搅拌过夜。将反应液垫硅藻土过滤，滤液浓缩至干得9.5g油状物，直接用于下一步反应。Add 3-amino-2-isopropenyl-pyridine-4-carboxylic acid methyl ester (9.3g), 5% palladium on carbon (1.86g), and tetrahydrofuran (120ml) into the flask. After the addition, the hydrogen gas is fully replaced, and the hydrogen balloon Stir overnight at room temperature under atmosphere. The reaction solution was filtered through Celite, and the filtrate was concentrated to dryness to obtain 9.5 g of oil, which was directly used in the next reaction.

于烧瓶中加入3-氨基-2-异丙基-吡啶-4-羧酸甲酯(19g)，干燥的四氢呋喃(150ml)，分批次加入氢化铝锂(17g)，加完后氮气置换，于80℃回流反应3小时。缓慢滴加饱和氯化铵水溶液淬灭反应，过滤，滤液用乙酸乙酯萃取2次，合并有机层，饱和食盐水洗2次，无水硫酸钠干燥，减压浓缩至干得产品，直接用于下一步反应。MS:m/z 167.1,[M+H] ⁺。 Add 3-amino-2-isopropyl-pyridine-4-carboxylic acid methyl ester (19g) and dry tetrahydrofuran (150ml) into the flask, add lithium aluminum hydride (17g) in batches, and replace with nitrogen after the addition. The reaction was refluxed at 80°C for 3 hours. Slowly add saturated aqueous ammonium chloride solution to quench the reaction, filter, extract the filtrate twice with ethyl acetate, combine the organic layers, wash twice with saturated brine, dry with anhydrous sodium sulfate, concentrate under reduced pressure to dryness to obtain the product, and use it directly Next reaction. MS: m/z 167.1, [M+H] ⁺ .

向上一步产品加入二氯甲烷(300ml)，活性二氧化锰(86g)，加完后于室温下搅拌2.5小时。垫硅藻土过滤，滤液减压浓缩，硅胶柱层析纯化，得产物12g。Add dichloromethane (300ml) and active manganese dioxide (86g) to the product of the previous step. After the addition, stir at room temperature for 2.5 hours. Filter through a pad of Celite, concentrate the filtrate under reduced pressure, and purify by silica gel column chromatography to obtain 12 g of the product.

于烧瓶中加入3-氨基-2-异丙基异烟醛(8.8g)，四氢呋喃(150ml)，氮气置换，降温至-55℃，滴加甲基溴化镁的四氢呋喃溶液(1M，162ml)，滴加完成后于-55℃反应1.5小时。缓慢滴加氯化铵溶液淬灭反应，再加入400ml水，升温至室温，乙酸乙酯萃取2次，合并有机层，饱和食盐水洗1次，无水硫酸钠干燥，减压浓缩至干，直接用于下一步反应。MS:m/z 181.1,[M+H] ⁺。 Add 3-amino-2-isopropylisonicotinaldehyde (8.8g), tetrahydrofuran (150ml) to the flask, replace with nitrogen, cool to -55℃, and add methylmagnesium bromide in tetrahydrofuran (1M, 162ml) dropwise After the addition is complete, react at -55°C for 1.5 hours. Slowly add ammonium chloride solution dropwise to quench the reaction, then add 400ml of water, warm to room temperature, extract twice with ethyl acetate, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, concentrate under reduced pressure to dryness, directly Used in the next reaction. MS: m/z 181.1, [M+H] ⁺ .

向上一步产物加入二氯甲烷(200ml)，活性二氧化锰(47g)，加完后室温搅拌2.5小时。垫硅藻土过滤，减压浓缩，硅胶柱层析纯化，得黄色油状物7.0g。MS:m/z 179.1,[M+H] ⁺。 Add dichloromethane (200ml) and active manganese dioxide (47g) to the product from the previous step. After the addition, stir at room temperature for 2.5 hours. Filter through a pad of Celite, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain 7.0 g of yellow oil. MS: m/z 179.1, [M+H] ⁺ .

向三口烧瓶中加入甲基三苯基溴化膦(15.4g)，叔丁醇钾(4.8g)，甲苯(200ml)，氮气置换后于60℃搅拌2小时。将反应液降温至40℃，滴加上一步产物(7.0g)的甲苯(20ml)溶液，滴加完成后继续搅拌30分钟。加入氯化铵溶液淬灭反应，再加入水，甲苯萃取2次，合并有机层，饱和盐水洗1次，无水硫酸钠干燥，减压浓缩，硅胶柱层析纯化，得4.7g浅黄色液体。 ¹H NMR(400MHz,CDCl ₃):δ8.01(d,J＝4.9Hz,1H),6.81(d,J＝4.9Hz,1H),5.37(t,J＝1.5Hz,1H),5.12(s,1H),3.85(s,2H),3.11-3.01(m,1H),2.08(s,3H),1.33(d,J＝6.8Hz,6H)；MS:m/z 177.1,[M+H] ⁺。 A three-necked flask was charged with methyltriphenylphosphonium bromide (15.4g), potassium tert-butoxide (4.8g), and toluene (200ml), replaced with nitrogen, and stirred at 60°C for 2 hours. The reaction solution was cooled to 40° C., and a toluene (20 ml) solution of the product of one step (7.0 g) was added dropwise, and stirring was continued for 30 minutes after the dropwise addition was completed. The reaction was quenched by adding ammonium chloride solution, then water was added, toluene was extracted twice, the organic layers were combined, washed with saturated brine once, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 4.7 g of light yellow liquid . ¹ H NMR (400MHz, CDCl ₃ ): δ8.01 (d, J = 4.9 Hz, 1H), 6.81 (d, J = 4.9 Hz, 1H), 5.37 (t, J = 1.5 Hz, 1H), 5.12 ( s,1H),3.85(s,2H),3.11-3.01(m,1H),2.08(s,3H),1.33(d,J=6.8Hz,6H); MS: m/z 177.1,[M+ H] ⁺ .

于烧瓶中加入2-异丙基-3-氨基-4-异丙烯基吡啶(3.0g)，四氢呋喃(30ml)和5％钯碳(0.6g)，加完后用氢气充分置换，氢气球压力下室温搅拌过夜。垫硅藻土过滤，减压浓缩至干，硅胶柱层析纯化，得黄色油状物3.0g。 ¹H NMR(400MHz,CDCl ₃):δ8.04(d,J＝5.0Hz,1H),6.93(d,J＝5.0Hz,1H),3.70(br s,2H),3.13-3.01(m,1H),2.97-2.84(m,1H),1.33(d,J＝6.8Hz,6H),1.27(d,J＝6.8Hz,6H)。 Add 2-isopropyl-3-amino-4-isopropenylpyridine (3.0g), tetrahydrofuran (30ml) and 5% palladium on carbon (0.6g) into the flask. After the addition, it is fully replaced with hydrogen. The pressure of the hydrogen balloon Stir overnight at room temperature. Filter through a pad of celite, concentrate under reduced pressure to dryness, and purify by silica gel column chromatography to obtain 3.0 g of yellow oil. ¹ H NMR (400MHz, CDCl ₃ ): δ8.04 (d, J = 5.0Hz, 1H), 6.93 (d, J = 5.0Hz, 1H), 3.70 (br s, 2H), 3.13-3.01 (m, 1H), 2.97-2.84 (m, 1H), 1.33 (d, J = 6.8 Hz, 6H), 1.27 (d, J = 6.8 Hz, 6H).

中间体8：Intermediate 8:

第一步first step

于50ml单口瓶中加入邻溴苯胺(3.0g)，碳酸钾(7.2g)，氘代碘甲烷(10.1g)和N,N-二甲基甲酰胺(30ml)，加完后升温至75℃搅拌2小时。反应完毕，反应液冷至室温，加水稀释，乙酸乙酯萃取，合并有机相，水洗两次，饱和食盐水洗一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化(正己烷洗脱)，得黄色液体3g。 ¹H NMR(400MHz,DMSO-d ₆):δ7.55(dd,J＝7.9,1.5Hz,1H),7.34-7.29(m,1H),7.16(dd,J＝8.0,1.6Hz,1H),6.96-6.91(m,1H)。 Add o-bromoaniline (3.0g), potassium carbonate (7.2g), deuterated methyl iodide (10.1g) and N,N-dimethylformamide (30ml) to a 50ml single-necked flask. After the addition, increase the temperature to 75℃ Stir for 2 hours. After the reaction, the reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, combined the organic phases, washed twice with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (n-hexane Elution) to obtain 3g of yellow liquid. ¹ H NMR (400MHz, DMSO-d ₆ ): δ7.55 (dd, J = 7.9, 1.5 Hz, 1H), 7.34-7.29 (m, 1H), 7.16 (dd, J = 8.0, 1.6 Hz, 1H) ,6.96-6.91(m,1H).

第二步Second step

于50ml三口瓶中加入上步产物(1.0g)，四氢呋喃(10ml)，降温至-75℃，滴加正丁基锂的正己烷溶液(2.9ml)，滴毕，继续搅拌1小时，再滴加硼酸三异丙酯(1.2g)，滴毕，继续搅拌2小时。将反应液倒入饱和氯化铵水溶液，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得淡黄色油状物400mg。 ¹H NMR(400MHz,DMSO-d ₆):δ9.12(s,2H),6.68(d,J＝6.9Hz,1H),7.43-7.31 (m,2H),7.11(t,J＝7.1Hz,1H).MS:m/z 172.1,[M+H] ⁺。 Add the product from the previous step (1.0g) and tetrahydrofuran (10ml) to a 50ml three-necked flask, and cool to -75°C. Add n-butyllithium n-hexane solution (2.9ml) dropwise, continue stirring for 1 hour, and then drop Add triisopropyl borate (1.2g), drop it off and continue stirring for 2 hours. The reaction solution was poured into saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 400 mg of light yellow oil. . ¹ H NMR (400MHz, DMSO-d ₆ ): δ9.12 (s, 2H), 6.68 (d, J = 6.9 Hz, 1H), 7.43-7.31 (m, 2H), 7.11 (t, J = 7.1 Hz ,1H). MS: m/z 172.1, [M+H] ⁺ .

中间体9：Intermediate 9:

第一步first step

于1000mL的反应瓶中加入3-氟苯胺(20.0g)，联硼酸频那醇酯(50.3g)，4,4-二-叔丁基联吡啶(0.96g)，正己烷(500ml)和铱催化剂(1.19g)，加完后氮气置换，于25℃下搅拌30分钟后，加热至65℃继续搅拌过夜。将反应液缓慢加入到水中淬灭，乙酸乙酯萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，产品再用正己烷打浆，得白色固体6.0g。 ¹H NMR(400MHz,DMSO-d ₆):δ7.27(t,J＝7.7Hz,1H),6.33(dd,J＝8.2,1.8Hz,1H),6.19(dd,J＝12.4,1.8Hz,1H),5.84(s,6H),1.24(s,12H).MS:m/z 238.1,[M+H] ⁺。 Add 3-fluoroaniline (20.0g), pinacol diborate (50.3g), 4,4-di-tert-butylbipyridine (0.96g), n-hexane (500ml) and iridium to a 1000mL reaction flask. The catalyst (1.19g) was replaced with nitrogen after the addition, and after stirring at 25°C for 30 minutes, it was heated to 65°C and stirring continued overnight. The reaction solution was slowly added to water for quenching, extracted with ethyl acetate, combined the organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, purified by silica gel column chromatography, and the product was slurried with n-hexane to obtain 6.0g white solid. ¹ H NMR (400MHz, DMSO-d ₆ ): δ7.27 (t, J = 7.7Hz, 1H), 6.33 (dd, J = 8.2, 1.8Hz, 1H), 6.19 (dd, J = 12.4, 1.8Hz , 1H), 5.84 (s, 6H), 1.24 (s, 12H). MS: m/z 238.1, [M+H] ⁺ .

第二步Second step

向50ml反应瓶中加入上步原料(2.0g)，N,N-二甲基甲酰胺(20ml)，碳酸钾(3.5g)和碘甲烷(4.8g)，加完后于75℃搅拌2小时。将反应液冷却至室温，加入水淬灭反应，乙酸乙酯萃取，合并有机层，水洗两次，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化(正己烷洗脱)，得类白色固体800mg。 ¹H NMR(400MHz,DMSO-d ₆):δ7.41(t,J＝8.0Hz,1H),6.48(dd,J＝8.5,2.2Hz,1H),6.35(dd,J＝13.6,2.2Hz,1H),2.94(s,6H),1.26(s,12H)。 Add the raw materials of the previous step (2.0g), N,N-dimethylformamide (20ml), potassium carbonate (3.5g) and methyl iodide (4.8g) to a 50ml reaction flask. After the addition, stir at 75℃ for 2 hours . The reaction solution was cooled to room temperature, water was added to quench the reaction, extracted with ethyl acetate, the organic layers were combined, washed twice with water, washed with saturated brine once, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography ( Eluted with n-hexane) to obtain 800 mg of off-white solid. ¹ H NMR (400MHz, DMSO-d ₆ ): δ7.41(t,J=8.0Hz,1H), 6.48(dd,J=8.5,2.2Hz,1H), 6.35(dd,J=13.6,2.2Hz ,1H), 2.94(s,6H), 1.26(s,12H).

参考以上的制备方案，使用氘代碘甲烷替代碘甲烷，可以得到以下的中间体：With reference to the above preparation scheme, using deuterated methyl iodide instead of methyl iodide, the following intermediates can be obtained:

制备方法如下：The preparation method is as follows:

于50ml单口瓶中加入3-氟-2-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯胺(500mg)，碳酸铯(2.1g)，氘代碘甲烷(1.5g)和异丙醇(10ml)，升温至65℃搅拌4小时。将反应液冷至室温，过滤，减压浓缩，硅胶柱层析纯化，得白色固体120mg。 ¹H NMR(400MHz,CDCl ₃):δ7.59(t,J＝8.0Hz,1H),6.45(dd,J＝8.4,2.3Hz,1H),6.32(dd,J＝13.3,2.3 Hz,1H),1.36(s,12H).MS:m/z 272.2,[M+H] ⁺。 Add 3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (500mg), cesium carbonate to a 50ml single-mouth bottle (2.1g), deuterated methyl iodide (1.5g) and isopropanol (10ml), heated to 65°C and stirred for 4 hours. The reaction solution was cooled to room temperature, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 120 mg of white solid. ¹ H NMR (400MHz, CDCl ₃ ): δ7.59 (t, J = 8.0 Hz, 1H), 6.45 (dd, J = 8.4, 2.3 Hz, 1H), 6.32 (dd, J = 13.3, 2.3 Hz, 1H ), 1.36 (s, 12H). MS: m/z 272.2, [M+H] ⁺ .

中间体11：Intermediate 11:

第一步first step

在反应瓶中加入2-氯-4-甲基-3-硝基吡啶(19g)，碳酸钾(14g)，1,4-二氧六环(100ml)，重水(60ml)，加完后于100℃回流24小时。将反应液冷却至室温，加水稀释，乙酸乙酯萃取，合并有机层，水洗一次，无水硫酸钠干燥，过滤，减压浓缩至干。照上述方法重复操作3次得产品。 ¹H NMR(400MHz,CDCl ₃):δ8.40(d,J＝5.0Hz,1H),7.27(d,J＝5.0Hz,1H).MS:m/z 176.0,[M+H] ⁺。 Add 2-chloro-4-methyl-3-nitropyridine (19g), potassium carbonate (14g), 1,4-dioxane (100ml), and heavy water (60ml) into the reaction flask. Reflux at 100°C for 24 hours. The reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, the organic layers were combined, washed once with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness. Repeat the operation 3 times according to the above method to obtain the product. ¹ H NMR (400MHz, CDCl ₃ ): δ8.40 (d, J=5.0 Hz, 1H), 7.27 (d, J=5.0 Hz, 1H). MS: m/z 176.0, [M+H] ⁺ .

第二步Second step

在500ml的单口瓶中，加入上步产物(15g)，碳酸铯(85.3g)，1,2-二甲氧基乙烷(240ml)，重水(60ml)，异丙烯基硼酸频那醇酯(17.6g)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(6.2g)，氮气置换，升温至80度回流反应3小时。将反应液冷却后加入200ml饱和碳酸氢钠溶液，乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得淡黄色油状物14g。 ¹H NMR(400MHz,CDCl ₃):δ8.54(d,J＝5.0Hz,1H),7.18(d,J＝5.0Hz,1H),5.37-5.31(m,1H),5.20(s,1H),2.20(t,J＝1.2Hz,3H)。 In a 500ml single-neck bottle, add the product of the previous step (15g), cesium carbonate (85.3g), 1,2-dimethoxyethane (240ml), heavy water (60ml), isopropenyl borate pinacol ester ( 17.6g), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (6.2g), replaced with nitrogen, heated to 80°C and refluxed for 3 hours. After cooling the reaction solution, add 200ml saturated sodium bicarbonate solution, extract with ethyl acetate, combine the organic layers, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain 14g of light yellow oil. ¹ H NMR (400MHz, CDCl ₃ ): δ8.54 (d, J = 5.0Hz, 1H), 7.18 (d, J = 5.0Hz, 1H), 5.37-5.31 (m, 1H), 5.20 (s, 1H) ), 2.20 (t, J = 1.2 Hz, 3H).

第三步third step

在500ml的单口瓶中加入上步产物(14g)，无水乙醇(200ml)和5％钯碳(7g)，氢气置换，在氢气袋压力下室温反应过夜。垫硅藻土过滤除去钯碳，滤液减压浓缩，硅胶柱层析纯化，得淡黄色油状物8g。 ¹H NMR(400MHz,CDCl ₃):δ7.96(d,J＝4.8Hz,1H),6.85(d,J＝4.8Hz,1H),3.63(br s,2H),3.12-2.97(m,1H),1.31(d,J＝6.8Hz,6H)。 Add the product of the previous step (14g), absolute ethanol (200ml) and 5% palladium carbon (7g) into a 500ml single-necked flask, replace with hydrogen, and react overnight at room temperature under hydrogen bag pressure. The palladium carbon was removed by filtration through a pad of diatomaceous earth, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 8 g of light yellow oil. ¹ H NMR (400MHz, CDCl ₃ ): δ7.96 (d, J = 4.8Hz, 1H), 6.85 (d, J = 4.8Hz, 1H), 3.63 (br s, 2H), 3.12-2.97 (m, 1H), 1.31 (d, J=6.8 Hz, 6H).

中间体12：Intermediate 12:

第一步first step

于500ml干燥三口瓶中加入2-溴苯胺(20.0g)和四氢呋喃(200ml)，氮气置换并降温到-78℃，缓慢滴加正丁基锂(2.5M in hexane，46.4mll)，滴毕，继续搅拌30分钟。滴加烯丙基溴(14.0g)，滴毕，自然升至室温，搅拌10小时。反应完毕，加饱和氯化铵水溶液淬灭反应，乙酸乙酯萃取，合并有机相，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色油状物(20.8g。 ¹H NMR(400MHz,CDCl ₃):δ7.47(dd,J＝7.9,1.5Hz,1H),7.21(td,J＝7.7,1.4Hz,1H),6.68(dd,J＝8.2,1.4Hz,1H),6.62(td,J＝7.6,1.5Hz,1H),6.06-5.94(m,1H),5.39-5.30(m,1H),5.27-5.22(m,1H),4.53(s,1H), 3.92-3.84(m,2H).MS:m/z 212.0,[M+H] ⁺。 Add 2-bromoaniline (20.0g) and tetrahydrofuran (200ml) to a 500ml dry three-necked flask, replace with nitrogen and cool to -78°C, slowly add n-butyllithium (2.5M in hexane, 46.4ml) dropwise, and finish dropping. Continue stirring for 30 minutes. Allyl bromide (14.0g) was added dropwise, after the dropping, the temperature was raised to room temperature naturally, and the mixture was stirred for 10 hours. After the reaction was completed, the reaction was quenched by adding saturated aqueous ammonium chloride solution, extracted with ethyl acetate, combined the organic phases, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain a yellow oil (20.8g. ¹ H NMR (400MHz, CDCl ₃ ): δ7.47 (dd, J = 7.9, 1.5 Hz, 1H), 7.21 (td, J = 7.7, 1.4 Hz, 1H), 6.68 (dd, J = 8.2,1.4Hz,1H),6.62(td,J=7.6,1.5Hz,1H),6.06-5.94(m,1H),5.39-5.30(m,1H),5.27-5.22(m,1H),4.53 (s, 1H), 3.92-3.84 (m, 2H). MS: m/z 212.0, [M+H] ⁺ .

第二步Second step

于500ml干燥三口瓶中加入N-烯丙基-2-溴苯胺(20.5g)和四氢呋喃(200ml)，氮气保护并降温到-78℃，缓慢滴加正丁基锂(2.5M in hexane，38.7ml)，滴毕，继续搅拌30分钟。滴加碘甲烷(13.7g)，滴毕，自然升至室温，搅拌10小时。反应完毕，加饱和氯化铵水溶液淬灭，乙酸乙酯萃取，合并有机相，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色油状物19.5g。 ¹H NMR(400MHz,CDCl ₃):δ7.59(dd,J＝7.9,1.5Hz,1H),7.28(td,J＝7.6,1.5Hz,1H),7.11(dd,J＝8.0,1.5Hz,1H),6.92(td,J＝7.6,1.6Hz,1H),6.04-5.91(m,1H),5.33-5.25(m,1H),5.25-5.19(m,1H),3.65(d,J＝6.3Hz,2H),2.77(s,3H).MS:m/z 226.0,[M+H] ⁺。 Add N-allyl-2-bromoaniline (20.5g) and tetrahydrofuran (200ml) into a 500ml dry three-necked flask, protect with nitrogen and cool to -78℃, slowly add n-butyllithium (2.5M in hexane, 38.7 ml), after dripping, continue to stir for 30 minutes. Iodomethane (13.7g) was added dropwise, after the dropping was completed, the temperature was raised to room temperature naturally, and the mixture was stirred for 10 hours. After the reaction, it was quenched by adding saturated aqueous ammonium chloride solution, extracted with ethyl acetate, combined the organic phases, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain a yellow oil 19.5 g. ¹ H NMR(400MHz, CDCl ₃ ): δ7.59(dd,J=7.9,1.5Hz,1H), 7.28(td,J=7.6,1.5Hz,1H), 7.11(dd,J=8.0,1.5Hz ,1H),6.92(td,J=7.6,1.6Hz,1H),6.04-5.91(m,1H),5.33-5.25(m,1H),5.25-5.19(m,1H),3.65(d,J = 6.3 Hz, 2H), 2.77 (s, 3H). MS: m/z 226.0, [M+H] ⁺ .

第三步third step

于500ml干燥三口瓶中加入N-烯丙基-2-溴-N-甲基苯胺(20.0g)和四氢呋喃(200ml)，氮气保护并降温到-78℃，滴加四甲基乙二胺(10.3g)，滴毕，搅拌10分钟后缓慢滴加正丁基锂(2.5M in hexane，38.9ml)，滴毕，继续搅拌30分钟。滴加硼酸三甲酯(10.1g)，滴毕，自然升至室温搅拌10小时。反应完毕，加饱和氯化铵水溶液淬灭，石油醚萃取3次，弃去有机相，水相用乙酸乙酯萃取4次，合并乙酸乙酯相，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩至干，得类白色固体7.3g。 ¹H NMR(400MHz,CDCl ₃):δ7.97(d,J＝5.6Hz,1H),7.54-7.38(m,1H),7.37-7.16(m,2H),6.00-5.76(m,1H),5.31-5.07(m,2H),3.55(s,2H),2.71(s,3H).MS:m/z 192.1,[M+H] ⁺。 Add N-allyl-2-bromo-N-methylaniline (20.0g) and tetrahydrofuran (200ml) into a 500ml dry three-necked flask, protect with nitrogen and cool to -78℃, add tetramethylethylenediamine ( 10.3g), after dripping, stir for 10 minutes and slowly add n-butyllithium (2.5M in hexane, 38.9ml) dropwise, after dripping, continue stirring for 30 minutes. Trimethyl borate (10.1g) was added dropwise, after the dropping, it was naturally raised to room temperature and stirred for 10 hours. After the reaction, it was quenched by adding saturated aqueous ammonium chloride solution, extracted with petroleum ether 3 times, the organic phase was discarded, the aqueous phase was extracted 4 times with ethyl acetate, the ethyl acetate phases were combined, washed with saturated brine, and dried with anhydrous sodium sulfate , Filtered and concentrated to dryness under reduced pressure to obtain 7.3 g of off-white solid. ¹ H NMR (400MHz, CDCl ₃ ): δ7.97 (d, J = 5.6Hz, 1H), 7.54-7.38 (m, 1H), 7.37-7.16 (m, 2H), 6.00-5.76 (m, 1H) ,5.31-5.07(m,2H),3.55(s,2H),2.71(s,3H). MS: m/z 192.1, [M+H] ⁺ .

参考文献中的制备方案(Journal of the American Chemical Society(2018),140(24),7458-7461；Journal of Chemical Physics(2014),141(6),064317/1-064317/13；Journal of Labelled Compounds and Radiopharmaceuticals(1988),25(3),263-75)及相应的氘代试剂，制备得到以下的中间体：Preparation schemes in references (Journal of the American Chemical Society(2018), 140(24), 7458-7461; Journal of Chemical Physics(2014), 141(6), 064317/1-064317/13; Journal of Labeled Compounds and Radiopharmaceuticals (1988), 25(3), 263-75) and the corresponding deuterated reagents, the following intermediates were prepared:

参考文献中的制备方案(J.Med.Chem.2014,57,3011-3029；Journal Organic Chemitry(2006),71(10),3977-3979；Journal of Organic Chemistry(1986),51(3),412-413；Journal of the American Chemical Society(2014),136(10),3740-3743)及相应的氘代试剂，制备得到以下的中间体：Preparation schemes in references (J.Med.Chem.2014,57,3011-3029; Journal Organic Chemistry(2006),71(10),3977-3979; Journal of Organic Chemistry(1986),51(3), 412-413; Journal of the American Chemical Society (2014), 136(10), 3740-3743) and the corresponding deuterated reagents, and the following intermediates were prepared:

参考文献中的制备方案(Journal of Organic Chemistry(1999),64(10),3563-3566；ACS Catalysis(2018),8(4),3516-3524；Molecular Catalysis(2018),460,1-6；ChemistrySelect(2018),3(2),713-718)及相应的氘代试剂，制备得到以下的中间体：Preparation schemes in references (Journal of Organic Chemistry(1999),64(10),3563-3566; ACS Catalysis(2018),8(4),3516-3524; MolecularCatalysis(2018),460,1-6 ; ChemistrySelect (2018), 3(2), 713-718) and the corresponding deuterated reagents to prepare the following intermediates:

参考文献中的制备方案(Synthesis(1985),(8),775-778；Chemical Communications(Cambridge,United Kingdom)(2009),(23),3357-3359；Journal of Chemical Physics(2014),141(6),064317/1-064317/13；US20130079554；Journal of Labelled Compounds and Radiopharmaceuticals(2011),54(12),743-748)及相应的氘代试剂，制备得到以下的中间体：Preparation schemes in references (Synthesis (1985), (8), 775-778; Chemical Communications (Cambridge, United Kingdom) (2009), (23), 3357-3359; Journal of Chemical Physics (2014), 141( 6), 064317/1-064317/13; US20130079554; Journal of Labeled Compounds and Radiopharmaceuticals (2011), 54(12), 743-748) and the corresponding deuterated reagents, and the following intermediates were prepared:

参考文献中的制备方案(Chemical Science(2015),6(10),5519-5525；Journal of Organic Chemistry(1979),44(12),1897-904；Angewandte Chemie,International Edition(2011),50(21),4983-4987,S4983/1-S4983/162；)及相应的氘代试剂，制备得到以下的中间体：Preparation schemes in references (Chemical Science(2015), 6(10), 5519-5525; Journal of Organic Chemistry(1979), 44(12), 1897-904; Angewandte Chemie, International Edition(2011), 50( 21), 4983-4987, S4983/1-S4983/162;) and the corresponding deuterated reagents, the following intermediates were prepared:

中间体16：Intermediate 16:

以P1为原料，进行氘代取代，得到P2，最后制备得到中间体16。(参考文献Organic Process Research&Development(2017),21(11),1741-1744；CN103265498)。Using P1 as a raw material, deuterated substitution is performed to obtain P2, and finally intermediate 16 is prepared. (Refer to Organic Process Research & Development (2017), 21(11), 1741-1744; CN103265498).

参考专利US2013079554A1，采用Lindlar催化剂催化氢化相应的炔基化合物，并进行酰氯化得到以下的中间体17：With reference to patent US2013079554A1, Lindlar catalyst is used to catalyze the hydrogenation of the corresponding alkynyl compound, and the acylation is carried out to obtain the following intermediate 17:

中间体18：Intermediate 18:

以X1为原料，经过化学反应转化得到中间体18(参考文献US20190374542)。Using X1 as a raw material, intermediate 18 is obtained through chemical conversion (reference US20190374542).

或者采用另一种制备方法，具体制备方法如下：Or adopt another preparation method, the specific preparation method is as follows:

步骤1 step 1

于250ml瓶中加入2-溴-4-氯-吡啶-3-胺(9.2g)，异丙烯基硼酸频哪醇酯(11.9g)，碳酸钾(7.6g)、PdCl ₂(dppf)(5.5gl)，1,4-二氧六环(85ml)和水(17ml)，氮气置换，升温至105℃，搅拌3小时。反应完毕，降温至室温，过滤，滤液中加入水，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤2次，无水硫酸钠干燥，过滤，滤液浓缩，硅胶柱层析纯化，得橙黄色固体9.3g。 ¹H NMR(400MHz,CDCl ₃):δ7.92(d,J＝5.2Hz,1H),7.11(d,J＝5.1Hz,1H),5.54-5.51(m,1H),5.36-5.34(m,1H),4.37(s,2H),2.18(t,J＝1.3Hz,3H)。 Add 2-bromo-4-chloro-pyridine-3-amine (9.2g), isopropenylboronic acid pinacol ester (11.9g), potassium carbonate (7.6g), PdCl ₂ (dppf) (5.5 gl), 1,4-dioxane (85ml) and water (17ml), replaced with nitrogen, heated to 105°C and stirred for 3 hours. After the reaction is complete, cool to room temperature, filter, add water to the filtrate, extract with ethyl acetate, combine the organic layers, wash twice with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate the filtrate, and purify by silica gel column chromatography to obtain orange yellow Solid 9.3g. ¹ H NMR (400MHz, CDCl ₃ ): δ7.92 (d, J = 5.2 Hz, 1H), 7.11 (d, J = 5.1 Hz, 1H), 5.54-5.51 (m, 1H), 5.36-5.34 (m , 1H), 4.37 (s, 2H), 2.18 (t, J = 1.3 Hz, 3H).

步骤2Step 2

于500ml中加入上步产物(10.0g)，乙烯基硼酸频哪醇酯(13.8g)，Pcy ₃(1.0g)，醋酸钯(0.5g)，碳酸铯(38.8g)，甲苯(200ml)，氮气置换，升温至120℃，搅拌反应12小时。反应完毕，降温至室温，加入水，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤2次，无水硫酸钠干燥，过滤，滤液浓缩，硅胶柱层析纯化，得棕色油状物7.1g。 ¹H NMR(400MHz,CDCl ₃):δ8.01(d,J＝4.9Hz,1H),7.06(d,J＝4.9Hz,1H),6.76(dd,J＝17.4,11.1Hz,1H),5.80(dd,J＝17.4,1.2Hz,1H),5.54–5.48(m,2H),5.30-5.28(m,1H),4.05(s,2H),2.18(t,J＝1.2Hz,3H).MS:m/z 161.1,[M+H] ⁺。 Add the product of the previous step (10.0g), vinyl boronic acid pinacol ester (13.8g), Pcy ₃ (1.0g), palladium acetate (0.5g), cesium carbonate (38.8g), toluene (200ml) to 500ml, Replace with nitrogen, increase the temperature to 120°C, and stir and react for 12 hours. After the reaction was completed, the temperature was lowered to room temperature, water was added, ethyl acetate extraction, the organic layers were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and purified by silica gel column chromatography to obtain 7.1 g of brown oil. ¹ H NMR (400MHz, CDCl ₃ ): δ8.01 (d, J = 4.9 Hz, 1H), 7.06 (d, J = 4.9 Hz, 1H), 6.76 (dd, J = 17.4, 11.1 Hz, 1H), 5.80(dd,J=17.4,1.2Hz,1H),5.54-5.48(m,2H),5.30-5.28(m,1H),4.05(s,2H),2.18(t,J=1.2Hz,3H) .MS: m/z 161.1, [M+H] ⁺ .

步骤3Step 3

于250ml单口瓶中加入上步产物(7.1g)，乙醇(150ml)，钯碳(0.7g)，氢气置换，室温搅拌过夜。反应毕，过滤，滤液浓缩，硅胶柱层析纯化，得***油状物5.5g。 ¹H NMR(400MHz,CDCl ₃):δ8.02(d,J＝4.9Hz,1H),6.88(d,J＝4.9Hz,1H),3.66(s,2H),3.12-3.01(m,1H),2.52(q,J＝7.6Hz,2H),1.32(d,J＝6.7Hz,6H),1.28(t,J＝7.5Hz,3H).MS:m/z165.1,[M+H] ⁺。 Add the product of the previous step (7.1g), ethanol (150ml), palladium carbon (0.7g) into a 250ml single-neck flask, replace with hydrogen, and stir overnight at room temperature. After the reaction is complete, filter, concentrate the filtrate, and purify by silica gel column chromatography to obtain 5.5 g of purple-red oil. ¹ H NMR (400MHz, CDCl ₃ ): δ8.02 (d, J = 4.9Hz, 1H), 6.88 (d, J = 4.9Hz, 1H), 3.66 (s, 2H), 3.12-3.01 (m, 1H) ),2.52(q,J=7.6Hz,2H),1.32(d,J=6.7Hz,6H),1.28(t,J=7.5Hz,3H).MS:m/z165.1,[M+H ] ⁺ .

然后参考中间体1，中间体2，中间体3和中间体4的制备方案，可以制备得到以下的中间体：Then referring to the preparation schemes of Intermediate 1, Intermediate 2, Intermediate 3 and Intermediate 4, the following intermediates can be prepared:

具体制备方法如下：The specific preparation method is as follows:

步骤1 step 1

于250ml的三口瓶中加入四氢呋喃(50ml)，氮气置换，降温至-5℃，缓慢滴入草酰氯(2.9g)，搅拌10分钟，分批加入2,5,6-三氯烟酰胺(4.4g)，升温至45℃，搅拌1小时。反应完毕，浓缩至干，加入四氢呋喃(25ml)，氮气置换，降温至-5℃，缓慢滴入2-异丙基-4-乙基吡啶-3-胺(2.1g)的四氢呋喃(18ml)溶液，室温搅拌1小时。反应完毕，浓缩至干，加入水和适量饱和碳酸钠水溶液至pH为7～8，二氯甲烷萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，滤液浓缩，得粉红色固体粗品。加入石油醚:乙酸乙酯＝10:1混合溶剂(110ml)，室温搅拌1小时，过滤，滤饼烘干，得类白色固体6.3g。MS:m/z 415.1,[M+H] ⁺。 Add tetrahydrofuran (50ml) to a 250ml three-necked flask, replace with nitrogen, cool to -5°C, slowly drip oxalyl chloride (2.9g), stir for 10 minutes, add 2,5,6-trichloronicotinamide (4.4 g), heat to 45°C, and stir for 1 hour. After the reaction is complete, concentrate to dryness, add tetrahydrofuran (25ml), replace with nitrogen, cool to -5°C, slowly drop in a solution of 2-isopropyl-4-ethylpyridin-3-amine (2.1g) in tetrahydrofuran (18ml) , Stir at room temperature for 1 hour. After the reaction is complete, concentrate to dryness, add water and an appropriate amount of saturated sodium carbonate aqueous solution to pH 7-8, extract with dichloromethane, combine the organic layers, wash once with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain pink Color solid crude product. Add petroleum ether: ethyl acetate = 10:1 mixed solvent (110 ml), stir at room temperature for 1 hour, filter, and dry the filter cake to obtain 6.3 g of off-white solid. MS: m/z 415.1, [M+H] ⁺ .

步骤2Step 2

于500ml三口瓶中加入上步产物(6.3g)和四氢呋喃(160ml)，氮气置换，降温至10～15℃，滴加LiHMDS(1M in THF,33.5ml)，室温搅拌2小时。反应完毕，加饱和氯化铵水溶液淬灭，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，滤液浓缩，浓缩至大量固体析出，加入MTBE(10ml)，过滤，滤饼烘干，得白色固体3.8g。MS:m/z 379.1,[M+H] ⁺。 Add the product from the previous step (6.3g) and tetrahydrofuran (160ml) to a 500ml three-necked flask, replace with nitrogen, and cool to 10-15°C. Add LiHMDS (1M in THF, 33.5ml) dropwise, and stir at room temperature for 2 hours. After the reaction was completed, it was quenched by adding saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic layers were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, concentrated until a large amount of solid precipitated, and MTBE (10ml) was added. Filter and dry the filter cake to obtain 3.8 g of white solid. MS: m/z 379.1, [M+H] ⁺ .

步骤3Step 3

于250ml三口瓶中加入上步产物(3.8g)，四氢呋喃(95ml)，DIPEA(7.8g)，(S)-4-N-叔丁基羰基-2-甲基哌嗪(2.0g),氮气置换，冰浴下缓慢滴入三氯氧磷(3.1g)，升温至30℃，搅拌15分钟，加入(S)-4-N-叔丁基羰基-2-甲基哌嗪(1.0g)，搅拌反应30分钟。反应完毕，加饱和氯化铵水溶液淬灭，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，滤液浓缩，浓缩得棕色固体5.7g。MS:m/z 561.2,[M+H] ⁺。 Add the product of the previous step (3.8g), tetrahydrofuran (95ml), DIPEA (7.8g), (S)-4-N-tert-butylcarbonyl-2-methylpiperazine (2.0g), and nitrogen to a 250ml three-necked flask. Replace, slowly drop phosphorus oxychloride (3.1g) in an ice bath, heat to 30°C, stir for 15 minutes, add (S)-4-N-tert-butylcarbonyl-2-methylpiperazine (1.0g) , Stir and react for 30 minutes. After the reaction was completed, it was quenched by adding saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic layers were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and concentrated to obtain 5.7 g of brown solid. MS: m/z 561.2, [M+H] ⁺ .

参考专利WO2019051291记载的超临界液相色谱(SFC)的分离方法，可以制备分离得到以下中间体。With reference to the separation method of supercritical liquid chromatography (SFC) described in patent WO2019051291, the following intermediates can be prepared and separated.

中间体19：Intermediate 19:

化合物A(按照WO2020050890，WO2019051291制备)称量5.00g于250mL圆底烧瓶中，加入50mL甲基四氢呋喃，于氮气保护下，75℃条件下保温搅拌30min，待溶解完全成为澄清溶液，加入溶解有10g的(+)-DBTA的20mL甲基四氢呋喃，将以上两个甲基四氢呋喃溶液混合后，继续在75℃条件下，滴加入50mL正庚烷，然后将以上混合物于25℃条件下，继续搅拌8小时，过滤固体，50℃条件下，鼓风干燥5h，得到目标复合物4g(>99％ee)。 ¹H NMR(400MHz,DMSO-d6)δ12.31(br.s,1H),8.60(s,1H),8.53-8.52(m,1H),7.99-7-96(m,2H),7.71-7-67(m,1H),7.57–7.53(m,2H),7.29–7.28(m,1H),5.77(s,1H),3.86-3.72(m,2H),3.58–3.52(m,1H),2.94–2.84(m,1H),2.05(s,3H),1.97–1.90(m,1H),1.85–1.74(m,1H),1.36-1.24(m,1H),1.13-1.12(m,3H),1.09-1.07(m,3H),1.02-1.00(m,3H)； ¹³C NMR(100MHz,DMSO-d6)δ168.0,165.2,164.6,160.5,151.7,150.1,149.9,149.7,146.3,139.7,134.1,129.8,129.6,129.3,128.7,124.4,124.1,112.8,74.8,72.0,67.2,33.2,30.0,25.9,22.7,22.3,21.4,17.5。 Compound A (prepared in accordance with WO2020050890, WO2019051291) weighed 5.00g into a 250mL round-bottomed flask, added 50mL methyltetrahydrofuran, and kept stirring at 75℃ for 30min under nitrogen protection. When it was completely dissolved, it became a clear solution. Add 10g dissolved (+)-DBTA 20mL methyltetrahydrofuran, after mixing the above two methyltetrahydrofuran solutions, continue to add 50mL n-heptane dropwise at 75℃, and then put the above mixture at 25℃, continue to stir 8 After hours, the solid was filtered, and air-dried at 50°C for 5 hours to obtain 4g (>99%ee) of the target compound. ¹ H NMR (400MHz, DMSO-d6) δ 12.31 (br.s, 1H), 8.60 (s, 1H), 8.53-8.52 (m, 1H), 7.99-7-96 (m, 2H), 7.71 7-67 (m, 1H), 7.57 - 7.53 (m, 2H), 7.29 - 7.28 (m, 1H), 5.77 (s, 1H), 3.86-3.72 (m, 2H), 3.58 - 3.52 (m, 1H) ), 2.94–2.84(m,1H),2.05(s,3H),1.97–1.90(m,1H),1.85–1.74(m,1H),1.36-1.24(m,1H),1.13-1.12(m ,3H),1.09-1.07(m,3H),1.02-1.00(m,3H); ¹³ C NMR(100MHz,DMSO-d6)δ168.0,165.2,164.6,160.5,151.7,150.1,149.9,149.7,146.3, 139.7, 134.1, 129.8, 129.6, 129.3, 128.7, 124.4, 124.1, 112.8, 74.8, 72.0, 67.2, 33.2, 30.0, 25.9, 22.7, 22.3, 21.4, 17.5.

