WO2024032600A1

WO2024032600A1 - Heterocyclic derivative, and composition thereof and pharmaceutical use thereof

Info

Publication number: WO2024032600A1
Application number: PCT/CN2023/111710
Authority: WO
Inventors: 张晨; 王健民; 黄正刚; 唐平明; 黄安邦; 余彦; 李瑶; 严庞科
Original assignee: 西藏海思科制药有限公司
Priority date: 2022-08-08
Filing date: 2023-08-08
Publication date: 2024-02-15

Abstract

Disclosed are a compound represented by general formula (I) or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic crystal thereof, an intermediate thereof, and a use thereof in EGFR-related diseases such as cancer.

Description

Heterocyclic derivative, composition and pharmaceutical application thereof

Technical field

The present invention relates to a compound of general formula (I) or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, intermediates and preparation methods thereof, and Use in EGFR related diseases such as cancer diseases.

Background technique

Epidermal growth factor receptor (EGFR) is a transmembrane protein tyrosine kinase that acts as a receptor for EGF family members to trigger the EGFR signaling pathway in human epithelial cells, thereby regulating cell proliferation, invasion, metastasis, apoptosis, and angiogenesis. (Nat. Rev. Cancer, 2007, 7, 169-181; Expert Opin. Ther. Targets, 2012, 16, 15-31.). Overexpression, mutation or amplification of the EGFR gene in the human body leads to an abnormal increase in EGFR activity, which can lead to many malignant tumors such as esophageal cancer, glioblastoma, anal cancer, head and neck epithelial cancer, breast cancer, lung cancer, especially non-small cell lung cancer. Generation of NSCLC (Cells, 2019, 8, 350-361.).

PROTAC (proteolysis targeting chimera) molecules are a type of bifunctional compounds that can simultaneously bind targeting proteins and E3 ubiquitin ligases. Such compounds can be recognized by the proteasome of cells, causing the degradation of targeted proteins, and can effectively reduce the target protein. The protein content in cells. By introducing ligands that can bind to different target proteins into PROTAC molecules, it is possible to apply PROTAC technology to the treatment of various diseases. This technology has also received widespread attention in recent years (ACS Chem. Biol. 2017, 12, 892-898; Drug Discovery Today Technol.2019,31,15-27.).

The development of new PROTAC drugs that combine EGFR protein and E3 ubiquitin ligase for the treatment of diseases related to EGFR protein will be full of application prospects.

Contents of the invention

The purpose of the present invention is to provide a compound with a novel structure, good efficacy, high bioavailability, safety, and the ability to inhibit and degrade EGFR for the treatment of EGFR-related diseases such as cancer.

The present invention provides a compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from the group consisting of compounds represented by general formula (I),

In some embodiments, Selected from

In some embodiments, Z is selected from -C(=O)- or -CH ₂ -;

In some embodiments, Z is selected from -C(=O)-;

In some embodiments, R ^b1 is each independently selected from halogen, OH, CN, C _1-4 alkyl, C _2-4 alkynyl, C _1-4 alkoxy, C _3-6 cycloalkyl, 3 To a 6-membered heterocycloalkyl group, the alkyl group, alkynyl group, alkoxy group, cycloalkyl group, and heterocycloalkyl group are optionally substituted by 1 to 4 selected from halogen, OH, =O, NH ₂ , CN, Substituted with COOH, C _1-4 alkyl, C _1-4 alkoxy or C _3-6 cycloalkyl substituents, the heterocycloalkyl group contains 1 to 3 hetero groups selected from O, S, N atom;

In some embodiments, R ^b1 is each independently selected from F, Cl, Br, I, OH, CN, methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl Or cyclohexyl, the methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl is optionally selected from 1 to 4 halogen, OH, =O Substituted with substituents of , NH ₂ , CN, COOH, C _1-4 alkyl, C _1-4 alkoxy or C _3-6 cycloalkyl;