然后按照中间体3的制备方案，制备得到以下的中间体3M(其单晶结构参见说明书附图1)：Then, according to the preparation scheme of Intermediate 3, the following Intermediate 3M was prepared (see attached figure 1 of the specification for its single crystal structure):

中间体3M结构表征数据( ¹H NMR(400MHz,CDCl ₃)) Intermediate 3M structure characterization data ( ¹ H NMR (400MHz, CDCl ₃ ))

序号Serial number	化学位移(ppm)Chemical shift (ppm)	多重性(J值/Hz)Multiplicity (J value/Hz)	质子数Number of protons
11	8.578.57	d(4.9)d(4.9)	11
22	8.058.05	s s	11
33	7.147.14	dd(4.9,0.6)dd(4.9,0.6)	11
44	5.01-4.645.01-4.64	m m	11
55	4.45-3.824.45-3.82	mm	33
66	3.683.68	br sbr s	11
77	3.44-2.913.44-2.91	mm	22
88	2.72-2.542.72-2.54	m m	11
99	2.032.03	ss	33
1010	1.511.51	ss	99
1111	1.491.49	d(6.8)d(6.8)	33
1212	1.221.22	d(6.8)d(6.8)	33
1313	1.131.13	d(6.7)d(6.7)	33

参考中间体19的制备方案，以(-)-DBTA为拆分试剂，制备得到以下的中间体20：Referring to the preparation scheme of Intermediate 19, using (-)-DBTA as the resolution reagent, the following Intermediate 20 was prepared:

可以制备得到以下中间体3P：The following intermediate 3P can be prepared:

采用中间体19和中间体20，参考中间体4的制备方案，可以制备得到以下的中间体：Using Intermediate 19 and Intermediate 20, referring to the preparation scheme of Intermediate 4, the following intermediates can be prepared:

采用中间体19和中间体20，参考中间体5的制备方案，可以制备得到以下的中间体：Using Intermediate 19 and Intermediate 20, referring to the preparation scheme of Intermediate 5, the following intermediates can be prepared:

中间体22：Intermediate 22:

以乙烯腈为原料，以重氧水为同位素来源，参考文献方法制备得到中间体22。(参考文献Journal of Biosciences(Bangalore,India)(2009),34(1),21-26；JP61282089；US20030148480等等)。Using vinyl nitrile as the raw material and deuterated water as the isotope source, the intermediate 22 was prepared by the reference method. (Refer to Journal of Biosciences (Bangalore, India) (2009), 34(1), 21-26; JP61282089; US20030148480, etc.).

具体制备方法如下：The specific preparation method is as follows:

向反应瓶中加入25ml pH 7.2的H ₂ ¹⁸O，约2ml丙烯氰和10mg氰基水解酶，加毕于28℃反应过夜。将HCl的二氧六环溶液缓慢加入，调pH至2～3，再加入二氯甲烷萃取2次，有机相用无水硫酸钠干燥，过滤，减压浓缩至干，得浅黄色油状物。然后溶解在二氯甲烷溶液中，加入二氯亚砜，回流反应2h。减压浓缩即得酰氯产物，直接用于反应使用。 Add 25ml of H ₂ ¹⁸ O with pH 7.2, about 2ml of acrylonitrile and 10mg of cyanohydrolase into the reaction flask, and react at 28°C overnight. The dioxane solution of HCl was slowly added, the pH was adjusted to 2-3, and dichloromethane was added for extraction twice, the organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain a light yellow oil. Then it was dissolved in dichloromethane solution, thionyl chloride was added, and the reaction was refluxed for 2h. Concentrate under reduced pressure to obtain the acid chloride product, which is directly used in the reaction.

中间体23：Intermediate 23:

于50ml三口瓶中加入四氢呋喃(20ml)，氮气置换，降温至-5℃，缓慢滴入草酰氯(1.3g)，搅拌10分钟，分批加入2,5,6-三氯烟酰胺(2.0g)，升温至45℃搅拌1小时。反应完毕，浓缩至断流，加入四氢呋喃(15ml)，氮气置换，降温至-5℃，缓慢滴入4,6-二异丙基吡啶-5-胺(1.1g)的四氢呋喃(10ml)溶液，室温搅拌1小时。反应完毕，加水淬灭，浓缩掉四氢呋喃，加入饱和碳酸钠水溶液调节水相pH为7～8，常温搅拌10分钟，过滤，滤饼烘干，得类白色固体2.6g。MS:m/z 430.1,[M+H] ⁺。 Add tetrahydrofuran (20ml) to a 50ml three-necked flask, replace with nitrogen, cool to -5°C, slowly drip oxalyl chloride (1.3g), stir for 10 minutes, add 2,5,6-trichloronicotinamide (2.0g) in batches ), the temperature was raised to 45°C and stirred for 1 hour. After the reaction is complete, concentrate to stop flow, add tetrahydrofuran (15ml), replace with nitrogen, cool to -5°C, slowly drop in 4,6-diisopropylpyridine-5-amine (1.1g) in tetrahydrofuran (10ml) solution, Stir at room temperature for 1 hour. After the reaction is completed, add water to quench, concentrate the tetrahydrofuran, add saturated sodium carbonate aqueous solution to adjust the pH of the water phase to 7-8, stir at room temperature for 10 minutes, filter, and dry the filter cake to obtain 2.6 g of off-white solid. MS: m/z 430.1, [M+H] ⁺ .

于250ml三口瓶中加入上步产物(2.6g)，四氢呋喃(100ml)，氮气置换，降温至10～15℃，滴加LiHMDS(1M in THF，13.6ml)，室温搅拌3小时。反应完毕，加饱和氯化铵水溶液淬灭，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，滤液浓缩，浓缩至大量固体析出，加入甲基叔丁基醚(3ml)，常温搅拌10分钟，过滤，滤饼烘干，得白色固体1.7g。MS:m/z 394.1,[M+H] ⁺。 Add the product from the previous step (2.6g) and tetrahydrofuran (100ml) to a 250ml three-necked flask, replace with nitrogen, cool to 10-15°C, add LiHMDS (1M in THF, 13.6ml) dropwise, and stir at room temperature for 3 hours. After the reaction is complete, add saturated ammonium chloride aqueous solution to quench, extract with ethyl acetate, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate the filtrate, concentrate until a large amount of solid precipitates, add methyl tert-butyl Ether (3ml), stirred at room temperature for 10 minutes, filtered, and dried the filter cake to obtain 1.7g of white solid. MS: m/z 394.1, [M+H] ⁺ .

于100ml三口瓶中加入上步产物(1.7g)，四氢呋喃(45ml)，DIPEA(3.3g)，(S)-4-N-叔丁基羰基-2-甲基哌嗪(861m g),氮气置换，冰浴下缓慢滴入三氯氧磷(1.3g)，常温搅拌30分钟，加入(S)-4-N-叔丁基羰基-2-甲基哌嗪(430m gl)，常温搅拌30分钟。反应完毕，加饱和氯化铵水溶液淬灭，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩，浓缩得棕色固体2.5g。MS:m/z 576.2,[M+H] ⁺。 Add the product of the previous step (1.7g), tetrahydrofuran (45ml), DIPEA (3.3g), (S)-4-N-tert-butylcarbonyl-2-methylpiperazine (861mg), nitrogen to a 100ml three-necked flask Replace, slowly drop in phosphorus oxychloride (1.3g) under ice bath, stir at room temperature for 30 minutes, add (S)-4-N-tert-butylcarbonyl-2-methylpiperazine (430 mgl), and stir at room temperature for 30 minutes. minute. After the reaction was completed, it was quenched by adding saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and concentrated to obtain 2.5 g of brown solid. MS: m/z 576.2, [M+H] ⁺ .

化合物制备Compound preparation

实施例1：Example 1:

第一步first step

于50ml单口瓶中加入(S)-4-(6,7-二氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(中间体3)(1.0g)，2-(二甲氨基)苯基硼酸(424mg)，醋酸钾(502mg)，1,4-二氧六环(20ml)，水(4ml)和[1,1'-双(二苯基膦)二茂铁]二氯化钯(132mg)，氮气置换后，升温至105℃，搅拌2小时。反应完毕，冷至室温，加水稀释，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体800mg。Add (S)-4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-di Hydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (Intermediate 3) (1.0g), 2-(dimethylamino)phenyl Boric acid (424mg), potassium acetate (502mg), 1,4-dioxane (20ml), water (4ml) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride ( 132 mg), after nitrogen replacement, the temperature was raised to 105°C and stirred for 2 hours. After the reaction is complete, cool to room temperature, dilute with water, extract with ethyl acetate, combine the organic layers, wash with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain 800 mg of yellow solid.

第二步Second step

于50ml单口瓶中加入上步产物(800mg)和二氯甲烷(10ml)，在10℃～15℃下，滴加三氟乙酸(10ml)，滴毕，继续搅拌1小时。将反应液浓缩至干，向残余物加入二氯甲烷(10ml)，降温至0℃，加入N,N-二异丙基乙胺(1.3ml)，再缓慢滴入丙烯酰氯(173mg)的二氯甲烷(1ml)溶液，滴毕，搅拌30分钟。缓慢倒入饱和碳酸氢钠水溶液淬灭反应，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得淡黄色固体580mg。R _f:0.55(DCM:MeOH＝10:1)。 ¹H NMR(400MHz,DMSO-d ₆):δ8.44-8.31(m,2H),7.37-7.28(m,1H),7.23-7.13(m,1H),7.13-7.02(m,1H),7.01-6.78(m,3H),6.22(dd,J＝16.8,3.4Hz,1H),5.86-5.71(m,1H),5.14-4.72(m,1H),4.51-4.02(m,3H),3.78-3.61(m,1H),3.33-3.04(m,2H),2.85-2.71(m,1H),2.44(s,6H),1.90(s,3H),1.41-1.29(m,3H),1.09(d,J＝6.6Hz,3H),1.05-0.92(m,3H)；MS:m/z 586.2741,[M+H] ⁺。 Add the product of the previous step (800mg) and dichloromethane (10ml) to a 50ml single-necked flask, add trifluoroacetic acid (10ml) dropwise at 10°C to 15°C, and continue stirring for 1 hour. The reaction solution was concentrated to dryness, dichloromethane (10ml) was added to the residue, the temperature was lowered to 0°C, N,N-diisopropylethylamine (1.3ml) was added, and the dichloromethane (173mg) of acryloyl chloride (173mg) was slowly added dropwise. A solution of methyl chloride (1ml), dripped and stirred for 30 minutes. Slowly poured into saturated sodium bicarbonate aqueous solution to quench the reaction, extracted with ethyl acetate, combined the organic layers, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 580 mg of pale yellow solid. R _f : 0.55 (DCM:MeOH=10:1). ¹ H NMR (400MHz, DMSO-d ₆ ): δ8.44-8.31 (m, 2H), 7.37-7.28 (m, 1H), 7.23-7.13 (m, 1H), 7.13-7.02 (m, 1H), 7.01-6.78(m,3H),6.22(dd,J=16.8,3.4Hz,1H),5.86-5.71(m,1H),5.14-4.72(m,1H),4.51-4.02(m,3H), 3.78-3.61 (m, 1H), 3.33-3.04 (m, 2H), 2.85-2.71 (m, 1H), 2.44 (s, 6H), 1.90 (s, 3H), 1.41-1.29 (m, 3H), 1.09 (d, J=6.6 Hz, 3H), 1.05-0.92 (m, 3H); MS: m/z 586.2741, [M+H] ⁺ .

实施例2：Example 2:

第一步first step

于50ml的单口瓶中加入(S)-4-(6,7-二氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(1.2g)，3-氟-N,N-二甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯胺(800mg)，醋酸钾(650mg)，1,4-二氧六环(20ml)，水(4ml)和[1,1'-双(二苯基膦)二茂铁]二氯化钯(161mg)，氮气置换后升温至105℃搅拌2小时。反应完毕，加入水稀释，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体920mg。Add (S)-4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2- Dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (1.2g), 3-fluoro-N,N-dimethyl-2 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (800mg), potassium acetate (650mg), 1,4-dioxane Ring (20ml), water (4ml) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (161mg), replaced with nitrogen, heated to 105°C and stirred for 2 hours. After the reaction is complete, add water to dilute, extract with ethyl acetate, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain 920 mg of yellow solid.

第二步Second step

于50ml单口瓶中加入上步产物(920mg)和二氯甲烷(10ml)，在10℃～15℃下，滴加三氟乙酸(10ml)，滴毕，室温搅拌1小时。将反应液浓缩至干，向残余物加入二氯甲烷(10ml)，降温至0℃，加入N,N-二异丙基乙胺(1.4ml)，再缓慢滴入丙烯酰氯(191mg)的二氯甲烷(1ml)溶液，滴毕，搅拌30分钟。缓慢倒入饱和氯化铵水溶液淬灭反应，二氯甲烷萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体640mg。R _f:0.57(DCM:MeOH＝10:1). ¹H NMR(400MHz,CDCl ₃):δ8.51(d,J＝4.9Hz,1H),8.04(s,1H),7.12-7.02(m,2H),6.74-6.51(m,1H),6.47-6.37(m,2H),6.33(dd,J＝14.2,2.2Hz,1H),5.82(dd,J＝10.4,1.5Hz,1H),5.25-4.22(m,3H),4.10-3.44(m,3H),3.32-3.00(m,1H),2.99(s,6H),2.82-2.54(m,1H),2.05-1.75(m,3H),1.59-1.40(m,3H),1.25-1.18(m,3H),1.11-1.00(m,3H)；MS:m/z 604.2637,[M+H] ⁺。 Add the product of the previous step (920mg) and dichloromethane (10ml) to a 50ml single-necked flask, add trifluoroacetic acid (10ml) dropwise at 10°C to 15°C, and stir at room temperature for 1 hour. The reaction solution was concentrated to dryness, dichloromethane (10ml) was added to the residue, the temperature was lowered to 0°C, N,N-diisopropylethylamine (1.4ml) was added, and the dichloromethane (191mg) of acryloyl chloride (191mg) was slowly added dropwise. A solution of methyl chloride (1ml), dripped and stirred for 30 minutes. Slowly poured into saturated aqueous ammonium chloride to quench the reaction, extracted with dichloromethane, combined the organic layers, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 640 mg of yellow solid. R _f : 0.57 (DCM: MeOH = 10:1). ¹ H NMR (400MHz, CDCl ₃ ): δ8.51 (d, J = 4.9 Hz, 1H), 8.04 (s, 1H), 7.12-7.02 (m ,2H),6.74-6.51(m,1H),6.47-6.37(m,2H),6.33(dd,J＝14.2,2.2Hz,1H),5.82(dd,J＝10.4,1.5Hz,1H), 5.25-4.22 (m, 3H), 4.10-3.44 (m, 3H), 3.32-3.00 (m, 1H), 2.99 (s, 6H), 2.82-2.54 (m, 1H), 2.05-1.75 (m, 3H) ), 1.59-1.40 (m, 3H), 1.25-1.18 (m, 3H), 1.11-1.00 (m, 3H); MS: m/z 604.2637, [M+H] ⁺ .

实施例3：Example 3:

参考是实施例1的制备方案，制备得到化合物3-2。R _f:0.54(DCM:MeOH＝10:1)；具体制备如下： Reference is the preparation scheme of Example 1, and compound 3-2 is prepared. R _f : 0.54 (DCM:MeOH=10:1); the specific preparation is as follows:

第一步first step

于50ml的单口瓶中加入(S)-4-(6,7-二氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(200mg)，2-(双(甲基-d ₃)氨基)苯硼酸(101mg)，醋酸钾(109mg)，1,4-二氧六环(20ml)，水(4ml)和[1,1'-双(二苯基膦)二茂铁]二氯化钯(29mg)，氮气置换后升温至95℃搅拌2小时。反应完毕，加入水稀释，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体210mg。MS:m/z 638.4,[M+H] ⁺。 Add (S)-4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2- Dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (200mg), 2-(bis(methyl-d ₃ )amino)benzene Boric acid (101mg), potassium acetate (109mg), 1,4-dioxane (20ml), water (4ml) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride ( 29mg), after nitrogen replacement, the temperature was raised to 95°C and stirred for 2 hours. After the reaction is complete, add water to dilute, extract with ethyl acetate, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain 210 mg of yellow solid. MS: m/z 638.4, [M+H] ⁺ .

第二步Second step

于50ml单口瓶中加入上步产物(200mg)和二氯甲烷(15ml)，在10℃～15℃下，滴加三氟乙酸(10ml)，滴毕，室温搅拌1小时。反应完毕，降温至0℃，缓慢加入饱和碳酸氢钠水溶液，调节pH至7～8，二氯甲烷萃取，合并有机层，无水硫酸钠干燥，过滤，减压浓缩至干，得黄色油状物，直接用于下一步。Add the product of the previous step (200mg) and dichloromethane (15ml) to a 50ml single-necked flask, add trifluoroacetic acid (10ml) dropwise at 10°C to 15°C, and stir at room temperature for 1 hour. After the reaction, the temperature was lowered to 0°C, saturated aqueous sodium bicarbonate was slowly added to adjust the pH to 7-8, extracted with dichloromethane, the organic layers were combined, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain a yellow oil , Used directly in the next step.

于50ml反应瓶中加入上一步产物(160mg)，二氯甲烷(25ml)和N,N-二异丙基乙胺(196mg)，氮气保护下降温至0℃，再缓慢滴入丙烯酰氯(36mg)，滴毕，搅拌30分钟。反应完毕，加水稀释，二氯甲烷萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得淡黄色固体100mg。 ¹H NMR(400MHz,CDCl ₃):δ8.48(d,J＝4.8Hz,1H),8.06(s,1H),7.35(t,J＝6.6Hz,1H),7.13-7.00(m,2H),7.00-6.87(m,2H),6.75-6.51(m,1H),6.42(d,J＝16.7Hz,1H),5.82(d,J＝10.5Hz,1H),4.86-4.62(m,1H),4.59-4.35(m,1H),4.32-3.98(m,1H),3.98-3.47(m,3H),3.40-3.06(m,1H),2.87-2.65(m,1H),2.02(br s,3H),1.57-1.38(m,3H),1.25(d,J＝6.6Hz,3H),1.08(br s,3H).MS:m/z 592.3163,[M+H] ⁺。 Add the product of the previous step (160mg), dichloromethane (25ml) and N,N-diisopropylethylamine (196mg) into a 50ml reaction flask, and reduce the temperature to 0℃ under nitrogen protection, and then slowly drop in acryloyl chloride (36mg). ), after dripping, stir for 30 minutes. After the reaction is complete, dilute with water, extract with dichloromethane, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain 100 mg of light yellow solid. ¹ H NMR (400MHz, CDCl ₃ ): δ8.48 (d, J = 4.8Hz, 1H), 8.06 (s, 1H), 7.35 (t, J = 6.6Hz, 1H), 7.13-7.00 (m, 2H) ), 7.00-6.87 (m, 2H), 6.75-6.51 (m, 1H), 6.42 (d, J = 16.7 Hz, 1H), 5.82 (d, J = 10.5 Hz, 1H), 4.86-4.62 (m, 1H), 4.59-4.35 (m, 1H), 4.32-3.98 (m, 1H), 3.98-3.47 (m, 3H), 3.40-3.06 (m, 1H), 2.87-2.65 (m, 1H), 2.02 ( br s, 3H), 1.57-1.38 (m, 3H), 1.25 (d, J=6.6 Hz, 3H), 1.08 (br s, 3H). MS: m/z 592.3163, [M+H] ⁺ .

实施例3-1M：Example 3-1M:

参考实施例3制备方案，采用中间体3M原料，制备得到化合物3-10M，R _f:0.52(DCM:MeOH＝10:1)。具体制备方法如下： Referring to the preparation scheme of Example 3, using the intermediate 3M raw material, the compound 3-10M was prepared, R _f :0.52 (DCM:MeOH=10:1). The specific preparation method is as follows:

第一步first step

于500ml单口瓶中依次加入叔丁基(S)-4-(7-氯-6-氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧-1,2-二氢吡啶基[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸(中间体3M)(6g)，(2-(双(甲基-d3)氨基)苯基)硼酸(2.8g)，醋酸钾(3.2g)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(448mg)，重水(12ml)和1,4-二氧六环(120ml)，氮气置换后，升温至95℃搅拌。反应完毕，加入水稀释，并用乙酸乙酯萃取4次，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体(6.1g)。 ¹HNMR(400MHz,Chloroform-d)δ8.49(d,J＝4.9Hz,1H),8.05(s,1H),7.38-7.32(m,1H),7.11-7.02(m,2H),7.01-6.91(m,2H),5.02-4.68(m,1H),4.54-4.21(m,2H),4.07-3.48(m,2H),3.43-3.02(m,2H),2.85(br s,1H),2.01(s,3H),1.61-1.51(m,3H),1.53(s,9H),1.29-1.26(m,3H),1.15-1.02(m,3H)；MS:m/z 638.3494,[M+H]。 Add tert-butyl(S)-4-(7-chloro-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1 into a 500ml single-neck bottle in turn ,2-Dihydropyridinyl[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid (Intermediate 3M)(6g), (2-(bis(methyl-d3 )Amino)phenyl)boronic acid (2.8g), potassium acetate (3.2g), [1,1'-bis(diphenylphosphine)ferrocene] palladium dichloride dichloromethane complex (448mg), After nitrogen replacement with heavy water (12ml) and 1,4-dioxane (120ml), the temperature was raised to 95°C and stirred. After the reaction is complete, add water to dilute, and extract 4 times with ethyl acetate, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain a yellow solid (6.1g) . ¹ HNMR (400MHz, Chloroform-d) δ8.49 (d, J = 4.9Hz, 1H), 8.05 (s, 1H), 7.38-7.32 (m, 1H), 7.11-7.02 (m, 2H), 7.01 6.91 (m, 2H), 5.02-4.68 (m, 1H), 4.54-4.21 (m, 2H), 4.07-3.48 (m, 2H), 3.43-3.02 (m, 2H), 2.85 (br s, 1H) ,2.01(s,3H),1.61-1.51(m,3H),1.53(s,9H),1.29-1.26(m,3H),1.15-1.02(m,3H); MS: m/z 638.3494,[ M+H].

第二步Second step

于100mL单口瓶中加入叔丁基(S)-4-(7-(2-(双(甲基-d3)氨基)苯基)-6-氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸(2.8g)和二氯甲烷(40mL)，在0℃下，滴加三氟乙酸(15g，9.8ml)，滴毕，逐渐升至10～15℃继续搅拌1小时。反应完毕，降温至0℃，缓慢加入饱和碳酸氢钠水溶液，调节pH至8～9，并用二氯甲烷萃取4次，合并有机反应液浓缩至干，得黄色油状物直接下一步反应。Add tert-butyl(S)-4-(7-(2-(bis(methyl-d3)amino)phenyl)-6-chloro-1-(2-isopropyl-4- (Methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid (2.8g) and Dichloromethane (40mL), at 0°C, add trifluoroacetic acid (15g, 9.8ml) dropwise, after dripping, gradually increase to 10-15°C and continue stirring for 1 hour. After the reaction was completed, the temperature was lowered to 0°C, a saturated aqueous sodium bicarbonate solution was slowly added to adjust the pH to 8-9, and the mixture was extracted 4 times with dichloromethane. The combined organic reaction solution was concentrated to dryness to obtain a yellow oil and proceed directly to the next step.

上一步反应产物中，加入二氯甲烷(25mL)和N,N-二异丙基乙胺(1.7g)，氮气保护下降温至0℃，再缓慢滴入丙烯酰氯(476mg)，滴毕，搅拌30分钟。反应完毕，加水稀释，并用二氯甲烷萃取3次，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，滤液浓缩，硅胶柱层析纯化得黄色固体(1.53g)。 ¹HNMR(400MHz,Chloroform-d)δ8.48(d,J＝4.9Hz,1H),8.06(s,1H),7.38-7.31(m,1H),7.13-7.01(m,2H),7.00-6.90(m,2H),6.74-6.53(m,1H),6.42(dd,J＝16.7,1.5Hz,1H),5.82(dd,J＝10.4,1.7Hz,1H),5.18-4.28(m,3H),4.05-3.47(m,3H),3.40-3.04(m,1H),2.83(br s,1H),2.02(s,3H),1.63-1.47(m,3H),1.26(s,3H),1.08(br s,3H)；MS:m/z 592.3074,[M+H] ⁺。 To the reaction product of the previous step, add dichloromethane (25mL) and N,N-diisopropylethylamine (1.7g), reduce the temperature to 0°C under nitrogen protection, and then slowly drip acryloyl chloride (476mg), and the dripping is complete. Stir for 30 minutes. After the reaction is complete, dilute with water and extract 3 times with dichloromethane. Combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate the filtrate, and purify by silica gel column chromatography to obtain a yellow solid (1.53 g). ¹ HNMR (400MHz, Chloroform-d) δ8.48 (d, J = 4.9Hz, 1H), 8.06 (s, 1H), 7.38-7.31 (m, 1H), 7.13-7.01 (m, 2H), 7.00- 6.90(m,2H),6.74-6.53(m,1H),6.42(dd,J=16.7,1.5Hz,1H), 5.82(dd,J=10.4,1.7Hz,1H), 5.18-4.28(m, 3H), 4.05-3.47 (m, 3H), 3.40-3.04 (m, 1H), 2.83 (br s, 1H), 2.02 (s, 3H), 1.63-1.47 (m, 3H), 1.26 (s, 3H) ), 1.08 (br s, 3H); MS: m/z 592.3074, [M+H] ⁺ .

实施例3-1：Example 3-1:

于100mL单口瓶中加入叔丁基(S)-4-(7-(2-(双(甲基-d3)氨基)苯基)-6-氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸(1.4g)和二氯甲烷(20mL)，在0℃下，滴加三氟乙酸(6g)，滴毕，逐渐升至10～15℃继续搅拌1小时。反应完毕，降温至0℃，缓慢加入饱和碳酸氢钠水溶液，调节pH至8～9，并用二氯甲烷萃取4次，合并有机反应液浓缩至干，得黄色油状物直接下一步反应。Add tert-butyl(S)-4-(7-(2-(bis(methyl-d3)amino)phenyl)-6-chloro-1-(2-isopropyl-4- (Methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid (1.4g) and Dichloromethane (20mL), add trifluoroacetic acid (6g) dropwise at 0°C, after the dropwise, gradually raise to 10-15°C and continue stirring for 1 hour. After the reaction was completed, the temperature was lowered to 0°C, a saturated aqueous sodium bicarbonate solution was slowly added to adjust the pH to 8-9, and the mixture was extracted 4 times with dichloromethane. The combined organic reaction solution was concentrated to dryness to obtain a yellow oil and proceed directly to the next step.

体系加入二氯甲烷(15mL)和N,N-二异丙基乙胺(1g)，氮气保护下降温至0℃，再缓慢滴入 ¹⁸O-丙烯酰氯(300mg)，滴毕，搅拌30分钟。反应完毕，加水稀释，并用二氯甲烷萃取3次，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，滤液浓缩，硅胶柱层析纯化得黄色固体。 Add dichloromethane (15mL) and N,N-diisopropylethylamine (1g) to the system, reduce the temperature to 0℃ under nitrogen protection, and then slowly drop in ¹⁸ O-acryloyl chloride (300mg), after dripping, stir for 30 minutes . After the reaction is complete, dilute with water and extract 3 times with dichloromethane, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate the filtrate, and purify by silica gel column chromatography to obtain a yellow solid.

实施例3-2：Example 3-2:

参考实施例3制备方案，采用中间体5M原料，制备得到化合物3-6MIS，R _f:0.50(DCM:MeOH＝10:1)。 Referring to the preparation scheme of Example 3, using the intermediate 5M raw material, the compound 3-6MIS was prepared with R _f :0.50 (DCM:MeOH=10:1).

实施例3-3：Example 3-3:

参考实施例3制备方案，采用中间体4M原料，制备得到化合物3-7MIS，R _f:0.52(DCM:MeOH＝10:1)。 Referring to the preparation scheme of Example 3, using the intermediate 4M raw material, the compound 3-7MIS was prepared, R _f : 0.52 (DCM:MeOH=10:1).

实施例3-1P：Example 3-1P:

参考实施例3制备方案，采用中间体3P为原料，制备得到化合物3-10P，R _f:0.53(DCM:MeOH＝10:1)。具体制备方法如下： Referring to the preparation scheme of Example 3, using intermediate 3P as a raw material, compound 3-10P was prepared, R _f : 0.53 (DCM:MeOH=10:1). The specific preparation method is as follows:

于500ml单口瓶中依次加入叔丁基(S,S)-4-(7-氯-6-氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧-1,2-二氢吡啶基[2,3-d]嘧啶-4-基)-二甲基哌嗪-1-甲酸(中间体3P)，(2-(双(甲基-d3)氨基)苯基)硼酸，醋酸钾，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物，重水和1,4-二氧六环，氮气置换后，升温搅拌。反应完毕，加入水稀释，并用乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体。Add tert-butyl(S,S)-4-(7-chloro-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxy -1,2-Dihydropyridyl[2,3-d]pyrimidin-4-yl)-dimethylpiperazine-1-carboxylic acid (Intermediate 3P), (2-(bis(methyl-d3)amino )Phenyl)boronic acid, potassium acetate, [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex, heavy water and 1,4-dioxane, nitrogen replacement After that, the temperature was raised and stirred. After the reaction was completed, it was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine once, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain a yellow solid.

于100mL单口瓶中加入上一步产物，和二氯甲烷，在0℃下，滴加三氟乙酸，滴毕，逐渐升温继续搅拌。反应完毕，降温，缓慢加入饱和碳酸氢钠水溶液，调节pH至8～9，并用二氯甲烷萃取，合并有机反应液浓缩至干，得黄色油状物直接下一步反应。上一步体系加入二氯甲烷和N,N-二异丙基乙胺，氮气保护下降温，再缓慢滴入丙烯酰氯，滴毕，搅拌。反应完毕，加水稀释，并用二氯甲烷萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，滤液浓缩，硅胶柱层析纯化得黄色固体。Add the product of the previous step and dichloromethane into a 100 mL single-necked flask, add trifluoroacetic acid dropwise at 0°C, and then gradually increase the temperature and continue stirring. After the reaction is completed, the temperature is lowered, and a saturated aqueous sodium bicarbonate solution is slowly added to adjust the pH to 8-9, and the mixture is extracted with dichloromethane. The combined organic reaction solution is concentrated to dryness to obtain a yellow oil and proceed directly to the next step. In the previous step, dichloromethane and N,N-diisopropylethylamine were added to the system, and the temperature was lowered under nitrogen protection, and then acryloyl chloride was slowly dripped, and the dripping was completed and stirred. After the reaction is complete, dilute with water, extract with dichloromethane, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate the filtrate, and purify by silica gel column chromatography to obtain a yellow solid.

实施例4：Example 4:

参考是实施例1的制备方案，制备得到化合物3-4。R _f:0.53(DCM:MeOH＝10:1)；具体制备如下： Reference is the preparation scheme of Example 1, and compound 3-4 is prepared. R _f : 0.53 (DCM:MeOH=10:1); the specific preparation is as follows:

第一步first step

在100ml单口瓶中，加入6,7-二氯-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮(2.0g)，甲苯(30ml)，N,N-二异丙基乙胺(2.1g)和1滴N-甲基吗啉，室温下滴加三氯氧磷(1.7g)，滴毕室温搅拌2小时。将反应液减压浓缩至干，向剩余物中加入乙腈(20ml)，N,N-二异丙基乙胺(2.1g)和(3S,5S)-3,5-二甲基-1-哌嗪羧酸叔丁酯(650mg)，加完升温至50℃搅拌3小时。将反应液倒入水中，乙酸乙酯萃取，合并有机层，饱和氯化钠洗涤，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体1.03g。MS:m/z 561.2,[M+H] ⁺。 Add 6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H, 3H)-diketone (2.0g), toluene (30ml), N,N-diisopropylethylamine (2.1g) and 1 drop of N-methylmorpholine, add phosphorus oxychloride (1.7g) dropwise at room temperature ), after dripping and stirring at room temperature for 2 hours. The reaction solution was concentrated to dryness under reduced pressure, and acetonitrile (20ml), N,N-diisopropylethylamine (2.1g) and (3S,5S)-3,5-dimethyl-1- Tert-butyl piperazine carboxylate (650 mg) was added and heated to 50°C and stirred for 3 hours. The reaction solution was poured into water, extracted with ethyl acetate, the organic layers were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 1.03 g of a yellow solid. MS: m/z 561.2, [M+H] ⁺ .

第二步Second step

于100ml的单口瓶中加入上步产物(1.03g)，2-(双(甲基-d ₃)氨基)苯硼酸(630mg)，醋酸钾(540mg)，1,4-二氧六环(20ml)，水(1ml)和[1,1'-双(二苯基膦)二茂铁]二氯化钯(135mg)，氮气置换后升温至80℃搅拌3小时。反应完毕，加入水稀释，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体860mg。MS:m/z 652.4,[M+H] ⁺。 Add the product of the previous step (1.03g), 2-(bis(methyl-d ₃ )amino)phenylboronic acid (630mg), potassium acetate (540mg), 1,4-dioxane (20ml) to a 100ml single-mouth bottle. ), water (1ml) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (135mg), replaced with nitrogen, heated to 80°C and stirred for 3 hours. After the reaction is complete, add water to dilute, extract with ethyl acetate, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain 860 mg of yellow solid. MS: m/z 652.4, [M+H] ⁺ .

第三步third step

于50ml单口瓶中加入上步产物(860mg)和二氯甲烷(10ml)，滴加三氟乙酸(2.5ml)，滴毕，室温搅拌2小时。反应完毕，降温至0℃，缓慢加入饱和碳酸氢钠水溶液，调节pH至7～8，二氯甲烷萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩至干。向残余物中加入二氯甲烷(20ml)，降温至0℃，加入N,N-二异丙基乙胺(526mg)，再缓慢滴入丙烯酰氯(122mg)的二氯甲烷(5ml)溶液，滴毕，继续搅拌30分钟。反应完毕，缓慢倒入饱和氯化铵水溶液淬灭，二氯甲烷萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，滤液浓缩，硅胶柱层析纯化，得黄色固体410mg。 ¹H NMR(400MHz,CDCl ₃):δ8.49(d,J＝4.9Hz,1H),8.19(s,1H),7.41-7.32(m,1H),7.16-7.03(m,2H),7.02-6.91(m,2H),6.72-6.59(m,1H),6.48-6.38(m,1H),5.83(dd,J＝10.5,1.8Hz,1H),4.52-4.24(m,2H),4.10-3.49(m,4H),2.81-2.66(m,1H),2.14-1.91(m,3H),1.52-1.31(m,6H),1.24(t,J＝6.0Hz,3H),1.18-0.93(m,3H).MS:m/z 606.3299,[M+H] ⁺。 Add the product of the previous step (860mg) and dichloromethane (10ml) to a 50ml single-necked flask, add trifluoroacetic acid (2.5ml) dropwise, and stir at room temperature for 2 hours. After the reaction is completed, the temperature is lowered to 0°C, a saturated aqueous sodium bicarbonate solution is slowly added to adjust the pH to 7-8, extracted with dichloromethane, the organic phases are combined, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness. Dichloromethane (20ml) was added to the residue, the temperature was lowered to 0°C, N,N-diisopropylethylamine (526mg) was added, and a solution of acryloyl chloride (122mg) in dichloromethane (5ml) was slowly added dropwise, After dripping, continue to stir for 30 minutes. After the reaction is complete, slowly pour into saturated aqueous ammonium chloride for quenching, extract with dichloromethane, combine the organic layers, wash with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate the filtrate, and purify by silica gel column chromatography to obtain 410 mg of yellow solid . ¹ H NMR (400MHz, CDCl ₃ ): δ8.49 (d, J = 4.9Hz, 1H), 8.19 (s, 1H), 7.41-7.32 (m, 1H), 7.16-7.03 (m, 2H), 7.02 -6.91(m,2H),6.72-6.59(m,1H),6.48-6.38(m,1H),5.83(dd,J=10.5,1.8Hz,1H),4.52-4.24(m,2H),4.10 -3.49(m,4H),2.81-2.66(m,1H),2.14-1.91(m,3H),1.52-1.31(m,6H),1.24(t,J=6.0Hz,3H),1.18-0.93 (m, 3H). MS: m/z 606.3299, [M+H] ⁺ .

实施例4-1M：Example 4-1M:

参考实施例4制备方案，采用中间体4M原料，制备得到化合物3-10M，R _f:0.52(DCM:MeOH＝10:1)。具体制备方法如下： Referring to the preparation scheme of Example 4, using the intermediate 4M raw material, the compound 3-10M was prepared, R _f :0.52 (DCM:MeOH=10:1). The specific preparation method is as follows:

于500ml单口瓶中依次加入叔丁基(S,S)-4-(7-氯-6-氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧-1,2-二氢吡啶基[2,3-d]嘧啶-4-基)-二甲基哌嗪-1-甲酸(中间体4M)，(2-(双(甲基-d3)氨基)苯基)硼酸，醋酸钾，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物，重水和1,4-二氧六环，氮气置换后，升温搅拌。反应完毕，加入水稀释，并用乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体。Add tert-butyl(S,S)-4-(7-chloro-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxy -1,2-Dihydropyridyl[2,3-d]pyrimidin-4-yl)-dimethylpiperazine-1-carboxylic acid (Intermediate 4M), (2-(bis(methyl-d3)amino )Phenyl)boronic acid, potassium acetate, [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex, heavy water and 1,4-dioxane, nitrogen replacement After that, the temperature was raised and stirred. After the reaction was completed, it was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine once, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain a yellow solid.

于100mL单口瓶中加上一步产物和二氯甲烷，在0℃下，滴加三氟乙酸，滴毕，逐渐升继续搅拌。反应完毕，降温，缓慢加入饱和碳酸氢钠水溶液，调节pH至8～9，并用二氯甲烷萃取，合并有机反应液浓缩至干，得黄色油状物直接下一步反应。上一步产物中，加入二氯甲烷和N,N-二异丙基乙胺，氮气保护下降温至0℃，再缓慢滴入丙烯酰氯，滴毕，搅拌。反应完毕，加水稀释，并用二氯甲烷萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，滤液浓缩，硅胶柱层析纯化得黄色固体。Add one-step product and dichloromethane to a 100 mL single-necked flask, add trifluoroacetic acid dropwise at 0°C, and then gradually increase and continue stirring. After the reaction is completed, the temperature is lowered, a saturated aqueous sodium bicarbonate solution is slowly added, the pH is adjusted to 8-9, and the mixture is extracted with dichloromethane, and the combined organic reaction solution is concentrated to dryness to obtain a yellow oil and proceed directly to the next step. To the product of the previous step, add dichloromethane and N,N-diisopropylethylamine, reduce the temperature to 0°C under nitrogen protection, and then slowly drip acryloyl chloride, and stir after the dripping is completed. After the reaction is complete, dilute with water, extract with dichloromethane, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate the filtrate, and purify by silica gel column chromatography to obtain a yellow solid.

实施例4-1P：Example 4-1P:

参考实施例4制备方案，采用中间体4P原料，制备得到化合物3-12P，R _f:0.53(DCM:MeOH＝10:1)。具体制备方法如下： Referring to the preparation scheme of Example 4, using the intermediate 4P raw material, the compound 3-12P was prepared, R _f : 0.53 (DCM:MeOH=10:1). The specific preparation method is as follows:

于100ml单口瓶中依次加入叔丁基-(S,S)-4-(7-氯-6-氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧-1,2-二氢吡啶基[2,3-d]嘧啶-4-基)-二甲基哌嗪-1-甲酸(中间体4P)，(2-(双(甲基-d3)氨基)苯基)硼酸，醋酸钾，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物，重水和1,4-二氧六环，氮气置换后，升温搅拌。反应完毕，加入水稀释，并用乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体。Add tert-butyl-(S,S)-4-(7-chloro-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2- Oxygen-1,2-dihydropyridyl[2,3-d]pyrimidin-4-yl)-dimethylpiperazine-1-carboxylic acid (intermediate 4P), (2-(bis(methyl-d3) Amino)phenyl)boronic acid, potassium acetate, [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex, heavy water and 1,4-dioxane, nitrogen After the replacement, the temperature was raised and stirred. After the reaction was completed, it was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine once, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain a yellow solid.

于50mL单口瓶中加上一步产物和二氯甲烷，滴加三氟乙酸，逐渐升继续搅拌。反应完毕，降温，缓慢加入饱和碳酸氢钠水溶液，调节pH至8～9，并用二氯甲烷萃取，合并有机相浓缩，得黄色油状物直接下一步反应。在上一步产物中，加入二氯甲烷和N,N-二异丙基乙胺，氮气保护下降温至0℃，再缓慢滴入丙烯酰氯，滴毕，搅拌。反应完毕，加水稀释，并用二氯甲烷萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，滤液浓缩，硅胶柱层析纯化得黄色固体。Add one-step product and dichloromethane to a 50mL single-necked flask, add trifluoroacetic acid dropwise, and continue stirring gradually. After the reaction is completed, the temperature is lowered, a saturated aqueous sodium bicarbonate solution is slowly added to adjust the pH to 8-9, and the mixture is extracted with dichloromethane, and the combined organic phases are concentrated to obtain a yellow oil and proceed directly to the next reaction. In the product of the previous step, add dichloromethane and N,N-diisopropylethylamine, reduce the temperature to 0°C under nitrogen protection, and then slowly drip acryloyl chloride, and stir after the dripping is completed. After the reaction is complete, dilute with water, extract with dichloromethane, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate the filtrate, and purify by silica gel column chromatography to obtain a yellow solid.

实施例5：Example 5:

参考是实施例2的制备方案，制备得到化合物3-5。R _f:0.56(DCM:MeOH＝10:1)；具体制备如下： Reference is the preparation scheme of Example 2, and compound 3-5 is prepared. R _f : 0.56 (DCM:MeOH=10:1); the specific preparation is as follows:

第一步first step

于50ml的单口瓶中加入(S)-4-(7-氯-6-氟-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(400mg)，3-氟-N,N-双(甲基-d ₃)-2-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯胺(225mg)，醋酸钾(218mg)，1,4-二氧六环(20ml)，水(4ml)和[1,1'-双(二苯基膦)二茂铁]二氯化钯(59mg)，氮气置换后升温至95℃搅拌2小时。反应完毕，加入水稀释，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体385mg。 ¹H NMR(400MHz,CDCl ₃):δ8.54(d,J＝4.9Hz,1H),7.74(d,J＝9.6Hz,1H),7.19-7.10(m,2H),6.42(dd,J＝8.8,2.5Hz,1H),6.34(dd,J＝14.4,2.5Hz,1H),5.02-4.71(m,1H),4.45-3.83(m,3H),3.80-3.49(m,1H),3.44-3.00(m,2H),2.83-2.65(m,1H),2.07(s,3H),1.55-1.46(m,3H),1.53(s,9H),1.27-1.22(m,3H),1.11-1.03(m,3H).MS:m/z 640.4,[M+H] ⁺。 Add (S)-4-(7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2 to a 50ml single-mouth bottle -Dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (400mg), 3-fluoro-N,N-bis(methyl- d ₃ )-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (225mg), potassium acetate (218mg), 1, 4-Dioxane (20ml), water (4ml) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (59mg), replaced with nitrogen, heated to 95°C and stirred for 2 hours . After the reaction is complete, add water to dilute, extract with ethyl acetate, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain 385 mg of yellow solid. ¹ H NMR (400MHz, CDCl ₃ ): δ8.54 (d, J = 4.9 Hz, 1H), 7.74 (d, J = 9.6 Hz, 1H), 7.19-7.10 (m, 2H), 6.42 (dd, J ＝8.8,2.5Hz,1H),6.34(dd,J＝14.4,2.5Hz,1H),5.02-4.71(m,1H),4.45-3.83(m,3H),3.80-3.49(m,1H), 3.44-3.00(m,2H),2.83-2.65(m,1H),2.07(s,3H),1.55-1.46(m,3H),1.53(s,9H),1.27-1.22(m,3H), 1.11-1.03 (m, 3H). MS: m/z 640.4, [M+H] ⁺ .

第二步Second step

于50ml单口瓶中加入上步产物(170mg)和二氯甲烷(20ml)，在10℃～15℃下，滴加三氟乙酸(10ml)，滴毕，室温搅拌1小时。反应完毕，降温至0℃，缓慢加入饱和碳酸氢钠水溶液，调节pH至8～9，二氯甲烷萃取，合并有机层，无水硫酸钠干燥，过滤，减压浓缩至干，得黄色油状物。向浓缩物中加入二氯甲烷(25ml)和N,N-二异丙基乙胺(102mg)，氮气保护下降温至0℃，再缓慢滴入丙烯酰氯(29mg)，滴毕，搅拌30分钟。反应完毕，加水稀释，二氯甲烷萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得淡黄色固体130mg。 ¹H NMR(400MHz,CDCl ₃):δ8.57(d,J＝4.8Hz,1H),7.75(d,J＝9.5Hz,1H),7.22-7.10(m,2H),6.75-6.53(m,1H),6.48-6.38(m,2H),6.34(dd,J＝14.4,2.4Hz,1H),5.83(dd,J＝10.4,1.5Hz,1H),5.21-4.24(m,3H),4.10-3.46(m,3H),3.37-2.98(m,1H),2.78(br s,1H),2.14-2.00(m,3H),1.60-1.41(m,3H),1.31-1.22(m,3H),1.15-1.04(m,3H).MS:m/z 594.3290,[M+H] ⁺。 Add the product of the previous step (170mg) and dichloromethane (20ml) to a 50ml single-necked flask, add trifluoroacetic acid (10ml) dropwise at 10°C to 15°C, and stir at room temperature for 1 hour. After the reaction is complete, cool to 0°C, slowly add a saturated aqueous sodium bicarbonate solution, adjust the pH to 8-9, extract with dichloromethane, combine the organic layers, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to dryness to obtain a yellow oil . Add dichloromethane (25ml) and N,N-diisopropylethylamine (102mg) to the concentrate, reduce the temperature to 0°C under nitrogen protection, and then slowly add acryloyl chloride (29mg) in drops, and then stir for 30 minutes. . After the reaction is complete, dilute with water, extract with dichloromethane, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain 130 mg of light yellow solid. ¹ H NMR (400MHz, CDCl ₃ ): δ8.57 (d, J = 4.8Hz, 1H), 7.75 (d, J = 9.5Hz, 1H), 7.22-7.10 (m, 2H), 6.75-6.53 (m ,1H), 6.48-6.38 (m, 2H), 6.34 (dd, J = 14.4, 2.4 Hz, 1H), 5.83 (dd, J = 10.4, 1.5 Hz, 1H), 5.21-4.24 (m, 3H), 4.10-3.46 (m, 3H), 3.37-2.98 (m, 1H), 2.78 (br s, 1H), 2.14-2.00 (m, 3H), 1.60-1.41 (m, 3H), 1.31-1.22 (m, 3H), 1.15-1.04 (m, 3H). MS: m/z 594.3290, [M+H] ⁺ .

实施例6：Example 6:

参考是实施例2的制备方案，制备得到化合物3-7。R _f:0.53(DCM:MeOH＝10:1)。 Reference is the preparation scheme of Example 2, and compound 3-7 is prepared. R _f : 0.53 (DCM:MeOH=10:1).

实施例7：Example 7:

参考是实施例1的制备方案，制备得到化合物3-10。R _f:0.54(DCM:MeOH＝10:1)。 Reference is the preparation scheme of Example 1, and compound 3-10 is prepared. R _f : 0.54 (DCM:MeOH=10:1).

实施例8：Example 8:

参考是实施例2的制备方案，制备得到化合物3-13。R _f:0.55(DCM:MeOH＝10:1)；具体制备如下： Refer to the preparation scheme of Example 2 to prepare compound 3-13. R _f : 0.55 (DCM:MeOH=10:1); the specific preparation is as follows:

于50ml单口瓶中加入(3S)-4-(7-(2-(双(甲基-d ₃)氨基)-6-氟苯基)-6-氟-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(215mg)和二氯甲烷(20ml)，在10℃～15℃下，滴加三氟乙酸(10ml)，滴毕，室温搅拌1小时。反应完毕，降温至0℃，缓慢加入饱和碳酸氢钠水溶液，调节pH至8～9，二氯甲烷萃取，合并有机层，无水硫酸钠干燥，过滤，减压浓缩至干。在另一烧瓶中加入2-氟丙烯酸(46mg)和二氯甲烷(5ml)，缓慢滴入氯化亚砜(67mg)，滴毕常温搅拌30分钟。 Add (3S)-4-(7-(2-(bis(methyl-d ₃ )amino)-6-fluorophenyl)-6-fluoro-1-(2-isopropyl- 4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyridine[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl Ester (215mg) and dichloromethane (20ml), add trifluoroacetic acid (10ml) dropwise at 10°C to 15°C, after dropping, stir at room temperature for 1 hour. After the reaction is completed, the temperature is lowered to 0°C, a saturated aqueous sodium bicarbonate solution is slowly added, the pH is adjusted to 8-9, dichloromethane extraction, the organic layers are combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. In another flask, 2-fluoroacrylic acid (46 mg) and dichloromethane (5 ml) were added, thionyl chloride (67 mg) was slowly added dropwise, and the mixture was stirred at room temperature for 30 minutes.

将脱Boc产物溶于二氯甲烷(25ml)，加入N,N-二异丙基乙胺(132mg)，氮气保护下降温至0℃，再缓慢滴入上述制备的2-氟丙烯酰氯，滴毕搅拌30分钟。反应完毕，加水稀释，二氯甲烷萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得淡黄色固体20mg。 ¹H NMR(400MHz,CDCl ₃):δ8.55(d,J＝4.9Hz,1H),7.73(d,J＝9.5Hz,1H),7.21-7.08(m,2H),6.41(dd,J＝8.8,2.4Hz,1H),6.33(dd,J＝14.4,2.3Hz,1H),5.41(dd,J＝47.4,3.4Hz,1H),5.24(dd,J＝16.8,3.5Hz,1H),4.95(br s,1H),4.70-4.23(m,2H),4.08-3.47(m,3H),3.41-3.08(m,1H),2.84-2.61(m,1H),2.10-1.99(m,3H),1.52(d,J＝6.4Hz,3H),1.29-1.19(m,3H),1.12-1.04(m,3H).MS:m/z 612.3200,[M+H] ⁺。 The de-Boc product was dissolved in dichloromethane (25ml), N,N-diisopropylethylamine (132mg) was added, the temperature was reduced to 0°C under nitrogen protection, and the 2-fluoroacryloyl chloride prepared above was slowly added dropwise. After stirring for 30 minutes. After the reaction is complete, dilute with water, extract with dichloromethane, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain 20 mg of pale yellow solid. ¹ H NMR (400MHz, CDCl ₃ ): δ8.55 (d, J = 4.9 Hz, 1H), 7.73 (d, J = 9.5 Hz, 1H), 7.21-7.08 (m, 2H), 6.41 (dd, J ＝8.8,2.4Hz,1H), 6.33(dd,J＝14.4,2.3Hz,1H), 5.41(dd,J＝47.4,3.4Hz,1H), 5.24(dd,J＝16.8,3.5Hz,1H) ,4.95(br s,1H),4.70-4.23(m,2H),4.08-3.47(m,3H),3.41-3.08(m,1H),2.84-2.61(m,1H),2.10-1.99(m , 3H), 1.52 (d, J=6.4 Hz, 3H), 1.29-1.19 (m, 3H), 1.12-1.04 (m, 3H). MS: m/z 612.3200, [M+H] ⁺ .

实施例9：Example 9:

参考是实施例1的制备方案，制备得到化合物4-4。R _f:0.56(DCM:MeOH＝10:1)。具体制备如下： Reference is the preparation scheme of Example 1, and compound 4-4 is prepared. R _f : 0.56 (DCM:MeOH=10:1). The specific preparation is as follows:

于50ml的单口瓶中加入(S,S)-4-(7-氯-6-氟-1-(2-异丙基-4-(甲基-d ₃)吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-二甲基哌嗪-1-羧酸叔丁酯，N,N-双(甲基-d ₃)-2-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯胺，醋酸钾，1,4-二氧六环，水和[1,1'-双(二苯基膦)二茂铁]二氯化钯，氮气置换后搅拌。加水稀释，乙酸乙酯萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩，硅胶柱层析纯化，得黄色固体。 Add (S,S)-4-(7-chloro-6-fluoro-1-(2-isopropyl-4-(methyl-d ₃ )pyridin-3-yl)-2 to a 50ml single-mouth bottle -Oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-dimethylpiperazine-1-carboxylic acid tert-butyl ester, N,N-bis(methyl-d ₃ )-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, potassium acetate, 1,4-dioxane, Water and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride were replaced with nitrogen and stirred. Dilute with water, extract with ethyl acetate, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter and concentrate, and purify by silica gel column chromatography to obtain a yellow solid.

于50ml单口瓶中加入上步产物和二氯甲烷，在0℃下，滴加三氟乙酸，滴毕，于室温搅拌。反应完毕，降温至0℃，缓慢加入饱和碳酸氢钠水溶液，调节pH至7～8，二氯甲烷萃取，合并有机层，无水硫酸钠干燥，过滤，减压浓缩至干，得淡黄色固体。取脱叔丁氧羰基(Boc)后产物溶入二氯甲烷，加入N,N-二异丙基乙胺，氮气保护下降温，再缓慢滴入丙烯酰氯，滴毕，搅拌。反应完毕，加水稀释，二氯甲烷萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，硅胶柱层析纯化，得黄色固体。Add the product of the previous step and dichloromethane to a 50ml single-necked flask, add trifluoroacetic acid dropwise at 0°C, and stir at room temperature. After the reaction is complete, cool to 0°C, slowly add a saturated aqueous sodium bicarbonate solution, adjust the pH to 7-8, extract with dichloromethane, combine the organic layers, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to dryness to obtain a light yellow solid . The product after the removal of tert-butoxycarbonyl (Boc) is dissolved in dichloromethane, N,N-diisopropylethylamine is added, the temperature is reduced under nitrogen protection, and acryloyl chloride is slowly dripped, and the dripping is completed, stirring. After the reaction is complete, dilute with water, extract with dichloromethane, combine the organic layers, wash with saturated brine, dry with anhydrous sodium sulfate, concentrate, and purify by silica gel column chromatography to obtain a yellow solid.

实施例10：Example 10:

参考是实施例2的制备方案，制备得到化合物4-5。R _f:0.54(DCM:MeOH＝10:1)；具体制备如下： Reference is the preparation scheme of Example 2, and compound 4-5 is prepared. R _f : 0.54 (DCM:MeOH=10:1); the specific preparation is as follows:

第一步first step

于50ml的单口瓶中加入(S)-4-(7-氯-6-氟-1-(2-异丙基-4-(甲基-d ₃)吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(397mg)，3-氟-N,N-双(甲基-d ₃)-2-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯胺(200mg)，醋酸钾(230mg)，1,4-二氧六环(10ml)，水(0.5ml)和[1,1'-双(二苯基膦)二茂铁]二氯化钯(60mg)，氮气置换后升温至90℃搅拌4小时。反应完毕，加入水稀释，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体400mg。MS:m/z 643.4,[M+H] ⁺。 Add (S)-4-(7-chloro-6-fluoro-1-(2-isopropyl-4-(methyl-d ₃ )pyridin-3-yl)-2-oxygen to a 50ml single-mouth bottle -1,2-Dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (397mg), 3-fluoro-N,N- Bis(methyl-d ₃ )-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (200mg), potassium acetate ( 230mg), 1,4-dioxane (10ml), water (0.5ml) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (60mg), heated after nitrogen replacement Stir at 90°C for 4 hours. After the reaction is complete, add water to dilute, extract with ethyl acetate, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain 400 mg of yellow solid. MS: m/z 643.4, [M+H] ⁺ .

第二步Second step

于50ml单口瓶中加入上步产物(400mg)和二氯甲烷(20ml)，在0℃下，滴加三氟乙酸(5ml)，滴毕，于室温搅拌1小时。反应完毕，降温至0℃，缓慢加入饱和碳酸氢钠水溶液，调节pH至7～8，二氯甲烷萃取，合并有机层，无水硫酸钠干燥，过滤，减压浓缩至干，得淡黄色固体330mg。Add the product of the previous step (400mg) and dichloromethane (20ml) to a 50ml single-necked flask, add trifluoroacetic acid (5ml) dropwise at 0°C, and stir at room temperature for 1 hour. After the reaction is complete, cool to 0°C, slowly add a saturated aqueous sodium bicarbonate solution, adjust the pH to 7-8, extract with dichloromethane, combine the organic layers, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to dryness to obtain a light yellow solid 330mg.

取脱叔丁氧羰基(Boc)后产物(115mg)溶入二氯甲烷(10ml)，加入N,N-二异丙基乙胺(121mg)，氮气保护下降温至0℃，再缓慢滴入丙烯酰氯(31mg)，滴毕，搅拌30分钟。反应完毕，加水稀释，二氯甲烷萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体100mg。 ¹H NMR(400MHz,CDCl ₃):δ8.55(d,J＝4.9Hz,1H),7.74(d,J＝9.6Hz,1H),7.20-7.09(m,2H),6.74-6.52(m,1H),6.46-6.37(m,2H),6.33(dd,J＝14.4,2.4Hz,1H),5.82(dd,J＝10.4,1.7Hz,1H),5.17-4.24(m,3H),4.10-3.45(m,3H),3.35-3.00(m,1H),2.84-2.58(m,1H),1.58-1.44(m,3H),1.29-1.18(m,3H),1.10-1.03(m,3H).MS:m/z 597.3496,[M+H] ⁺。 Dissolve the product (115mg) after removing tert-butoxycarbonyl (Boc) into dichloromethane (10ml), add N,N-diisopropylethylamine (121mg), reduce the temperature to 0°C under nitrogen protection, and then slowly drop in Acryloyl chloride (31 mg), after dripping, stir for 30 minutes. After the reaction is complete, dilute with water, extract with dichloromethane, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain 100 mg of yellow solid. ¹ H NMR (400MHz, CDCl ₃ ): δ8.55 (d, J = 4.9 Hz, 1H), 7.74 (d, J = 9.6 Hz, 1H), 7.20-7.09 (m, 2H), 6.74-6.52 (m ,1H),6.46-6.37(m,2H),6.33(dd,J=14.4,2.4Hz,1H), 5.82(dd,J=10.4,1.7Hz,1H), 5.17-4.24(m,3H), 4.10-3.45(m,3H),3.35-3.00(m,1H),2.84-2.58(m,1H),1.58-1.44(m,3H),1.29-1.18(m,3H),1.10-1.03(m , 3H). MS: m/z 597.3496, [M+H] ⁺ .

实施例11：Example 11:

参考是实施例2的制备方案，制备得到化合物4-7。R _f:0.53(DCM:MeOH＝10:1) For reference, the preparation scheme of Example 2 was used to prepare compound 4-7. R _f :0.53(DCM:MeOH＝10:1)

实施例12：Example 12:

参考是实施例1的制备方案，制备得到化合物4-10。R _f:0.56(DCM:MeOH＝10:1)。 Reference is the preparation scheme of Example 1, and compound 4-10 was prepared. R _f : 0.56 (DCM:MeOH=10:1).

实施例13：Example 13:

参考是实施例2的制备方案，制备得到化合物5-1。R _f:0.55(DCM:MeOH＝10:1)；具体制备路线如下： Reference is the preparation scheme of Example 2, and compound 5-1 is prepared. R _f : 0.55 (DCM: MeOH = 10:1); the specific preparation route is as follows:

第一步first step

在100ml单口瓶中加入7-氯-1-(2,4-二异丙基吡啶-3-基)-6-氟吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮(1.5g)和乙腈(60ml)，降温至0℃，加入N,N-二异丙基乙胺(3.1g)，滴加三氯氧磷(3.7g)，滴毕继续搅拌20分钟，再升温至80℃反应1小时。将反应液浓缩至干，向浓缩物中加入乙腈(50ml)，N,N-二异丙基乙胺(5ml)，降温至0℃，滴加(S)-3-甲基哌嗪-1-羧酸叔丁酯(881mg)的二氯甲烷(10ml)溶液，滴毕室温反应1.5小时。将反应液倒入水中，乙酸乙酯萃取，合并有机层，饱和氯化铵洗涤，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得浅黄色固体1.96g。 ¹H NMR(400MHz,CDCl ₃):δ8.67(d,J＝5.1Hz,1H),7.80(d,J＝7.6Hz,1H),7.24(dd,J＝5.2,1.2Hz,1H),4.98-4.65(m,1H),4.42-3.86(m,3H),3.81-3.51(br s,1H),3.43-3.01(m,2H),2.70-2.40(m,2H),1.56-1.46(m,12H),1.27-1.18(m,6H),1.10(t,J＝7.1Hz,3H),1.04(t,J＝7.0Hz,3H).MS:m/z 559.3,[M+H] ⁺。 Add 7-chloro-1-(2,4-diisopropylpyridin-3-yl)-6-fluoropyrido[2,3-d]pyrimidine-2,4(1H,3H) to a 100ml single-mouth bottle -Dione (1.5g) and acetonitrile (60ml), reduce the temperature to 0℃, add N,N-diisopropylethylamine (3.1g), add phosphorus oxychloride (3.7g) dropwise, continue stirring after dropping for 20 Minutes, then the temperature is raised to 80°C and reacted for 1 hour. The reaction solution was concentrated to dryness, acetonitrile (50ml), N,N-diisopropylethylamine (5ml) were added to the concentrate, the temperature was reduced to 0℃, and (S)-3-methylpiperazine-1 was added dropwise -A solution of tert-butyl carboxylate (881 mg) in dichloromethane (10 ml), and the reaction is completed at room temperature for 1.5 hours. The reaction solution was poured into water, extracted with ethyl acetate, the organic layers were combined, washed with saturated ammonium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 1.96 g of a light yellow solid. ¹ H NMR (400MHz, CDCl ₃ ): δ8.67 (d, J = 5.1Hz, 1H), 7.80 (d, J = 7.6Hz, 1H), 7.24 (dd, J = 5.2, 1.2Hz, 1H), 4.98-4.65(m,1H),4.42-3.86(m,3H),3.81-3.51(br s,1H),3.43-3.01(m,2H),2.70-2.40(m,2H),1.56-1.46( m,12H),1.27-1.18(m,6H),1.10(t,J=7.1Hz,3H),1.04(t,J=7.0Hz,3H).MS:m/z 559.3,[M+H] ⁺ .

第二步Second step

于50ml的单口瓶中加入上步产物(558mg)，3-氟-N,N-双(甲基-d ₃)-2-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯胺(325mg)，醋酸钾(294mg)，1,4-二氧六环(20ml)，水(4ml)和[1,1'-双(二苯基膦)二茂铁]二氯化钯(73mg)，氮气置换后升温至95℃搅拌3小时。反应完毕，加入水稀释，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体500mg。 ¹H NMR(400MHz,CDCl ₃):δ8.62(d,J＝5.1Hz,1H),7.74(d,J＝9.6Hz,1H),7.21(d,J＝5.2Hz,1H),7.14(t,J＝8.6Hz,1H),6.40(dd,J＝8.8,2.5Hz,1H),6.33(dd,J＝14.4,2.4Hz,1H),5.01-4.73(m,1H),4.46-3.86(m,3H),3.72-3.51(m,1H),3.44-3.01(m,2H),2.78-2.50(m,2H),1.56-1.46(m,12H),1.26-1.18(m,6H),1.02(t,J＝6.4Hz,3H),0.97(t,J＝6.2Hz,3H).MS:m/z 668.4,[M+H] ⁺。 Add the product of the previous step (558mg), 3-fluoro-N,N-bis(methyl-d ₃ )-2-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl)aniline (325mg), potassium acetate (294mg), 1,4-dioxane (20ml), water (4ml) and [1,1'-bis( Diphenylphosphine)ferrocene]palladium dichloride (73mg), replaced with nitrogen, heated to 95°C and stirred for 3 hours. After the reaction is complete, add water to dilute, extract with ethyl acetate, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain 500 mg of yellow solid. ¹ H NMR (400MHz, CDCl ₃ ): δ8.62 (d, J = 5.1 Hz, 1H), 7.74 (d, J = 9.6 Hz, 1H), 7.21 (d, J = 5.2 Hz, 1H), 7.14 ( t,J=8.6Hz,1H),6.40(dd,J=8.8,2.5Hz,1H),6.33(dd,J=14.4,2.4Hz,1H),5.01-4.73(m,1H),4.46-3.86 (m,3H),3.72-3.51(m,1H),3.44-3.01(m,2H),2.78-2.50(m,2H),1.56-1.46(m,12H),1.26-1.18(m,6H) , 1.02 (t, J=6.4 Hz, 3H), 0.97 (t, J=6.2 Hz, 3H). MS: m/z 668.4, [M+H] ⁺ .

第三步third step

于50ml单口瓶中加入上步产物(190mg)，二氯甲烷(10ml)和三氟乙酸(5ml)，滴毕，室温搅拌1小时。反应完毕，降温至0℃，缓慢加入饱和碳酸氢钠水溶液，调节pH至弱碱性，二氯甲烷萃取，合并有机层，无水硫酸钠干燥，过滤，减压浓缩至干。向浓缩物中加入二氯甲烷(10ml)，N,N-二异丙基乙胺(108mg)，氮气保护下降温至0℃，缓慢滴加丙烯酰氯(38mg)，滴毕搅拌30分钟。反应完毕，加水稀释，二氯甲烷萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体55mg。 ¹H NMR(400MHz,CDCl ₃):δ8.62(d,J＝5.2Hz,1H),7.74(d,J＝9.6Hz,1H),7.20(d,J＝5.2Hz,1H),7.13(t,J＝8.6Hz,1H),6.73-6.51(m,1H),6.45-6.35(m,2H),6.31(dd,J＝14.4,2.4Hz,1H),5.81(dd,J＝10.4,1.7Hz,1H),5.18-4.24(m,3H),4.08-3.47(m,3H),3.36-2.96(m,1H),2.80-2.41(m,2H),1.58-1.42(m,3H),1.26-1.17(m,6H),1.05-0.92(m,6H).MS:m/z 622.3699,[M+H] ⁺。 Add the product of the previous step (190mg), dichloromethane (10ml) and trifluoroacetic acid (5ml) to a 50ml single-necked flask, drop it off, and stir at room temperature for 1 hour. After the reaction was completed, the temperature was lowered to 0°C, saturated aqueous sodium bicarbonate solution was slowly added, the pH was adjusted to weakly alkaline, the dichloromethane extraction was performed, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. Dichloromethane (10ml), N,N-diisopropylethylamine (108mg) were added to the concentrate, the temperature was reduced to 0°C under nitrogen protection, acryloyl chloride (38mg) was slowly added dropwise, and the mixture was stirred for 30 minutes. After the reaction is completed, dilute with water, extract with dichloromethane, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain 55 mg of yellow solid. ¹ H NMR (400MHz, CDCl ₃ ): δ8.62(d,J=5.2Hz,1H), 7.74(d,J=9.6Hz,1H), 7.20(d,J=5.2Hz,1H), 7.13( t,J=8.6Hz,1H),6.73-6.51(m,1H),6.45-6.35(m,2H),6.31(dd,J=14.4,2.4Hz,1H),5.81(dd,J=10.4, 1.7Hz, 1H), 5.18-4.24 (m, 3H), 4.08-3.47 (m, 3H), 3.36-2.96 (m, 1H), 2.80-2.41 (m, 2H), 1.58-1.42 (m, 3H) , 1.26-1.17 (m, 6H), 1.05-0.92 (m, 6H). MS: m/z 622.3699, [M+H] ⁺ .

实施例14：Example 14:

参考是实施例1的制备方案，制备得到化合物5-6。R _f:0.56(DCM:MeOH＝10:1)；具体制备如下： Reference is the preparation scheme of Example 1, and compound 5-6 is prepared. R _f : 0.56 (DCM:MeOH=10:1); the specific preparation is as follows:

第一步first step

于50ml单口瓶中加入(S)-4-(6,7-二氯-1-(2,4-二异丙基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(280mg)，2-(双(甲基-d ₃)氨基)苯硼酸(100mg)，醋酸钾(147mg)，1,4-二氧六环(10ml)，水(0.5ml)和[1,1'-双(二苯基膦)二茂铁]二氯化钯(73mg)，氮气置换后，升温至105℃，搅拌2小时。反应完毕，冷至室温，加水稀释，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体154mg。MS:m/z 666.4,[M+H] ⁺。 Add (S)-4-(6,7-dichloro-1-(2,4-diisopropylpyridin-3-yl)-2-oxo-1,2-dihydropyridine to a 50ml single-mouth bottle And[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (280mg), 2-(bis(methyl-d ₃ )amino)phenylboronic acid (100mg ), potassium acetate (147mg), 1,4-dioxane (10ml), water (0.5ml) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (73mg) After nitrogen replacement, the temperature was raised to 105°C and stirred for 2 hours. After the reaction is complete, cool to room temperature, dilute with water, extract with ethyl acetate, combine the organic layers, wash with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain 154 mg of yellow solid. MS: m/z 666.4, [M+H] ⁺ .

第二步Second step

于50ml单口瓶中加入上步产物(154mg)和二氯甲烷(5ml)，在10℃～15℃下，滴加三氟乙酸(3ml)，滴毕，继续搅拌1.5小时。将反应液浓缩至干，向残余物加入二氯甲烷(10ml)，降温至0℃，加入N,N-二异丙基乙胺(155mg)，再缓慢滴入丙烯酰氯(27mg)的二氯甲烷(1ml)溶液，滴毕，搅拌30分钟。缓慢倒入饱和氯化铵水溶液淬灭反应，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体106mg。 ¹H NMR(400MHz,CDCl ₃):δ8.58(d,J＝5.1Hz,1H),8.07(s,1H),7.39-7.30(m,1H),7.18(br s,1H),7.03(d,J＝8.2Hz,1H),6.95(d,J＝4.3Hz,2H),6.74-6.53(m,1H),6.43(d,J＝16.6Hz,1H),5.83(d,J＝10.4Hz,1H),4.87-4.66(m,1H),4.57-4.41(m,1H),3.96-3.46(m,3H),3.44-2.97(m,1H),2.83-2.37(m,3H),1.58-1.42(m,3H),1.28-1.18(m,6H),1.14-0.98(m,6H).MS:m/z 620.3399,[M+H] ⁺。 Add the product of the previous step (154mg) and dichloromethane (5ml) to a 50ml single-necked flask, add trifluoroacetic acid (3ml) dropwise at 10°C to 15°C, and continue stirring for 1.5 hours after the drop. The reaction solution was concentrated to dryness, dichloromethane (10ml) was added to the residue, the temperature was reduced to 0°C, N,N-diisopropylethylamine (155mg) was added, and the dichloride of acryloyl chloride (27mg) was slowly added dropwise Methane (1ml) solution, after dripping, stir for 30 minutes. Slowly poured into saturated aqueous ammonium chloride to quench the reaction, extracted with ethyl acetate, combined the organic layers, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 106 mg of yellow solid. ¹ H NMR (400MHz, CDCl ₃ ): δ8.58 (d, J = 5.1Hz, 1H), 8.07 (s, 1H), 7.39-7.30 (m, 1H), 7.18 (br s, 1H), 7.03 ( d, J = 8.2 Hz, 1H), 6.95 (d, J = 4.3 Hz, 2H), 6.74-6.53 (m, 1H), 6.43 (d, J = 16.6 Hz, 1H), 5.83 (d, J = 10.4 Hz, 1H), 4.87-4.66 (m, 1H), 4.57-4.41 (m, 1H), 3.96-3.46 (m, 3H), 3.44-2.97 (m, 1H), 2.83-2.37 (m, 3H), 1.58-1.42 (m, 3H), 1.28-1.18 (m, 6H), 1.14-0.98 (m, 6H). MS: m/z 620.3399, [M+H] ⁺ .

实施例15：Example 15:

参考是实施例2的制备方案，制备得到化合物5-9。R _f:0.54(DCM:MeOH＝10:1)。 Refer to the preparation scheme of Example 2 to prepare compound 5-9. R _f : 0.54 (DCM:MeOH=10:1).

实施例16：Example 16:

参考是实施例1的制备方案，制备得到化合物4-4B。R _f:0.52(DCM:MeOH＝10:1)。 For reference, the preparation scheme of Example 1 was used to prepare compound 4-4B. R _f : 0.52 (DCM:MeOH=10:1).

实施例17：Example 17:

参考是实施例2的制备方案，制备得到化合物4-5B。R _f:0.55(DCM:MeOH＝10:1)。 Reference is the preparation scheme of Example 2, and compound 4-5B is prepared. R _f : 0.55 (DCM:MeOH=10:1).

实施例18：Example 18:

第一步first step

于50ml的单口瓶中加入(S)-4-(7-氯-6-氟-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(200mg)，2-(双(甲基-d ₃)氨基)苯硼酸(101mg)，醋酸钾(109mg)，1,4-二氧六环(20ml)，水(4ml)和[1,1'-双(二苯基膦)二茂铁]二氯化钯(29mg)，氮气置换后升温至95℃搅拌2小时。反应完毕，加入水稀释，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体201mg。MS:m/z 622.4,[M+H] ⁺。 Add (S)-4-(7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2 to a 50ml single-mouth bottle -Dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (200mg), 2-(bis(methyl-d ₃ )amino) Phenylboronic acid (101mg), potassium acetate (109mg), 1,4-dioxane (20ml), water (4ml) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (29mg), after nitrogen replacement, the temperature was raised to 95°C and stirred for 2 hours. After the reaction is complete, add water to dilute, extract with ethyl acetate, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain 201 mg of yellow solid. MS: m/z 622.4, [M+H] ⁺ .

第二步Second step

于50ml反应瓶中加入上一步产物(170mg)，二氯甲烷(25ml)和N,N-二异丙基乙胺(196mg)，氮气保护下降温至0℃，再缓慢滴入丙烯酰氯(36mg)，滴毕，搅拌30分钟。反应完毕，加水稀释，二氯甲烷萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得淡黄色固体110mg。 ¹H NMR(400MHz,CDCl ₃):δ8.50(d,J＝4.9Hz,1H),7.76(dd,J＝8.9,2.7Hz,1H),7.40-7.32(m,1H),7.12-7.05(m,2H),7.05-6.93(m,2H),6.74-6.51(m,1H),6.42(d,J＝16.7Hz,1H),5.83(dd,J＝10.4,1.7Hz,1H),5.25-4.21(m,3H),4.11-3.49(m,3H),3.39-3.00(m,1H),2.89-2.65(m,1H),2.09-1.99(m,3H),1.49-1.36(m,3H),1.26(d,J＝6.7Hz,3H),1.08(d,J＝6.7Hz,3H).MS:m/z 576.3458,[M+H] ⁺。 Add the product of the previous step (170mg), dichloromethane (25ml) and N,N-diisopropylethylamine (196mg) into a 50ml reaction flask, and reduce the temperature to 0℃ under nitrogen protection, and then slowly drop in acryloyl chloride (36mg). ), after dripping, stir for 30 minutes. After the reaction is complete, dilute with water, extract with dichloromethane, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain 110 mg of light yellow solid. ¹ H NMR (400MHz, CDCl ₃ ): δ8.50 (d, J = 4.9Hz, 1H), 7.76 (dd, J = 8.9, 2.7Hz, 1H), 7.40-7.32 (m, 1H), 7.12-7.05 (m,2H),7.05-6.93(m,2H),6.74-6.51(m,1H), 6.42(d,J=16.7Hz,1H), 5.83(dd,J=10.4,1.7Hz,1H), 5.25-4.21 (m, 3H), 4.11-3.49 (m, 3H), 3.39-3.00 (m, 1H), 2.89-2.65 (m, 1H), 2.09-1.99 (m, 3H), 1.49-1.36 (m , 3H), 1.26 (d, J = 6.7 Hz, 3H), 1.08 (d, J = 6.7 Hz, 3H). MS: m/z 576.3458, [M+H] ⁺ .

实施例19：Example 19:

第一步first step

于50ml的单口瓶中加入(3S,5S)-4-(7-氯-6-氟-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3,5-二甲基哌嗪-1-羧酸叔丁酯(136mg)，3-氟-N,N-双(甲基-d ₃)-2-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯胺(100mg)，醋酸钾(74mg)，1,4-二氧六环(10ml)，水(2ml)和[1,1'-双(二苯基膦)二茂铁]二氯化钯(20mg)，氮气置换后升温至95℃搅拌过夜。反应完毕，加入水稀释，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体150mg。MS:m/z 654.4,[M+H] ⁺。 Add (3S,5S)-4-(7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1 to a 50ml single-mouth bottle ,2-Dihydropyrido[2,3-d]pyrimidin-4-yl)-3,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (136mg), 3-fluoro-N,N- Bis(methyl-d ₃ )-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (100mg), potassium acetate ( 74mg), 1,4-dioxane (10ml), water (2ml) and [1,1'-bis(diphenylphosphine)ferrocene] palladium dichloride (20mg), replaced with nitrogen and heated to Stir at 95°C overnight. After the reaction is complete, add water to dilute, extract with ethyl acetate, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain 150 mg of yellow solid. MS: m/z 654.4, [M+H] ⁺ .

第二步Second step

于50ml单口瓶中加入上步产物(150mg)和二氯甲烷(20ml)，在10℃～15℃下，滴加三氟乙酸(15ml)，滴毕，室温搅拌1小时。反应完毕，降温至0℃，缓慢加入饱和碳酸氢钠水溶液，调节pH至8～9，二氯甲烷萃取，合并有机层，无水硫酸钠干燥，过滤，减压浓缩至干，得黄色固体130mg。在另一烧瓶中加入2-氟丙烯酸(40mg)和二氯甲烷(5ml)，缓慢滴入氯化亚砜(57mg)，滴毕，常温搅拌30分钟。Add the product of the previous step (150mg) and dichloromethane (20ml) to a 50ml single-necked flask, add trifluoroacetic acid (15ml) dropwise at 10°C-15°C, and stir at room temperature for 1 hour. After the reaction, the temperature was lowered to 0°C, saturated sodium bicarbonate aqueous solution was slowly added, the pH was adjusted to 8-9, dichloromethane extraction, the organic layers were combined, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain a yellow solid 130mg . Add 2-fluoroacrylic acid (40mg) and dichloromethane (5ml) into another flask, slowly drop thionyl chloride (57mg), and then stir at room temperature for 30 minutes.

将脱Boc产物(100mg)溶于二氯甲烷(10ml)，加入N,N-二异丙基乙胺(116mg)，氮气保护下降温至0℃，再缓慢滴入上述制备的2-氟丙烯酰氯，滴毕搅拌30分钟。反应完毕，加水稀释，二氯甲烷萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体40mg。 ¹H NMR(400MHz,DMSO-d ₆):δ8.47(d,J＝4.8Hz,1H),8.29(dd,J＝10.2,1.9Hz,1H),7.25(t,J＝4.3Hz,1H),7.06(t,J＝8.7Hz,1H),6.58-6.44(m,2H),5.42(s,1H),5.33(dd,J＝30.0,4.0Hz,1H),4.43(br s,2H),4.12-3.80(m,2H),3.66(d,J＝9.8Hz,2H),2.74-2.60(m,1H),1.94(d,J＝6.5Hz,3H),1.36-1.21(m,6H),1.08(dd,J＝6.6,2.6Hz,3H),0.98(dd,J＝10.9,6.7Hz,3H).MS:m/z 626.3378,[M+H] ⁺。 The de-Boc product (100mg) was dissolved in dichloromethane (10ml), N,N-diisopropylethylamine (116mg) was added, the temperature was reduced to 0°C under nitrogen protection, and the 2-fluoropropene prepared above was slowly added dropwise The acid chloride was dripped and stirred for 30 minutes. After the reaction is completed, dilute with water, extract with dichloromethane, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain 40 mg of yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ): δ8.47(d,J=4.8Hz,1H), 8.29(dd,J=10.2,1.9Hz,1H), 7.25(t,J=4.3Hz,1H ), 7.06 (t, J = 8.7Hz, 1H), 6.58-6.44 (m, 2H), 5.42 (s, 1H), 5.33 (dd, J = 30.0, 4.0 Hz, 1H), 4.43 (br s, 2H) ),4.12-3.80(m,2H),3.66(d,J=9.8Hz,2H),2.74-2.60(m,1H),1.94(d,J=6.5Hz,3H),1.36-1.21(m, 6H), 1.08 (dd, J=6.6, 2.6 Hz, 3H), 0.98 (dd, J=10.9, 6.7 Hz, 3H). MS: m/z 626.3378, [M+H] ⁺ .

实施例20：Example 20:

第一步first step

于50ml的单口瓶中加入(S)-4-(6,7-二氯-1-(2-异丙基-4-(甲基-d ₃)吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(270mg)，2-(双(甲基-d ₃)氨基)苯硼酸(140mg)，醋酸钾(145mg)，1,4-二氧六环(20ml)，水(4ml)和[1,1'-双(二苯基膦)二茂铁]二氯化钯(73mg)，氮气置换后升温至95℃搅拌5小时。反应完毕，加入水稀释，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体150mg。MS:m/z 641.4,[M+H] ⁺。 Add (S)-4-(6,7-dichloro-1-(2-isopropyl-4-(methyl-d ₃ )pyridin-3-yl)-2-oxo to a 50ml single-mouth bottle -1,2-Dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (270mg), 2-(bis(methyl-d ₃ ) Amino)phenylboronic acid (140mg), potassium acetate (145mg), 1,4-dioxane (20ml), water (4ml) and [1,1'-bis(diphenylphosphine)ferrocene] Palladium dichloride (73 mg) was replaced with nitrogen and heated to 95°C and stirred for 5 hours. After the reaction is complete, add water to dilute, extract with ethyl acetate, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain 150 mg of yellow solid. MS: m/z 641.4, [M+H] ⁺ .

第二步Second step

于50ml单口瓶中加入上步产物(150mg)和二氯甲烷(10ml)，在0℃下，滴加三氟乙酸(10ml)，滴毕，于10～15℃搅拌1小时。反应完毕，降温至0℃，缓慢加入饱和碳酸氢钠水溶液，调节pH至7～8，二氯甲烷萃取，合并有机层，无水硫酸钠干燥，过滤，减压浓缩至干，得淡黄色固体。向浓缩物中加入二氯甲烷(10ml)和N,N-二异丙基乙胺(65mg)，氮气保护下降温至0℃，再缓慢滴入丙烯酰氯(35mg)的二氯甲烷(3ml)溶液，滴毕，搅拌30分钟。反应完毕，加水稀释，二氯甲烷萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得淡黄色固体95mg。 ¹H NMR(400MHz,CDCl ₃):δ8.49(d,J＝4.9Hz,1H),8.07(s,1H),7.40-7.31(m,1H), 7.13-7.01(m,2H),7.01-6.88(m,2H),6.74-6.52(m,1H),6.43(dd,J＝16.7,1.2Hz,1H),5.83(dd,J＝10.4,1.7Hz,1H),5.33-4.19(m,3H),4.10-3.45(m,3H),3.43-2.95(m,1H),2.92-2.56(m,1H),1.65-1.42(m,3H),1.30-1.20(m,3H),1.09(br s,3H).MS:m/z 595.3307,[M+H] ⁺。 Add the product of the previous step (150mg) and dichloromethane (10ml) to a 50ml single-necked flask, add trifluoroacetic acid (10ml) dropwise at 0°C, and stir at 10-15°C for 1 hour. After the reaction is complete, cool to 0°C, slowly add a saturated aqueous sodium bicarbonate solution, adjust the pH to 7-8, extract with dichloromethane, combine the organic layers, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to dryness to obtain a light yellow solid . Add dichloromethane (10ml) and N,N-diisopropylethylamine (65mg) to the concentrate, reduce the temperature to 0°C under nitrogen protection, and slowly drop acryloyl chloride (35mg) in dichloromethane (3ml) After dripping the solution, stir for 30 minutes. After the reaction is complete, dilute with water, extract with dichloromethane, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain 95 mg of light yellow solid. ¹ H NMR (400MHz, CDCl ₃ ): δ8.49 (d, J = 4.9Hz, 1H), 8.07 (s, 1H), 7.40-7.31 (m, 1H), 7.13-7.01 (m, 2H), 7.01 -6.88(m,2H),6.74-6.52(m,1H),6.43(dd,J=16.7,1.2Hz,1H),5.83(dd,J=10.4,1.7Hz,1H),5.33-4.19(m ,3H),4.10-3.45(m,3H),3.43-2.95(m,1H),2.92-2.56(m,1H),1.65-1.42(m,3H),1.30-1.20(m,3H),1.09 (br s, 3H). MS: m/z 595.3307, [M+H] ⁺ .