In some embodiments, R ^b1 is each independently selected from F, Cl, Br, I, OH, CN, methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl Or cyclohexyl, the methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl is optionally selected from 1 to 4 F, Cl, Br, Substituted by I, OH, CN, methyl, and ethyl substituents;

In some embodiments, each R ^b1 is independently selected from F, Cl, Br, I, CF ₃ , cyclopropyl, cyclobutyl,

In some embodiments, R ^b2 is selected from halogen, C _1-4 alkyl, C _1-4 alkoxy, and the alkyl or alkoxy is optionally substituted by 1 to 4 selected from halogen, CN, OH , C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl substituents;

In some embodiments, R ^b2 is selected from H, F, Cl, Br, I, methyl, ethyl, and the methyl or ethyl group is optionally substituted by 1 to 4 selected from halogen, CN, OH, C Substituted with substituents of _1-4 alkyl, C _1-4 alkoxy, and C _3-6 cycloalkyl;

In some embodiments, R ^b2 is selected from H, F, Cl, Br, I, methyl, and ethyl, and the methyl or ethyl group is optionally replaced by 1 to 4 selected from F, Cl, Br, I , CN, OH, methyl or ethyl substituent;

In some embodiments, R ^b2 is selected from F, Cl, Br, I, CF ₃ , CHF ₂ , CH ₂ F, methyl, ethyl;

In some embodiments, R ^b3 is selected from H, halogen, C _1-4 alkyl, C _1-4 alkoxy, and the alkyl or alkoxy is optionally replaced by 1 to 4 selected from halogen, CN , OH, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl substituents;

In some embodiments, R ^b3 is selected from H, F, Cl, Br, I, methyl, ethyl, methoxy or ethoxy, said methyl, ethyl, methoxy or ethoxy Optionally substituted by 1 to 4 substituents selected from halogen, CN, OH, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl;

In some embodiments, R ^b3 is selected from H, F, Cl, Br, I, methyl, ethyl, methoxy or ethoxy, said methyl, ethyl, methoxy or ethoxy Optionally substituted by 1 to 4 substituents selected from F, Cl, Br, I, CN, OH, methyl or ethyl;

In some embodiments, R ^b3 is selected from methoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy;

In some embodiments, R ^b4 is selected from H, halogen, CN, OH, C _1-4 alkyl, C _1-4 alkoxy, or 5- to 6-membered heteroaryl, The alkyl group, alkoxy group or heteroaryl group is optionally substituted by 1 to 4 C 1-4 alkyl groups selected from halogen, CN, OH, C _1-4 alkyl, halogen substituted C _1-4 alkyl, C _1-4 alkyl Substituted with oxygen group and C _3-6 cycloalkyl substituent, the heteroaryl group contains 1 to 3 heteroatoms selected from O, S, and N;

In some embodiments, R ^b4 is selected from pyrazolyl, imidazolyl, pyrrolyl, and triazolyl, and the pyrazolyl, imidazolyl, pyrrolyl, and triazolyl are optionally selected from 1 to 4 Substituted from halogen, CN, OH, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl substituents;

In some embodiments, R ^b4 is selected from pyrazolyl, imidazolyl, pyrrolyl, and triazolyl, and the pyrazolyl, imidazolyl, pyrrolyl, and triazolyl are optionally selected from 1 to 4 Substituted from substituents of F, Cl, Br, I, CN, OH, CH ₂ F, CHF ₂ , CF ₃ , methyl, and ethyl;

In some embodiments, R ^b4 is selected from

In some embodiments, R ^b5 is each independently selected from H, halogen, CN, OH, C _1-4 alkyl, C _1-4 alkoxy, and the alkyl and alkoxy are optionally replaced by 1 to Substituted by 4 substituents selected from halogen, CN, OH, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl;

In some embodiments, R ^b5 is each independently selected from H, F, Cl, Br, I, OH, methyl, ethyl, methoxy or ethoxy, and the methyl, ethyl, methoxy The base or ethoxy group is optionally substituted by 1 to 4 substituents selected from halogen, CN, OH, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl;

In some embodiments, R ^b5 is each independently selected from H, F, Cl, Br, I, OH, methyl, ethyl, methoxy or ethoxy, and the methyl, ethyl, methoxy The base or ethoxy group is optionally substituted by 1 to 4 substituents selected from F, Cl, Br, I, CN, OH, methyl, and ethyl;

In some embodiments, R ^a and R ^b are each independently selected from H, halogen, and C _1-4 alkyl;

In some embodiments, R ^a and R ^b are each independently selected from H or F;

In some embodiments, ^Ra , ^Rb are selected from H;

In some embodiments, Cy1 and Cy2 are each independently selected from a 4-7 membered nitrogen-containing heteromonocyclic ring, a 4-10-membered nitrogen-containing heterocyclic ring, a 5-12-membered nitrogen-containing heterospirocyclic ring, and the heteromonocyclic ring, Heterocyclic rings and heterospirocyclic rings are optionally substituted by 1 to 4 selected from halogen, OH, COOH, CN, NH ₂ , =O, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, hydroxyl Substituted with C _1-4 alkyl or C _1-4 alkoxy substituents, the heteromonocyclic ring, heterocyclic ring, heterobridged ring, heterospiro ring or heteroaryl group contains 1 to 4 selected from O , S, N heteroatoms;

In some embodiments, Cy1 and Cy2 are each independently selected from piperazinyl, piperidinyl, azetidinyl, azetipentyl, cyclobutylspiroazetihexyl, azetidinylspiroazine Heterocyclohexyl, cyclobutylspiroazetidinyl, azetidinylspiroazetidinyl, azetidinylspiroazetidinyl, cyclohexylspiroazetidinyl, cyclopentylaza Cyclopentyl, azacyclopentyl and azocyclopentyl, the Cy1 and Cy2 are optionally substituted by 1 to 4 selected from halogen, OH, NH ₂ , COOH, CN, =O, C _1-4 alkyl , substituted by a halogen-substituted C _1-4 alkyl group, a hydroxyl-substituted C _1-4 alkyl group or a C _1-4 alkoxy group substituent;

In some embodiments, Cy1 and Cy2 are each independently selected from piperazinyl, piperidinyl, and azetidinyl, and Cy1 and Cy2 are optionally substituted by 1 to 4 selected from F, CF ₃ , methyl, =Substituted by substituents of O, hydroxymethyl, OH, COOH, CN or NH ₂ ;

In some embodiments, Cy1 and Cy2 are each independently selected from

In some embodiments, R ^k1 is each independently selected from H, halogen, OH, NH ₂ , CN, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, Alkyl, alkoxy, and cycloalkyl are optionally substituted by 1 to 4 substituents selected from halogen, OH, CN, C _1-4 alkyl, C _1-4 alkoxy, and C _3-6 cycloalkyl. replaced;

In some embodiments, each R ^k1 is independently selected from H, F, Cl, Br, I, CF ₃ , CHF ₂ , CH ₂ F, methyl, ethyl;

In some embodiments, R ^k1 is selected from F, Cl, Br;

In some embodiments, two R ^k1 together with the atoms to which they are connected form a C _3-6 carbocyclic ring or a 4 to 7 membered heterocyclic ring, which is optionally substituted by 1 to 4 atoms selected from H, halogen , OH, =O, NH ₂ , CN, C _1-4 alkyl or C _1-4 alkoxy substituents, the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, N ;

In some embodiments, ^Rk2 is each independently selected from H, halogen, OH, CN, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, said alkyl, Alkoxy and cycloalkyl are optionally substituted by 1 to 4 substituents selected from halogen, OH, CN, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl;

In some embodiments, two R ^k2 and the carbon atom or ring skeleton directly connected to the two together form a C _3-6 carbocyclic ring or a 3-8 membered heterocyclic ring, which is optionally substituted by 1 to Substituted with 4 substituents selected from halogen, OH, =O, NH ₂ , CN, C _1-4 alkyl or C _1-4 alkoxy, the heterocyclic ring contains 1 to 4 selected from O, S , N heteroatoms;