实施例20-1M：Example 20-1M:

参考实施例3制备方案，采用中间体5M原料，制备得到化合物4-10M，R _f:0.53(DCM:MeOH＝10:1)。 With reference to the preparation scheme of Example 3, using intermediate 5M raw materials, compound 4-10M was prepared, R _f :0.53 (DCM:MeOH=10:1).

实施例20-1P：Example 20-1P:

参考实施例3制备方案，采用中间体5P原料，制备得到化合物4-10P，R _f:0.52(DCM:MeOH＝10:1)。 Referring to the preparation scheme of Example 3, using the intermediate 5P raw material, compound 4-10P was prepared, R _f :0.52 (DCM:MeOH=10:1).

实施例20：Example 20:

第一步first step

在100ml单口瓶中加入7-氯-6-氟-1-(2-异丙基-4-(甲基-d ₃)吡啶-3-基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮(616mg)，乙腈(20ml)和N,N-二异丙基乙胺(452mg)，降温至10℃以下，滴加三氯氧磷(402mg)，滴毕，再加入2滴N-甲基吗啉，加毕于10℃～20℃搅拌反应1小时。将反应液减压浓缩至干，依次加入乙腈(20ml)，N,N-二异丙基乙胺(452mg)和(3S,5S)-3,5-二甲基哌嗪-1-羧酸叔丁酯(375mg)，加完室温搅拌30分钟，加入N,N-二甲基甲酰胺(5ml)，升温至50℃搅拌2小时。将反应液倒入水中，乙酸乙酯萃取，合并有机层，饱和氯化钠洗涤，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体610mg。MS:m/z 548.3,[M+H] ⁺。 Add 7-chloro-6-fluoro-1-(2-isopropyl-4-(methyl-d ₃ )pyridin-3-yl)pyrido[2,3-d]pyrimidine-2 into a 100ml single-mouth bottle ,4(1H,3H)-dione (616mg), acetonitrile (20ml) and N,N-diisopropylethylamine (452mg), lower the temperature to below 10℃, add phosphorus oxychloride (402mg) dropwise After that, add 2 drops of N-methylmorpholine, and stir and react at 10°C to 20°C for 1 hour. The reaction solution was concentrated to dryness under reduced pressure, and acetonitrile (20ml), N,N-diisopropylethylamine (452mg) and (3S,5S)-3,5-dimethylpiperazine-1-carboxylic acid were added sequentially Tert-butyl ester (375mg), after adding at room temperature, stirring for 30 minutes, adding N,N-dimethylformamide (5ml), heating to 50°C and stirring for 2 hours. The reaction solution was poured into water, extracted with ethyl acetate, the organic layers were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 610 mg of a yellow solid. MS: m/z 548.3, [M+H] ⁺ .

第二步Second step

于50ml的单口瓶中加入上步产物(202mg)，3-氟-N,N-双(甲基-d ₃)-2-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯胺(100mg)，醋酸钾(109mg)，1,4-二氧六环(10ml)，水(0.5ml)和[1,1'-双(二苯基膦)二茂铁]二氯化钯(27mg)，氮气置换后升温至95℃搅拌3小时。反应完毕，加入水稀释，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄绿色固体195mg。MS:m/z 657.4,[M+H] ⁺。 Add the product of the previous step (202mg), 3-fluoro-N,N-bis(methyl-d ₃ )-2-(4,4,5,5-tetramethyl-1,3, 2-Dioxolpan-2-yl)aniline (100mg), potassium acetate (109mg), 1,4-dioxane (10ml), water (0.5ml) and [1,1'-bis (Diphenylphosphine)ferrocene]palladium dichloride (27 mg), replaced with nitrogen, heated to 95°C and stirred for 3 hours. After the reaction is complete, add water to dilute, extract with ethyl acetate, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain 195 mg of yellow-green solid. MS: m/z 657.4, [M+H] ⁺ .

第三步third step

于50ml单口瓶中加入上步产物(190mg)和二氯甲烷(10ml)，在10℃～15℃下，滴加三氟乙酸(2.5ml)，滴毕，室温搅拌2小时。反应完毕，降温至0℃，缓慢加入饱和碳酸氢钠水溶液，调节pH至8～9，二氯甲烷萃取，合并有机层，无水硫酸钠干燥，过滤，减压浓缩至干，得黄色固体180mg。在另一烧瓶中加入2-氟丙烯酸(25mg)和二氯甲烷(5ml)，缓慢滴入氯化亚砜(36mg)，滴毕常温搅拌30分钟。Add the product of the previous step (190mg) and dichloromethane (10ml) to a 50ml single-necked flask, add trifluoroacetic acid (2.5ml) dropwise at 10°C-15°C, and stir at room temperature for 2 hours. After the reaction is complete, cool to 0°C, slowly add saturated aqueous sodium bicarbonate solution, adjust the pH to 8-9, extract with dichloromethane, combine the organic layers, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to dryness to obtain 180 mg of yellow solid . In another flask, 2-fluoroacrylic acid (25mg) and dichloromethane (5ml) were added, thionyl chloride (36mg) was slowly added dropwise, and the mixture was stirred at room temperature for 30 minutes.

将脱Boc产物(100mg)溶于二氯甲烷(10ml)，加入N,N-二异丙基乙胺(139mg)，氮气保护下降温至0℃，再缓慢滴入上述制备的2-氟丙烯酰氯，滴毕搅拌30分钟。反应完毕，加水稀释，二氯甲烷萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体43mg。 ¹H NMR(400MHz,CDCl ₃):δ8.55(d,J＝4.5Hz,1H),7.85(d,J＝9.3Hz,1H),7.23-7.04(m,2H),6.42(d,J＝8.5Hz,1H),6.34(d,J＝14.3Hz,1H),5.41(d,J＝47.4Hz,1H),5.24(dd,J＝16.7,2.7Hz,1H),4.30(br s,2H),4.06-3.53(m,4H),2.80-2.63(m,1H),1.38(d,J＝5.9Hz,6H),1.31-1.18(m,3H),1.10(dd,J＝ 15.8,6.5Hz,3H).MS:m/z 629.3557,[M+H] ⁺。 The de-Boc product (100mg) was dissolved in dichloromethane (10ml), N,N-diisopropylethylamine (139mg) was added, the temperature was reduced to 0°C under nitrogen protection, and the 2-fluoropropene prepared above was slowly added dropwise The acid chloride was dripped and stirred for 30 minutes. After the reaction is complete, dilute with water, extract with dichloromethane, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain 43 mg of yellow solid. ¹ H NMR (400MHz, CDCl ₃ ): δ8.55 (d, J = 4.5 Hz, 1H), 7.85 (d, J = 9.3 Hz, 1H), 7.23-7.04 (m, 2H), 6.42 (d, J =8.5Hz, 1H), 6.34 (d, J = 14.3 Hz, 1H), 5.41 (d, J = 47.4 Hz, 1H), 5.24 (dd, J = 16.7, 2.7 Hz, 1H), 4.30 (br s, 2H),4.06-3.53(m,4H),2.80-2.63(m,1H),1.38(d,J=5.9Hz,6H),1.31-1.18(m,3H),1.10(dd,J=15.8, 6.5 Hz, 3H). MS: m/z 629.3557, [M+H] ⁺ .

实施例21：Example 21:

第一步first step

于50ml的单口瓶中加入(S)-4-(6,7-二氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(100mg)，3-氟-N,N-双(甲基-d ₃)-2-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯胺(54mg)，醋酸钾(53mg)，1,4-二氧六环(20ml)，水(4ml)和[1,1'-双(二苯基膦)二茂铁]二氯化钯(15mg)，氮气置换后升温至95℃搅拌2小时。反应完毕，加入水稀释，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体110mg。MS:m/z 656.3,[M+H] ⁺。 Add (S)-4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2- Dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (100mg), 3-fluoro-N,N-bis(methyl-d ₃ )-2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (54mg), potassium acetate (53mg), 1,4 -Dioxane (20ml), water (4ml) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (15mg), replaced with nitrogen, heated to 95°C and stirred for 2 hours. After the reaction is complete, add water to dilute, extract with ethyl acetate, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain 110 mg of yellow solid. MS: m/z 656.3, [M+H] ⁺ .

第二步Second step

于50ml单口瓶中加入上步产物(110mg)和二氯甲烷(20ml)，在10℃～15℃下，滴加三氟乙酸(10ml)，滴毕，室温搅拌1小时。反应完毕，降温至0℃，缓慢加入饱和碳酸氢钠水溶液，调节pH至7～8，二氯甲烷萃取，合并有机层，无水硫酸钠干燥，过滤，减压浓缩至干，得黄色油状物。向浓缩物中加入二氯甲烷(25ml)和N,N-二异丙基乙胺(61mg)，氮气保护下降温至0℃，再缓慢滴入丙烯酰氯(19mg)，滴毕，搅拌30分钟。反应完毕，加水稀释，二氯甲烷萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得淡黄色固体47mg。 ¹H NMR(400MHz,CDCl ₃):δ8.51(d,J＝4.8Hz,1H),8.03(s,1H),7.13-6.97(m,2H),6.75-6.49(m,1H),6.48-6.35(m,2H),6.31(d,J＝14.2Hz,1H),5.81(d,J＝10.6Hz,1H),5.21-4.23(m,3H),4.08-3.43(m,3H),3.36-2.97(m,1H),2.83-2.55(m,1H),2.05-1.90(m,3H),1.59-1.40(m,3H),1.25-1.18(m,3H),1.12-1.00(m,3H).MS:m/z 610.3001,[M+H] ⁺。 Add the product from the previous step (110mg) and dichloromethane (20ml) to a 50ml single-necked flask, add trifluoroacetic acid (10ml) dropwise at 10°C to 15°C, and stir at room temperature for 1 hour. After the reaction, the temperature was lowered to 0°C, saturated aqueous sodium bicarbonate was slowly added to adjust the pH to 7-8, extracted with dichloromethane, the organic layers were combined, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain a yellow oil . Add dichloromethane (25ml) and N,N-diisopropylethylamine (61mg) to the concentrate, reduce the temperature to 0°C under nitrogen protection, and then slowly drop in acryloyl chloride (19mg), and stir for 30 minutes. . After the reaction is complete, dilute with water, extract with dichloromethane, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain 47 mg of pale yellow solid. ¹ H NMR (400MHz, CDCl ₃ ): δ8.51 (d, J = 4.8Hz, 1H), 8.03 (s, 1H), 7.13-6.97 (m, 2H), 6.75-6.49 (m, 1H), 6.48 -6.35(m,2H),6.31(d,J=14.2Hz,1H),5.81(d,J=10.6Hz,1H),5.21-4.23(m,3H),4.08-3.43(m,3H), 3.36-2.97(m,1H),2.83-2.55(m,1H),2.05-1.90(m,3H),1.59-1.40(m,3H),1.25-1.18(m,3H),1.12-1.00(m ,3H). MS: m/z 610.3001, [M+H] ⁺ .

实施例22：Example 22:

向反应瓶中加入7-(2-(双(甲基-d ₃)氨基)-6-氟苯基)-6-氟-1-(2-异丙基-4-(甲基-d ₃)吡啶-3-基)-4-((S)-2-甲基哌嗪-1-基)吡啶并[2,3-d]嘧啶-2(1H)-酮(115mg)，二氯甲烷(10ml)，N,N-二异丙基乙胺(82mg)，2-氟丙烯酸(50mg)和2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(150mg)，加完后室温搅拌30分钟。反应完毕，加水稀释，二氯甲烷萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体100mg。 ¹H NMR(400MHz,CDCl ₃):δ8.54(d,J＝4.9Hz,1H),7.73(d,J＝9.5Hz,1H),7.18-7.09(m,2H),6.41(dd,J＝8.8,2.4Hz,1H),6.33(dd,J＝14.4,2.4Hz,1H),5.40(dd,J＝47.4,3.4Hz,1H),5.24(dd,J＝16.8,3.6Hz,1H),4.95(br s,1H),4.69-4.32(m,2H),4.16-3.88(m,1H),3.83-3.44(m,2H),3.42-3.02(m,1H),2.80-2.61(m,1H),1.52(d,J＝6.6Hz,3H),1.24(dd,J＝6.7,2.7Hz,3H),1.07(dd,J＝6.7,4.5Hz,3H).MS:m/z 615.3415,[M+H] ⁺。 Add 7-(2-(bis(methyl-d ₃ )amino)-6-fluorophenyl)-6-fluoro-1-(2-isopropyl-4-(methyl-d ₃ )Pyridin-3-yl)-4-((S)-2-methylpiperazin-1-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (115mg), dichloromethane (10ml), N,N-diisopropylethylamine (82mg), 2-fluoroacrylic acid (50mg) and 2-(7-azobenzotriazole)-N,N,N',N'- Tetramethylurea hexafluorophosphate (150 mg) was added and stirred at room temperature for 30 minutes. After the reaction is complete, dilute with water, extract with dichloromethane, combine the organic layers, wash with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain 100 mg of yellow solid. ¹ H NMR (400MHz, CDCl ₃ ): δ8.54 (d, J = 4.9 Hz, 1H), 7.73 (d, J = 9.5 Hz, 1H), 7.18-7.09 (m, 2H), 6.41 (dd, J ＝8.8,2.4Hz,1H),6.33(dd,J＝14.4,2.4Hz,1H), 5.40(dd,J＝47.4,3.4Hz,1H), 5.24(dd,J＝16.8,3.6Hz,1H) , 4.95 (br s, 1H), 4.69-4.32 (m, 2H), 4.16-3.88 (m, 1H), 3.83-3.44 (m, 2H), 3.42-3.02 (m, 1H), 2.80-2.61 (m ,1H), 1.52 (d, J = 6.6 Hz, 3H), 1.24 (dd, J = 6.7, 2.7 Hz, 3H), 1.07 (dd, J = 6.7, 4.5 Hz, 3H). MS: m/z 615.3415 ,[M+H] ⁺ .

实施例23：Example 23:

参考实施例1～3，制备得到化合物2-2N。R _f:0.54(DCM:MeOH＝10:1)；具体制备如下： With reference to Examples 1 to 3, compound 2-2N was prepared. R _f : 0.54 (DCM:MeOH=10:1); the specific preparation is as follows:

第一步first step

于50ml的单口瓶中加入(S)-4-(6,7-二氯-1-(2-异丙基-4-(丙-1-烯-2-基)吡啶-3-基)-2-氧代-1,2-二氢吡啶[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(1.0g)，2-(二甲氨基)苯基硼酸(390mg)，醋酸钾(582mg)，1,4-二氧六环(30ml)，水(3ml)和[1,1'-双(二苯基膦)二茂铁]二氯化钯(124mg)，氮气置换后，升温至105℃，搅拌2.5小时。反应完毕，加入水稀释，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体850mg。MS:m/z 658.3,[M+H] ⁺。 Add (S)-4-(6,7-dichloro-1-(2-isopropyl-4-(prop-1-en-2-yl)pyridin-3-yl)- 2-oxo-1,2-dihydropyridine[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (1.0g), 2-(dimethyl Amino) phenylboronic acid (390mg), potassium acetate (582mg), 1,4-dioxane (30ml), water (3ml) and [1,1'-bis(diphenylphosphine)ferrocene] two Palladium chloride (124 mg) was replaced with nitrogen, the temperature was raised to 105°C, and the mixture was stirred for 2.5 hours. After the reaction is complete, add water to dilute, extract with ethyl acetate, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain 850 mg of yellow solid. MS: m/z 658.3, [M+H] ⁺ .

第二步Second step

于50ml单口瓶中加入上步产物(707mg)，二氯甲烷(15ml)和三氟乙酸(10ml)，加毕，室温搅拌1.5小时。反应完毕，减压浓缩至干，向浓缩物中加入二氯甲烷(20ml)，N,N-二异丙基乙胺(0.94ml)，氮气保护下降温至0℃，缓慢滴加丙烯酰氯(117mg)，滴毕搅拌20分钟。反应完毕，加水稀释，二氯甲烷萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体617mg。 ¹H NMR(400MHz,CDCl ₃):δ8.57(d,J＝5.0Hz,1H),8.03(s,1H),7.40-7.31(m,1H),7.11-7.02(m,2H),7.02-6.89(m,2H),6.73-6.52(m,1H),6.42(d,J＝16.6Hz,1H),5.82(d,J＝10.4Hz,1H),5.25-4.17(m,5H),4.08-3.43(m,3H),3.41-2.93(m,1H),2.80(br s,1H),2.51(s,6H),1.89(s,3H),1.60-1.38(m,3H),1.30-1.21(m,3H),1.19-1.01(m,3H).MS:m/z 612.2870,[M+H] ⁺。 Add the product of the previous step (707mg), dichloromethane (15ml) and trifluoroacetic acid (10ml) into a 50ml single-necked flask. After the addition, stir at room temperature for 1.5 hours. After the reaction is complete, concentrate under reduced pressure to dryness, add dichloromethane (20ml), N,N-diisopropylethylamine (0.94ml) to the concentrate, reduce the temperature to 0°C under nitrogen protection, and slowly add acryloyl chloride ( 117mg), and stir for 20 minutes after dropping. After the reaction is complete, dilute with water, extract with dichloromethane, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain 617 mg of yellow solid. ¹ H NMR (400MHz, CDCl ₃ ): δ8.57 (d, J = 5.0Hz, 1H), 8.03 (s, 1H), 7.40-7.31 (m, 1H), 7.11-7.02 (m, 2H), 7.02 -6.89(m,2H),6.73-6.52(m,1H),6.42(d,J=16.6Hz,1H), 5.82(d,J=10.4Hz,1H),5.25-4.17(m,5H), 4.08-3.43 (m, 3H), 3.41-2.93 (m, 1H), 2.80 (br s, 1H), 2.51 (s, 6H), 1.89 (s, 3H), 1.60-1.38 (m, 3H), 1.30 -1.21 (m, 3H), 1.19-1.01 (m, 3H). MS: m/z 612.2870, [M+H] ⁺ .

实施例24：Example 24:

参考实施例1～3，制备得到化合物2-4N。R _f:0.53(DCM:MeOH＝10:1)；具体制备如下： With reference to Examples 1 to 3, compound 2-4N was prepared. R _f : 0.53 (DCM:MeOH=10:1); the specific preparation is as follows:

第一步first step

在100ml单口瓶中加入6,7-二氯-1-(2-异丙基-4-(丙-1-烯-2-基)吡啶-3-基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮(780mg)，乙腈(20ml)，三氯氧磷(0.9ml)和N,N-二异丙基乙胺(1.74ml)，加毕于80℃搅拌2.5小时。减压浓缩至干，向残余物中加入N,N-二甲基乙酰胺(20ml)，N,N-二异丙基乙胺(1.74ml)和(3S,5S)-3,5-二甲基哌嗪-1-羧酸叔丁酯(535mg)，加毕于室温搅拌30分钟。将反应液倒入水中，乙酸乙酯萃取，合并有机层，饱和氯化钠洗涤，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体851mg。MS:m/z 587.2,[M+H] ⁺。 Add 6,7-dichloro-1-(2-isopropyl-4-(prop-1-en-2-yl)pyridin-3-yl)pyrido[2,3-d] into a 100ml single-mouth bottle Pyrimidine-2,4(1H,3H)-dione (780mg), Acetonitrile (20ml), Phosphorus oxychloride (0.9ml) and N,N-Diisopropylethylamine (1.74ml), added at 80 Stir at °C for 2.5 hours. Concentrate to dryness under reduced pressure, add N,N-dimethylacetamide (20ml), N,N-diisopropylethylamine (1.74ml) and (3S,5S)-3,5-di to the residue Tert-butyl methylpiperazine-1-carboxylate (535 mg) was added and stirred at room temperature for 30 minutes. The reaction solution was poured into water, extracted with ethyl acetate, the organic layers were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 851 mg of yellow solid. MS: m/z 587.2, [M+H] ⁺ .

第二步Second step

于100ml的单口瓶中加入上步产物(851mg)，2-(二甲氨基)苯基硼酸(288mg)，醋酸钾(428mg)，1,4-二氧六环(20ml)，水(2ml)和[1,1'-双(二苯基膦)二茂铁]二氯化钯(110mg)，氮气置换后，升温至105℃，搅拌2.5小时。反应完毕，加入水稀释，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体750mg。MS:m/z 672.3,[M+H] ⁺。 Add the product of the previous step (851mg), 2-(dimethylamino)phenylboronic acid (288mg), potassium acetate (428mg), 1,4-dioxane (20ml), water (2ml) to a 100ml single-mouth bottle And [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (110 mg), and after nitrogen replacement, the temperature was raised to 105°C and stirred for 2.5 hours. After the reaction is complete, add water to dilute, extract with ethyl acetate, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain 750 mg of yellow solid. MS: m/z 672.3, [M+H] ⁺ .

第三步third step

于100ml单口瓶中加入上步产物(567mg)，二氯甲烷(15ml)和三氟乙酸(10ml)，加毕，室温搅拌1.5小时。反应完毕，减压浓缩至干，向浓缩物中加入二氯甲烷(15ml)，N,N-二异丙基乙胺(0.74ml)，氮气保护下降温至0℃，缓慢滴加丙烯酰氯(91mg)，滴毕搅拌20分钟。反应完毕，加水稀释，二氯甲烷萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体484mg。 ¹H NMR(400MHz,CDCl ₃):δ8.62-8.52(m,1H),8.15(d,J＝3.7Hz,1H),7.40-7.30(m,1H),7.06(d,J＝8.1Hz,2H),6.97(d,J＝3.7Hz,2H),6.70-6.57(m,1H),6.45-6.34(m,1H),5.81(dd,J＝10.4,1.6Hz,1H),5.03-4.56(m,2H),4.48-4.17(m,2H),4.09-3.35(m,4H),2.84-2.70(m,1H),2.51(d,J＝1.2Hz,6H),1.86(d,J＝4.6Hz,3H),1.48-1.22(m,9H),1.22-0.96(m,3H).MS:m/z 626.3022,[M+H] ⁺。 Add the product of the previous step (567mg), dichloromethane (15ml) and trifluoroacetic acid (10ml) into a 100ml single-necked flask. After the addition, stir at room temperature for 1.5 hours. After the reaction is complete, concentrate under reduced pressure to dryness, add dichloromethane (15ml), N,N-diisopropylethylamine (0.74ml) to the concentrate, reduce the temperature to 0℃ under nitrogen protection, and slowly add acryloyl chloride ( 91mg), after dripping and stirring for 20 minutes. After the reaction is complete, dilute with water, extract with dichloromethane, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain 484 mg of yellow solid. ¹ H NMR(400MHz, CDCl ₃ ): δ8.62-8.52(m,1H), 8.15(d,J=3.7Hz,1H), 7.40-7.30(m,1H), 7.06(d,J=8.1Hz ,2H),6.97(d,J=3.7Hz,2H),6.70-6.57(m,1H),6.45-6.34(m,1H),5.81(dd,J=10.4,1.6Hz,1H),5.03- 4.56(m,2H),4.48-4.17(m,2H),4.09-3.35(m,4H),2.84-2.70(m,1H),2.51(d,J=1.2Hz,6H),1.86(d, J=4.6 Hz, 3H), 1.48-1.22 (m, 9H), 1.22-0.96 (m, 3H). MS: m/z 626.3022, [M+H] ⁺ .

实施例25：Example 25:

参考实施例1～3，制备得到化合物3-2N。R _f:0.56(DCM:MeOH＝10:1)； With reference to Examples 1 to 3, compound 3-2N was prepared. R _f : 0.56 (DCM:MeOH=10:1);

实施例26：Example 26:

参考实施例1～3，制备得到化合物3-14N。R _f:0.54(DCM:MeOH＝10:1)；具体制备如下： With reference to Examples 1 to 3, compound 3-14N was prepared. R _f : 0.54 (DCM:MeOH=10:1); the specific preparation is as follows:

第一步first step

于50ml的单口瓶中加入(S)-4-(6,7-二氯-1-(2-异丙基-4-(丙-1-烯-2-基-3,3,3-d ₃)吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(1.2g)，2-(双(甲基-d ₃)氨基)苯硼酸(715mg)，醋酸钾(620mg)，1,4-二氧六环(30ml)和[1,1'-双(二苯基膦)二茂铁]二氯化钯(154mg)，氮气置换后升温至90℃搅拌3小时。反应完毕，加入水稀释，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体1.3g。 ¹H NMR(400MHz,CDCl ₃):δ8.57(d,J＝4.9Hz,1H),8.02(d,J＝3.8Hz,1H),7.39-7.31(m,1H),7.11-6.90(m,4H),5.05-4.60(m,3H),4.50-3.89(m,3H),3.78-3.52(m,1H),3.44-2.96(m,2H),2.81(br s,1H),1.57-1.40(m,3H),1.53(s,9H),1.30-1.22(m,3H),1.17-1.00(m,3H).MS:m/z 667.4,[M+H] ⁺。 Add (S)-4-(6,7-dichloro-1-(2-isopropyl-4-(prop-1-en-2-yl-3,3,3-d ₃ ) Pyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (1.2g), 2-(bis(methyl-d ₃ )amino)phenylboronic acid (715mg), potassium acetate (620mg), 1,4-dioxane (30ml) and [1,1'-bis( Diphenylphosphine)ferrocene]palladium dichloride (154 mg), replaced with nitrogen, heated to 90°C and stirred for 3 hours. After the reaction is complete, add water to dilute, extract with ethyl acetate, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain 1.3 g of yellow solid. ¹ H NMR (400MHz, CDCl ₃ ): δ8.57 (d, J = 4.9 Hz, 1H), 8.02 (d, J = 3.8 Hz, 1H), 7.39-7.31 (m, 1H), 7.11-6.90 (m ,4H),5.05-4.60(m,3H),4.50-3.89(m,3H),3.78-3.52(m,1H),3.44-2.96(m,2H),2.81(br s,1H),1.57- 1.40 (m, 3H), 1.53 (s, 9H), 1.30 to 1.22 (m, 3H), 1.17-1.00 (m, 3H). MS: m/z 667.4, [M+H] ⁺ .

第二步Second step

于50ml单口瓶中加入上一步产物(1.3g)和二氯甲烷(20ml)，在0℃下，滴加三氟乙酸(20ml)，滴毕，逐渐升至10～15℃继续搅拌1小时。反应完毕，降温至0℃，将反应液缓慢加入饱和碳酸氢钠水溶液，调节pH至7～8，二氯甲烷萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得淡黄色固体1.1g。将该产品溶于二氯甲烷(30ml)，加入N,N-二异丙基乙胺(504mg)，氮气保护下降温至0℃，缓慢滴入丙烯酰氯(265mg)的二氯甲烷(3ml)溶液，滴毕，搅拌30分钟。反应完毕，加水稀释，二氯甲烷萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，滤液浓缩，硅胶柱层析纯化，得淡黄色固体900mg。 ¹H NMR(400MHz,CDCl ₃):δ8.56(d,J＝5.0Hz,1H),8.03(s,1H),7.39-7.31(m,1H),7.11-7.01(m,2H),7.01-6.89(m,2H),6.73-6.52(m,1H),6.42(dd,J＝16.7,1.5Hz,1H),5.82(dd,J＝10.4,1.7Hz,1H),5.30-4.17(m,5H),4.08-3.43(m,3H),3.41-2.92(m,1H),2.80(br s,1H),1.64-1.39(m,3H),1.30-1.21(m,3H),1.20-0.97(m,3H).MS:m/z 621.3443,[M+H] ⁺。 Add the product of the previous step (1.3g) and dichloromethane (20ml) to a 50ml single-necked flask, add trifluoroacetic acid (20ml) dropwise at 0°C, and then gradually increase to 10-15°C and continue stirring for 1 hour. After the reaction is completed, the temperature is lowered to 0°C, the reaction solution is slowly added to a saturated aqueous sodium bicarbonate solution, the pH is adjusted to 7-8, extracted with dichloromethane, the organic layers are combined, washed once with saturated brine, dried with anhydrous sodium sulfate, filtered, and reduced It is concentrated by pressure and purified by silica gel column chromatography to obtain 1.1 g of light yellow solid. Dissolve the product in dichloromethane (30ml), add N,N-diisopropylethylamine (504mg), reduce the temperature to 0°C under nitrogen protection, and slowly drop acryloyl chloride (265mg) in dichloromethane (3ml) After dripping the solution, stir for 30 minutes. After the reaction is complete, dilute with water, extract with dichloromethane, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate the filtrate, and purify by silica gel column chromatography to obtain 900 mg of light yellow solid. ¹ H NMR (400MHz, CDCl ₃ ): δ8.56 (d, J = 5.0Hz, 1H), 8.03 (s, 1H), 7.39-7.31 (m, 1H), 7.11-7.01 (m, 2H), 7.01 -6.89(m,2H),6.73-6.52(m,1H),6.42(dd,J=16.7,1.5Hz,1H), 5.82(dd,J=10.4,1.7Hz,1H),5.30-4.17(m ,5H),4.08-3.43(m,3H),3.41-2.92(m,1H),2.80(br s,1H),1.64-1.39(m,3H),1.30-1.21(m,3H),1.20- 0.97 (m, 3H). MS: m/z 621.3443, [M+H] ⁺ .

实施例27：Example 27:

参考实施例1～3，制备得到化合物3-15N。R _f:0.52(DCM:MeOH＝10:1)； With reference to Examples 1 to 3, compound 3-15N was prepared. R _f : 0.52 (DCM:MeOH=10:1);

实施例28：Example 28:

参考实施例1～3，制备得到化合物3-16N。R _f:0.54(DCM:MeOH＝10:1)；具体制备如下： With reference to Examples 1 to 3, compound 3-16N was prepared. R _f : 0.54 (DCM:MeOH=10:1); the specific preparation is as follows:

第一步first step

在100ml单口瓶中，加入6,7-二氯-1-(2-异丙基-4-(丙-1-烯-2-基-3,3,3-d ₃)吡啶-3-基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮(1.3g)，甲苯(20ml)，N,N-二异丙基乙胺(1.3g)和2滴N-甲基吗啉，室温下滴加三氯氧磷(1.0g)，加毕升温至80℃搅拌1小时。将反应液减压浓缩至干，向其加入乙腈(20ml)，N,N-二异丙基乙胺(1.3g)和(3S,5S)-3,5-二甲基哌嗪-1-羧酸叔丁酯(700mg)，加完后于50℃搅拌2小时。将反应液倒入水中，乙酸乙酯萃取，合并有机层，饱和氯化钠洗涤，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体515mg。MS:m/z 590.3,[M+H] ⁺。 In a 100ml single-mouth bottle, add 6,7-dichloro-1-(2-isopropyl-4-(prop-1-en-2-yl-3,3,3-d ₃ )pyridin-3-yl )Pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (1.3g), toluene (20ml), N,N-diisopropylethylamine (1.3g) and 2 drops N-methylmorpholine, phosphorus oxychloride (1.0g) was added dropwise at room temperature, and after the addition, the temperature was raised to 80°C and stirred for 1 hour. The reaction solution was concentrated to dryness under reduced pressure, and acetonitrile (20ml), N,N-diisopropylethylamine (1.3g) and (3S,5S)-3,5-dimethylpiperazine-1- Tert-butyl carboxylate (700 mg), after the addition, stir at 50°C for 2 hours. The reaction solution was poured into water, extracted with ethyl acetate, the organic layers were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 515 mg of a yellow solid. MS: m/z 590.3, [M+H] ⁺ .

第二步Second step

于50ml的单口瓶中加入上步产物(510mg)，2-(双(甲基-d ₃)氨基)苯硼酸(300mg)，醋酸钾(254mg)，1,4-二氧六环(10ml)，水(0.5ml)和[1,1'-双(二苯基膦)二茂铁]二氯化钯(63mg)，氮气置换后升温至85℃搅拌2小时。反应完毕，加入水稀释，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体530mg。MS:m/z 681.4,[M+H] ⁺。 Add the product of the previous step (510mg), 2-(bis(methyl-d ₃ )amino)phenylboronic acid (300mg), potassium acetate (254mg), 1,4-dioxane (10ml) to a 50ml single-mouth bottle , Water (0.5ml) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (63mg), replaced with nitrogen, heated to 85°C and stirred for 2 hours. After the reaction is complete, add water to dilute, extract with ethyl acetate, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain 530 mg of yellow solid. MS: m/z 681.4, [M+H] ⁺ .

第三步third step

于50ml单口瓶中加入上步产物(530mg)和二氯甲烷(10ml)，室温下，滴加三氟乙酸(2.5ml)，滴毕，继续搅拌1小时。反应完毕，降温至0℃，缓慢加入饱和碳酸氢钠水溶液，调节pH至弱碱性，二氯甲烷萃取，合并有机层，无水硫酸钠干燥，过滤，减压浓缩至干。向浓缩物中加入二氯甲烷(20ml)，N,N-二异丙基乙胺(302mg)，氮气保护下降温至0℃，缓慢滴加丙烯酰氯(77mg)的二氯甲烷溶液(5ml)，滴毕搅拌30分钟。反应完毕，加水稀释，二氯甲烷萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体290mg。 ¹H NMR(400MHz,CDCl ₃):δ8.58(dd,J＝4.9,3.6Hz,1H),8.16(d,J＝3.7Hz,1H),7.41-7.31(m,1H),7.15-7.02(m,2H),6.97(d,J＝4.4Hz,2H),6.70-6.57(m,1H),6.47-6.34(m,1H),5.82(dd,J＝10.4,1.8Hz,1H),5.05-4.56(m,2H),4.56-4.18(m,2H),4.09-3.36(m,4H),2.85-2.69(m,1H),1.56-1.32(m,6H),1.32-1.24(m,3H),1.24-0.93(m,3H).MS:m/z 635.3578,[M+H] ⁺。 Add the product of the previous step (530mg) and dichloromethane (10ml) to a 50ml single-necked flask, add trifluoroacetic acid (2.5ml) dropwise at room temperature, and continue stirring for 1 hour. After the reaction was completed, the temperature was lowered to 0°C, saturated aqueous sodium bicarbonate solution was slowly added, the pH was adjusted to weakly alkaline, the dichloromethane extraction was performed, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. Add dichloromethane (20ml), N,N-diisopropylethylamine (302mg) to the concentrate, reduce the temperature to 0°C under nitrogen protection, and slowly add acryloyl chloride (77mg) in dichloromethane (5ml) dropwise , Stir for 30 minutes after dripping. After the reaction is complete, dilute with water, extract with dichloromethane, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain 290 mg of yellow solid. ¹ H NMR (400MHz, CDCl ₃ ): δ8.58 (dd, J = 4.9, 3.6 Hz, 1H), 8.16 (d, J = 3.7 Hz, 1H), 7.41-7.31 (m, 1H), 7.15-7.02 (m, 2H), 6.97 (d, J = 4.4 Hz, 2H), 6.70-6.57 (m, 1H), 6.47-6.34 (m, 1H), 5.82 (dd, J = 10.4, 1.8 Hz, 1H), 5.05-4.56(m,2H),4.56-4.18(m,2H),4.09-3.36(m,4H),2.85-2.69(m,1H),1.56-1.32(m,6H),1.32-1.24(m , 3H), 1.24-0.93 (m, 3H). MS: m/z 635.3578, [M+H] ⁺ .

实施例29：Example 29:

参考实施例1～3，制备得到化合物3-10N。Rf:0.54(DCM:MeOH＝10:1)；具体制备如下：With reference to Examples 1 to 3, compound 3-10N was prepared. Rf: 0.54 (DCM: MeOH = 10:1); the specific preparation is as follows:

第一步first step

于100ml的单口瓶中加入2,5,6-三氯烟酰胺(594mg)和四氢呋喃(10ml)，氮气保护，降温至0℃，滴加草酰氯(390mg)，滴毕，升温至70℃搅拌1小时。将反应液冷至室温，减压浓缩，并用甲苯共沸一次，向剩余物加入四氢呋喃(100ml)，降温至0℃，并加入2-异丙基-4-(异丙烯基-d ₅)吡啶-3-胺(400mg)，滴加三乙胺(246mg)，滴毕，室温搅拌0.5小时。反应完毕，将反应液倒入饱和氯化铵水溶液，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得白色固体400mg。MS:m/z 432.1,[M+H] ⁺。 Add 2,5,6-trichloronicotinic acid amide (594mg) and tetrahydrofuran (10ml) into a 100ml single-necked flask, under nitrogen protection, cool to 0°C, add oxalyl chloride (390mg) dropwise, and stir at 70°C. 1 hour. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and azeotroped once with toluene. Tetrahydrofuran (100ml) was added to the residue, the temperature was reduced to 0°C, and 2-isopropyl-4-(isopropenyl-d ₅ )pyridine was added. -3-amine (400mg), triethylamine (246mg) was added dropwise, after dropping, the mixture was stirred at room temperature for 0.5 hour. After the reaction was completed, the reaction solution was poured into saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic layers were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain a white solid 400mg. MS: m/z 432.1, [M+H] ⁺ .

第二步Second step

于100ml的单口瓶中加入上步产物(400mg)和四氢呋喃(10ml)，降温至0℃，滴加双(三甲基硅基)氨基钾(2.1ml)，滴毕，室温搅拌0.5小时。反应完毕，将反应液倒入饱和氯化铵水溶液，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得白色固体270mg。MS:m/z 396.1,[M+H] ⁺。 Add the product of the previous step (400mg) and tetrahydrofuran (10ml) to a 100ml single-neck flask, cool to 0°C, add potassium bis(trimethylsilyl)amide (2.1ml) dropwise, and stir at room temperature for 0.5 hours. After the reaction was completed, the reaction solution was poured into saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic layers were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain a white solid 270mg. MS: m/z 396.1, [M+H] ⁺ .

第三步third step

于50ml的单口瓶中加入上步产物(270mg)，乙腈(10ml)，N,N-二异丙基乙胺(264mg)和一滴N-甲基吗啉，滴加三氯氧磷(209mg)，滴毕，升温至80℃，搅拌1小时。减压浓缩，并用甲苯共沸一次，向残余物中加入乙腈(10ml)和N,N-二异丙基乙胺(264mg)，再加入(S)-4-N-叔丁氧羰基-2-甲基哌嗪(273mg)，加毕，室温搅拌0.5小时。反应完毕加入饱和氯化铵水溶液，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，滤液浓缩，硅胶柱层析纯化，得黄色固体160mg。MS:m/z 578.2,[M+H] ⁺。 Add the product of the previous step (270mg), acetonitrile (10ml), N,N-diisopropylethylamine (264mg) and a drop of N-methylmorpholine to a 50ml single-mouth bottle, and add phosphorus oxychloride (209mg) dropwise , After dripping, heat up to 80°C and stir for 1 hour. Concentrate under reduced pressure and azeotrope once with toluene. Add acetonitrile (10ml) and N,N-diisopropylethylamine (264mg) to the residue, and then add (S)-4-N-tert-butoxycarbonyl-2 -Methylpiperazine (273mg), after addition, stir at room temperature for 0.5 hours. After the reaction was completed, a saturated aqueous ammonium chloride solution was added, extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and purified by silica gel column chromatography to obtain 160 mg of a yellow solid. MS: m/z 578.2, [M+H] ⁺ .

第四步the fourth step

于50ml的单口瓶中加入上步产物(160mg)，2-(双(甲基-d ₃)氨基)苯硼酸(50mg)，醋酸钾(79mg)，1,4-二氧六环(10ml)，水(0.5ml)和[1,1'-双(二苯基膦)二茂铁]二氯化钯(20mg)，氮气置换后，升温至80℃，搅拌2小时。反应完毕，加入水稀释，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体110mg。MS:m/z 669.4,[M+H] ⁺。 Add the product of the previous step (160mg), 2-(bis(methyl-d ₃ )amino)phenylboronic acid (50mg), potassium acetate (79mg), 1,4-dioxane (10ml) to a 50ml single-mouth bottle , Water (0.5ml) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (20mg), replaced with nitrogen, heated to 80°C and stirred for 2 hours. After the reaction is complete, add water to dilute, extract with ethyl acetate, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain 110 mg of yellow solid. MS: m/z 669.4, [M+H] ⁺ .

第五步the fifth step

于50ml单口瓶中加入上步产物(110mg)和二氯甲烷(5ml)，滴加三氟乙酸(1ml)，滴毕，室温搅拌1小时。反应完毕，降温至0℃，缓慢加入饱和碳酸氢钠水溶液，调节pH至7～8，二氯甲烷萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩至干。向残余物中加入二氯甲烷(5ml)，降温至0℃，加入N,N-二异丙基乙胺(78mg)，再缓慢滴入丙烯酰氯(21mg)的二氯甲烷(1ml)溶液，滴毕，搅拌30分钟。反应完毕，缓慢倒入饱和氯化铵水溶液淬灭，二氯甲烷萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，滤液浓缩，硅胶柱层析纯化，得黄色固体45mg。 ¹H NMR(400MHz,CDCl ₃):δ8.58(d,J＝4.9Hz,1H),8.03(s,1H),7.40-7.32(m,1H),7.13-6.90(m,4H),6.74-6.54(m,1H),6.43(d,J＝16.8Hz,1H),5.84(d,J＝10.4Hz,1H),5.29-4.19(m,3H),4.09-3.45(m,3H),3.41-2.94(m,1H),2.81(br s,1H),1.87(s,3H),1.60-1.40(m,3H),1.36-1.21(m,3H),1.12(br s,3H).MS:m/z 623.3569,[M+H] ⁺。 Add the product from the previous step (110mg) and dichloromethane (5ml) to a 50ml single-necked flask, add trifluoroacetic acid (1ml) dropwise, and stir at room temperature for 1 hour. After the reaction is completed, the temperature is lowered to 0°C, a saturated aqueous sodium bicarbonate solution is slowly added to adjust the pH to 7-8, extracted with dichloromethane, the organic phases are combined, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness. Dichloromethane (5ml) was added to the residue, the temperature was lowered to 0°C, N,N-diisopropylethylamine (78mg) was added, and a solution of acryloyl chloride (21mg) in dichloromethane (1ml) was slowly added dropwise, After dripping, stir for 30 minutes. After the reaction was completed, slowly poured into saturated aqueous ammonium chloride for quenching, extracted with dichloromethane, combined the organic layers, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated the filtrate, and purified by silica gel column chromatography to obtain 45 mg of yellow solid . ¹ H NMR (400MHz, CDCl ₃ ): δ8.58 (d, J = 4.9Hz, 1H), 8.03 (s, 1H), 7.40-7.32 (m, 1H), 7.13-6.90 (m, 4H), 6.74 -6.54(m,1H),6.43(d,J=16.8Hz,1H), 5.84(d,J=10.4Hz,1H), 5.29-4.19(m,3H),4.09-3.45(m,3H), 3.41-2.94 (m, 1H), 2.81 (br s, 1H), 1.87 (s, 3H), 1.60-1.40 (m, 3H), 1.36-1.21 (m, 3H), 1.12 (br s, 3H). MS: m/z 623.3569, [M+H] ⁺ .