In some embodiments, b1 and b5 are each independently selected from 0, 1, 2 or 3;

In some embodiments, b1 is selected from 0, 1 or 2;

In some embodiments, b5 is selected from 0, 1;

In some embodiments, p1 or p2 are each independently selected from 0, 1, 2, 3, 4 or 5;

In some embodiments, p2 is 0;

In some embodiments, p1 is selected from 0 or 1;

In some embodiments, the compound represented by general formula (I) contains more than 1 F;

In some embodiments, the compound represented by general formula (I) contains more than 2 F;

optionally, when Selected from When, at least one of R ^b2 , R ^b3 , R ^b4 , Cy1 and Cy2 contains F;

At least one of R ^b2 , R ^b3 , R ^b4 , Cy1 and Cy2 contains F means that at least one of R ^b2 , R ^b3 , R ^b4 , Cy1 and Cy2 is selected from F, substituted by F or substituted by F Substituted by substituents (such as CF ₃ );

And the compound does not have the following structure:

As a first embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,

Z is selected from -C(=O)- or -CH ₂ -;

R ^b1 is each independently selected from halogen, OH, CN, C _1-4 alkyl, C _2-4 alkynyl, C _1-4 alkoxy, C _3-6 cycloalkyl, 3 to 6-membered heterocycloalkyl The alkyl group, alkynyl group, alkoxy group, cycloalkyl group and heterocycloalkyl group are optionally substituted by 1 to 4 selected from halogen, OH, =O, NH ₂ , CN, COOH, C _1-4 Substituted with a substituent of alkyl, C _1-4 alkoxy or C _3-6 cycloalkyl, the heterocycloalkyl contains 1 to 3 heteroatoms selected from O, S, and N;

R ^b2 is selected from halogen, C _1-4 alkyl, C _1-4 alkoxy, and the alkyl or alkoxy group is optionally substituted by 1 to 4 selected from halogen, CN, OH, C _1-4 alkyl Substituted with substituents of base, C _1-4 alkoxy group, and C _3-6 cycloalkyl group;

R ^b3 is selected from H, halogen, C _1-4 alkyl, C _1-4 alkoxy, and the alkyl or alkoxy group optionally has 1 to 4 selected from halogen, CN, OH, C _1- Substituted with substituents of ₄ alkyl, C _1-4 alkoxy, and C _3-6 cycloalkyl;

R ^b4 is selected from H, halogen, CN, OH, C _1-4 alkyl, C _1-4 alkoxy or 5 to 6-membered heteroaryl, and the alkyl, alkoxy or heteroaryl is optional Substituted by 1 to 4 substituents selected from halogen, CN, OH, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl , the heteroaryl group contains 1 to 3 heteroatoms selected from O, S, and N;

R ^b5 is each independently selected from H, halogen, CN, OH, C _1-4 alkyl, C _1-4 alkoxy, and the alkyl and alkoxy groups are optionally substituted by 1 to 4 selected from halogen, Substituted with substituents of CN, OH, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl;

R ^a and R ^b are each independently selected from H, halogen, and C _1-4 alkyl;

Cy1 and Cy2 are each independently selected from the group consisting of 4-7 membered nitrogen-containing heteromonocyclic rings, 4-10-membered nitrogen-containing heterocyclic rings, and 5-12-membered nitrogen-containing heterospirocyclic rings. The ring is optionally substituted by 1 to 4 atoms selected from halogen, OH, COOH, CN, NH ₂ , =O, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, and hydroxyl-substituted C _1-4 alkyl. Or substituted by a C _1-4 alkoxy substituent, the heteromonocyclic ring, heterocyclic ring, heterobridged ring, heterospirocyclic ring or heteroaryl group contains 1 to 4 heterocyclic groups selected from O, S, N atom;

R ^k1 is each independently selected from H, halogen, OH, NH ₂ , CN, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, the alkyl, alkoxy , cycloalkyl is optionally substituted by 1 to 4 substituents selected from halogen, OH, CN, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl;