实施例30：Example 30:

参考实施例1～3，制备得到化合物3-12N。R _f:0.56(DCM:MeOH＝10:1)。 With reference to Examples 1 to 3, compound 3-12N was prepared. R _f : 0.56 (DCM:MeOH=10:1).

实施例31：Example 31:

第一步first step

于50ml的单口瓶中加入(3S,5S)-4-(7-氯-1-(2,4-二异丙基吡啶-3-基)-6-氟-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3,5-二甲基哌嗪-1-羧酸叔丁酯(176mg)，3-氟-N,N-双(甲基-d ₃)-2-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯胺(100mg)，醋酸钾(91mg)，1,4-二氧六环(10ml)，水(1ml)和[1,1'-双(二苯基膦)二茂铁]二氯化钯(44mg)，氮气置换后升温至105℃搅拌2.5小时。完毕，加入水稀释，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得橙黄色固体207mg。MS:m/z 682.4,[M+H] ⁺。 Add (3S,5S)-4-(7-chloro-1-(2,4-diisopropylpyridin-3-yl)-6-fluoro-2-oxo-1,2 to a 50ml single-mouth bottle -Dihydropyrido[2,3-d]pyrimidin-4-yl)-3,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (176mg), 3-fluoro-N,N-bis( Methyl-d ₃ )-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (100mg), potassium acetate (91mg) , 1,4-dioxane (10ml), water (1ml) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (44mg), replaced with nitrogen and heated to 105℃ Stir for 2.5 hours. When finished, add water to dilute, extract with ethyl acetate, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain 207 mg of orange solid. MS: m/z 682.4, [M+H] ⁺ .

第二步Second step

于50ml单口瓶中加入上步产物(100mg)，二氯甲烷(5ml)和三氟乙酸(2ml)，滴毕，室温搅拌1.5小时。反应完毕，降温至0℃，缓慢加入饱和碳酸氢钠水溶液，调节pH至弱碱性，二氯甲烷萃取，合并有机层，无水硫酸钠干燥，过滤，减压浓缩至干，备用。在另一烧瓶中加入2-氟丙烯酸(20mg)和二氯甲烷(5ml)，缓慢滴入氯化亚砜(31mg)，滴毕常温搅拌30分钟。Add the product of the previous step (100mg), dichloromethane (5ml) and trifluoroacetic acid (2ml) into a 50ml single-necked flask. After dripping, stir at room temperature for 1.5 hours. After the reaction is completed, the temperature is lowered to 0°C, a saturated aqueous sodium bicarbonate solution is slowly added, the pH is adjusted to weakly alkaline, the dichloromethane extraction is performed, the organic layers are combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and set aside. In another flask were added 2-fluoroacrylic acid (20 mg) and dichloromethane (5 ml), and thionyl chloride (31 mg) was slowly dropped into the flask. After dropping, the mixture was stirred at room temperature for 30 minutes.

将脱Boc产物溶于二氯甲烷(10ml)，加入N,N-二异丙基乙胺(95mg)，氮气保护下降温至0℃，再缓慢滴入上述制备的2-氟丙烯酰氯，滴毕搅拌30分钟。反应完毕，加水稀释，二氯甲烷萃取，合并有机层，食盐水洗一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得浅黄色固体30mg。 ¹H NMR(400MHz,CDCl ₃):δ8.64(d,J＝5.1Hz,1H),7.86(d,J＝9.4Hz,1H),7.22(t,J＝5.4Hz,1H),7.19-7.10(m,1H),6.44-6.37(m,1H),6.33(dd,J＝14.4,2.4Hz,1H),5.42(dd,J＝47.4,3.5Hz,1H),5.24(dd,J＝16.8,3.5Hz,1H),4.41-4.25(m,2H),4.06-3.51(m,4H),2.74-2.62(m,1H),2.62-2.51(m,1H),1.40(dd,J＝6.3,1.4Hz,6H),1.27-1.17(m,6H),1.10-0.95(m,6H).MS:m/z 654.3663,[M+H] ⁺。 The de-Boc product was dissolved in dichloromethane (10ml), N,N-diisopropylethylamine (95mg) was added, the temperature was reduced to 0°C under nitrogen protection, and the 2-fluoroacryloyl chloride prepared above was slowly dropped into the solution. After stirring for 30 minutes. After the reaction is completed, dilute with water, extract with dichloromethane, combine the organic layers, wash with brine once, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain 30 mg of light yellow solid. ¹ H NMR (400MHz, CDCl ₃ ): δ8.64(d,J=5.1Hz,1H), 7.86(d,J=9.4Hz,1H), 7.22(t,J=5.4Hz,1H), 7.19- 7.10 (m, 1H), 6.44-6.37 (m, 1H), 6.33 (dd, J = 14.4, 2.4 Hz, 1H), 5.42 (dd, J = 47.4, 3.5 Hz, 1H), 5.24 (dd, J = 16.8,3.5Hz,1H),4.41-4.25(m,2H),4.06-3.51(m,4H),2.74-2.62(m,1H),2.62-2.51(m,1H),1.40(dd,J= 6.3, 1.4 Hz, 6H), 1.27-1.17 (m, 6H), 1.10-0.95 (m, 6H). MS: m/z 654.3663, [M+H] ⁺ .

实施例32：Example 32:

参考实施例1～3，制备得到化合物1-38。R _f:0.53(DCM:MeOH＝10:1)。 With reference to Examples 1 to 3, compound 1-38 was prepared. R _f : 0.53 (DCM:MeOH=10:1).

实施例33：Example 33:

参考实施例1～3，制备得到化合物1-39。R _f:0.54(DCM:MeOH＝10:1)。 With reference to Examples 1 to 3, compound 1-39 was prepared. R _f : 0.54 (DCM:MeOH=10:1).

实施例34：Example 34:

参考实施例1～3，制备得到化合物1-42。Rf:0.55(DCM:MeOH＝10:1)。With reference to Examples 1 to 3, compounds 1-42 were prepared. Rf: 0.55 (DCM:MeOH=10:1).

实施例35：Example 35:

参考实施例1～3，制备得到化合物1-43。R _f:0.54(DCM:MeOH＝10:1)。 With reference to Examples 1 to 3, compounds 1-43 were prepared. R _f : 0.54 (DCM:MeOH=10:1).

实施例36：Example 36:

第一步first step

于100ml的单口瓶中加入2,5,6-三氯烟酰胺(0.86g)和四氢呋喃(20ml)，氮气保护，降温至0℃，滴加草酰氯(0.37ml)，滴毕，升温至75℃搅拌2小时。将反应液冷至室温，减压浓缩，并用甲苯共沸两次，向剩余物加入四氢呋喃(20ml)，降温至0℃，并加入2-异丙基-4-(乙烯基-2,2-d ₂)吡啶-3-胺(484mg)的四氢呋喃(10ml)溶液，加毕，回温至10℃～15℃搅拌1小时。反应完毕，将反应液倒入饱和氯化铵水溶液，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得白色固体760mg。 ¹H NMR(400MHz,DMSO-d ₆):δ11.34(s,1H),9.60(s,1H),8.68(s,1H),8.46(d,J＝5.1Hz,1H),7.52(d,J＝5.1Hz,1H),6.87-6.77(m,1H),3.35-3.25(m,1H),1.18(d,J＝6.8Hz,6H).MS:m/z 415.0,[M+H] ⁺。 Add 2,5,6-trichloronicotinamide (0.86g) and tetrahydrofuran (20ml) into a 100ml single-necked flask, protect with nitrogen, and cool down to 0°C. Add oxalyl chloride (0.37ml) dropwise. Stir at °C for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and azeotroped twice with toluene. Tetrahydrofuran (20ml) was added to the residue, the temperature was reduced to 0°C, and 2-isopropyl-4-(vinyl-2,2- d ₂ ) A solution of pyridine-3-amine (484mg) in tetrahydrofuran (10ml), after the addition, warm to 10°C-15°C and stir for 1 hour. After the reaction was completed, the reaction solution was poured into saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic layers were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain a white solid 760mg. ¹ H NMR (400MHz, DMSO-d ₆ ): δ11.34 (s, 1H), 9.60 (s, 1H), 8.68 (s, 1H), 8.46 (d, J = 5.1 Hz, 1H), 7.52 (d ,J=5.1Hz,1H),6.87-6.77(m,1H),3.35-3.25(m,1H),1.18(d,J=6.8Hz,6H).MS:m/z 415.0,[M+H ] ⁺ .

第二步Second step

于50ml的单口瓶中加入上步产物(760mg)和四氢呋喃(8ml)，降温至0℃，滴加双(三甲基硅基)氨基钾(4.6ml)，滴毕，回温至10℃～15℃搅拌1小时。反应完毕，将反应液倒入饱和氯化铵水溶液，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得白色固体260mg。 ¹H NMR(400MHz,DMSO):δ12.28(s,1H),8.64(d,J＝5.1Hz,1H),8.60(s,1H),7.66(d,J＝5.1Hz,1H),6.71-6.61(m,1H),2.96-2.81(m,1H),1.09(d,J＝6.7Hz,3H),1.01(t,J＝6.6Hz,3H).MS:m/z 379.1,[M+H] ⁺。 Add the product of the previous step (760mg) and tetrahydrofuran (8ml) to a 50ml single-neck bottle, cool to 0°C, add potassium bis(trimethylsilyl)amide (4.6ml) dropwise, and warm up to 10°C~ Stir at 15°C for 1 hour. After the reaction was completed, the reaction solution was poured into saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic layers were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain a white solid 260mg. ¹ H NMR (400MHz, DMSO): δ12.28 (s, 1H), 8.64 (d, J = 5.1 Hz, 1H), 8.60 (s, 1H), 7.66 (d, J = 5.1 Hz, 1H), 6.71 -6.61(m,1H),2.96-2.81(m,1H),1.09(d,J=6.7Hz,3H),1.01(t,J=6.6Hz,3H).MS:m/z 379.1,[M +H] ⁺ .

第三步third step

于100ml的单口瓶中加入上步产物(260mg)，乙腈(10ml)和N,N-二异丙基乙胺(445mg)，降温至10℃以下，滴加三氯氧磷(423mg)，滴毕，再加入2滴N-甲基吗啉，回温至10℃～20℃，搅拌2小时。减压浓缩，并用甲苯共沸一次，在0℃～5℃条件下，向残余物中加入乙腈(10ml)和N,N-二异丙基乙胺(445mg)，再加入(S)-4-N-叔丁氧羰基-2-甲基哌嗪(207mg)，加毕，回温至10℃～15℃搅拌1小时。反应完毕加入饱和氯化铵水溶液，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，滤液浓缩，硅胶柱层析纯化，得黄色固体280mg。 ¹H NMR(400MHz,DMSO-d ₆):δ8.60(d,J＝5.1 Hz,1H),8.46(d,J＝19.4Hz,1H),7.63(dd,J＝5.1,1.2Hz,1H),6.45-6.32(m,1H),4.88(d,J＝37.7Hz,1H),4.19(dd,J＝36.6,13.6Hz,1H),4.03-3.56(m,3H),3.31-2.95(m,2H),2.66-2.55(m,1H),1.46(s,9H),1.34(dd,J＝12.1,6.7Hz,3H),1.07(d,J＝6.6Hz,3H),1.00(d,J＝6.6Hz,3H).MS:m/z 561.2,[M+H] ⁺。 Add the product of the previous step (260mg), acetonitrile (10ml) and N,N-diisopropylethylamine (445mg) into a 100ml single-necked bottle, cool to below 10°C, dropwise add phosphorus oxychloride (423mg), dropwise After that, add 2 drops of N-methylmorpholine, warm to 10°C to 20°C, and stir for 2 hours. Concentrate under reduced pressure and azeotrope once with toluene. At 0℃～5℃, add acetonitrile (10ml) and N,N-diisopropylethylamine (445mg) to the residue, and then add (S)-4 -N-tert-Butoxycarbonyl-2-methylpiperazine (207mg), after the addition, warm to 10℃～15℃ and stir for 1 hour. After the reaction, a saturated aqueous ammonium chloride solution was added, extracted with ethyl acetate, the organic layers were combined, washed with saturated brine once, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and purified by silica gel column chromatography to obtain 280 mg of yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ): δ8.60 (d, J = 5.1 Hz, 1H), 8.46 (d, J = 19.4 Hz, 1H), 7.63 (dd, J = 5.1, 1.2 Hz, 1H ), 6.45-6.32 (m, 1H), 4.88 (d, J = 37.7Hz, 1H), 4.19 (dd, J = 36.6, 13.6Hz, 1H), 4.03-3.56 (m, 3H), 3.31-2.95 ( m, 2H), 2.66-2.55 (m, 1H), 1.46 (s, 9H), 1.34 (dd, J = 12.1, 6.7 Hz, 3H), 1.07 (d, J = 6.6 Hz, 3H), 1.00 (d , J=6.6 Hz, 3H). MS: m/z 561.2, [M+H] ⁺ .

第四步the fourth step

于50ml的单口瓶中加入上步产物(280mg)，2-(双(甲基-d ₃)氨基)苯硼酸(111mg)，醋酸钾(147mg)，1,4-二氧六环(10ml)，水(2ml)和[1,1'-双(二苯基膦)二茂铁]二氯化钯(37mg)，氮气置换后，升温至80℃，搅拌16小时。反应完毕，加入水稀释，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体200mg。MS:m/z 652.4,[M+H] ⁺。 Add the product of the previous step (280mg), 2-(bis(methyl-d ₃ )amino)phenylboronic acid (111mg), potassium acetate (147mg), 1,4-dioxane (10ml) to a 50ml single-mouth bottle , Water (2ml) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (37mg), replaced with nitrogen, heated to 80°C and stirred for 16 hours. After the reaction is complete, add water to dilute, extract with ethyl acetate, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain 200 mg of yellow solid. MS: m/z 652.4, [M+H] ⁺ .

第五步the fifth step

于50ml单口瓶中加入上步产物(200mg)和二氯甲烷(5ml)，在0℃下，滴加三氟乙酸(5ml)，滴毕，逐渐升至10～15℃继续搅拌1小时。反应完毕，降温至0℃，缓慢加入饱和碳酸氢钠水溶液，调节pH至7～8，二氯甲烷萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩至干。向残余物中加入二氯甲烷(5ml)，降温至0℃，加入N,N-二异丙基乙胺(240mg)，再缓慢滴入丙烯酰氯(42mg)的二氯甲烷(1ml)溶液，滴毕，搅拌30分钟。反应完毕，缓慢倒入饱和氯化铵水溶液淬灭，二氯甲烷萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，滤液浓缩，薄层层析纯化(乙酸乙酯)，得黄色固体90mg。 ¹H NMR(400MHz,CDCl ₃):δ8.58(d,J＝5.1Hz,1H),8.05(s,1H),7.40-7.30(m,2H),7.03(d,J＝8.1Hz,1H),6.99-6.86(m,2H),6.74-6.51(m,1H),6.43(d,J＝16.5Hz,1H),6.28(br s,1H),5.83(dd,J＝10.4,1.6Hz,1H),5.44-4.18(m,3H),4.10-3.45(m,3H),3.43-2.97(m,1H),2.88(br s,1H),1.66-1.38(m,3H),1.30-1.21(m,3H),1.09(br s,3H).MS:m/z 606.3184,[M+H] ⁺。 Add the product of the previous step (200mg) and dichloromethane (5ml) to a 50ml single-necked flask, add trifluoroacetic acid (5ml) dropwise at 0°C, and then gradually increase to 10-15°C and continue stirring for 1 hour. After the reaction is completed, the temperature is lowered to 0°C, a saturated aqueous sodium bicarbonate solution is slowly added to adjust the pH to 7-8, extracted with dichloromethane, the organic phases are combined, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness. Dichloromethane (5ml) was added to the residue, the temperature was lowered to 0°C, N,N-diisopropylethylamine (240mg) was added, and a solution of acryloyl chloride (42mg) in dichloromethane (1ml) was slowly added dropwise, After dripping, stir for 30 minutes. After the reaction is complete, slowly pour into saturated aqueous ammonium chloride to quench, extract with dichloromethane, combine the organic layers, wash once with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate the filtrate, and purify by thin layer chromatography (ethyl acetate) , A yellow solid 90mg. ¹ H NMR (400MHz, CDCl ₃ ): δ8.58 (d, J = 5.1Hz, 1H), 8.05 (s, 1H), 7.40-7.30 (m, 2H), 7.03 (d, J = 8.1 Hz, 1H ), 6.99-6.86 (m, 2H), 6.74-6.51 (m, 1H), 6.43 (d, J = 16.5Hz, 1H), 6.28 (br s, 1H), 5.83 (dd, J = 10.4, 1.6Hz ,1H),5.44-4.18(m,3H),4.10-3.45(m,3H),3.43-2.97(m,1H),2.88(br s,1H),1.66-1.38(m,3H),1.30- 1.21 (m, 3H), 1.09 (br s, 3H). MS: m/z 606.3184, [M+H] ⁺ .

实施例37：Example 37:

第一步first step

于100ml的单口瓶中加入2,5,6-三氯烟酰胺(1.27g)和四氢呋喃(20ml)，氮气保护，降温至0℃，滴加草酰氯(0.55ml)，滴毕，升温至75℃搅拌2小时。将反应液冷至室温，减压浓缩，并用甲苯共沸两次，向剩余物加入四氢呋喃(20ml)，降温至0℃，并加入2-异丙基-3-氨基-4-乙烯基吡啶(700mg)的四氢呋喃(10ml)溶液，加毕，回温至10℃～15℃搅拌1小时。反应完毕，将反应液倒入饱和氯化铵水溶液，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得白色固体1.15g。 ¹H NMR(400MHz,DMSO-d ₆):δ11.34(s,1H),9.61(br s,1H),8.68(s,1H),8.46(d,J＝5.1Hz,1H),7.52(d,J＝5.1Hz,1H),6.82(dd,J＝17.6,11.0Hz,1H),6.09(d,J＝17.6Hz,1H),5.57(d,J＝11.8Hz,1H),3.37-3.25(m,1H),1.18(d,J＝6.7Hz,6H).MS:m/z 413.0,[M+H] ⁺。 Add 2,5,6-trichloronicotinic acid amide (1.27g) and tetrahydrofuran (20ml) into a 100ml single-necked flask, under nitrogen protection, reduce the temperature to 0°C, add oxalyl chloride (0.55ml) dropwise, and increase the temperature to 75 Stir at °C for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and azeotroped twice with toluene. Tetrahydrofuran (20ml) was added to the residue, the temperature was reduced to 0°C, and 2-isopropyl-3-amino-4-vinylpyridine was added ( 700mg) in tetrahydrofuran (10ml) solution, after the addition, warm to 10℃～15℃ and stir for 1 hour. After the reaction was completed, the reaction solution was poured into saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic layers were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain a white solid 1.15g. ¹ H NMR (400MHz, DMSO-d ₆ ): δ11.34 (s, 1H), 9.61 (br s, 1H), 8.68 (s, 1H), 8.46 (d, J = 5.1 Hz, 1H), 7.52 ( d, J = 5.1Hz, 1H), 6.82 (dd, J = 17.6, 11.0 Hz, 1H), 6.09 (d, J = 17.6 Hz, 1H), 5.57 (d, J = 11.8 Hz, 1H), 3.37- 3.25 (m, 1H), 1.18 (d, J=6.7 Hz, 6H). MS: m/z 413.0, [M+H] ⁺ .

第二步Second step

于100ml的单口瓶中加入上步产物(1.63g)和四氢呋喃(30ml)，降温至0℃，滴加双(三甲基硅基)氨基钾(8.3ml)，滴毕，回温至10℃～15℃搅拌1小时。反应完毕，将反应液倒入饱和氯化铵水溶液，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得白色固体1.2g。 ¹H NMR(400MHz,DMSO-d ₆):δ12.28(s,1H),8.64(d,J＝5.1Hz,1H),8.60(s,1H),7.66(d,J＝5.1Hz,1H),6.66(dd,J＝17.3,11.0Hz,1H),6.11(dd,J＝17.2,0.8Hz,1H),5.47(dd,J＝11.0,0.8Hz,1H),2.96-2.83(m,1H),1.09(d,J＝6.7Hz,3H),1.01(d,J＝6.6Hz,3H).MS:m/z 377.1,[M+H] ⁺。 Add the product of the previous step (1.63g) and tetrahydrofuran (30ml) to a 100ml single-neck bottle, cool to 0°C, add potassium bis(trimethylsilyl)amide (8.3ml) dropwise, and warm up to 10°C. Stir at ~15°C for 1 hour. After the reaction was completed, the reaction solution was poured into saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic layers were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain a white solid 1.2g. ¹ H NMR (400MHz, DMSO-d ₆ ): δ12.28 (s, 1H), 8.64 (d, J = 5.1Hz, 1H), 8.60 (s, 1H), 7.66 (d, J = 5.1Hz, 1H ), 6.66 (dd, J = 17.3, 11.0 Hz, 1H), 6.11 (dd, J = 17.2, 0.8 Hz, 1H), 5.47 (dd, J = 11.0, 0.8 Hz, 1H), 2.96-2.83 (m, 1H), 1.09 (d, J = 6.7 Hz, 3H), 1.01 (d, J = 6.6 Hz, 3H). MS: m/z 377.1, [M+H] ⁺ .

第三步third step

于100ml的单口瓶中加入上步产物(630mg)，乙腈(6ml)和N,N-二异丙基乙胺(1.7ml)，降温至0～5℃，滴加三氯氧磷(0.9ml)，滴毕，升温至80℃，搅拌1小时。减压浓缩，并用甲苯共沸一次，在0℃～5℃条件下，向残余物中加入乙腈(6ml)和N,N-二异丙基乙胺(1.7ml)，再加入(S)-4-N-叔丁氧羰基-2-甲基哌嗪(502mg)，加毕，回温至10℃～15℃搅拌1小时。反应完毕加入饱和氯化铵水溶液，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，滤液浓缩，硅胶柱层析纯化，得黄色固体600mg。 ¹H NMR(400MHz,CDCl ₃):δ8.67(d,J＝5.1Hz,1H),8.05(s,1H),7.41(dd,J＝5.1,2.1Hz,1H),6.40-6.22(m,1H),5.88(dd,J＝17.4,5.6Hz,1H),5.37(dd,J＝11.4,4.8Hz,1H),4.86(br s,1H),4.43-3.83(m,3H),3.68(br s,1H),3.45-2.90(m,2H),2.72-2.49(m,1H),1.54-1.45(m,3H),1.52(s,9H),1.24(dd,J＝6.7,2.8Hz,3H),1.13(dd,J＝6.6,5.4Hz,3H).MS:m/z 559.2,[M+H] ⁺。 Add the product of the previous step (630mg), acetonitrile (6ml) and N,N-diisopropylethylamine (1.7ml) to a 100ml single-neck bottle, cool to 0～5℃, and add phosphorus oxychloride (0.9ml ), after dripping, heat up to 80°C and stir for 1 hour. Concentrate under reduced pressure and azeotrope once with toluene. At 0℃～5℃, add acetonitrile (6ml) and N,N-diisopropylethylamine (1.7ml) to the residue, and then add (S)- 4-N-tert-Butoxycarbonyl-2-methylpiperazine (502mg), after the addition, warm up to 10℃～15℃ and stir for 1 hour. After the reaction, a saturated aqueous ammonium chloride solution was added, extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and purified by silica gel column chromatography to obtain 600 mg of yellow solid. ¹ H NMR (400MHz, CDCl ₃ ): δ8.67 (d, J = 5.1 Hz, 1H), 8.05 (s, 1H), 7.41 (dd, J = 5.1, 2.1 Hz, 1H), 6.40-6.22 (m ,1H), 5.88(dd,J=17.4,5.6Hz,1H),5.37(dd,J=11.4,4.8Hz,1H), 4.86(br s,1H),4.43-3.83(m,3H),3.68 (br s,1H),3.45-2.90(m,2H),2.72-2.49(m,1H),1.54-1.45(m,3H),1.52(s,9H),1.24(dd,J=6.7,2.8 Hz, 3H), 1.13 (dd, J=6.6, 5.4 Hz, 3H). MS: m/z 559.2, [M+H] ⁺ .

第四步the fourth step

于50ml的单口瓶中加入上步产物(1.6g)，2-(二甲氨基)苯基硼酸(613mg)，醋酸钾(842mg)，1,4-二氧六环(30ml)，水(5ml)和[1,1'-双(二苯基膦)二茂铁]二氯化钯(212mg)，氮气置换后，升温至80℃，搅拌16小时。反应完毕，加入水稀释，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体1.4g。MS:m/z 644.3,[M+H] ⁺。 Add the product of the previous step (1.6g), 2-(dimethylamino)phenylboronic acid (613mg), potassium acetate (842mg), 1,4-dioxane (30ml), water (5ml) to a 50ml single-mouth bottle. ) And [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (212 mg), after nitrogen replacement, the temperature was raised to 80°C and stirred for 16 hours. After the reaction is complete, add water to dilute, extract with ethyl acetate, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain 1.4 g of yellow solid. MS: m/z 644.3, [M+H] ⁺ .

第五步the fifth step

于50ml单口瓶中加入上步产物(1.4g)和二氯甲烷(15ml)，在0℃下，滴加三氟乙酸(15ml)，滴毕，逐渐升至10～15℃继续搅拌1小时。反应完毕，减压浓缩至干，向残余物中加入二氯甲烷(10ml)，降温至0℃，加入N,N-二异丙基乙胺(1.9ml)，再缓慢滴入丙烯酰氯(295mg)的二氯甲烷(1ml)溶液，滴毕，搅拌30分钟。反应完毕，缓慢倒入饱和氯化铵水溶液淬灭，二氯甲烷萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，滤液浓缩，硅胶柱层析纯化，得黄色固体800mg。 ¹H NMR(400MHz,CDCl ₃):δ8.58(d,J＝5.1Hz,1H),8.05(s,1H),7.39-7.30(m,2H),7.05(d,J＝8.2Hz,1H),6.99-6.85(m,2H),6.74-6.50(m,1H),6.43(dd,J＝16.7,1.2Hz,1H),6.38-6.17(m,1H),5.83(dd,J＝10.4,1.8Hz,2H),5.32(br s,1H),5.18-4.19(m,3H),4.10-3.45(m,3H),3.43-2.97(m,1H),2.88(br s,1H),2.49(s,6H),1.65-1.42(m,3H),1.30-1.24(m,3H),1.17-1.01(m,3H).MS:m/z 598.2708,[M+H] ⁺。 Add the product of the previous step (1.4g) and dichloromethane (15ml) to a 50ml single-neck flask, add trifluoroacetic acid (15ml) dropwise at 0°C, and then gradually increase to 10-15°C and continue stirring for 1 hour. After the reaction is complete, concentrate under reduced pressure to dryness, add dichloromethane (10ml) to the residue, cool to 0°C, add N,N-diisopropylethylamine (1.9ml), and slowly drop acryloyl chloride (295mg ) Solution in dichloromethane (1ml), after dripping, stir for 30 minutes. After the reaction is complete, slowly pour into saturated aqueous ammonium chloride for quenching, extract with dichloromethane, combine the organic layers, wash once with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate the filtrate, and purify by silica gel column chromatography to obtain 800 mg of yellow solid . ¹ H NMR (400MHz, CDCl ₃ ): δ8.58 (d, J = 5.1Hz, 1H), 8.05 (s, 1H), 7.39-7.30 (m, 2H), 7.05 (d, J = 8.2 Hz, 1H) ), 6.99-6.85 (m, 2H), 6.74-6.50 (m, 1H), 6.43 (dd, J = 16.7, 1.2 Hz, 1H), 6.38-6.17 (m, 1H), 5.83 (dd, J = 10.4 , 1.8Hz, 2H), 5.32 (br s, 1H), 5.18-4.19 (m, 3H), 4.10-3.45 (m, 3H), 3.43-2.97 (m, 1H), 2.88 (br s, 1H), 2.49 (s, 6H), 1.65-1.42 (m, 3H), 1.30-1.24 (m, 3H), 1.17-1.01 (m, 3H). MS: m/z 598.2708, [M+H] ⁺ .

实施例38：Example 38:

第一步first step

于50ml的单口瓶中加入(S)-4-(6,7-二氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(1.0g)，2-吡咯烷基苯硼酸(420mg)，醋酸钾(540mg)，1,4-二氧六环(20ml)，水(1ml)和[1,1'-双(二苯基膦)二茂铁]二氯化钯(134mg)，氮气置换后升温至85℃搅拌3小时。反应完毕，加入水稀释，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体650mg。MS:m/z 658.3,[M+H] ⁺。 Add (S)-4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2- Dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (1.0g), 2-pyrrolidinylphenylboronic acid (420mg), potassium acetate (540mg), 1,4-dioxane (20ml), water (1ml) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (134mg), heated after nitrogen replacement Stir at 85°C for 3 hours. After the reaction was completed, diluted with water, extracted with ethyl acetate, combined the organic layers, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 650 mg of yellow solid. MS: m/z 658.3, [M+H] ⁺ .

第二步Second step

于50ml单口瓶中加入上步产物(630mg)和二氯甲烷(10ml)，室温下，滴加三氟乙酸(2.5ml)，滴毕，继续搅拌1小时。反应完毕，降温至0℃，缓慢加入饱和碳酸氢钠水溶液，调节pH至弱碱性，二氯甲烷萃取，合并有机层，无水硫酸钠干燥，过滤，减压浓缩至干。向浓缩物中加入二氯甲烷(20ml)，N,N-二异丙基乙胺(370mg)，氮气保护下降温至0℃，缓慢滴加丙烯酰氯(95mg)的二氯甲烷溶液(1ml)，滴毕搅拌30分钟。反应完毕，加水稀释，二氯甲烷萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体315mg。 ¹H NMR(400MHz,CDCl ₃):δ8.50(d,J＝4.9Hz,1H),8.06-7.98(m,1H),7.35-7.24(m,1H),7.15-7.04(m,1H),6.99-6.86(m,1H),6.78(d,J＝8.4Hz,1H),6.71(t,J＝7.5Hz,1H),6.68-6.56(m,1H),6.44(dd,J＝16.6,1.2Hz,1H),5.84(dd,J＝10.4,1.8Hz,1H),5.35-4.19(m,3H),4.11-3.56(m,3H),3.42-3.01(m,1H),3.00-2.66(m,5H),2.14-1.97(m,3H),1.94-1.69(m,4H),1.64-1.41(m,3H),1.38-1.21(m,3H), 1.17-0.97(m,3H).MS:m/z 612.2891,[M+H] ⁺。 Add the product of the previous step (630mg) and dichloromethane (10ml) into a 50ml single-necked flask, add trifluoroacetic acid (2.5ml) dropwise at room temperature, and continue stirring for 1 hour. After the reaction was completed, the temperature was lowered to 0°C, saturated aqueous sodium bicarbonate solution was slowly added, the pH was adjusted to weakly alkaline, the dichloromethane extraction was performed, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. Add dichloromethane (20ml), N,N-diisopropylethylamine (370mg) to the concentrate, reduce the temperature to 0℃ under nitrogen protection, and slowly add acryloyl chloride (95mg) in dichloromethane (1ml) dropwise , Stir for 30 minutes after dripping. After the reaction is completed, dilute with water, extract with dichloromethane, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain 315 mg of yellow solid. ¹ H NMR (400MHz, CDCl ₃ ): δ8.50 (d, J = 4.9Hz, 1H), 8.06-7.98 (m, 1H), 7.35-7.24 (m, 1H), 7.15-7.04 (m, 1H) ,6.99-6.86(m,1H), 6.78(d,J=8.4Hz,1H), 6.71(t,J=7.5Hz,1H), 6.68-6.56(m,1H), 6.44(dd,J=16.6 ,1.2Hz,1H),5.84(dd,J=10.4,1.8Hz,1H),5.35-4.19(m,3H),4.11-3.56(m,3H),3.42-3.01(m,1H),3.00- 2.66(m,5H),2.14-1.97(m,3H),1.94-1.69(m,4H),1.64-1.41(m,3H),1.38-1.21(m,3H), 1.17-0.97(m,3H) ). MS: m/z 612.2891, [M+H] ⁺ .

实施例39：Example 39:

第一步first step

于50mL的单口瓶中加入(S)-4-(6,7-二氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(2.4g)，2-(烯丙基(甲基)氨基)苯硼酸(1.26g)，醋酸钾(1.3g)，1,4-二氧六环(20ml)，水(5ml)和[1,1'-双(二苯基膦)二茂铁]二氯化钯(322mg)，氮气置换后，升温至90℃，搅拌14小时。反应完毕，加入水稀释，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得红色固体2.1g。 ¹H NMR(400MHz,CDCl ₃):δ8.59(d,J＝4.9Hz,1H),8.13(s,1H),7.62(dd,J＝7.9,1.5Hz,1H),7.28(td,J＝7.8,1.5Hz,1H),7.17(d,J＝5.0Hz,1H),6.67(t,J＝7.6Hz,1H),6.60(d,J＝8.3Hz,1H),5.96(s,1H),5.11-4.81(m,1H),4.52-3.55(m,4H),3.44-2.98(m,2H),2.83-2.68(m,1H),2.42(d,J＝3.8Hz,3H),2.10(s,3H),1.57-1.47(m,3H),1.53(s,9H),1.30-1.23(m,3H),1.07(d,J＝6.8Hz,3H).MS:m/z 618.3,[M+H] ⁺。 Add (S)-4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2- Dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (2.4g), 2-(allyl(methyl)amino)benzene Boric acid (1.26g), potassium acetate (1.3g), 1,4-dioxane (20ml), water (5ml) and [1,1'-bis(diphenylphosphine)ferrocene] dichloride Palladium (322 mg) was replaced with nitrogen, the temperature was raised to 90°C, and the mixture was stirred for 14 hours. After the reaction is complete, add water to dilute, extract with ethyl acetate, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain 2.1 g of red solid. ¹ H NMR (400MHz, CDCl ₃ ): δ8.59 (d, J = 4.9Hz, 1H), 8.13 (s, 1H), 7.62 (dd, J = 7.9, 1.5Hz, 1H), 7.28 (td, J ＝7.8,1.5Hz,1H), 7.17(d,J＝5.0Hz,1H), 6.67(t,J＝7.6Hz,1H), 6.60(d,J＝8.3Hz,1H), 5.96(s,1H ),5.11-4.81(m,1H),4.52-3.55(m,4H),3.44-2.98(m,2H),2.83-2.68(m,1H),2.42(d,J=3.8Hz,3H), 2.10(s,3H),1.57-1.47(m,3H),1.53(s,9H),1.30-1.23(m,3H),1.07(d,J=6.8Hz,3H).MS: m/z 618.3 ,[M+H] ⁺ .

第二步Second step

于120ml的封管中加入上步产物(1.5g)，碳酸钾(671mg)，N,N-二甲基甲酰胺(30ml)和烯丙基溴(588mg)，氮气置换后，升温至65℃，搅拌16小时。反应完毕，加入水稀释，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体890mg。MS:m/z 658.3,[M+H] ⁺。 Add the product of the previous step (1.5g), potassium carbonate (671mg), N,N-dimethylformamide (30ml) and allyl bromide (588mg) into a 120ml sealed tube. After nitrogen replacement, the temperature is raised to 65°C , Stir for 16 hours. After the reaction is complete, add water to dilute, extract with ethyl acetate, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain 890 mg of yellow solid. MS: m/z 658.3, [M+H] ⁺ .

第三步third step

于50ml单口瓶中加入上步产物(890mg)和二氯甲烷(10mL)，在0℃下，滴加三氟乙酸(10ml)，滴毕，于室温搅拌1小时。反应完毕，减压浓缩至干，向剩余物中加入二氯甲烷(10ml)，降温至0℃，加入N,N-二异丙基乙胺(1.3ml)，再缓慢滴入丙烯酰氯(184mg)的二氯甲烷溶液(1ml)，滴毕，搅拌30分钟。缓慢倒入饱和氯化铵水溶液淬灭，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，滤液浓缩，硅胶柱层析纯化，得黄色固体410mg。 ¹H NMR(400MHz,CDCl ₃):δ8.48(d,J＝4.9Hz,1H),8.03(s,1H),7.35(td,J＝7.7,1.7Hz,1H),7.17-6.88(m,4H),6.74-6.52(m,1H),6.42(dd,J＝16.7,1.5Hz,1H),5.83(dd,J＝10.4,1.7Hz,1H),5.42(br s,1H),5.20-4.18(m,5H),4.10-3.43(m,3H),3.39-2.97(m,3H),2.81(br s,1H),2.55(s,3H),2.06-1.87(m,3H),1.70-1.44(m,3H),1.29-1.21(m,3H),1.20-0.95(m,3H).MS:m/z 612.2903,[M+H] ⁺。 Add the product of the previous step (890mg) and dichloromethane (10mL) to a 50ml single-necked flask, add trifluoroacetic acid (10ml) dropwise at 0°C, and stir at room temperature for 1 hour. After the reaction is complete, concentrate under reduced pressure to dryness, add dichloromethane (10ml) to the residue, cool to 0°C, add N,N-diisopropylethylamine (1.3ml), and slowly drop acryloyl chloride (184mg ) In dichloromethane solution (1ml), after dripping, stir for 30 minutes. Slowly pour into saturated aqueous ammonium chloride for quenching, extract with ethyl acetate, combine the organic layers, wash once with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate the filtrate, and purify by silica gel column chromatography to obtain 410 mg of yellow solid. ¹ H NMR (400MHz, CDCl ₃ ): δ8.48 (d, J = 4.9 Hz, 1H), 8.03 (s, 1H), 7.35 (td, J = 7.7, 1.7 Hz, 1H), 7.17-6.88 (m ,4H),6.74-6.52(m,1H),6.42(dd,J=16.7,1.5Hz,1H),5.83(dd,J=10.4,1.7Hz,1H),5.42(br s,1H),5.20 -4.18 (m, 5H), 4.10-3.43 (m, 3H), 3.39-2.97 (m, 3H), 2.81 (br s, 1H), 2.55 (s, 3H), 2.06-1.87 (m, 3H), 1.70-1.44 (m, 3H), 1.29-1.21 (m, 3H), 1.20-0.95 (m, 3H). MS: m/z 612.2903, [M+H] ⁺ .

实施例40：Example 40:

第一步first step

于100ml的单口瓶中加入2,5,6-三氯烟酰胺(1.27g)和四氢呋喃(20ml)，氮气保护，降温至0℃，滴加草酰氯(0.55ml)，滴毕，升温至75℃搅拌1小时。将反应液冷至室温，减压浓缩，并用甲苯共沸两次，向剩余物加入四氢呋喃(20ml)，降温至0℃，并加入2-异丙基-4-(异丙烯基-1,1-d ₂)吡啶-3-胺(560mg)的四氢呋喃(10ml)溶液，加毕，回温至10℃～15℃搅拌1小时。反应完毕，将反应液倒入饱和氯化铵水溶液，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得白色固体800mg。 ¹H NMR(400MHz,DMSO-d ₆):δ11.51(s,1H),9.90(s,1H),8.64(d,J＝5.5Hz,2H),7.64(s,1H),3.56-3.37(m,1H),2.07(s,3H),1.34(d,J＝6.8Hz,6H).MS:m/z 429.1,[M+H] ⁺。 Add 2,5,6-trichloronicotinamide (1.27g) and tetrahydrofuran (20ml) into a 100ml single-necked flask, under nitrogen protection, and cool to 0°C. Add oxalyl chloride (0.55ml) dropwise. After the drop, the temperature is raised to 75. Stir at °C for 1 hour. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and azeotroped twice with toluene. Tetrahydrofuran (20ml) was added to the residue, the temperature was reduced to 0°C, and 2-isopropyl-4-(isopropenyl-1,1 -d ₂ ) A solution of pyridine-3-amine (560mg) in tetrahydrofuran (10ml), after the addition, warm to 10°C-15°C and stir for 1 hour. After the reaction, the reaction solution was poured into saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic layers were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain a white solid 800mg. ¹ H NMR (400MHz, DMSO-d ₆ ): δ 11.51 (s, 1H), 9.90 (s, 1H), 8.64 (d, J = 5.5 Hz, 2H), 7.64 (s, 1H), 3.56-3.37 (m, 1H), 2.07 (s, 3H), 1.34 (d, J=6.8 Hz, 6H). MS: m/z 429.1, [M+H] ⁺ .

第二步Second step

于10ml的单口瓶中加入上步产物(0.8g)和四氢呋喃(50ml)，降温至0℃，滴加双 (三甲基硅基)氨基钾(4.1ml)，滴毕，回温至10℃～15℃搅拌1小时。反应完毕，将反应液倒入饱和氯化铵水溶液，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得淡黄色固体0.6g。 ¹H NMR(400MHz,DMSO-d ₆):δ12.34(s,1H),8.65(d,J＝4.9Hz,1H),8.60(s,1H),7.31(d,J＝4.9Hz,1H),3.05-2.93(m,1H),1.84(s,3H),1.12(d,J＝6.6Hz,3H),1.04(d,J＝6.6Hz,3H).MS:m/z 393.1,[M+H] ⁺。 Add the product of the previous step (0.8g) and tetrahydrofuran (50ml) into a 10ml single-necked flask, cool to 0℃, add potassium bis(trimethylsilyl)amide (4.1ml) dropwise, and warm to 10℃ Stir at ~15°C for 1 hour. After the reaction, the reaction solution was poured into saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic layers were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain a pale yellow Solid 0.6g. ¹ H NMR (400MHz, DMSO-d ₆ ): δ12.34 (s, 1H), 8.65 (d, J = 4.9 Hz, 1H), 8.60 (s, 1H), 7.31 (d, J = 4.9 Hz, 1H ),3.05-2.93(m,1H),1.84(s,3H),1.12(d,J=6.6Hz,3H),1.04(d,J=6.6Hz,3H).MS:m/z 393.1,[ M+H] ⁺ .

第三步third step

于50ml的单口瓶中加入上步产物(600mg)，乙腈(10ml)和N,N-二异丙基乙胺(1.6ml)，降温至10℃以下，滴加三氯氧磷(0.85ml)，滴毕，升温至80℃，搅拌1小时。减压浓缩，并用甲苯共沸一次，在0℃～5℃条件下，向残余物中加入乙腈(10ml)和N,N-二异丙基乙胺(1.6ml)，再加入(S)-4-N-叔丁氧羰基-2-甲基哌嗪(336mg)，加毕，回温至10℃～15℃搅拌1小时。反应完毕加入饱和氯化铵水溶液，乙酸乙酯萃取，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，浓缩，硅胶柱层析纯化，得黄色固体500mg。 ¹H NMR(400MHz,CDCl ₃):δ8.67(d,J＝5.0Hz,1H),8.02(d,J＝3.7Hz,1H),7.13(d,J＝5.0Hz,1H),4.88-4.62(m,1H),4.40-3.86(m,3H),3.79-3.47(m,1H),3.43-2.95(m,2H),2.80-2.62(m,1H),1.89(d,J＝1.6Hz,3H),1.57-1.41(m,3H),1.52(s,9H),1.32-1.24(m,3H),1.13(t,J＝6.2Hz,3H).MS:m/z 575.2,[M+H] ⁺。 Add the product of the previous step (600mg), acetonitrile (10ml) and N,N-diisopropylethylamine (1.6ml) to a 50ml single-necked flask, cool to below 10℃, and add phosphorus oxychloride (0.85ml) dropwise , After dripping, heat up to 80°C and stir for 1 hour. Concentrate under reduced pressure and azeotrope once with toluene. At 0℃～5℃, add acetonitrile (10ml) and N,N-diisopropylethylamine (1.6ml) to the residue, and then add (S)- 4-N-tert-Butoxycarbonyl-2-methylpiperazine (336mg), after the addition, warm up to 10℃～15℃ and stir for 1 hour. After the reaction was completed, a saturated aqueous ammonium chloride solution was added, extracted with ethyl acetate, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain 500 mg of a yellow solid. ¹ H NMR (400MHz, CDCl ₃ ): δ8.67(d,J=5.0Hz,1H), 8.02(d,J=3.7Hz,1H), 7.13(d,J=5.0Hz,1H), 4.88- 4.62(m,1H),4.40-3.86(m,3H),3.79-3.47(m,1H),3.43-2.95(m,2H),2.80-2.62(m,1H),1.89(d,J=1.6 Hz,3H),1.57-1.41(m,3H),1.52(s,9H),1.32-1.24(m,3H),1.13(t,J=6.2Hz,3H).MS:m/z 575.2,[ M+H] ⁺ .

第四步the fourth step

于50ml的单口瓶中加入上步产物(500mg)，2-(双(甲基-d ₃)氨基)苯硼酸(223mg)，醋酸钾(255mg)，1,4-二氧六环(10ml)，水(2ml)和[1,1'-双(二苯基膦)二茂铁]二氯化钯(66mg)，氮气置换后，升温至80℃，搅拌3小时。反应完毕，加入水稀释，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体410mg。 ¹H NMR(400MHz,CDCl ₃):δ8.56(d,J＝5.0Hz,1H),8.02(d,J＝3.6Hz,1H),7.35(td,J＝7.5,2.0Hz,1H),7.10-6.90(m,4H),5.02-4.62(m,2H),4.49-3.86(m,2H),3.80-3.48(m,1H),3.46-2.97(m,2H),2.81(s,1H),1.88(s,3H),1.53(s,9H),1.53-1.41(m,3H),1.32-1.22(m,3H),1.10(br s,3H).MS:m/z 666.4,[M+H] ⁺。 Add the product of the previous step (500mg), 2-(bis(methyl-d ₃ )amino)phenylboronic acid (223mg), potassium acetate (255mg), 1,4-dioxane (10ml) to a 50ml single-mouth bottle , Water (2ml) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (66mg), replaced with nitrogen, heated to 80°C and stirred for 3 hours. After the reaction was completed, diluted with water, extracted with ethyl acetate, combined the organic layers, washed with saturated brine once, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 410 mg of yellow solid. ¹ H NMR (400MHz, CDCl ₃ ): δ8.56 (d, J = 5.0Hz, 1H), 8.02 (d, J = 3.6 Hz, 1H), 7.35 (td, J = 7.5, 2.0 Hz, 1H), 7.10-6.90(m,4H),5.02-4.62(m,2H),4.49-3.86(m,2H),3.80-3.48(m,1H),3.46-2.97(m,2H),2.81(s,1H) ),1.88(s,3H),1.53(s,9H),1.53-1.41(m,3H),1.32-1.22(m,3H),1.10(br s,3H).MS:m/z 666.4,[ M+H] ⁺ .

第五步the fifth step

于50ml单口瓶中加入上步产物(200mg)和二氯甲烷(5ml)，在0℃下，滴加三氟乙酸(5ml)，滴毕，逐渐升至10～15℃继续搅拌1小时。反应完毕，降温至0℃，缓慢加入饱和碳酸氢钠水溶液，调节pH至7～8，二氯甲烷萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩至干。向残余物中加入二氯甲烷(5ml)，降温至0℃，加入N,N-二异丙基乙胺(240mg)，再缓慢滴入丙烯酰氯(42mg)的二氯甲烷(1ml)溶液，滴毕，搅拌30分钟。反应完毕，缓慢倒入饱和氯化铵水溶液淬灭，二氯甲烷萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，滤液浓缩，硅胶柱层析纯化，得黄色固体110mg。 ¹H NMR(400MHz,CDCl ₃):δ8.55(d,J＝5.0Hz,1H),8.02(s,1H),7.40-7.30(m,1H),7.10-7.00(m,2H),7.00-6.88(m,2H),6.73-6.51(m,1H),6.40(d,J＝16.9Hz,1H),5.81(d,J＝10.4Hz,1H),5.25-4.16(m,3H),4.09-3.45(m,3H),3.41-2.92(m,1H),2.79(br s,1H),1.87(s, 3H),1.60-1.38(m,3H),1.30-1.21(m,3H),1.09(br s,3H).MS:m/z 620.3,[M+H] ⁺。 Add the product of the previous step (200mg) and dichloromethane (5ml) to a 50ml single-necked flask, add trifluoroacetic acid (5ml) dropwise at 0°C, and then gradually increase to 10-15°C and continue stirring for 1 hour. After the reaction is completed, the temperature is lowered to 0°C, a saturated aqueous sodium bicarbonate solution is slowly added to adjust the pH to 7-8, extracted with dichloromethane, the organic phases are combined, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness. Dichloromethane (5ml) was added to the residue, the temperature was lowered to 0°C, N,N-diisopropylethylamine (240mg) was added, and a solution of acryloyl chloride (42mg) in dichloromethane (1ml) was slowly added dropwise, After dripping, stir for 30 minutes. After the reaction is complete, slowly pour into saturated aqueous ammonium chloride for quenching, extract with dichloromethane, combine the organic layers, wash once with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate the filtrate, and purify by silica gel column chromatography to obtain 110 mg of yellow solid . ¹ H NMR (400MHz, CDCl ₃ ): δ8.55 (d, J = 5.0Hz, 1H), 8.02 (s, 1H), 7.40-7.30 (m, 1H), 7.10-7.00 (m, 2H), 7.00 -6.88(m,2H),6.73-6.51(m,1H),6.40(d,J=16.9Hz,1H), 5.81(d,J=10.4Hz,1H),5.25-4.16(m,3H), 4.09-3.45 (m, 3H), 3.41-2.92 (m, 1H), 2.79 (br s, 1H), 1.87 (s, 3H), 1.60-1.38 (m, 3H), 1.30-1.21 (m, 3H) , 1.09 (br s, 3H). MS: m/z 620.3, [M+H] ⁺ .

实施例41：Example 41:

第一步first step

于50ml的单口瓶中加入(S)-4-(7-氯-6-氟-1-(2-异丙基-4-(丙-1-烯-2-基-3,3,3-d ₃)吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(200mg)，2-(双(甲基-d ₃)氨基)苯硼酸(74mg)，醋酸钾(105mg)，1,4-二氧六环(10ml)，水(1ml)和[1,1'-双(二苯基膦)二茂铁]二氯化钯(52mg)，氮气置换后升温至105℃搅拌3.5小时。反应完毕，加入水稀释，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体231mg。MS:m/z 651.4,[M+H] ⁺。 Add (S)-4-(7-chloro-6-fluoro-1-(2-isopropyl-4-(prop-1-en-2-yl-3,3,3- d ₃ )Pyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl Ester (200mg), 2-(bis(methyl-d ₃ )amino)phenylboronic acid (74mg), potassium acetate (105mg), 1,4-dioxane (10ml), water (1ml) and [1, 1'-Bis(diphenylphosphine)ferrocene]palladium dichloride (52 mg), replaced with nitrogen, heated to 105°C and stirred for 3.5 hours. After the reaction is complete, add water to dilute, extract with ethyl acetate, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain 231 mg of yellow solid. MS: m/z 651.4, [M+H] ⁺ .

第二步Second step

于50ml单口瓶中加入上步产物(231mg)和二氯甲烷(6ml)，室温下，滴加三氟乙酸(4ml)，滴毕，继续搅拌1小时。减压浓缩至干，向浓缩物中加入二氯甲烷(10ml)，N,N-二异丙基乙胺(233mg)，氮气保护下降温至0℃，缓慢滴加丙烯酰氯(39mg)的二氯甲烷溶液(1ml)，滴毕搅拌30分钟。反应完毕，加水稀释，二氯甲烷萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体182mg。 ¹H NMR(400MHz,CDCl ₃):δ8.60(d,J＝5.0Hz,1H),7.73(d,J＝9.0Hz,1H),7.38(td,J＝7.7,1.6Hz,1H),7.13-7.03(m,3H),6.98(t,J＝7.4Hz,1H),6.74-6.54(m,1H),6.43(d,J＝16.8Hz,1H),5.84(d,J＝10.4Hz,1H),5.12-4.20(m,5H),4.10-3.46(m,3H),3.40-2.99(m,1H),2.91-2.68(m,1H),1.54-1.32(m,3H),1.31-1.23(m,3H),1.15-1.06(m,3H).MS:m/z 605.3740,[M+H] ⁺。 Add the product of the previous step (231mg) and dichloromethane (6ml) to a 50ml single-necked flask, add trifluoroacetic acid (4ml) dropwise at room temperature, and continue stirring for 1 hour. Concentrate to dryness under reduced pressure, add dichloromethane (10ml), N,N-diisopropylethylamine (233mg) to the concentrate, reduce the temperature to 0°C under nitrogen protection, and slowly add dichloromethane (39mg) of acryloyl chloride (39mg) dropwise. The methyl chloride solution (1ml) was dripped and stirred for 30 minutes. After the reaction is complete, dilute with water, extract with dichloromethane, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain 182 mg of yellow solid. ¹ H NMR (400MHz, CDCl ₃ ): δ8.60 (d, J = 5.0Hz, 1H), 7.73 (d, J = 9.0Hz, 1H), 7.38 (td, J = 7.7, 1.6Hz, 1H), 7.13-7.03 (m, 3H), 6.98 (t, J = 7.4 Hz, 1H), 6.74-6.54 (m, 1H), 6.43 (d, J = 16.8 Hz, 1H), 5.84 (d, J = 10.4 Hz ,1H),5.12-4.20(m,5H),4.10-3.46(m,3H),3.40-2.99(m,1H),2.91-2.68(m,1H),1.54-1.32(m,3H),1.31 -1.23 (m, 3H), 1.15-1.06 (m, 3H). MS: m/z 605.3740, [M+H] ⁺ .

实施例42：Example 42:

第一步first step

于100ml的单口瓶中加入7-氯-6-氟-1-(2-异丙基-4-(丙-1-烯-2-基)吡啶-3-基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮(307mg)，乙腈(15ml)和N,N-二异丙基乙胺(530mg)，滴加三氯氧磷(629mg)，滴毕，升温至80℃，搅拌2小时。减压浓缩至干，甲苯共沸两次，向残余物中加入N,N-二甲基乙酰胺(10ml)，N,N-二异丙基乙胺(530mg)和(3S,5S)-3,5-二甲基-1-哌嗪羧酸叔丁酯(228mg)，加毕，室温搅拌0.5小时。缓慢倒入饱和碳酸氢钠水溶液淬灭反应，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩后经硅胶柱层析纯化，得黄色固体257mg。MS:m/z 571.3,[M+H] ⁺。 Add 7-chloro-6-fluoro-1-(2-isopropyl-4-(prop-1-en-2-yl)pyridin-3-yl)pyrido[2,3- d] Pyrimidine-2,4(1H,3H)-dione (307mg), acetonitrile (15ml) and N,N-diisopropylethylamine (530mg), dropwise add phosphorus oxychloride (629mg), drop it , The temperature was raised to 80°C and stirred for 2 hours. It was concentrated to dryness under reduced pressure, and toluene was azeotroped twice. To the residue was added N,N-dimethylacetamide (10ml), N,N-diisopropylethylamine (530mg) and (3S,5S)- 3,5-Dimethyl-1-piperazinecarboxylic acid tert-butyl ester (228mg), after addition, stir at room temperature for 0.5 hour. Slowly poured into saturated sodium bicarbonate aqueous solution to quench the reaction, extracted with ethyl acetate, combined the organic layers, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by silica gel column chromatography to obtain 257 mg of yellow solid. MS: m/z 571.3, [M+H] ⁺ .

第二步Second step

于50ml的单口瓶中加入上步产物(257mg)，2-(双(甲基-d ₃)氨基)苯硼酸(93mg)，醋酸钾(133mg)，1,4-二氧六环(15ml)，水(1.5ml)和[1,1'-双(二苯基膦)二茂铁]二氯化钯(66mg)，氮气置换后升温至105℃搅拌2.5小时。反应完毕，加入水稀释，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体269mg。MS:m/z 662.4,[M+H] ⁺。 Add the product of the previous step (257mg), 2-(bis(methyl-d ₃ )amino)phenylboronic acid (93mg), potassium acetate (133mg), 1,4-dioxane (15ml) to a 50ml single-mouth bottle. , Water (1.5ml) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (66mg), replaced with nitrogen, heated to 105°C and stirred for 2.5 hours. After the reaction is complete, add water to dilute, extract with ethyl acetate, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain 269 mg of yellow solid. MS: m/z 662.4, [M+H] ⁺ .

第三步third step

于50ml单口瓶中加入上步产物(269mg)和二氯甲烷(6ml)，室温下，滴加三氟乙酸(4ml)，滴毕，继续搅拌2小时。减压浓缩至干，向浓缩物中加入二氯甲烷(10ml)，N,N-二异丙基乙胺(258mg)，氮气保护下降温至0℃，缓慢滴加丙烯酰氯(44mg)，滴毕搅拌30分钟。反应完毕，加水稀释，二氯甲烷萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体216mg。 ¹H NMR(400MHz,CDCl ₃):δ8.60(dd,J＝4.9,3.2Hz,1H),7.84(dd,J＝9.0,4.3Hz,1H),7.38(t,J＝7.7Hz,1H),7.12-7.03(m,3H),6.98(td,J＝7.4,1.4Hz,1H),6.71-6.58(m,1H),6.42(ddd,J＝16.7,3.4,1.8Hz,1H),5.82(dd,J＝10.5,1.4Hz,1H),4.95-4.88(m,1H),4.77(d,J＝16.2Hz,1H),4.42-4.30(m,1H),4.30-4.18(m,1H),4.05-3.76(m,3H),3.76-3.42(m,1H),2.87-2.74(m,1H),1.87(s,3H),1.41(d,J＝5.9Hz,3H),1.32-1.25(m,6H),1.16-1.08(m,3H).MS:m/z 616.3749,[M+H] ⁺。 Add the product of the previous step (269mg) and dichloromethane (6ml) to a 50ml single-necked flask, add trifluoroacetic acid (4ml) dropwise at room temperature, and continue stirring for 2 hours. Concentrate to dryness under reduced pressure, add dichloromethane (10ml), N,N-diisopropylethylamine (258mg) to the concentrate, reduce the temperature to 0℃ under nitrogen protection, slowly add acryloyl chloride (44mg) dropwise, dropwise After stirring for 30 minutes. After the reaction is completed, dilute with water, extract with dichloromethane, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain 216 mg of yellow solid. ¹ H NMR (400MHz, CDCl ₃ ): δ8.60 (dd, J = 4.9, 3.2 Hz, 1H), 7.84 (dd, J = 9.0, 4.3 Hz, 1H), 7.38 (t, J = 7.7 Hz, 1H ),7.12-7.03(m,3H),6.98(td,J=7.4,1.4Hz,1H),6.71-6.58(m,1H),6.42(ddd,J=16.7,3.4,1.8Hz,1H), 5.82(dd,J=10.5,1.4Hz,1H),4.95-4.88(m,1H),4.77(d,J=16.2Hz,1H),4.42-4.30(m,1H),4.30-4.18(m, 1H),4.05-3.76(m,3H),3.76-3.42(m,1H),2.87-2.74(m,1H),1.87(s,3H),1.41(d,J=5.9Hz,3H),1.32 -1.25 (m, 6H), 1.16-1.08 (m, 3H). MS: m/z 616.3749, [M+H] ⁺ .

实施例43：Example 43:

第一步first step

于100ml的单口瓶中加入(S)-4-(6,7-二氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(3.0g)，2-氨基苯硼酸频哪醇酯(1.5g)，醋酸钾(1.6g)，1,4-二氧六环(20ml)，水(4ml)和[1,1'-双(二苯基膦)二茂铁]二氯化钯(0.4g)，氮气置换后升温至80℃搅拌10小时。反应完毕，加水稀释，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩，硅胶柱层析纯化，得红色固体2.8g。 ¹H NMR(400MHz,CDCl ₃):δ8.55(d,J＝4.9Hz,1H),8.14(d,J＝2.2Hz,1H),7.59(dd,J＝7.9,1.3Hz,1H),7.21-7.11(m,2H),6.72(td,J＝7.6,0.9Hz,1H),6.60(d,J＝8.1Hz,1H),5.19-4.75(m,1H),4.63-4.12(m,4H),4.12-3.52(m,2H),3.47-2.99(m,2H),2.90-2.68(m,1H),2.11-.203(m,3H),1.61-1.47(m,3H),1.53(s,9H),1.30-1.21(m,3H),1.09-1.03(m,3H).MS:m/z 604.3,[M+H] ⁺。 Add (S)-4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2- Dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (3.0g), 2-aminophenylboronic acid pinacol ester (1.5g) , Potassium acetate (1.6g), 1,4-dioxane (20ml), water (4ml) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.4g) After nitrogen replacement, the temperature was raised to 80°C and stirred for 10 hours. After the reaction is complete, dilute with water, extract with ethyl acetate, combine the organic layers, wash with saturated brine, dry with anhydrous sodium sulfate, filter and concentrate, and purify by silica gel column chromatography to obtain 2.8 g of red solid. ¹ H NMR (400MHz, CDCl ₃ ): δ8.55 (d, J = 4.9 Hz, 1H), 8.14 (d, J = 2.2 Hz, 1H), 7.59 (dd, J = 7.9, 1.3 Hz, 1H), 7.21-7.11 (m, 2H), 6.72 (td, J = 7.6, 0.9 Hz, 1H), 6.60 (d, J = 8.1 Hz, 1H), 5.19-4.75 (m, 1H), 4.63-4.12 (m, 4H),4.12-3.52(m,2H),3.47-2.99(m,2H),2.90-2.68(m,1H),2.11-.203(m,3H),1.61-1.47(m,3H),1.53 (s, 9H), 1.30-1.21 (m, 3H), 1.09-1.03 (m, 3H). MS: m/z 604.3, [M+H] ⁺ .

第二步Second step

于100ml单口瓶中依次加入上步产物(2.0g)，碳酸钾(1.4g)，N,N-二甲基甲酰胺(15ml)和3-溴丙烯(0.8g)，加毕，升温至65℃，搅拌4.5小时。反应完毕，向反应液中加水稀释，乙酸乙酯萃取，合并有机相，水洗两次，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体1.5g。MS:m/z 644.3,[M+H] ⁺。 Add the product of the previous step (2.0g), potassium carbonate (1.4g), N,N-dimethylformamide (15ml) and 3-bromopropene (0.8g) in a 100ml single-necked flask in sequence. After the addition, the temperature is raised to 65. ℃, stirring for 4.5 hours. After the reaction, the reaction solution was diluted with water, extracted with ethyl acetate, combined the organic phases, washed twice with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain a yellow solid 1.5g. MS: m/z 644.3, [M+H] ⁺ .

第三步third step

于100ml单口瓶中加入上步产物(1.5g)，二氯甲烷(10ml)和三氟乙酸(2ml)，加毕，室温搅拌15分钟。反应完毕，减压浓缩至干，向浓缩物中加入二氯甲烷(15ml)，N,N-二异丙基乙胺(1.5g)，氮气保护下降温至0℃，缓慢滴加丙烯酰氯(190mg)，滴毕搅拌15分钟。反应完毕，加水稀释，二氯甲烷萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，经高效液相制备得黄色固体0.55g。 ¹H NMR(400MHz,CDCl ₃):δ8.56(d,J＝4.9Hz,1H),8.16(s,1H),7.56(d,J＝7.7Hz,1H),7.23(td,J＝7.8,1.4Hz,1H),7.16(d,J＝4.2Hz,1H),6.74-6.53(m,1H),6.68(t,J＝7.3Hz,1H),6.59(d,J＝8.4Hz, 1H),6.44(d,J＝16.8Hz,1H),6.07(br s,1H),5.84(dd,J＝10.4,1.6Hz,1H),5.66-5.52(m,1H),5.27-4.26(m,3H),5.06(dd,J＝10.4,1.2Hz,1H),4.94(d,J＝17.5Hz,1H),4.12-3.55(m,3H),3.46(s,2H),3.36-3.01(m,1H),2.87-2.63(m,1H),2.17-2.05(m,3H),1.62-1.45(m,3H),1.29-1.21(m,3H),1.07(d,J＝5.8Hz,3H).MS:m/z 598.2722,[M+H] ⁺。 Add the product of the previous step (1.5g), dichloromethane (10ml) and trifluoroacetic acid (2ml) into a 100ml single-necked flask, after the addition, stir at room temperature for 15 minutes. After the reaction is complete, concentrate under reduced pressure to dryness, add dichloromethane (15ml), N,N-diisopropylethylamine (1.5g) to the concentrate, reduce the temperature to 0°C under nitrogen protection, and slowly add acryloyl chloride ( 190mg), and stir for 15 minutes after dropping. After the reaction is completed, dilute with water, extract with dichloromethane, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and prepare 0.55 g of yellow solid through high performance liquid phase. ¹ H NMR (400MHz, CDCl ₃ ): δ8.56 (d, J = 4.9 Hz, 1H), 8.16 (s, 1H), 7.56 (d, J = 7.7 Hz, 1H), 7.23 (td, J = 7.8 ,1.4Hz,1H),7.16(d,J=4.2Hz,1H),6.74-6.53(m,1H),6.68(t,J=7.3Hz,1H),6.59(d,J=8.4Hz, 1H ), 6.44 (d, J = 16.8 Hz, 1H), 6.07 (br s, 1H), 5.84 (dd, J = 10.4, 1.6 Hz, 1H), 5.66-5.52 (m, 1H), 5.27-4.26 (m ,3H),5.06(dd,J=10.4,1.2Hz,1H),4.94(d,J=17.5Hz,1H),4.12-3.55(m,3H),3.46(s,2H),3.36-3.01( m,1H),2.87-2.63(m,1H),2.17-2.05(m,3H),1.62-1.45(m,3H),1.29-1.21(m,3H),1.07(d,J=5.8Hz, 3H). MS: m/z 598.2722, [M+H] ⁺ .

实施例44：Example 44:

参考实施例39和实施例43，制备得到化合物B-7。Rf:0.53(DCM:MeOH＝10:1)。具体制备方法如下：With reference to Example 39 and Example 43, compound B-7 was prepared. Rf: 0.53 (DCM:MeOH=10:1). The specific preparation method is as follows:

于100ml的封管中加入起始原料，碳酸钾，N,N-二甲基甲酰胺和氘代烯丙基溴，升温搅拌。反应完毕，加入水稀释，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体。Add the starting materials, potassium carbonate, N,N-dimethylformamide and deuterated allyl bromide to a 100ml sealed tube, and stir at elevated temperature. After the reaction is complete, add water to dilute, extract with ethyl acetate, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain a yellow solid.

于50ml单口瓶中加入上步产物和二氯甲烷，滴加三氟乙酸(10ml)，滴毕，于室温搅拌。反应完毕，减压浓缩至干，向剩余物中加入二氯甲烷，降温后加入N,N-二异丙基乙胺，再缓慢滴入丙烯酰氯的二氯甲烷溶液，滴毕，搅拌30分钟。缓慢倒入饱和氯化铵水溶液淬灭，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，浓缩，硅胶柱层析纯化，得黄色固体。Add the product of the previous step and dichloromethane to a 50ml single-neck flask, add trifluoroacetic acid (10ml) dropwise, and stir at room temperature. After the reaction is completed, concentrate under reduced pressure to dryness, add dichloromethane to the residue, add N,N-diisopropylethylamine after cooling, and then slowly drop in the dichloromethane solution of acryloyl chloride, and stir for 30 minutes. . Slowly poured into saturated aqueous ammonium chloride for quenching, extracted with ethyl acetate, combined the organic layers, washed with saturated brine once, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain a yellow solid.

实施例45：Example 45:

参考实施例39和实施例43，制备得化合物B-13。Rf:0.54(DCM:MeOH＝10:1)。具体制备方法如下：With reference to Example 39 and Example 43, compound B-13 was prepared. Rf: 0.54 (DCM:MeOH=10:1). The specific preparation method is as follows:

于50ml的封管中加入起始原料，碳酸钾，N,N-二甲基甲酰胺和氘代烯丙基溴，氮气置换后，升温搅拌16小时。反应完毕，加入水稀释，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体。The starting materials, potassium carbonate, N,N-dimethylformamide and deuterated allyl bromide were added to a 50ml sealed tube. After nitrogen replacement, the temperature was increased and stirred for 16 hours. After the reaction is complete, add water to dilute, extract with ethyl acetate, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain a yellow solid.

于50ml单口瓶中加入上步产物和二氯甲烷，在0℃下，滴加三氟乙酸(10ml)，滴毕，于室温搅拌1小时。反应完毕，减压浓缩至干，向剩余物中加入二氯甲烷，降温至0℃，加入N,N-二异丙基乙胺，再缓慢滴入氘代丙烯酰氯的二氯甲烷溶液，滴毕，搅拌。缓慢倒入饱和氯化铵水溶液淬灭，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，硅胶柱层析纯化，得黄色固体。Add the product from the previous step and dichloromethane to a 50ml single-necked flask, add trifluoroacetic acid (10ml) dropwise at 0°C, and stir at room temperature for 1 hour. After the reaction is complete, concentrate to dryness under reduced pressure, add dichloromethane to the residue, cool to 0°C, add N,N-diisopropylethylamine, and then slowly drop the dichloromethane solution of deuterated acryloyl chloride, dropwise After that, stir. Slowly pour into saturated aqueous ammonium chloride for quenching, extract with ethyl acetate, combine the organic layers, wash once with saturated brine, dry with anhydrous sodium sulfate, filter, and purify by silica gel column chromatography to obtain a yellow solid.

实施例46：Example 46:

参考实施例39和实施例43，制备得化合物B-19。Rf:0.52(DCM:MeOH＝10:1)。具体制备方法如下：With reference to Example 39 and Example 43, compound B-19 was prepared. Rf: 0.52 (DCM:MeOH=10:1). The specific preparation method is as follows:

于100ml的封管中加入起始原料，碳酸钾，N,N-二甲基甲酰胺和氘代烯丙基溴，氮气置换后，升温至65℃，搅拌16小时。反应完毕，加入水稀释，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体。The starting materials, potassium carbonate, N,N-dimethylformamide and deuterated allyl bromide were added to a 100ml sealed tube. After nitrogen replacement, the temperature was raised to 65°C and stirred for 16 hours. After the reaction is complete, add water to dilute, extract with ethyl acetate, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain a yellow solid.

于50ml单口瓶中加入上步产物和二氯甲烷，在0℃下，滴加三氟乙酸(10ml)，滴毕，于室温搅拌。反应完毕，减压浓缩至干，向剩余物中加入二氯甲烷，降温至0℃，加入N,N-二异丙基乙胺，再缓慢滴入氘代丙烯酰氯的二氯甲烷溶液，滴毕，搅拌30分钟。缓慢倒入饱和氯化铵水溶液淬灭，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，硅胶柱层析纯化，得黄色固体。Add the product of the previous step and dichloromethane to a 50ml single-neck flask, add trifluoroacetic acid (10ml) dropwise at 0°C, and stir at room temperature. After the reaction is complete, concentrate to dryness under reduced pressure, add dichloromethane to the residue, cool to 0°C, add N,N-diisopropylethylamine, and then slowly drop the dichloromethane solution of deuterated acryloyl chloride, dropwise After that, stir for 30 minutes. Slowly pour into saturated aqueous ammonium chloride for quenching, extract with ethyl acetate, combine the organic layers, wash once with saturated brine, dry with anhydrous sodium sulfate, filter, and purify by silica gel column chromatography to obtain a yellow solid.

实施例47：Example 47:

参考实施例39和实施例43，制备得化合物B-25。Rf:0.53(DCM:MeOH＝10:1)。具体制备方法如下：With reference to Example 39 and Example 43, compound B-25 was prepared. Rf: 0.53 (DCM:MeOH=10:1). The specific preparation method is as follows:

于120ml的封管中加入起始原料，碳酸钾，N,N-二甲基甲酰胺和氘代烯丙基溴，氮气置换后，升温至65℃，搅拌16小时。反应完毕，加入水稀释，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体。The starting materials, potassium carbonate, N,N-dimethylformamide and deuterated allyl bromide were added to a 120ml sealed tube. After nitrogen replacement, the temperature was raised to 65°C and stirred for 16 hours. After the reaction is complete, add water to dilute, extract with ethyl acetate, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain a yellow solid.

于50ml单口瓶中加入上步产物和二氯甲烷，滴加三氟乙酸(10ml)，滴毕，于室温搅拌1小时。反应完毕，减压浓缩至干，向剩余物中加入二氯甲烷，降温至0℃，加入N,N- 二异丙基乙胺，再缓慢滴入氘代丙烯酰氯的二氯甲烷溶液，滴毕，搅拌。缓慢倒入饱和氯化铵水溶液淬灭，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，硅胶柱层析纯化，得黄色固体。Add the product from the previous step and dichloromethane to a 50ml single-necked flask, add trifluoroacetic acid (10ml) dropwise, and stir at room temperature for 1 hour. After the reaction is complete, concentrate under reduced pressure to dryness, add dichloromethane to the residue, cool to 0°C, add N,N-diisopropylethylamine, and slowly drop the dichloromethane solution of deuterated acryloyl chloride, dropwise After that, stir. Slowly pour into saturated aqueous ammonium chloride for quenching, extract with ethyl acetate, combine the organic layers, wash once with saturated brine, dry with anhydrous sodium sulfate, filter, and purify by silica gel column chromatography to obtain a yellow solid.

实施例48：Example 48:

参考实施例39和实施例43，制备得化合物B-40。Rf:0.54(DCM:MeOH＝10:1)。具体制备方法如下：With reference to Example 39 and Example 43, compound B-40 was prepared. Rf: 0.54 (DCM:MeOH=10:1). The specific preparation method is as follows:

于50ml的封管中加入起始原料，碳酸钾，N,N-二甲基甲酰胺和氘代烯丙基溴，氮气置换后，升温至65℃，搅拌。反应完毕，加入水稀释，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体。The starting materials, potassium carbonate, N,N-dimethylformamide and deuterated allyl bromide were added to a 50ml sealed tube. After nitrogen replacement, the temperature was raised to 65°C and stirred. After the reaction is complete, add water to dilute, extract with ethyl acetate, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain a yellow solid.

实施例49：Example 49:

参考实施例39和实施例43，制备得化合物B-41。Rf:0.54(DCM:MeOH＝10:1)。具体制备方法如下：With reference to Example 39 and Example 43, compound B-41 was prepared. Rf: 0.54 (DCM:MeOH=10:1). The specific preparation method is as follows:

于50ml单口瓶中加入上步产物和二氯甲烷，在0℃下，滴加三氟乙酸(10ml)，滴毕，于室温搅拌1小时。反应完毕，减压浓缩至干，向剩余物中加入二氯甲烷，降温至0℃，加入N,N-二异丙基乙胺，再缓慢滴入氘代丙烯酰氯的二氯甲烷溶液，滴毕，搅拌30分钟。缓慢倒入饱和氯化铵水溶液淬灭，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，硅胶柱层析纯化，得黄色固体。Add the product from the previous step and dichloromethane to a 50ml single-necked flask, add trifluoroacetic acid (10ml) dropwise at 0°C, and stir at room temperature for 1 hour. After the reaction is complete, concentrate under reduced pressure to dryness, add dichloromethane to the residue, reduce the temperature to 0°C, add N,N-diisopropylethylamine, and then slowly drop in the dichloromethane solution of deuterated acryloyl chloride. After that, stir for 30 minutes. Slowly pour into saturated aqueous ammonium chloride for quenching, extract with ethyl acetate, combine the organic layers, wash once with saturated brine, dry with anhydrous sodium sulfate, filter, and purify by silica gel column chromatography to obtain a yellow solid.

实施例50：Example 50:

参考实施例39和实施例43，制备得到化合物C-7。Rf:0.53(DCM:MeOH＝10:1)。具体制备方法如下：With reference to Example 39 and Example 43, compound C-7 was prepared. Rf: 0.53 (DCM:MeOH=10:1). The specific preparation method is as follows:

于50ml单口瓶中加入上步产物和二氯甲烷，在0℃下，滴加三氟乙酸(10ml)，滴毕，于室温搅拌。反应完毕，减压浓缩至干，向剩余物中加入二氯甲烷，降温至0℃，加入N,N-二异丙基乙胺，再缓慢滴入氘代丙烯酰氯的二氯甲烷溶液，滴毕，搅拌30分钟。缓慢倒入饱和氯化铵水溶液淬灭，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，硅胶柱层析纯化，得黄色固体。Add the product of the previous step and dichloromethane to a 50ml single-neck flask, add trifluoroacetic acid (10ml) dropwise at 0°C, and stir at room temperature. After the reaction is complete, concentrate under reduced pressure to dryness, add dichloromethane to the residue, cool to 0°C, add N,N-diisopropylethylamine, and slowly drop the dichloromethane solution of deuterated acryloyl chloride, dropwise After that, stir for 30 minutes. Slowly pour into saturated aqueous ammonium chloride for quenching, extract with ethyl acetate, combine the organic layers, wash once with saturated brine, dry with anhydrous sodium sulfate, filter, and purify by silica gel column chromatography to obtain a yellow solid.

实施例51：Example 51:

参考实施例39和实施例43，制备得化合物C-13。Rf:0.51(DCM:MeOH＝10:1)。具体制备方法如下：With reference to Example 39 and Example 43, compound C-13 was prepared. Rf: 0.51 (DCM: MeOH = 10:1). The specific preparation method is as follows:

于120ml的封管中加入起始原料，碳酸钾，N,N-二甲基甲酰胺和氘代烯丙基溴，氮气置换后，升温至65℃，搅拌。反应完毕，加入水稀释，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体。The starting materials, potassium carbonate, N,N-dimethylformamide and deuterated allyl bromide were added to a 120ml sealed tube. After nitrogen replacement, the temperature was raised to 65°C and stirred. After the reaction is complete, add water to dilute, extract with ethyl acetate, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain a yellow solid.

于50ml单口瓶中加入上步产物和二氯甲烷，在0℃下，滴加三氟乙酸(10ml)，滴毕，于室温搅拌1小时。反应完毕，减压浓缩至干，向剩余物中加入二氯甲烷，降温，加入N,N-二异丙基乙胺，再缓慢滴入氘代丙烯酰氯的二氯甲烷溶液，滴毕，搅拌30分钟。缓慢倒入饱和氯化铵水溶液淬灭，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，硅胶柱层析纯化，得黄色固体。Add the product from the previous step and dichloromethane to a 50ml single-necked flask, add trifluoroacetic acid (10ml) dropwise at 0°C, and stir at room temperature for 1 hour. After the reaction is complete, concentrate under reduced pressure to dryness, add dichloromethane to the residue, cool down, add N,N-diisopropylethylamine, and then slowly drop in the dichloromethane solution of deuterated acryloyl chloride, drip and stir. 30 minutes. Slowly pour into saturated aqueous ammonium chloride for quenching, extract with ethyl acetate, combine the organic layers, wash once with saturated brine, dry with anhydrous sodium sulfate, filter, and purify by silica gel column chromatography to obtain a yellow solid.

实施例52：Example 52:

参考实施例39和实施例43，制备得到化合物C-19。Rf:0.54(DCM:MeOH＝10:1)。具体制备方法如下：With reference to Example 39 and Example 43, compound C-19 was prepared. Rf: 0.54 (DCM:MeOH=10:1). The specific preparation method is as follows:

于50ml单口瓶中加入上步产物和二氯甲烷，在0℃下，滴加三氟乙酸(10ml)，滴毕，于室温搅拌1小时。反应完毕，减压浓缩至干，向剩余物中加入二氯甲烷，降温至0℃，加入N,N-二异丙基乙胺，再缓慢滴入氘代丙烯酰氯的二氯甲烷溶液，滴毕，搅拌30分钟。缓慢倒入饱和氯化铵水溶液淬灭，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，硅胶柱层析纯化，得黄色固体。Add the product from the previous step and dichloromethane to a 50ml single-necked flask, add trifluoroacetic acid (10ml) dropwise at 0°C, and stir at room temperature for 1 hour. After the reaction is complete, concentrate to dryness under reduced pressure, add dichloromethane to the residue, cool to 0°C, add N,N-diisopropylethylamine, and then slowly drop the dichloromethane solution of deuterated acryloyl chloride, dropwise After that, stir for 30 minutes. Slowly pour into saturated aqueous ammonium chloride for quenching, extract with ethyl acetate, combine the organic layers, wash once with saturated brine, dry with anhydrous sodium sulfate, filter, and purify by silica gel column chromatography to obtain a yellow solid.

实施例53：Example 53:

参考实施例39和实施例43，制备得化合物C-25。Rf:0.54(DCM:MeOH＝10:1)。具体制备方法如下：With reference to Example 39 and Example 43, compound C-25 was prepared. Rf: 0.54 (DCM:MeOH=10:1). The specific preparation method is as follows:

于50ml单口瓶中加入上步产物和二氯甲烷，在0℃下，滴加三氟乙酸(10ml)，滴毕，于室温搅拌1小时。反应完毕，减压浓缩至干，向剩余物中加入二氯甲烷，降温至0℃，加入N,N-二异丙基乙胺，再缓慢滴入氘代丙烯酰氯的二氯甲烷溶液，滴毕，搅拌30分钟。缓慢倒入饱和氯化铵水溶液淬灭，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，硅胶柱层析纯化，得黄色固体。Add the product from the previous step and dichloromethane to a 50ml single-necked flask, add trifluoroacetic acid (10ml) dropwise at 0°C, after the dropwise, stir at room temperature for 1 hour. After the reaction is complete, concentrate to dryness under reduced pressure, add dichloromethane to the residue, cool to 0°C, add N,N-diisopropylethylamine, and then slowly drop the dichloromethane solution of deuterated acryloyl chloride, dropwise After that, stir for 30 minutes. Slowly pour into saturated aqueous ammonium chloride for quenching, extract with ethyl acetate, combine the organic layers, wash once with saturated brine, dry with anhydrous sodium sulfate, filter, and purify by silica gel column chromatography to obtain a yellow solid.

实施例54：Example 54:

参考实施例39和实施例43，制备得化合物C-40。Rf:0.54(DCM:MeOH＝10:1)。具体制备方法如下：With reference to Example 39 and Example 43, compound C-40 was prepared. Rf: 0.54 (DCM:MeOH=10:1). The specific preparation method is as follows:

实施例55：Example 55:

参考实施例39和实施例43，制备得化合物C-41。Rf:0.55(DCM:MeOH＝10:1)。具体制备方法如下：With reference to Example 39 and Example 43, compound C-41 was prepared. Rf: 0.55 (DCM:MeOH=10:1). The specific preparation method is as follows:

于50ml单口瓶中加入上步产物和二氯甲烷，在0℃下，滴加三氟乙酸(10ml)，滴毕，于室温搅拌。反应完毕，减压浓缩至干，向剩余物中加入二氯甲烷，降温至0℃，加入N,N-二异丙基乙胺，再缓慢滴入氘代丙烯酰氯的二氯甲烷溶液，滴毕，搅拌30分钟。缓慢倒入饱和氯化铵水溶液淬灭，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥，过滤，硅胶柱层析纯化，得黄色固体。Add the product of the previous step and dichloromethane to a 50ml single-neck flask, add trifluoroacetic acid (10ml) dropwise at 0°C, and stir at room temperature. After the reaction is complete, concentrate to dryness under reduced pressure, add dichloromethane to the residue, cool to 0°C, add N,N-diisopropylethylamine, and then slowly drop the dichloromethane solution of deuterated acryloyl chloride, dropwise After that, stir for 30 minutes. Slowly poured into saturated aqueous ammonium chloride for quenching, extracted with ethyl acetate, combined the organic layers, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and purified by silica gel column chromatography to obtain a yellow solid.

实施例56：Example 56:

参考实施例1，制备得到化合物2-5。Rf:0.54(DCM:MeOH＝10:1)。具体制备方法如下：Referring to Example 1, compound 2-5 was prepared. Rf: 0.54 (DCM:MeOH=10:1). The specific preparation method is as follows:

第一步first step

于50ml单口瓶中加入(S)-4-(6,7-二氯-1-(2-异丙基-4-乙基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯，2-(氘代二甲氨基)苯基硼酸，醋酸钾，1,4-二氧六环，水和[1,1'-双(二苯基膦)二茂铁]二氯化钯，氮气置换后，升温至，搅拌。反应完毕，冷至室温，加水稀释，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体。Add (S)-4-(6,7-dichloro-1-(2-isopropyl-4-ethylpyridin-3-yl)-2-oxo-1,2-di Hydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester, 2-(deuterated dimethylamino)phenylboronic acid, potassium acetate, 1, 4-Dioxane, water and [1,1'-bis(diphenylphosphine)ferrocene] palladium dichloride were replaced with nitrogen, the temperature was raised to the temperature and stirred. After the reaction is complete, cool to room temperature, dilute with water, extract with ethyl acetate, combine the organic layers, wash with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain a yellow solid.