Alternatively, two R ^k1 and the atoms to which they are connected together form a C _3-6 carbocyclic ring or a 4 to 7-membered heterocyclic ring, and the said carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 atoms selected from H, halogen, OH, =O, NH ₂ , CN, C _1-4 alkyl or C _1-4 alkoxy substituents substituted, the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, N;

^Rk2 is each independently selected from H, halogen, OH, CN, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, the alkyl, alkoxy, cycloalkyl The base is optionally substituted by 1 to 4 substituents selected from halogen, OH, CN, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl;

Or two R ^k2 and the carbon atoms or ring skeleton directly connected to the two together form a C _3-6 carbocyclic ring or a 3-8 membered heterocyclic ring, and the carbocyclic ring or heterocyclic ring is optionally selected from 1 to 4 halogens. , OH, =O, NH ₂ , CN, C _1-4 alkyl or C _1-4 alkoxy substituents, the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, N ;

b1 and b5 are each independently selected from 0, 1, 2 or 3;

p1 or p2 are each independently selected from 0, 1, 2, 3, 4 or 5;

The condition is when Selected from When, R ^b2 , R ^b3 , R ^b4 , At least one of Cy1 and Cy2 contains F;

And the compound does not have the following structure:

As a second embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,

R ^b1 is each independently selected from F, Cl, Br, I, OH, CN, methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, the The methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl groups are optionally replaced by 1 to 4 selected from halogen, OH, =O, NH ₂ , CN, Substituted with substituents of COOH, C _1-4 alkyl, C _1-4 alkoxy or C _3-6 cycloalkyl;

R ^b2 is selected from H, F, Cl, Br, I, methyl, and ethyl, and the methyl or ethyl group is optionally substituted by 1 to 4 selected from halogen, CN, OH, C _1-4 alkyl, Substituted with substituents of C _1-4 alkoxy and C _3-6 cycloalkyl;

R ^b3 is selected from H, F, Cl, Br, I, methyl, ethyl, methoxy or ethoxy, and the methyl, ethyl, methoxy or ethoxy is optionally replaced by 1 to 4 Substituted with a substituent selected from halogen, CN, OH, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl;

R ^b4 is selected from pyrazolyl, imidazolyl, pyrrolyl, and triazolyl, and the pyrazolyl, imidazolyl, pyrrolyl, and triazolyl are optionally substituted by 1 to 4 selected from halogen, CN, OH , C _1-4 alkyl, halogen-substituted C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl substituents;

R ^b5 is each independently selected from H, F, Cl, Br, I, OH, methyl, ethyl, methoxy or ethoxy, and the methyl, ethyl, methoxy or ethoxy is any Substituted by 1 to 4 substituents selected from halogen, CN, OH, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl;

R ^a and R ^b are each independently selected from H or F;

Cy1 and Cy2 are each independently selected from piperazinyl, piperidinyl, azetidinyl, azetipentyl, cyclobutylspiroazetihexyl, azetidinylspiroazetihexyl, cyclobutyl Azetidinyl, azetidinylspiroazetidinyl, azetidinylspiroazetidinyl, azetidinylspiroazetidinyl, cyclohexylspiroazetidinyl, cyclopentylspiroazetidinyl, azepine Cyclopentazacyclopentyl, the Cy1 and Cy2 are optionally substituted by 1 to 4 C 1 selected from halogen, OH, NH ₂ , COOH, CN, =O, C _1-4 alkyl, and _halogen Substituted by _-4 alkyl, hydroxy-substituted C _1-4 alkyl or C _1-4 alkoxy substituents;

R ^k1 is each independently selected from H, F, Cl, Br, I, CF ₃ , CHF ₂ , CH ₂ F, methyl, and ethyl;

p2 is 0;

The definitions of the remaining groups are the same as in the first embodiment of the present invention.

As the third embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,

R ^b1 is each independently selected from F, Cl, Br, I, OH, CN, methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclopropyl Butyl, cyclopentyl or cyclohexyl, the methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl is optionally selected from 1 to 4 Substituted by F, Cl, Br, I, OH, CN, methyl, and ethyl substituents;

R ^b2 is selected from H, F, Cl, Br, I, methyl, and ethyl. The methyl or ethyl group is optionally substituted by 1 to 4 selected from F, Cl, Br, I, CN, OH, methane, etc. Substituted with ethyl or ethyl substituents;

R ^b3 is selected from H, F, Cl, Br, I, methyl, ethyl, methoxy or ethoxy, and the methyl, ethyl, methoxy or ethoxy is optionally replaced by 1 to 4 Substituted with a substituent selected from F, Cl, Br, I, CN, OH, methyl or ethyl;

R ^b4 is selected from pyrazolyl, imidazolyl, pyrrolyl, and triazolyl, and the pyrazolyl, imidazolyl, pyrrolyl, and triazolyl are optionally substituted by 1 to 4 selected from F, Cl, Br , I, CN, OH, CH ₂ F, CHF ₂ , CF ₃ , methyl, ethyl substituents;

R ^b5 is each independently selected from H, F, Cl, Br, I, OH, methyl, ethyl, methoxy or ethoxy, and the methyl, ethyl, methoxy or ethoxy is any Replaced by 1 to 4 substituents selected from F, Cl, Br, I, CN, OH, methyl, and ethyl;

Cy1 and Cy2 are each independently selected from piperazinyl, piperidinyl, and azetidinyl, and Cy1 and Cy2 are optionally substituted by 1 to 4 selected from F, CF ₃ , methyl, =O, and hydroxymethyl Substituted with OH, COOH, CN or NH ₂ substituents;

The definitions of the remaining groups are the same as in the first or second embodiment of the present invention.

As the fourth embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,

Z is selected from -C(=O)-;

R ^b1 is each independently selected from F, Cl, Br, I, CF ₃ , cyclopropyl, cyclobutyl,

R ^b2 is selected from F, Cl, Br, I, CF ₃ , CHF ₂ , CH ₂ F, methyl, and ethyl;

R ^b3 is selected from methoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy;

R ^b4 is selected from

Cy1 and Cy2 are each independently selected from

R ^a and R ^b are selected from H;

R ^k1 is selected from F, Cl, Br;

b1 is selected from 0, 1 or 2;

b5 is selected from 0 and 1;

p1 is chosen from 0 or 1.

The present invention relates to a compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from one of the structures in Table E-1.

Table E-1

The present invention relates to a pharmaceutical composition, including the above-mentioned compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, and pharmaceutically acceptable carrier.

The present invention relates to a pharmaceutical composition, including a therapeutically effective amount of the above-mentioned compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, and pharmaceutical acceptable carrier.

In some embodiments, the pharmaceutical composition of the present invention may be in the form of a unit preparation (the amount of the main drug in a unit preparation is also referred to as "preparation strength").

"Effective amount" or "therapeutically effective amount" as used herein refers to administration of a sufficient amount of a compound disclosed herein that will alleviate to some extent the disease or disorder being treated (e.g., inhibit or degrade EGFR-related diseases such as One or more symptoms of cancer. In some embodiments, the result is reduction and/or alleviation of signs, symptoms, or causes of disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a compound disclosed herein required to provide a clinically significant reduction in disease symptoms. Examples of therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 2-600 mg, 3-600 mg, 4-600 mg, 5 -600mg, 6-600mg, 10-600mg, 20-600mg, 25-600mg, 30-600mg, 40-600mg, 50-600mg, 60-600mg, 70-600mg, 75-600mg, 80-600mg, 90-600mg , 100-600mg, 200-600mg, 1-500mg, 2-500mg, 3-500mg, 4-500mg, 5-500mg, 6-500mg, 10-500mg, 20-500mg, 25-500mg, 30-500mg, 40 -500mg, 50-500mg, 60-500mg, 70-500mg, 75-500mg, 80-500mg, 90-500mg, 100-500mg, 125-500mg, 150-500mg, 200-500mg, 250-500mg, 300-500mg , 400-500mg, 5-400mg, 10-400mg, 20-400mg, 25-400mg, 30-400mg, 40-400mg, 50-400mg, 60-400mg, 70-400mg, 75-400mg, 80-400mg, 90 -400mg, 100-400mg, 125-400mg, 150-400mg, 200-400mg, 250-400mg, 300-400mg, 1-300mg, 2-300mg, 5-300mg, 10-300mg, 20-300mg, 25-300mg , 30-300mg, 40-300mg, 50-300mg, 60-300mg, 70-300mg, 75-300mg, 80-300mg, 90-300mg, 100-300mg, 125-300mg, 150-300mg, 200-300mg, 250 -300mg, 1-200mg, 2-200mg, 5-200mg, 10-200mg, 20-200mg, 25-200mg, 30-200mg, 40-200mg, 50-200mg, 60-200mg, 70-200mg, 75-200mg , 80-200mg, 90-200mg, 100-200mg, 125-200mg, 150-200mg, 80-1000mg, 80-800mg.