第二步Second step

于50ml单口瓶中加入上步产物和二氯甲烷，在10℃～15℃下，滴加三氟乙酸，滴毕，继续搅拌1小时。将反应液浓缩至干，向残余物加入二氯甲烷，降温至0℃，加入N,N-二异丙基乙胺，再缓慢滴入丙烯酰氯的二氯甲烷溶液，滴毕，搅拌30分钟。缓慢倒入饱和碳酸氢钠水溶液淬灭反应，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得淡黄色固体。Add the product of the previous step and dichloromethane to a 50ml single-necked flask, add trifluoroacetic acid dropwise at 10°C to 15°C, and continue stirring for 1 hour. The reaction solution was concentrated to dryness, dichloromethane was added to the residue, the temperature was reduced to 0°C, N,N-diisopropylethylamine was added, and the dichloromethane solution of acryloyl chloride was slowly dropped into the residue, and the solution was stirred for 30 minutes. . Slowly pour into saturated sodium bicarbonate aqueous solution to quench the reaction, extract with ethyl acetate, combine the organic layers, wash with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain a pale yellow solid.

实施例57：Example 57:

参考实施例1，制备得到化合物3-20。Rf:0.52(DCM:MeOH＝10:1)。具体制备方法如下：Referring to Example 1, compound 3-20 was prepared. Rf: 0.52 (DCM:MeOH=10:1). The specific preparation method is as follows:

第一步first step

第二步Second step

实施例58：Example 58:

参考实施例1，制备得到化合物2-8。Rf:0.54(DCM:MeOH＝10:1)。具体制备方法如下：With reference to Example 1, compound 2-8 was prepared. Rf: 0.54 (DCM:MeOH=10:1). The specific preparation method is as follows:

第一步first step

第二步Second step

实施例59：Example 59:

参考实施例1，制备得到化合物3-13M。Rf:0.53(DCM:MeOH＝10:1)。具体制备方法如下：Referring to Example 1, compound 3-13M was prepared. Rf: 0.53 (DCM:MeOH=10:1). The specific preparation method is as follows:

于500ml的单口瓶中加入中间体19，乙腈和N,N-二异丙基乙胺，降温至0℃，滴加三氯氧磷，滴毕，升温至80℃搅拌2小时。减压浓缩至干，甲苯共沸两次，向残余物中加入乙腈，降温至0℃，加入N,N-二异丙基乙胺，再分批加入氘代-(S)-4-N-叔丁氧羰基-2-甲基哌嗪，加毕后于室温搅拌1小时。缓慢倒入饱和碳酸氢钠水溶液淬灭反应，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体。Intermediate 19, acetonitrile and N,N-diisopropylethylamine were added to a 500ml single-necked flask, the temperature was lowered to 0°C, phosphorus oxychloride was added dropwise, and the temperature was raised to 80°C and stirred for 2 hours. Concentrate to dryness under reduced pressure, azeotrope twice with toluene, add acetonitrile to the residue, lower the temperature to 0°C, add N,N-diisopropylethylamine, and add deuterated-(S)-4-N in batches -Tert-Butoxycarbonyl-2-methylpiperazine, stir at room temperature for 1 hour after addition. Slowly pour into saturated sodium bicarbonate aqueous solution to quench the reaction, extract with ethyl acetate, combine the organic layers, wash with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain a yellow solid.

于500ml单口瓶中依次加入上一步中间体3M类似物，(2-(双(甲基-d3)氨基)苯基)硼酸，醋酸钾，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物，重水和1,4-二氧六环，氮气置换后，升温至95℃搅拌。反应完毕，加入水稀释，并用乙酸乙酯萃取4次，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体。Add the 3M analogues of the previous step intermediate, (2-(bis(methyl-d3)amino)phenyl)boronic acid, potassium acetate, [1,1'-bis(diphenylphosphine) bis Ferrocene] palladium dichloride dichloromethane complex, heavy water and 1,4-dioxane, after nitrogen replacement, the temperature was raised to 95°C and stirred. After the reaction is complete, add water to dilute, and extract 4 times with ethyl acetate, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain a yellow solid.

于100mL单口瓶中加叔丁基(S)-4-(7-(2-(双(甲基-d3)氨基)苯基)-6-氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸和二氯甲烷，在0℃下，滴加三氟乙酸，滴毕，逐渐升至10～15℃继续搅拌1小时。反应完毕，降温至0℃，缓慢加入饱和碳酸氢钠水溶液，调节pH至8～9，并用二氯甲烷萃取4次，合并有机反应液浓缩至干，得黄色油状物直接下一步反应。Add tert-butyl(S)-4-(7-(2-(bis(methyl-d3)amino)phenyl)-6-chloro-1-(2-isopropyl-4- (Methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid and dichloromethane, At 0°C, add trifluoroacetic acid dropwise, after dropping, gradually increase to 10-15°C and continue stirring for 1 hour. After the reaction was completed, the temperature was lowered to 0°C, a saturated aqueous sodium bicarbonate solution was slowly added to adjust the pH to 8-9, and the mixture was extracted 4 times with dichloromethane. The combined organic reaction solution was concentrated to dryness to obtain a yellow oil and proceed directly to the next step.

体系加入二氯甲烷(25mL)和N,N-二异丙基乙胺，氮气保护下降温至0℃，再缓慢滴入丙烯酰氯，滴毕，搅拌30分钟。反应完毕，加水稀释，并用二氯甲烷萃取3次，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，滤液浓缩，硅胶柱层析纯化得黄色固体。Add dichloromethane (25mL) and N,N-diisopropylethylamine to the system, reduce the temperature to 0°C under nitrogen protection, and then slowly add acryloyl chloride in drops, and stir for 30 minutes. After the reaction is complete, dilute with water and extract 3 times with dichloromethane, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate the filtrate, and purify by silica gel column chromatography to obtain a yellow solid.

实施例60：Example 60:

第一步first step

于500ml单口瓶中依次加入叔丁基(S)-4-(7-氯-6-氯-1-(二异丙基吡啶-3-基)-2-氧-1,2-二氢吡啶基[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸，(2-(双(甲基-d3)氨基)苯基)硼酸，醋酸钾，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物，重水和1,4-二氧六环，氮气置换后，升温搅拌。反应完毕，加入水稀释，并用乙酸乙酯萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩，硅胶柱层析纯化，得黄色固体。Add tert-butyl(S)-4-(7-chloro-6-chloro-1-(diisopropylpyridin-3-yl)-2-oxo-1,2-dihydropyridine into a 500ml single-neck bottle [2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid, (2-(bis(methyl-d3)amino)phenyl)boronic acid, potassium acetate, [1, 1'-bis(diphenylphosphine)ferrocene]dichloride palladium dichloromethane complex, heavy water and 1,4-dioxane, after nitrogen replacement, heated and stirred. After the reaction was completed, it was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by silica gel column chromatography to obtain a yellow solid.

第二步Second step

于100mL单口瓶中加入上一步原料和二氯甲烷，在0℃下，滴加三氟乙酸，滴毕，逐渐升至10～15℃继续搅拌。反应完毕，降温至0℃，缓慢加入饱和碳酸氢钠水溶液，调节pH至8～9，并用二氯甲烷萃取4次，合并有机反应液浓缩至干，得黄色油状物直接下一步反应。上一步反应产物中，加入二氯甲烷和N,N-二异丙基乙胺，氮气保护下降温，再缓慢滴入丙烯酰氯，滴毕，搅拌30分钟。反应完毕，加水稀释，并用二氯甲烷萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩，硅胶柱层析纯化得黄色固体。MS:m/z 615.3,[M+H] ⁺。 Add the raw materials of the previous step and dichloromethane to a 100 mL single-necked flask, add trifluoroacetic acid dropwise at 0°C, and then gradually increase to 10-15°C and continue stirring. After the reaction was completed, the temperature was lowered to 0°C, a saturated aqueous sodium bicarbonate solution was slowly added to adjust the pH to 8-9, and the mixture was extracted 4 times with dichloromethane. The combined organic reaction solution was concentrated to dryness to obtain a yellow oil and proceed directly to the next step. In the reaction product of the previous step, add dichloromethane and N,N-diisopropylethylamine, reduce the temperature under nitrogen protection, and then slowly drip acryloyl chloride, after the dripping is completed, and stir for 30 minutes. After the reaction is complete, dilute with water, extract with dichloromethane, combine the organic layers, wash with saturated brine, dry with anhydrous sodium sulfate, filter and concentrate, and purify by silica gel column chromatography to obtain a yellow solid. MS: m/z 615.3, [M+H] ⁺ .

实施例61：Example 61:

于50ml的单口瓶中加入(S)-4-(6,7-二氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(中间体3)，2-氨基苯硼酸频哪醇酯，醋酸钾，1,4-二氧六环，水和[1,1'-双(二苯基膦)二茂铁]二氯化钯，氮气置换后升温至搅拌反应完毕，加水稀释，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩，硅胶柱层析纯化，得红色固体。MS:m/z 604.3,[M+H] ⁺。 Add (S)-4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2- Dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (Intermediate 3), 2-aminophenylboronic acid pinacol ester, potassium acetate , 1,4-dioxane, water and [1,1'-bis(diphenylphosphine)ferrocene] palladium dichloride, replace with nitrogen and heat up until the reaction is complete, add water to dilute, and extract with ethyl acetate Combine the organic layers, wash with saturated brine, dry with anhydrous sodium sulfate, filter and concentrate, and purify by silica gel column chromatography to obtain a red solid. MS: m/z 604.3, [M+H] ⁺ .

于50ml单口瓶中依次加入上步产物，碳酸钾，N,N-二甲基甲酰胺和炔丙基溴，加毕，升温至65℃，搅拌。反应完毕，向反应液中加水稀释，乙酸乙酯萃取，合并有机相，水洗两次，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析纯化，得黄色固体。MS:m/z 642.3,[M+H] ⁺。 Add the products of the previous step, potassium carbonate, N,N-dimethylformamide and propargyl bromide to a 50ml single-necked flask in sequence. After the addition, the temperature is raised to 65°C and stirred. After the reaction, the reaction solution was diluted with water, extracted with ethyl acetate, combined the organic phases, washed twice with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain a yellow solid . MS: m/z 642.3, [M+H] ⁺ .

于25ml单口瓶中加入上步产物，二氯甲烷和三氟乙酸，加毕，室温搅拌15分钟。反应完毕，减压浓缩至干，向浓缩物中加入二氯甲烷，N,N-二异丙基乙胺，氮气保护下降温至0℃，缓慢滴加丙烯酰氯，滴毕搅拌15分钟。反应完毕，加水稀释，二氯甲烷萃取，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析制备得黄色固体。MS:m/z 596.2,[M+H] ⁺。 Add the product of the previous step, dichloromethane and trifluoroacetic acid to a 25ml single-necked flask. After the addition, stir at room temperature for 15 minutes. After the reaction is completed, the mixture is concentrated to dryness under reduced pressure, dichloromethane, N,N-diisopropylethylamine are added to the concentrate, the temperature is reduced to 0° C. under nitrogen protection, acryloyl chloride is slowly added dropwise, and the mixture is stirred for 15 minutes. After the reaction is complete, dilute with water, extract with dichloromethane, combine the organic layers, wash with saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and prepare a yellow solid by silica gel column chromatography. MS: m/z 596.2, [M+H] ⁺ .

生物测试Biological test

1.NCI-H358的细胞增殖抑制活性IC50值[3D模型测试]1. The cell proliferation inhibitory activity IC50 value of NCI-H358 [3D model test]

将100μl高浓度的琼脂糖凝胶铺板于96孔板中作为底层琼脂糖凝胶层；将低浓度的琼脂糖和含细胞的生长培养基混合后铺于底层琼脂层上，冷却凝固后37℃培养过夜；将受试化合物用DMSO配制成母液，用RPMI 1640生长培养基进行梯度稀释，向含有上层琼脂凝胶-细胞的96孔中加入梯度稀释的不同浓度的待测化合物溶液，设置溶剂对照孔，放置于二氧化碳培养箱培养；期间更换含药培养基，观察细胞生长情况；培养结束后，细胞用NBT进行染色后计数细胞集落形成数，并得出化合物抑制细胞增殖的IC ₅₀值。 Pave 100μl of high-concentration agarose gel on a 96-well plate as the bottom agarose gel layer; mix low-concentration agarose and cell-containing growth medium on the bottom agar layer, cool and solidify at 37°C Incubate overnight; prepare the test compound as a mother liquor with DMSO, use RPMI 1640 growth medium for gradient dilution, add gradient dilutions of different concentrations of the test compound solution to the 96 wells containing the upper agarose-cells, and set the solvent control The wells were placed in a carbon dioxide incubator for culture; during the period, the medicated medium was replaced to observe the cell growth; after the culture was completed, the cells were stained with NBT and the number of cell colonies formed was counted, and the IC ₅₀ value of the compound inhibiting cell proliferation was obtained.

本发明部分代表性化合物的活性如下：The activities of some representative compounds of the present invention are as follows:

其中“A”代表IC ₅₀值(nM)<50； Wherein "A" represents IC ₅₀ value (nM)<50;

“B”代表IC ₅₀值(nM)50～150(不含150)； "B" represents IC ₅₀ value (nM) 50～150 (excluding 150);

“C”代表IC ₅₀值(nM)150～300； "C" stands for IC ₅₀ value (nM) 150～300;

“D”代表IC ₅₀值(nM)>300； "D" represents IC ₅₀ value (nM)>300;

化合物1-30，化合物1-34，化合物3-2，化合物3-4，化合物5-6等化合物对KRAS G12C突变型细胞H358显示了显著的细胞抗增殖活性。Compound 1-30, Compound 1-34, Compound 3-2, Compound 3-4, Compound 5-6 and other compounds showed significant cell anti-proliferation activity on KRAS G12C mutant cell H358.

2.CellTiter-Glo试剂检测MIA-PACA2细胞增殖活力2. CellTiter-Glo reagent detects the proliferation activity of MIA-PACA2 cells

将指数生长期的MIA PaCa-2细胞用胰酶-EDTA消化，以每孔2000～3000个细胞铺板于96孔板，于37℃，5％CO ₂条件下培养过夜。将受试化合物用DMSO配制成母液，用DMEM生长培养基进行浓度梯度稀释后加入96孔板中，于37℃，5％CO ₂条件下培养箱中孵育72小时。孵育结束后，每孔加入等体积CellTiter-Glo检测试剂，振荡后孵育，用酶标仪测定化学发光值，GraphPad Prism软件拟合并计算受试物抑制MIA PaCa-2细胞增殖IC ₅₀值。 The MIA PaCa-2 cells in the exponential growth phase were digested with trypsin-EDTA, plated on a 96-well plate with 2000-3000 cells per well, and cultured overnight _{at 37°C under 5% CO 2 conditions.} The test compound was prepared into mother liquor with DMSO, diluted in concentration gradient with DMEM growth medium, and then added to a 96-well plate, and incubated in an incubator _{at 37° C. and 5% CO 2 for 72 hours.} After the incubation, each well was added an equal volume of CellTiter-Glo reagent detected after incubation with shaking, chemiluminescent value measured with a microplate reader, GraphPad Prism software calculates the value of the test substance inhibiting ₅₀ MIA PaCa-2 cell proliferation IC to be merged.

其中“A”代表IC ₅₀值(nM)<50；“B”代表IC ₅₀值(nM)50～150(不含150)；“C”代表IC ₅₀值(nM)150～300；“D”代表IC ₅₀值(nM)>300； "A" represents IC ₅₀ value (nM)<50;"B" represents IC ₅₀ value (nM) 50～150 (excluding 150); "C" represents IC ₅₀ value (nM) 150～300; "D" Represents IC ₅₀ value (nM)>300;

化合物1-30，化合物3-2，化合物3-4，化合物4-2，化合物5-1，化合物2-2N，化合物3-10N，化合物3-14N，化合物3-16N，化合物4-6N，化合物1-37a，化合物B-2a等化合物对KRAS G12C突变型细胞MIA PaCa-2显示了显著的细胞抗增殖活性。Compound 1-30, Compound 3-2, Compound 3-4, Compound 4-2, Compound 5-1, Compound 2-2N, Compound 3-10N, Compound 3-14N, Compound 3-16N, Compound 4-6N, Compound 1-37a, compound B-2a and other compounds showed significant cell anti-proliferation activity on KRAS G12C mutant cells MIA PaCa-2.

3.CellTiter-Glo试剂检测NCI-H358细胞增殖活力3. CellTiter-Glo reagent detects the proliferation activity of NCI-H358 cells

将指数生长期的NCI-H358细胞用胰酶-EDTA消化，以每孔2000～3000个细胞铺板于96孔板，于37℃，5％CO ₂条件下培养过夜。将受试化合物用DMSO配制成母液，用RPMI1640生长培养基进行梯度稀释后加入96孔板中，于37℃，5％CO ₂条件下培养箱中孵育72小时。孵育结束后，每孔加入等体积CellTiter-Glo检测试剂，振荡后孵育，用酶标仪测定化学发光值，GraphPad Prism软件拟合并计算受试物抑制NCI-H358细胞增殖IC ₅₀值。 The NCI-H358 cells in the exponential growth phase were digested with trypsin-EDTA, plated on a 96-well plate with 2000-3000 cells per well, and cultured overnight _{at 37°C under 5% CO 2 conditions.} The test compound was prepared into mother liquor with DMSO, diluted with RPMI1640 growth medium and then added to a 96-well plate, and incubated in an incubator _{at 37° C. and 5% CO 2 for 72 hours.} After the incubation, each well was added an equal volume of CellTiter-Glo reagent detected after incubation with shaking, chemiluminescent value measured with a microplate reader, GraphPad Prism software to be merged test inhibit ₅₀ calculates the value of NCI-H358 cell proliferation IC.

其中“A”代表IC ₅₀值(nM)小于或者等于50；“B”代表IC ₅₀值(nM)大于50； Wherein "A" represents the IC ₅₀ value (nM) is less than or equal to 50; "B" represents the IC ₅₀ value (nM) is greater than 50;

实验结果表明：化合物2-5，化合物2-8，化合物3-20，化合物3-13M，化合物3-10M，化合物3-12M，等化合物对KRAS G12C突变型细胞H358显示了显著的细胞抗增殖活性。The experimental results showed that: compound 2-5, compound 2-8, compound 3-20, compound 3-13M, compound 3-10M, compound 3-12M, and other compounds showed significant cell anti-proliferation on KRAS G12C mutant cell H358 active.

具有轴手性R构型化合物3-10M，对NCI-H358的细胞增殖抑制活性，显著优于其对应的轴手性S构型化合物3-10P，R构型化合物3-10M的细胞增殖抑制活性是其对应的轴手性S构型化合物3-10P的5倍以上。The compound 3-10M with axial chiral R configuration has a cell proliferation inhibitory activity against NCI-H358, which is significantly better than its corresponding axial chiral S configuration compound 3-10P, and the R configuration compound 3-10M inhibits cell proliferation. The activity is more than 5 times that of the corresponding axial chiral S configuration compound 3-10P.

具有轴手性R构型化合物3-12M，对NCI-H358的细胞增殖抑制活性，显著优于其对应的轴手性S构型化合物3-12P；The compound 3-12M with axial chiral R configuration has a cell proliferation inhibitory activity on NCI-H358, which is significantly better than its corresponding axial chiral S configuration compound 3-12P;

具有轴手性R构型化合物4-10M对NCI-H358的细胞增殖抑制活性，显著优于其对应的轴手性S构型化合物4-10P。The cell proliferation inhibitory activity of compound 4-10M with axial chirality R configuration on NCI-H358 is significantly better than its corresponding axial chiral S configuration compound 4-10P.

4.检测化合物对H358细胞增殖活力抑制试验4. Test for inhibiting the proliferation of H358 cells by the detection compound

参照生物测试试验3的方法，测试化合物对NCI-H358细胞增殖活力的抑制作用，实验结果如下：Refer to the method of biological test test 3 to test the inhibitory effect of the compound on the proliferation of NCI-H358 cells. The experimental results are as follows:

实验结果表明：化合物3-5MIS，化合物3-6MIS，化合物3-7MIS，对KRAS G12C突变型细胞H358显示了显著的细胞抗增殖活性。The experimental results showed that compound 3-5MIS, compound 3-6MIS, and compound 3-7MIS showed significant cell anti-proliferation activity on KRAS G12C mutant cell H358.

5.化合物的初步安全性实验5. Preliminary safety experiment of the compound

供试样品：化合物3-2，化合物3-4，化合物3-10M。Test samples: compound 3-2, compound 3-4, compound 3-10M.

动物种属及数量：Balb/c；每组6只(雌雄各半)；Animal species and quantity: Balb/c; 6 animals per group (half male and half male);

给药方式：口服灌胃；Administration method: oral gavage;

动物分组和给药剂量：溶媒空白组，化合物3-2组(200mg/kg，400mg/kg，800mg/kg)，化合物3-4(200mg/kg，400mg/kg，800mg/kg)，化合物3-10M(200mg/kg，400mg/kg，800mg/kg)；Animal grouping and dosage: vehicle blank group, compound 3-2 group (200mg/kg, 400mg/kg, 800mg/kg), compound 3-4 (200mg/kg, 400mg/kg, 800mg/kg), compound 3 -10M (200mg/kg, 400mg/kg, 800mg/kg);

给药频率：每天1次，给药5天。Dosing frequency: once a day for 5 days.

试验过程：Experimental procedure:

给药后进行笼旁观察急性毒性反应4小时，对出现明显异常表现的动物，进行详细临床观察。一般临床观察包括试验期间每天2次(上午和下午各观察1次)。观察死亡、发病、呼吸、分泌物、粪便以及饮食、饮水情况等，并记录给药期间小鼠体重变化。给药结束后对各组动物进行安乐死处理，所有动物均进行解剖及大体观察。After the administration, the acute toxicity reaction was observed in the cage for 4 hours, and the animals with obvious abnormal manifestations were subjected to detailed clinical observation. General clinical observation includes 2 times a day during the test period (1 observation each in the morning and afternoon). Observe death, morbidity, breathing, secretions, feces, diet, drinking water, etc., and record the weight change of mice during the administration period. After the administration, the animals in each group were euthanized, and all animals were dissected and grossly observed.

组别 Group		第1天Day 1	第2天Day 2	第3天Day 3	第4天Day 4	第5天Day 5
溶媒组Solvent group	//	//	//	//	//
化合物3-2组Compound 3-2 group	200mg/kg200mg/kg	200mg/kg200mg/kg	400mg/kg400mg/kg	400mg/kg400mg/kg	800mg/kg800mg/kg
化合物3-4组Compound 3-4 group	200mg/kg200mg/kg	200mg/kg200mg/kg	400mg/kg400mg/kg	400mg/kg400mg/kg	800mg/kg800mg/kg

化合物3-10M组Compound 3-10M group

200mg/kg200mg/kg

400mg/kg400mg/kg

800mg/kg800mg/kg

实验结果：化合物3-2，化合物3-4和化合物3-10M在给药周期内，所有剂量组动物进水进食正常，活动正常，体重正常，无明显异常表现。初步提示化合物化合物3-2，化合物3-4和化合物3-10M的最大耐受剂量大于800mg/kg。Experimental results: During the administration period of compound 3-2, compound 3-4 and compound 3-10M, the animals in all dose groups had normal water intake, normal activity, and normal weight, without obvious abnormalities. It is preliminarily suggested that the maximum tolerated dose of compound 3-2, compound 3-4 and compound 3-10M is greater than 800 mg/kg.

6.肿瘤细胞MIA PaCa-2异种移植瘤模型药效学试验6. Tumor cell MIA PaCa-2 xenograft tumor model pharmacodynamic test

模型建立和给药方案：Model establishment and dosing schedule:

动物种属及数量：Balb/c Nude，每组6只；Animal species and quantity: Balb/c Nude, 6 animals per group;

供试样品：化合物3-2，化合物3-4，化合物3-10M；Test samples: compound 3-2, compound 3-4, compound 3-10M;

试验组别：空白溶剂对照组；化合物3-2(10mg/kg，QD×15天)，化合物3-4(10mg/kg，QD×15天)；化合物3-10M(10mg/kg，QD×15天)；Test group: blank solvent control group; compound 3-2 (10mg/kg, QD×15 days), compound 3-4 (10mg/kg, QD×15 days); compound 3-10M (10mg/kg, QD× 15 days);

动物模型建立：体外培养并收集对数生长期的MIA paca-2肿瘤细胞，以5×10 ⁶个细胞/只数量皮下接种于裸鼠的右侧背部皮下，待瘤体积生长至150～300mm ³时对荷瘤裸鼠进行随机分组。随后，对每组动物进行给药，并将首次给药当天定义为试验第1天； Animal model establishment: in vitro culture and collection of MIA paca-2 tumor cells in logarithmic growth phase, ^{subcutaneously inoculate 5×10 6} cells/cell into the right back of nude mice subcutaneously, and wait until the tumor volume grows to 150～300mm ³ When the tumor-bearing nude mice were randomly grouped. Subsequently, each group of animals was administered, and the day of the first administration was defined as the first day of the experiment;

给药途径和频率：口服灌胃；每天1次；Route and frequency of administration: oral gavage; once a day;

一般状态观察：观察时间与频率：每天1次；观察指标或内容：包括但不限于动物给药局部、外观体征、一般行为活动、精神状态、死亡等情况及其它异常表现。试验结束后对动物实施安乐死。General status observation: observation time and frequency: once a day; observation indicators or content: including but not limited to animal administration, appearance signs, general behavioral activities, mental status, death, and other abnormal manifestations. After the experiment, the animals were euthanized.

肿瘤体积计算：V＝1/2×长径×短径 ²(mm ³)。用肿瘤生长抑制率TGI(％)评价化合物的抑瘤疗效。TGI(％)＝[1－(治疗组给药结束时平均瘤体积－治疗组给药开始时平均瘤体积)/(对照组给药结束时平均瘤体积－对照组给药开始时平均瘤体积)]×100％。 Tumor volume calculation: V=1/2×long diameter×short diameter ² (mm ³ ). The tumor growth inhibition rate TGI (%) was used to evaluate the anti-tumor efficacy of the compound. TGI (%) = [1-(average tumor volume at the end of the treatment group-average tumor volume at the beginning of the treatment group) / (average tumor volume at the end of the control group-average tumor volume at the beginning of the control group )]×100%.

“+”表示抑瘤率<60％；“++”表示抑瘤率60％～80％；“+++”表示抑瘤率>80％。"+" means tumor inhibition rate <60%; "++" means tumor inhibition rate 60% to 80%; "+++" means tumor inhibition rate >80%.

化合物Compound	抑瘤率(％)Tumor inhibition rate (%)
3-23-2	++++++
3-43-4	++++++
3-10M3-10M	++++++

实验结果：Experimental results:

(1)化合物3-2，化合物3-4和化合物3-10M对胰腺癌MIA-paca-2细胞裸小鼠皮下移植瘤生长具有显著抑制作用。(1) Compound 3-2, Compound 3-4 and Compound 3-10M have a significant inhibitory effect on the growth of pancreatic cancer MIA-paca-2 cells transplanted subcutaneously in nude mice.

(2)在给药试验周期中，实验动物进水进食正常，活动正常，体重正常，并没有展现出毒性。(2) During the dosing test period, the experimental animals had normal water and food intake, normal activities, and normal body weight, and showed no toxicity.

7.化合物对KRAS(G12C)酶活性的影响7. The effect of the compound on KRAS (G12C) enzyme activity

实验原理：Eu标记的GST抗体结合带GST标签的KRAS ^G12C蛋白；d2标记的6HIS抗体结合带6HIS标签的c-Raf蛋白；当KRAS ^G12C蛋白与GTP结合后被激活，与c-Raf蛋白结合，从而将Eu与d2拉近；Eu作为供体受到光源(320nm)激发后，将能量共振转移到临近的受体d2上，受体将发出665nm发射光；665nm波长信号强度与KRAS ^G12C蛋白结合c-Raf蛋白的量成正比；当添加抑制剂后，KRAS ^G12C和c-Raf的结合被抑制。以此评价化合物对KRAS ^G12C酶活性的抑制水平。 Experimental principle: Eu-labeled GST antibody binds to GST-labeled KRAS ^G12C protein; d2-labeled 6HIS antibody binds to 6HIS-labeled c-Raf protein; when KRAS ^G12C protein binds to GTP, it is activated and binds to c-Raf protein. Thereby, Eu and d2 are brought closer; Eu as a donor is excited by the light source (320nm), the energy resonance is transferred to the adjacent acceptor d2, and the acceptor will emit 665nm emission light; ^665nm wavelength signal intensity binds to the KRAS G12C protein c -The amount of Raf protein is proportional; when the inhibitor is added, ^{the binding of KRAS G12C} and c-Raf is inhibited. In this way, the inhibitory level of the ^{compound on KRAS G12C enzyme activity was evaluated.}

其中化合物AMG510按照文献(Jouranl.Medicinal.Chemistry.2020,63,52-65)方法制备得到。The compound AMG510 was prepared according to the literature (Jouranl. Medicinal. Chemistry. 2020, 63, 52-65) method.

化合物稀释：Compound dilution:

取化合物储液，将待测化合物在DMSO中梯度稀释；以上稀释好的化合物加入定量体积的酶反应缓冲液中；在微孔板振荡器上震荡20min。Take the compound stock solution, and dilute the test compound in DMSO gradiently; add the above diluted compound to a quantitative volume of enzyme reaction buffer; shake on the microplate shaker for 20 minutes.

化合物测试：Compound test:

转移4μL的酶到384反应板中，加入1μL的待测化合物到384反应板中；用封板膜封板，将化合物反应板1000rpm离心1min，孵育60min；转移5μL底物及抗体混合物到384孔反应板中，用封板膜封板后1000rpm离心1min，室温孵育120min；使用多功能酶标仪设置激发光为320nM，发射光为615nM和665nM，读615nm(Eu)和665nm(d2)的荧光信号。Transfer 4μL of enzyme to 384 reaction plate, add 1μL of test compound to 384 reaction plate; seal the plate with sealing film, centrifuge the compound reaction plate at 1000rpm for 1min, and incubate for 60min; transfer 5μL substrate and antibody mixture to 384 well In the reaction plate, seal the plate with a sealing film and centrifuge at 1000 rpm for 1 min, and incubate at room temperature for 120 min; use the multi-function microplate reader to set the excitation light to 320nM, the emission light to 615nM and 665nM, and read the fluorescence at 615nm (Eu) and 665nm (d2) Signal.

数据分析：data analysis:

Ratio阳性对照：10个阳性对照孔比值的平均值；Ratio阴性对照：10个阴性对照孔比值的平均值。Ratio positive control: the average of the ratios of 10 positive control wells; Ratio negative control: the average of the ratios of 10 negative control wells.

实验结果：Experimental results:

其中“A”代表IC ₅₀值(nM)小于或者等于10；“B”代表IC ₅₀值(nM)大于10，且小于或者等于40；“C”代表IC ₅₀值(nM)大于40； "A" represents IC ₅₀ value (nM) less than or equal to 10; "B" represents IC ₅₀ value (nM) greater than 10 and less than or equal to 40; "C" represents IC ₅₀ value (nM) greater than 40;

化合物Compound	IC ₅₀(nM) IC ₅₀ (nM)
3-10M3-10M	AA
AMG510AMG510	CC

实验结果表明，化合物3-10M的KRAS ^G12C酶抑制活性显著大于AMG510。 The experimental results show that the KRAS ^G12C enzyme inhibitory activity of compound 3-10M is significantly greater than that of AMG510.

8.化合物对肿瘤细胞MIA PaCa-2的增殖抑制检测8. Detection of the compound's proliferation inhibition of tumor cells MIA PaCa-2

抑制活性测试方法同生物测试部分试验2。The inhibitory activity test method is the same as the biological test part test 2.

供试样品：化合物1-30，化合物2-4N，化合物3-2，化合物3-4；化合物3-10M；Test samples: compound 1-30, compound 2-4N, compound 3-2, compound 3-4; compound 3-10M;

实验结果：其中“A”代表IC ₅₀值(nM)<10；“B”代表IC ₅₀值(nM)10～40(不含40)；“C”代表IC ₅₀值(nM)40～100；“D”代表IC ₅₀值(nM)>100； Experimental results: "A" represents IC ₅₀ value (nM)<10;"B" represents IC ₅₀ value (nM) 10-40 (excluding 40); "C" represents IC ₅₀ value (nM) 40-100; "D" represents IC ₅₀ value (nM)>100;

化合物Compound	IC ₅₀(nM) IC ₅₀ (nM)
1-301-30	AA
2-4N2-4N	BB

3-23-2	AA
3-43-4	AA
3-10M3-10M	AA
AMG510AMG510	CC

实验结果表明，化合物1-30，化合物2-4N，化合物3-2，化合物3-4，化合物3-10M的MIA PaCa-2的细胞抑制活性均优于AMG510。The experimental results show that the cytostatic activity of MIA PaCa-2 of compound 1-30, compound 2-4N, compound 3-2, compound 3-4, and compound 3-10M is better than that of AMG510.

9.有关治疗安全窗的分析9. Analysis of the treatment safety window

连续给药安全性试验揭示，化合物3-2，化合物3-4，化合物3-10M，五天连续给药试验中，从剂量200mg/kg逐渐递增至800mg/kg，所有剂量组动物进水进食正常，活动正常，体重正常，无明显异常表现。The safety test of continuous administration revealed that compound 3-2, compound 3-4, compound 3-10M, in a five-day continuous administration test, the dose was gradually increased from 200 mg/kg to 800 mg/kg, and animals in all dose groups received water and food. Normal, normal activity, normal weight, no obvious abnormalities.

另一方面，体内药效学试验揭示，化合物3-2，3-4，3-10M的肿瘤抑制起效剂量小于10mg/kg，这些化合物治疗安全窗宽(毒性剂量与起效剂量的比值大于80倍)，具有重大的应用潜力。On the other hand, in vivo pharmacodynamic experiments revealed that the tumor suppressive effective dose of compound 3-2, 3-4, 3-10M is less than 10 mg/kg, and these compounds have a wide therapeutic safety window (the ratio of the toxic dose to the effective dose is greater than 80 times), has great application potential.

10.化合物1-30和3-2药代动力学研究10. Studies on the pharmacokinetics of compounds 1-30 and 3-2

动物种属及数量：SD雄性大鼠，6只；Animal species and quantity: SD male rats, 6;

供试样品及配制方法：化合物1-30，化合物3-2；分别精密称取适量药物，按配制终体积10％DMSO，60％PEG400，30％H ₂O的比例依次加入，超声、涡漩混匀。分别配制成5mg/ml药物浓度。 Test sample and preparation method: compound 1-30, compound 3-2; respectively accurately weigh appropriate amounts of drugs, and add them in the _{final volume of 10% DMSO, 60% PEG400, and 30% H 2 O. Ultrasound and vortex.} Mix well. Respectively formulated to 5mg/ml drug concentration.

给药剂量和给药体积：20mg/kg，4mL/kg；Dosage and volume: 20mg/kg, 4mL/kg;

给药途径：灌胃给药；Route of administration: intragastric administration;

采血方式：眼眶静脉丛；Blood collection method: orbital venous plexus;

试验主要过程：健康成年SD大鼠6只，分成2组禁食过夜(自由饮水)后，灌胃给药，于给药后0.5h采集全血，经EDTA-K2抗凝后于离心5min分离血浆，于-80℃保存待测。The main process of the test: 6 healthy adult SD rats were divided into 2 groups, fasted overnight (free drinking water), and then administered by gavage. Whole blood was collected 0.5h after the administration, anticoagulated by EDTA-K2, and centrifuged for 5min. Plasma should be stored at -80°C for testing.

试验结果：test results:

(1)化合物1-30研究组结果(1) Results of compound 1-30 research group

化合物Compound	相对含量Relative content
1-30原型1-30 prototype	<10％<10%
1-30代谢产物TMA-11-30 Metabolite TMA-1	>30％>30%

(2)化合物3-2研究组结果(2) Compound 3-2 research group results

化合物Compound	相对含量Relative content
3-2原型3-2 prototype	>30％>30%
3-2代谢产物TMA-13-2 Metabolite TMA-1	<10％<10%

其中，TMA-1为化合物1-30脱除双甲基的代谢产物(即是：化合物3-2脱除氘代双甲基的代谢产物)。Among them, TMA-1 is the metabolite of compound 1-30 with removal of dimethyl (that is: the metabolite of compound 3-2 with removal of deuterated dimethyl).

从以上数据可以看出，化合物1-30的原型药物剩余量相对含量显著少于化合物3-2原型药物相对含量；化合物1-30脱除双甲基代谢产物(TMA-1)相对含量，大于化合物3-2的脱除脱双氘代甲基代谢产物(TMA-1)相对含量，化合物3-2的代谢稳定性优于化合物1-30。It can be seen from the above data that the relative content of the remaining prototype drug of compound 1-30 is significantly less than the relative content of the prototype drug of compound 3-2; the relative content of compound 1-30 after removing the dimethyl metabolite (TMA-1) is greater than The relative content of the deuteromethyl metabolite (TMA-1) of compound 3-2, the metabolic stability of compound 3-2 is better than that of compound 1-30.

11.肿瘤细胞NCI-H358异种移植瘤模型药效学试验11. The pharmacodynamic test of tumor cell NCI-H358 xenograft tumor model

动物种属及数量：Balb/c Nude；每组6只；Animal species and quantity: Balb/c Nude; 6 animals per group;

供试样品：化合物3-2，化合物TMA-1(参照WO2019051291中实施例3，实施例6，实施例9等相应方法制备得到)；Test sample: compound 3-2, compound TMA-1 (prepared by referring to Example 3, Example 6, Example 9 and other corresponding methods in WO2019051291);

试验组别：空白溶,组，化合物3-2(8mg/kg，QD×17天)，化合物TMA-1(8mg/kg，QD×17天)；Test group: blank solution, group, compound 3-2 (8mg/kg, QD×17 days), compound TMA-1 (8mg/kg, QD×17 days);

动物模型建立：Animal model establishment:

体外培养并收集对数生长期的NCI-H358肿瘤细胞，以5×10 ⁶个细胞/只数量皮下接种于裸鼠的右侧背部皮下，待瘤体积生长至150～300mm ³时对荷瘤裸鼠进行随机分组。随后，对每组动物进行给药，并将首次给药当天定义为试验第1天； NCI-H358 tumor cells in the logarithmic growth phase were cultured and collected in vitro, and 5×10 ⁶ cells/piece were subcutaneously inoculated into the right back of nude mice subcutaneously. When the tumor volume grew to 150-300mm ³ , the tumor-bearing tumor cells were exposed to the nude mice. Rats were randomly grouped. Subsequently, each group of animals was administered, and the day of the first administration was defined as the first day of the experiment;

一般状态观察：观察时间与频率：每天1次；观察指标或内容：包括但不限于动物给药局部、外观体征、一般行为活动、精神状态、死亡等情况及其它异常表现。试验结束后对动物实施安乐死。General state observation: observation time and frequency: once a day; observation indicators or content: including but not limited to animal administration, physical signs, general behavior, mental state, death, and other abnormal manifestations. After the experiment, the animals were euthanized.

肿瘤体积计算：V＝1/2×长径×短径 ²(mm ³)。 Tumor volume calculation: V=1/2×long diameter×short diameter ² (mm ³ ).

“+”表示抑瘤率<50％；“++”表示抑瘤率50％～100％；“+++”表示抑瘤率>100％。"+" means tumor inhibition rate <50%; "++" means tumor inhibition rate 50%-100%; "+++" means tumor inhibition rate >100%.

化合物Compound	抑瘤率(％)Tumor inhibition rate (%)
3-23-2	++++++
TMA-1TMA-1	++

实验结果：Experimental results:

化合物3-2，对肺癌NCI-H358细胞裸小鼠皮下移植瘤生长具有显著抑制作用，显著优于TMA-1，在给药试验周期中，实验动物进水进食正常，活动正常，体重正常，并没有展现出毒性。Compound 3-2 has a significant inhibitory effect on the growth of lung cancer NCI-H358 cell subcutaneously transplanted tumors in nude mice, which is significantly better than TMA-1. During the administration test period, the experimental animals have normal water and food intake, normal activities, and normal weight. It does not exhibit toxicity.

12.化合物1-30和化合物1-34的急性毒性试验12. Acute toxicity test of compound 1-30 and compound 1-34

供试样品：化合物1-30，化合物1-34。Test samples: compound 1-30, compound 1-34.

动物种属及数量：SD大鼠；每组6只(雌雄各半)；Animal species and quantity: SD rats; 6 in each group (half male and half male);

给药方式：口服灌胃；Administration method: oral gavage;

动物分组和给药剂量：溶媒空白组，化合物1-30组(500mg/kg，1000mg/kg，2000mg/kg)，化合物1-34(500mg/kg，1000mg/kg，2000mg/kg)；Animal grouping and dosage: vehicle blank group, compound 1-30 group (500mg/kg, 1000mg/kg, 2000mg/kg), compound 1-34 (500mg/kg, 1000mg/kg, 2000mg/kg);

给药频率：给药1次。Dosing frequency: 1 dose.

试验过程：Experimental procedure:

给药当天药后笼旁观察：观察频率和时间：各组动物给药后笼旁观察急性毒性反应4小时，对出现明显异常表现的动物，进行详细临床观察。观察死亡、发病、呼吸、分泌物、粪便以及饮食、饮水情况等，并记录给药期间大鼠体重变化。详细临床观察内容包括但不限于行为活动、皮肤、被毛、眼、耳、鼻、腹部、外生殖器、***、四肢、足、呼吸。观察期结束后对各组动物进行安乐死处理，所有动物均进行解剖及大体观察。Observation in the cage after the drug on the day of administration: Frequency and time of observation: Acute toxicity was observed in the cage for 4 hours after the administration of the animals in each group, and the animals with obvious abnormal manifestations were subjected to detailed clinical observation. Observe death, morbidity, respiration, secretions, feces, diet, drinking water, etc., and record the weight change of rats during the administration period. Detailed clinical observations include but are not limited to behavioral activities, skin, coat, eyes, ears, nose, abdomen, external genitalia, anus, limbs, feet, and breathing. After the end of the observation period, the animals in each group were euthanized, and all animals were dissected and grossly observed.

实验结果：化合物1-30，化合物1-34，以500、1000、2000mg/kg的剂量单次灌胃给予SD大鼠，各组动物均未见死亡或濒死，各剂量组动物大体观察未见与供试品相关的改变。在本试验条件下，化合物1-30，化合物1-34，最大耐受剂量(MTD)分别大于或者等于2000mg/kg。Experimental results: Compound 1-30 and Compound 1-34 were administered to SD rats by single gavage at doses of 500, 1000, and 2000 mg/kg. Animals in each group were not dead or dying. Animals in each dose group were not generally observed. See changes related to the test article. Under the experimental conditions, the maximum tolerated dose (MTD) of compound 1-30 and compound 1-34 were greater than or equal to 2000 mg/kg, respectively.

13.化合物1-30和化合物1-34的14天重复给药安全性试验13. 14-day repeated administration safety test of compound 1-30 and compound 1-34

给药方式：口服灌胃；Administration method: oral gavage;

动物分组和给药剂量：溶媒空白组，化合物1-30组(50mg/kg，150mg/kg，400mg/kg)，化合物1-34(50mg/kg，150mg/kg，400mg/kg)；Animal grouping and dosage: vehicle blank group, compound 1-30 group (50mg/kg, 150mg/kg, 400mg/kg), compound 1-34 (50mg/kg, 150mg/kg, 400mg/kg);

给药频率：每天1次，给药14天。Dosing frequency: once a day for 14 days.

试验过程：Experimental procedure:

给药后进行笼旁观察急性毒性反应4小时，对出现明显异常表现的动物，进行详细临床观察。一般临床观察包括试验期间每天2次(上午和下午各观察1次)。观察死亡、发病、呼吸、分泌物、粪便以及饮食、饮水情况等，并记录给药期间大鼠体重变化。详细临床观察内容包括但不限于行为活动、皮肤、被毛、眼、耳、鼻、腹部、外生殖器、***、四肢、足、呼吸。给药结束后对各组动物进行安乐死处理，所有动物均进行解剖及大体观察。After the administration, the acute toxicity reaction was observed in the cage for 4 hours, and the animals with obvious abnormal manifestations were subjected to detailed clinical observation. General clinical observation includes 2 times a day during the test period (1 observation each in the morning and afternoon). Observe death, morbidity, respiration, secretions, feces, diet, drinking water, etc., and record the weight change of rats during the administration period. Detailed clinical observations include but are not limited to behavioral activities, skin, coat, eyes, ears, nose, abdomen, external genitalia, anus, limbs, feet, and breathing. After the administration, the animals in each group were euthanized, and all animals were dissected and grossly observed.

实验结果：化合物1-30，化合物1-34，在给药周期(14天)内，所有剂量组动物进水进食正常，活动正常，体重正常，无明显异常表现。Experimental results: Compound 1-30, Compound 1-34, within the dosing cycle (14 days), animals in all dose groups had normal water intake, normal activity, and normal body weight, with no obvious abnormalities.

14.化合物1-30的胶囊制剂产品初步研究14. Preliminary research on capsule preparation products of compound 1-30

配方组成：Formula composition:

胶囊制备方法：Capsule preparation method:

将已称好的化合物1-30，淀粉，羧甲淀粉钠加入湿法混合制粒机中进行混合。称取纯化水，在搅拌状态下，缓缓加入适量淀粉，搅拌分散均匀制备得到黏合剂——淀粉浆。采用湿法混合制粒机，控制搅拌转速和剪切转速，缓缓加入淀粉浆，搅拌，剪切，制得软材。将制得的软材采用摇摆式制粒机24目筛制粒，得湿颗粒，然后鼓风干燥得干燥颗粒。将干燥颗粒采用摇摆式制粒机筛整粒，得整粒后的颗粒，称量。将整粒后的颗粒混合数次，再加入硬脂酸镁并混合，得总混颗粒。采用手工胶囊填充板，将总混颗粒充填至1号明胶空心胶囊，筛选出合格胶囊。最终得到外观整洁的胶囊样品。Add the weighed compound 1-30, starch, and sodium starch glycolate into a wet mixing granulator for mixing. Weigh the purified water, slowly add an appropriate amount of starch under stirring, stir and disperse uniformly to prepare a binder-starch slurry. The wet mixing granulator is used to control the stirring speed and the shearing speed, slowly adding the starch slurry, stirring and shearing, to obtain the soft material. The prepared soft material is granulated with a 24-mesh sieve in a swing granulator to obtain wet granules, and then air-dried to obtain dry granules. The dry granules are sieved and sieved by a swing granulator to obtain sized granules and weighed. The granulated granules are mixed several times, and then magnesium stearate is added and mixed to obtain a total mixed granule. A manual capsule filling board is used to fill the total mixed particles into No. 1 gelatin hollow capsules, and the qualified capsules are screened out. Finally, a neat-looking capsule sample was obtained.

Claims

一种式(AI)化合物，其立体异构体，互变异构体或药学上可接受的盐，A compound of formula (AI), its stereoisomer, tautomer or pharmaceutically acceptable salt,

其中，J为氮原子，或者CH；Among them, J is a nitrogen atom, or CH;

环B为芳基，杂芳基；Ring B is aryl, heteroaryl;

C为以下基团：C is the following group:

其中，“3”位碳原子与环A连接，“7”位碳原子与环B连接；Wherein, the carbon atom at position "3" is connected to ring A, and the carbon atom at position "7" is connected to ring B;

U为氮原子或者CR ^U，其中R ^U为氢或者氘； U is a nitrogen atom or CR ^U , where R ^U is hydrogen or deuterium;

M为氧原子，或者硫原子；M is an oxygen atom or a sulfur atom;

X为氮原子或者CR ¹，Y为氮原子或者CR ²，Z为氮原子或者CR ³； X is a nitrogen atom or CR ¹ , Y is a nitrogen atom or CR ² , and Z is a nitrogen atom or CR ³ ;

R ^a，R ^b各自独立地选自氢，氘，卤素； R ^a and R ^b are each independently selected from hydrogen, deuterium, and halogen;

R ¹，R ²，R ³，R ^d，R ^e各自独立地选自氢，氘，卤素，烷基，氘代烷基，卤代烷基，环烷基，氘代环烷基，羟基，氨基，砜基，磺酰胺基，碳酰胺基，烯基，或炔基； ^{^{^{R 1, R 2, R 3}}} , R d, R e are each independently selected from hydrogen, deuterium, halo, alkyl, deuterated alkyl, haloalkyl, cycloalkyl, deuterated cycloalkyl group, a hydroxyl group, an amino group, Sulfone, sulfonamido, carbonamido, alkenyl, or alkynyl;

环A为5至12元含氮杂环基，为以下结构：Ring A is a 5- to 12-membered nitrogen-containing heterocyclic group and has the following structure:

其中，R ^15a，R ^15b，R ^17a，R ^17b，R ^17c，R ^17d，R ^17e，R ^17f，R ^17g，R ^17h各自独立地选自氢，氘，卤素，烷基，氘代烷基，烯基烷基，炔基烷基，氘代烯基烷基，或氘代炔基烷基； Wherein, R ^15a , R ^15b , R ^17a , R ^17b , R ^17c , R ^17d , R ^17e , R ^17f , R ^17g , R ^17h are each independently selected from hydrogen, deuterium, halogen, alkyl, and deuterated alkyl, Alkenyl alkyl, alkynyl alkyl, deuterated alkenyl alkyl, or deuterated alkynyl alkyl;

或者R ^15a，R ^15b与其连接的氮原子共同组成含氮杂环基团； Or R ^15a , R ^15b and the nitrogen atom to which they are connected together form a nitrogen-containing heterocyclic group;

Q为-C(O)-，-C(S)-，-S(O)-，-S(O) ₂-，-C( ¹⁸O)-，； Q is -C(O)-, -C(S)-, -S(O)-, -S(O) ₂ -, -C( ¹⁸ O)-,;

L为炔基，烯基，卤代烷基。L is alkynyl, alkenyl, haloalkyl.
一种式(I)化合物，其立体异构体，互变异构体或药学上可接受的盐，A compound of formula (I), its stereoisomer, tautomer or pharmaceutically acceptable salt,

其中，环B为芳基，杂芳基；Wherein, ring B is aryl, heteroaryl;

C为以下基团：C is the following group:

其中，“3”位碳原子与环A连接，“7”位碳原子与环B连接；Wherein, the carbon atom at position "3" is connected to ring A, and the carbon atom at position "7" is connected to ring B;

U为氮原子或者CR ^U，其中R ^U为氢或者氘； U is a nitrogen atom or CR ^U , where R ^U is hydrogen or deuterium;

M为氧原子，或者硫原子；M is an oxygen atom or a sulfur atom;

X为氮原子或者CR ¹，Y为氮原子或者CR ²，Z为氮原子或者CR ³； X is a nitrogen atom or CR ¹ , Y is a nitrogen atom or CR ² , and Z is a nitrogen atom or CR ³ ;

R ^a，R ^b各自独立地选自氢，氘，卤素； R ^a and R ^b are each independently selected from hydrogen, deuterium, and halogen;

R ¹，R ²，R ³，R ^d，R ^e各自独立地选自氢，氘，卤素，烷基，氘代烷基，卤代烷基，环烷基，氘代环烷基，羟基，氨基，砜基，磺酰胺基，碳酰胺基，烯基，或炔基； ^{^{^{R 1, R 2, R 3}}} , R d, R e are each independently selected from hydrogen, deuterium, halo, alkyl, deuterated alkyl, haloalkyl, cycloalkyl, deuterated cycloalkyl group, a hydroxyl group, an amino group, Sulfone, sulfonamido, carbonamido, alkenyl, or alkynyl;

环A为5至7元含氮杂环基，为以下结构：Ring A is a 5- to 7-membered nitrogen-containing heterocyclic group and has the following structure:

其中，R ^15a，R ^15b，R ^17a，R ^17b，R ^17c，R ^17d，R ^17e，R ^17f，R ^17g，R ^17h各自独立地选自氢，氘，卤素，烷基，氘代烷基，烯基烷基，炔基烷基，氘代烯基烷基，或氘代炔基烷基，且R ^15a，R ^15b不同时为氢； Wherein, R ^15a , R ^15b , R ^17a , R ^17b , R ^17c , R ^17d , R ^17e , R ^17f , R ^17g , R ^17h are each independently selected from hydrogen, deuterium, halogen, alkyl, and deuterated alkyl, Alkenyl alkyl, alkynyl alkyl, deuterated alkenyl alkyl, or deuterated alkynyl alkyl, and R ^15a and R ^{15b are} not hydrogen at the same time;

或者R ^15a，R ^15b与其连接的氮原子共同组成含氮杂环基团； Or R ^15a , R ^15b and the nitrogen atom to which they are connected together form a nitrogen-containing heterocyclic group;

Q为-C(O)-，-C(S)-，-S(O)-，-S(O) ₂-； Q is -C(O)-, -C(S)-, -S(O)-, -S(O) ₂ -;

L为炔基，烯基，卤代烷基；L is alkynyl, alkenyl, haloalkyl;

其中，以下结构片段：Among them, the following structure fragments:

选自以下基团：
Selected from the following groups:

环A选自以下基团：Ring A is selected from the following groups:

选自以下基团：
Selected from the following groups:

选自以下基团：
Selected from the following groups:
一种式(I)化合物，其立体异构体，互变异构体或药学上可接受的盐，A compound of formula (I), its stereoisomer, tautomer or pharmaceutically acceptable salt,

其中，环B为芳基，杂芳基；Wherein, ring B is aryl, heteroaryl;

C为以下基团：C is the following group:

其中，“3”位碳原子与环A连接，“7”位碳原子与环B连接；Wherein, the carbon atom at position "3" is connected to ring A, and the carbon atom at position "7" is connected to ring B;

U为氮原子或者CR ^U，其中R ^U为氢或者氘； U is a nitrogen atom or CR ^U , where R ^U is hydrogen or deuterium;

M为氧原子，或者硫原子；M is an oxygen atom or a sulfur atom;

X为氮原子或者CR ¹，Y为氮原子或者CR ²，Z为氮原子或者CR ³； X is a nitrogen atom or CR ¹ , Y is a nitrogen atom or CR ² , and Z is a nitrogen atom or CR ³ ;

R ^a，R ^b各自独立地选自氢，氘，或卤素； R ^a and R ^b are each independently selected from hydrogen, deuterium, or halogen;

R ^d，R ^e各自独立地选自氢，氘，卤素，烷基，氘代烷基，羟基，氨基，砜基，磺酰胺基，碳酰胺基，烯基，或炔基； R ^d, R ^e are each independently selected from hydrogen, deuterium, halo, alkyl, deuterated alkyl group, a hydroxyl group, an amino group, a sulfone group, a sulfonamide group, carbonamide group, an alkenyl group, or an alkynyl group;

环A为5至7元含氮杂环基，为以下结构：Ring A is a 5- to 7-membered nitrogen-containing heterocyclic group and has the following structure:

R ^15a，R ^15b，R ^17a，R ^17b，R ^17c，R ^17d，R ^17e，R ^17f，R ^17g，R ¹⁷各自独立地选自氢，氘，卤素，烷基，或氘代烷基，且，R ^15a，R ^15b不同时为氢； R ^15a , R ^15b , R ^17a , R ^17b , R ^17c , R ^17d , R ^17e , R ^17f , R ^17g , and R ¹⁷ are each independently selected from hydrogen, deuterium, halogen, alkyl, or deuterated alkyl, and , R ^15a and R ^{15b are} not hydrogen at the same time;

Q为-C(O)-，-C(S)-，-S(O)-，-S(O) ₂-；L为炔基，烯基，卤代烷基； Q is -C(O)-, -C(S)-, -S(O)-, -S(O) ₂ -; L is alkynyl, alkenyl, haloalkyl;

以下结构片段：The following structure fragment:

选自以下基团：
Selected from the following groups:

环A选自自以下基团：Ring A is selected from the following groups:

选自以下基团：
Selected from the following groups:

选自以下基团：
Selected from the following groups:
下列化合物，其立体异构体，互变异构体或药学上可接受的盐，The following compounds, their stereoisomers, tautomers or pharmaceutically acceptable salts,
下列化合物，其立体异构体，互变异构体或药学上可接受的盐，The following compounds, their stereoisomers, tautomers or pharmaceutically acceptable salts,
下列化合物，其立体异构体，互变异构体或药学上可接受的盐，The following compounds, their stereoisomers, tautomers or pharmaceutically acceptable salts,
下列化合物，其立体异构体，互变异构体或药学上可接受的盐，The following compounds, their stereoisomers, tautomers or pharmaceutically acceptable salts,
下列化合物，其立体异构体，互变异构体或药学上可接受的盐，The following compounds, their stereoisomers, tautomers or pharmaceutically acceptable salts,
下列化合物，其立体异构体，互变异构体或药学上可接受的盐，The following compounds, their stereoisomers, tautomers or pharmaceutically acceptable salts,
下列化合物，其立体异构体，互变异构体或药学上可接受的盐，The following compounds, their stereoisomers, tautomers or pharmaceutically acceptable salts,
一种式(II)化合物，其立体异构体，互变异构体或药学上可接受的盐，A compound of formula (II), its stereoisomer, tautomer or pharmaceutically acceptable salt,

其中，X为氮原子或者CR ⁴，Y为氮原子或者CR ⁵， Where X is a nitrogen atom or CR ⁴ , and Y is a nitrogen atom or CR ⁵ ,

U为氮原子或者CR ^U，其中R ^U为氢或者氘； U is a nitrogen atom or CR ^U , where R ^U is hydrogen or deuterium;

R ¹，R ^2a，R ^2b，R ^2c，R ^2d，R ^2e，R ^2f，R ^2g，R ^3a，R ^3b，R ^3c，R ⁴，R ⁵，R ¹²，R ¹³，R ¹⁴，R ^15a，R ¹⁵各自独立地选自氢，氘，烷基，氘代烷基，卤代烷基，烯基烷基，炔基烷基，氘代烯基烷基，或氘代炔基烷基，且，R ^15a，R ^15b不同时为氢； R ¹ , R ^2a , R ^2b , R ^2c , R ^2d , R ^2e , R ^2f , R ^2g , R ^3a , R ^3b , R ^3c , R ⁴ , R ⁵ , R ¹² , R ¹³ , R ¹⁴ , R ^15a , R ¹⁵ are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkenylalkyl, alkynylalkyl, deuterated alkenylalkyl, or deuterated alkynylalkyl, and, R ^15a and R ^{15b are} not hydrogen at the same time;

或者R ^15a，R ^15b与其连接的氮原子共同组成含氮杂环基团； Or R ^15a , R ^15b and the nitrogen atom to which they are connected together form a nitrogen-containing heterocyclic group;

R ^6a，R ^6b，R ^6c，R ^6d，R ^6e，R ^6f，R ^6g，R ^6h各自独立地选自氢，氘，甲基，或三氘甲基； R ^6a , R ^6b , R ^6c , R ^6d , R ^6e , R ^6f , R ^6g , and R ^6h are each independently selected from hydrogen, deuterium, methyl, or tri-deuterium methyl;

R ⁷为氢，氟，氯； R ⁷ is hydrogen, fluorine, chlorine;

R ⁸，R ⁹，R ¹⁰，R ¹¹各自独立地选自氢，氘，或氟； R ⁸ , R ⁹ , R ¹⁰ , and R ¹¹ are each independently selected from hydrogen, deuterium, or fluorine;

结构片段
Structure fragment

选自以下结构：Selected from the following structures:

结构片段
Structure fragment

选自以下结构：Selected from the following structures:

结构片段
Structure fragment

选自以下结构：Selected from the following structures:

结构片段
Structure fragment

选自以下结构：Selected from the following structures:
一种式(II-1)化合物，其立体异构体，互变异构体或药学上可接受的盐，A compound of formula (II-1), its stereoisomer, tautomer or pharmaceutically acceptable salt,

其中，X为氮原子或者CR ⁴，Y为氮原子或者CR ⁵， Where X is a nitrogen atom or CR ⁴ , and Y is a nitrogen atom or CR ⁵ ,

U为氮原子或者CR ^U，其中R ^U为氢或者氘； U is a nitrogen atom or CR ^U , where R ^U is hydrogen or deuterium;

R ¹，R ^2a，R ^2b，R ^2c，R ^2d，R ^2e，R ^2f，R ^2g，R ^3a，R ^3b，R ^3c，R ⁴，R ⁵，R ¹²，R ¹³，R ¹⁴，R ^15a，R ^15b各自独立地选自氢，氘，烷基，或氘代烷基； R ¹ , R ^2a , R ^2b , R ^2c , R ^2d , R ^2e , R ^2f , R ^2g , R ^3a , R ^3b , R ^3c , R ⁴ , R ⁵ , R ¹² , R ¹³ , R ¹⁴ , R ^15a , R ^15b are each independently selected from hydrogen, deuterium, alkyl, or deuterated alkyl;

R ⁶为氢，氘，甲基，或三氘甲基； R ⁶ is hydrogen, deuterium, methyl, or tri-deuterium methyl;

R ⁷为氟，氯； R ⁷ is fluorine, chlorine;

R ⁸，R ⁹，R ¹⁰，R ¹¹各自独立地选自氢，氘，或氟； R ⁸ , R ⁹ , R ¹⁰ , and R ¹¹ are each independently selected from hydrogen, deuterium, or fluorine;

结构片段
Structure fragment

选自以下结构：Selected from the following structures:

结构片段
Structure fragment

选自以下结构：Selected from the following structures:

结构片段
Structure fragment

选自以下结构：Selected from the following structures:

结构片段
Structure fragment

选自以下结构：Selected from the following structures:
下列化合物，其立体异构体，互变异构体或药学上可接受的盐，The following compounds, their stereoisomers, tautomers or pharmaceutically acceptable salts,
下列化合物，其立体异构体，互变异构体，药学上可接受的盐，The following compounds, their stereoisomers, tautomers, pharmaceutically acceptable salts,
下列化合物，其立体异构体，互变异构体，药学上可接受的盐，The following compounds, their stereoisomers, tautomers, pharmaceutically acceptable salts,
一种式(III)化合物，其立体异构体，互变异构体或药学上可接受的盐，A compound of formula (III), its stereoisomer, tautomer or pharmaceutically acceptable salt,

其中，X为氮原子或者CR ⁴，Y为氮原子或者CR ⁵， Where X is a nitrogen atom or CR ⁴ , and Y is a nitrogen atom or CR ⁵ ,

R ¹，R ^2a，R ^2b，R ^2c，R ^2d，R ^2e，R ^2f，R ^2g，R ⁴，R ⁵，R ¹²，R ¹³，R ¹⁴，R ^15a，R ^15b各自独立地选自氢，氘，烷基，氘代烷基，烯基烷基，炔基烷基，氘代烯基烷基，或氘代炔基烷基，且，R ^15a，R ^15b不同时为氢； R ¹ , R ^2a , R ^2b , R ^2c , R ^2d , R ^2e , R ^2f , R ^2g , R ⁴ , R ⁵ , R ¹² , R ¹³ , R ¹⁴ , R ^15a and R ^15b are each independently selected from hydrogen , Deuterium, alkyl, deuterated alkyl, alkenyl alkyl, alkynyl alkyl, deuterated alkenyl alkyl, or deuterated alkynyl alkyl, and R ^15a and R ^{15b are} not hydrogen at the same time;

或者R ^15a，R ^15b与其连接的氮原子共同组成含氮杂环基团； Or R ^15a , R ^15b and the nitrogen atom to which they are connected together form a nitrogen-containing heterocyclic group;

R ^6a，R ^6b，R ^6c，R ^6d，R ^6e，R ^6f，R ^6g，R ^6h各自独立地选自氢，氘，甲基，或三氘甲基； R ^6a , R ^6b , R ^6c , R ^6d , R ^6e , R ^6f , R ^6g , and R ^6h are each independently selected from hydrogen, deuterium, methyl, or tri-deuterium methyl;

R ⁷为氟，氯； R ⁷ is fluorine, chlorine;

R ⁸，R ⁹，R ¹⁰，R ¹¹各自独立地选自氢，氘，或氟； R ⁸ , R ⁹ , R ¹⁰ , and R ¹¹ are each independently selected from hydrogen, deuterium, or fluorine;

结构片段
Structure fragment

选自以下结构：Selected from the following structures:

结构片段
Structure fragment

选自以下结构：Selected from the following structures:

结构片段
Structure fragment

选自以下结构：Selected from the following structures:
一种式(III-1)化合物，其立体异构体，互变异构体或药学上可接受的盐，A compound of formula (III-1), its stereoisomer, tautomer or pharmaceutically acceptable salt,

其中，X为氮原子或者CR ⁴，Y为氮原子或者CR ⁵， Where X is a nitrogen atom or CR ⁴ , and Y is a nitrogen atom or CR ⁵ ,

R ¹，R ^2a，R ^2b，R ^2c，R ^2d，R ^2e，R ^2f，R ^2g，R ⁴，R ⁵，R ¹²，R ¹³，R ¹⁴，R ^15a，R ^15b各自独立地选自氢，氘，烷基，或氘代烷基； R ¹ , R ^2a , R ^2b , R ^2c , R ^2d , R ^2e , R ^2f , R ^2g , R ⁴ , R ⁵ , R ¹² , R ¹³ , R ¹⁴ , R ^15a and R ^15b are each independently selected from hydrogen , Deuterium, alkyl, or deuterated alkyl;

R ⁶为氢，氘，甲基，三氘甲基； R ⁶ is hydrogen, deuterium, methyl, tri-deuterium methyl;

R ⁷为氟，氯； R ⁷ is fluorine, chlorine;

R ⁸，R ⁹，R ¹⁰，R ¹¹各自独立地选自氢，氘，或氟； R ⁸ , R ⁹ , R ¹⁰ , and R ¹¹ are each independently selected from hydrogen, deuterium, or fluorine;

结构片段
Structure fragment

选自以下结构：Selected from the following structures:

结构片段
Structure fragment

选自以下结构：Selected from the following structures:

结构片段
Structure fragment

选自以下结构：Selected from the following structures:

结构片段
Structure fragment

选自以下结构：Selected from the following structures:
下列化合物，其立体异构体，互变异构体或药学上可接受的盐，The following compounds, their stereoisomers, tautomers or pharmaceutically acceptable salts,
下列化合物，其立体异构体，互变异构体或药学上可接受的盐，The following compounds, their stereoisomers, tautomers or pharmaceutically acceptable salts,
下列化合物，其立体异构体，互变异构体或药学上可接受的盐，The following compounds, their stereoisomers, tautomers or pharmaceutically acceptable salts,
一种式(IV)化合物，其立体异构体，互变异构体或药学上可接受的盐，A compound of formula (IV), its stereoisomer, tautomer or pharmaceutically acceptable salt,

其中，X为氮原子或者CR ⁴，Y为氮原子或者CR ⁵， Where X is a nitrogen atom or CR ⁴ , and Y is a nitrogen atom or CR ⁵ ,

R ¹，R ^2a，R ^2b，R ^2c，R ^2d，R ^2e，R ^2f，R ^2g，R ⁴，R ⁵，R ¹²，R ¹³，R ¹⁴，R ^15a，R ^15b各自独立地选自氢，氘，烷基，氘代烷基，烯基烷基，炔基烷基，氘代烯基烷基，或氘代炔基烷基，且，R ^15a，R ^15b不同时为氢； R ¹ , R ^2a , R ^2b , R ^2c , R ^2d , R ^2e , R ^2f , R ^2g , R ⁴ , R ⁵ , R ¹² , R ¹³ , R ¹⁴ , R ^15a and R ^15b are each independently selected from hydrogen , Deuterium, alkyl, deuterated alkyl, alkenyl alkyl, alkynyl alkyl, deuterated alkenyl alkyl, or deuterated alkynyl alkyl, and R ^15a and R ^{15b are} not hydrogen at the same time;

或者R ^15a，R ^15b与其连接的氮原子共同组成含氮杂环基团； Or R ^15a , R ^15b and the nitrogen atom to which they are connected together form a nitrogen-containing heterocyclic group;

R ^6a，R ^6b，R ^6c，R ^6d，R ^6e，R ^6f，R ^6g，R ^6h各自独立地选自氢，氘，甲基，或三氘甲基； R ^6a , R ^6b , R ^6c , R ^6d , R ^6e , R ^6f , R ^6g , and R ^6h are each independently selected from hydrogen, deuterium, methyl, or tri-deuterium methyl;

R ⁷为氟，氯； R ⁷ is fluorine, chlorine;

R ⁸，R ⁹，R ¹⁰，R ¹¹各自独立地选自氢，氘，或氟； R ⁸ , R ⁹ , R ¹⁰ , and R ¹¹ are each independently selected from hydrogen, deuterium, or fluorine;

结构片段
Structure fragment

选自以下结构：Selected from the following structures:

结构片段
Structure fragment

选自以下结构：Selected from the following structures:

结构片段
Structure fragment

选自以下结构：Selected from the following structures:
一种式(IV-1)化合物，其立体异构体，互变异构体或药学上可接受的盐，A compound of formula (IV-1), its stereoisomer, tautomer or pharmaceutically acceptable salt,

其中，X为氮原子或者CR ⁴，Y为氮原子或者CR ⁵， Where X is a nitrogen atom or CR ⁴ , and Y is a nitrogen atom or CR ⁵ ,

R ¹，R ^2a，R ^2b，R ^2c，R ^2d，R ^2e，R ^2f，R ^2g，R ⁴，R ⁵，R ¹²，R ¹³，R ¹⁴，R ^15a，R ^15b各自独立地选自氢，氘，烷基，或氘代烷基； R ¹ , R ^2a , R ^2b , R ^2c , R ^2d , R ^2e , R ^2f , R ^2g , R ⁴ , R ⁵ , R ¹² , R ¹³ , R ¹⁴ , R ^15a and R ^15b are each independently selected from hydrogen , Deuterium, alkyl, or deuterated alkyl;

R ⁶为氢，氘，甲基，或三氘甲基； R ⁶ is hydrogen, deuterium, methyl, or tri-deuterium methyl;

R ⁷为氟，氯； R ⁷ is fluorine, chlorine;

R ⁸，R ⁹，R ¹⁰，R ¹¹各自独立地选自氢，氘，或氟； R ⁸ , R ⁹ , R ¹⁰ , and R ¹¹ are each independently selected from hydrogen, deuterium, or fluorine;

结构片段
Structure fragment

选自以下结构：Selected from the following structures:

结构片段
Structure fragment

选自以下结构：Selected from the following structures:

结构片段
Structure fragment

选自以下结构：Selected from the following structures:

结构片段
Structure fragment

选自以下结构：Selected from the following structures:
下列化合物，其立体异构体，互变异构体或药学上可接受的盐，The following compounds, their stereoisomers, tautomers or pharmaceutically acceptable salts,
下列化合物，其立体异构体，互变异构体或药学上可接受的盐，The following compounds, their stereoisomers, tautomers or pharmaceutically acceptable salts,
下列化合物，其立体异构体，互变异构体或药学上可接受的盐，The following compounds, their stereoisomers, tautomers or pharmaceutically acceptable salts,
一种式(V)化合物，其立体异构体，互变异构体或药学上可接受的盐，A compound of formula (V), its stereoisomer, tautomer or pharmaceutically acceptable salt,

其中，X为氮原子或者CR ⁴，Y为氮原子或者CR ⁵， Where X is a nitrogen atom or CR ⁴ , and Y is a nitrogen atom or CR ⁵ ,

R ¹，R ^2a，R ^2b，R ^2c，R ^2d，R ^2e，R ^2f，R ^2g，R ⁴，R ⁵，R ¹²，R ¹³，R ¹⁴，R ^15a，R ^15b，R ^15c各自独立地选自氢，氘，烷基，氘代烷基，烯基烷基，炔基烷基，氘代烯基烷基，氘代炔基烷基，且，R ^15a，R ^15b不同时为氢； R ¹ , R ^2a , R ^2b , R ^2c , R ^2d , R ^2e , R ^2f , R ^2g , R ⁴ , R ⁵ , R ¹² , R ¹³ , R ¹⁴ , R ^15a , R ^15b , R ^15c are each independently Selected from hydrogen, deuterium, alkyl, deuterated alkyl, alkenyl alkyl, alkynyl alkyl, deuterated alkenyl alkyl, deuterated alkynyl alkyl, and R ^15a and R ^{15b are} not hydrogen at the same time;

或者R ^15a，R ^15b与其连接的氮原子共同组成含氮杂环基团； Or R ^15a , R ^15b and the nitrogen atom to which they are connected together form a nitrogen-containing heterocyclic group;

R ^6a，R ^6b，R ^6c，R ^6d，R ^6e，R ^6f，R ^6g，R ^6h各自独立地选自氢，氘，甲基，或三氘甲基； R ^6a , R ^6b , R ^6c , R ^6d , R ^6e , R ^6f , R ^6g , and R ^6h are each independently selected from hydrogen, deuterium, methyl, or tri-deuterium methyl;

R ⁷为氟，氯； R ⁷ is fluorine, chlorine;

R ⁸，R ⁹，R ¹⁰，R ¹各自独立地选自氢，氘，或氟； R ⁸ , R ⁹ , R ¹⁰ , and R ¹ are each independently selected from hydrogen, deuterium, or fluorine;

结构片段
Structure fragment

选自以下结构：Selected from the following structures:

结构片段
Structure fragment

选自以下结构：Selected from the following structures:

结构片段
Structure fragment

选自以下结构：Selected from the following structures:
一种式(V-1)化合物，其立体异构体，互变异构体或药学上可接受的盐，A compound of formula (V-1), its stereoisomer, tautomer or pharmaceutically acceptable salt,

其中，X为氮原子或者CR ⁴，Y为氮原子或者CR ⁵， Where X is a nitrogen atom or CR ⁴ , and Y is a nitrogen atom or CR ⁵ ,

R ¹，R ^2a，R ^2b，R ^2c，R ^2d，R ^2e，R ^2f，R ^2g，R ⁴，R ⁵，R ¹²，R ¹³，R ¹⁴，R ^15a，R ^15b，R ^15c各自独立地选自氢，氘，烷基，或氘代烷基； R ¹ , R ^2a , R ^2b , R ^2c , R ^2d , R ^2e , R ^2f , R ^2g , R ⁴ , R ⁵ , R ¹² , R ¹³ , R ¹⁴ , R ^15a , R ^15b , R ^15c are each independently Selected from hydrogen, deuterium, alkyl, or deuterated alkyl;

R ⁶为氢，氘，甲基，或三氘甲基； R ⁶ is hydrogen, deuterium, methyl, or tri-deuterium methyl;

R ⁷为氟，氯； R ⁷ is fluorine, chlorine;

R ⁸，R ⁹，R ¹⁰，R ¹¹各自独立地选自氢，氘，或氟； R ⁸ , R ⁹ , R ¹⁰ , and R ¹¹ are each independently selected from hydrogen, deuterium, or fluorine;

结构片段
Structure fragment

选自以下结构：Selected from the following structures:

结构片段
Structure fragment

选自以下结构：Selected from the following structures:

结构片段
Structure fragment

选自以下结构：Selected from the following structures:

结构片段
Structure fragment

选自以下结构：Selected from the following structures:
下列化合物，其立体异构体，互变异构体或药学上可接受的盐，The following compounds, their stereoisomers, tautomers or pharmaceutically acceptable salts,
下列化合物，其立体异构体，互变异构体或药学上可接受的盐，The following compounds, their stereoisomers, tautomers or pharmaceutically acceptable salts,
一种式(VI)化合物，其立体异构体，互变异构体或药学上可接受的盐，A compound of formula (VI), its stereoisomer, tautomer or pharmaceutically acceptable salt,

其中，环E的1位氮原子与环F的1′位的碳原子连接构成的轴手性立体构型为光学纯；Among them, the axial chiral configuration formed by connecting the nitrogen atom at position 1 of ring E and the carbon atom at position 1′ of ring F is optically pure;

X为氮原子或者CR ⁴，Y为氮原子或者CR ⁵， X is a nitrogen atom or CR ⁴ , Y is a nitrogen atom or CR ⁵ ,

R ¹，R ^2a，R ^2b，R ^2c，R ^2d，R ^2e，R ^2f，R ^2g，R ⁴，R ⁵，R ¹²，R ¹³，R ¹⁴，R ^15a，R ^15b各自独立地选自氢，氘，烷基，氘代烷基，烯基烷基，炔基烷基，氘代烯基烷基，或氘代炔基烷基，且R ^15a，R ^15b不同时为氢； R ¹ , R ^2a , R ^2b , R ^2c , R ^2d , R ^2e , R ^2f , R ^2g , R ⁴ , R ⁵ , R ¹² , R ¹³ , R ¹⁴ , R ^15a and R ^15b are each independently selected from hydrogen , Deuterium, alkyl, deuterated alkyl, alkenyl alkyl, alkynyl alkyl, deuterated alkenyl alkyl, or deuterated alkynyl alkyl, and R ^15a and R ^{15b are} not hydrogen at the same time;

或者R ^15a，R ^15b与其连接的氮原子共同组成含氮杂环基团； Or R ^15a , R ^15b and the nitrogen atom to which they are connected together form a nitrogen-containing heterocyclic group;

R ^6a，R ^6b，R ^6c，R ^6d，R ^6e，R ^6f，R ^6g，R ^6h各自独立地选自氢，氘，甲基，或三氘代甲基； R ^6a , R ^6b , R ^6c , R ^6d , R ^6e , R ^6f , R ^6g , and R ^6h are each independently selected from hydrogen, deuterium, methyl, or tri-deuterated methyl;

R ⁷为氢，氟，氯； R ⁷ is hydrogen, fluorine, chlorine;

R ⁸，R ⁹，R ¹⁰，R ¹¹各自独立地选自氢，氘，氟； R ⁸ , R ⁹ , R ¹⁰ , and R ¹¹ are each independently selected from hydrogen, deuterium, and fluorine;

R ¹⁷为氢，烷基，氘代烷基，甲基，乙基，丙基，环丙基，氘代甲基，氘代乙基，氘代丙基，或氘代环丙基。 R ¹⁷ is hydrogen, alkyl, deuterated alkyl, methyl, ethyl, propyl, cyclopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, or deuterated cyclopropyl.
一种式(IIIM)化合物，其轴手性立体构型为R构型，其互变异构体或药学上可接受的盐，A compound of formula (IIIM) whose axial chiral configuration is R configuration, its tautomers or pharmaceutically acceptable salts,

其中，R ¹，R ^2a，R ^2b，R ^2c，R ^2d，R ^2e，R ^2f，R ^2g，R ¹²，R ¹³，R ¹⁴，R ^15a，R ^15b各自独立地选自氢，氘，烷基，氘代烷基，烯基烷基，炔基烷基，氘代烯基烷基，或氘代炔基烷基，且R ^15a，R ^15b不同时为氢； Wherein, R ¹ , R ^2a , R ^2b , R ^2c , R ^2d , R ^2e , R ^2f , R ^2g , R ¹² , R ¹³ , R ¹⁴ , R ^15a , R ^15b are each independently selected from hydrogen, deuterium, and alkane R ^15a and R ^{15b are} not hydrogen at the same time;

或者R ^15a，R ^15b与其连接的氮原子共同组成含氮杂环基团； Or R ^15a , R ^15b and the nitrogen atom to which they are connected together form a nitrogen-containing heterocyclic group;

R ^6a，R ^6b，R ^6c，R ^6d，R ^6e，R ^6f，R ^6g，R ^6h各自独立地选自氢，氘，甲基，或三氘代甲基； R ^6a , R ^6b , R ^6c , R ^6d , R ^6e , R ^6f , R ^6g , and R ^6h are each independently selected from hydrogen, deuterium, methyl, or tri-deuterated methyl;

R ⁷为氢，氟，氯； R ⁷ is hydrogen, fluorine, chlorine;

R ⁸，R ⁹，R ¹⁰，R ¹¹各自独立地选自氢，氘，或氟； R ⁸ , R ⁹ , R ¹⁰ , and R ¹¹ are each independently selected from hydrogen, deuterium, or fluorine;

R ¹⁷为氢，氘，甲基，乙基，氘代甲基，氘代乙基； R ¹⁷ is hydrogen, deuterium, methyl, ethyl, deuterated methyl, deuterated ethyl;

结构片段
Structure fragment

选自以下结构：Selected from the following structures:

其中，结构片段
Among them, the structure fragment

选自以下结构：Selected from the following structures:

其中，结构片段
Among them, the structure fragment

选自以下结构：Selected from the following structures:
下列化合物，其立体异构体，互变异构体或药学上可接受的盐，The following compounds, their stereoisomers, tautomers or pharmaceutically acceptable salts,
下列化合物，其立体异构体，互变异构体或药学上可接受的盐，The following compounds, their stereoisomers, tautomers or pharmaceutically acceptable salts,
下列化合物，其轴手性立体构型为R构型，互变异构体，药学上可接受的盐，The following compounds, whose axial chiral configuration is R configuration, tautomers, pharmaceutically acceptable salts,
下列化合物，其立体异构体，互变异构体，药学上可接受的盐，The following compounds, their stereoisomers, tautomers, pharmaceutically acceptable salts,
一种药物组合物，其包括治疗有效剂量的权利要求1至35中任一项所述化合物或其立体异构体，互变异构体或药学上可接受的盐及可药用的载体。A pharmaceutical composition comprising a therapeutically effective dose of the compound according to any one of claims 1 to 35 or its stereoisomer, tautomer or pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.
根据权利要求1至35中任意一项所述的化合物或其可药用的盐或根据权利要求36所述的药物组合物，在制备用于预防和/或治疗与KRAS突变介导的癌症有关的疾病的药物中的用途，该用途包括可单独使用权利要求1至35中任意一项所述的化合物或其可药用的盐或根据权利要求36所述的药物组合物，或者与包括免疫疗法在内的其他治疗方法联合使用，预防和/或治疗与KRAS突变介导的癌症疾病。The compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 36, in preparation for the prevention and/or treatment of cancers mediated by KRAS mutations The use of the compound or the pharmaceutically acceptable salt of any one of claims 1 to 35 or the pharmaceutical composition according to claim 36, or the use of the compound described in any one of claims 1 to 35 or the pharmaceutical composition according to claim 36 Therapies, including other treatment methods, are used in combination to prevent and/or treat cancer diseases mediated by KRAS mutations.
根据权利要求1至35中任意一项所述的化合物或其可药用的盐或根据权利要求36所述的药物组合物，在制备用于预防和/或治疗与KRAS G12C突变介导的癌症有关的疾病的药物中的用途，该用途包括可单独使用权利要求1至35中任意一项所述的化合物或其可药用的盐或根据权利要求36所述的药物组合物，或者与包括免疫疗法在内的其他治疗方法联合使用，预防和/或治疗与KRAS G12C突变介导的癌症疾病。The compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 36, in preparation for the prevention and/or treatment of cancer mediated by KRAS G12C mutation The use in medicine for related diseases, which includes the use of the compound described in any one of claims 1 to 35 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 36 alone, or in combination with Other treatment methods, including immunotherapy, are used in combination to prevent and/or treat cancer diseases mediated by KRAS G12C mutations.
根据权利要求37和权利要求38中的用途，其中所述与KRAS功能有关的各种癌症疾病为肝癌，食管癌，胃癌，肾细胞癌，肉瘤，胆管癌，结肠癌，***癌，卵巢癌，乳腺癌，血液学癌症，胰腺癌，MYH相关息肉癌，结直肠癌，肺癌，子宫癌，间皮瘤，***，膀胱癌。The use according to claim 37 and claim 38, wherein the various cancer diseases related to KRAS function are liver cancer, esophageal cancer, gastric cancer, renal cell carcinoma, sarcoma, cholangiocarcinoma, colon cancer, prostate cancer, ovarian cancer, Breast cancer, hematological cancer, pancreatic cancer, MYH-related polyp cancer, colorectal cancer, lung cancer, uterine cancer, mesothelioma, cervical cancer, bladder cancer.