In some embodiments, the pharmaceutical composition includes, but is not limited to, 1-1500 mg, 1-1000 mg, 20-800 mg, 40-800 mg, 40-400mg, 25-200mg, 1mg, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 110mg, 120mg, 125mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 300mg, 320mg, 400mg, 480mg, 500mg, 600mg, 800mg, 1000mg of the compound of the invention or Its stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals.

A method for treating diseases in mammals, the method comprising administering to a subject a therapeutically effective amount of a compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable The salt or co-crystal, the therapeutically effective dose is preferably 1-1500 mg, and the disease is preferably renal disease.

A method for treating diseases in mammals. The method includes: adding a pharmaceutical compound of the present invention or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal to A daily dose of 1-1500 mg/day is administered to the subject, and the daily dose may be a single dose or divided dose. In some embodiments, the daily dose includes, but is not limited to, 10-1500 mg/day, 10-1200 mg/day, 10 -1000mg/day, 10-800mg/day, 25-800mg/day, 50-800mg/day, 100-800mg/day, 100-1000mg/day, 200-1000mg/day, 200-800mg/day, 25-400mg /day, 50-400mg/day, 100-400mg/day, 200-400mg/day, in some embodiments, the daily dosage includes but is not limited to 10mg/day, 20mg/day, 25mg/day, 50mg/day, 100mg /day, 125mg/day, 150mg/day, 200mg/day, 400mg/day, 600mg/day, 800mg/day, 1000mg/day, 1200mg/day, 1400mg/day.

The present invention relates to the above-mentioned compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, or the above-mentioned pharmaceutical composition used in the preparation of treatments and Application in drugs for diseases related to EGFR activity or expression.

The present invention relates to the above-mentioned compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, or the above-mentioned pharmaceutical composition used in the preparation of treatments and Applications in drugs that inhibit or degrade EGFR-related diseases.

The present invention relates to the application of the above-mentioned compounds of the present invention or their stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, or the above-mentioned pharmaceutical compositions. Selected from cancer.

The present invention relates to a kit, which may include a composition in a single dose or multiple dose form. The kit contains a compound of the invention or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutical The amount of the compound of the present invention or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals is the same as that in the above pharmaceutical composition. The amount is the same.

The amounts of the compounds of the invention or of their stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals are in each case converted to the free base form.

The present invention relates to a preparation method of compound MH, which is prepared through the following reaction:

Compound M-G reacts in the presence of a reducing agent to obtain compound M-H. The reducing agent is preferably ammonium chloride/zinc or ammonium chloride/iron.

The present invention relates to a preparation method of compound MG, which is prepared through the following reaction:

Compound M-F and compound M-F-1 react in the presence of an alkaline reagent to obtain compound M-G. The alkaline reagent is preferably N,N-diisopropylethylamine.

The present invention relates to a preparation method of compound MF, which is prepared through the following reaction:

Compound M-E is reacted in the presence of a deamination protecting reagent to obtain compound M-F. The deamination protecting reagent is preferably hydrogen chloride.

The present invention relates to a preparation method of compound ME, which is prepared through the following reaction:

Compound M-C and compound M-D react in the presence of a palladium-containing metal catalyst to obtain compound M-E. The palladium-containing metal catalyst is preferably [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride. Methyl chloride complex.

The present invention relates to a preparation method of compound 1E, which is prepared through the following reaction:

Compound M-A and compound M-B react in the presence of an alkaline reagent to obtain compound M-C. The alkaline reagent is preferably potassium carbonate.

The present invention relates to a compound shown below,

Unless otherwise stated, the terms used in the specification and claims have the following meanings.

The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds described in the present invention all include their isotope conditions, and the carbon involved in the groups and compounds described in the present invention , hydrogen, oxygen, sulfur or nitrogen are optionally replaced by one or more of their corresponding isotopes, where the isotopes of carbon include ¹² C, ¹³ C and ¹⁴ C, and the isotopes of hydrogen include protium (H), deuterium (D), and (called deuterium), tritium (T, also called superheavy hydrogen), oxygen isotopes include ¹⁶ O, ¹⁷ O and ¹⁸ O, sulfur isotopes include ³² S, ³³ S, ³⁴ S and ³⁶ S, and nitrogen isotopes include ¹⁴ N and ¹⁵ N, fluorine isotopes include ¹⁷ F and ¹⁹ F, chlorine isotopes include ³⁵ Cl and ³⁷ Cl, and bromine isotopes include ⁷⁹ Br and ⁸¹ Br.

"Halogen" refers to F, Cl, Br or I.

"Halo-substituted" means substituted by F, Cl, Br or I, including but not limited to 1 to 10 substituents selected from F, Cl, Br or I, 1 to 6 selected from F, Cl, Br Or substituted by I substituent, substituted by 1 to 4 substituents selected from F, Cl, Br or I. "Halo-substituted" is simply referred to as "halogenated."

"Alkyl" refers to a substituted or unsubstituted linear or branched saturated aliphatic hydrocarbon group, including but not limited to alkyl groups of 1 to 20 carbon atoms, alkyl groups of 1 to 8 carbon atoms, alkyl groups of 1 to 6 carbon atoms, Alkyl group of carbon atoms, alkyl group of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neo-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and its various branched chain isomers; the alkyl group appearing in this article has the same definition as this definition. Alkyl groups may be monovalent, divalent, trivalent or tetravalent.

"Hydrocarbyl" refers to a substituted or unsubstituted, linear or branched, saturated or unsaturated group composed of carbon and hydrogen atoms. The hydrocarbyl group may be monovalent, divalent, trivalent or tetravalent.

"Alkylene" refers to substituted or unsubstituted linear and branched divalent saturated hydrocarbon groups, including -(CH ₂ ) _v - (v is an integer from 1 to 10). Examples of alkylene include but are not Limited to methylene, ethylene, propylene, butylene, etc.

"Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon group, usually having 3 to 10 carbon atoms. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloalkyl. Gengji et al. Cycloalkyl groups appearing herein are as defined above. The cycloalkyl group may be monovalent, divalent, trivalent or tetravalent.

"Heterocycloalkyl" refers to a substituted or unsubstituted saturated cyclic hydrocarbon group containing heteroatoms, including but not limited to 3 to 10 atoms, 3 to 8 atoms, including 1 to 3 selected from N, O or The heteroatoms of S and the selectively substituted N and S in the heterocycloalkyl ring can be oxidized to various oxidation states. The heterocycloalkyl group can be connected to a heteroatom or a carbon atom, the heterocycloalkyl group can be connected to an aromatic ring or a non-aromatic ring, the heterocycloalkyl group can be connected to a bridged ring or a spiro ring, non-limiting examples include rings Oxyethyl, azetidinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolanyl, dioxanyl, pyrrolidinyl, Piperidinyl, imidazolidinyl, oxazolidinyl, oxazinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl. Heterocycloalkyl groups may be monovalent, divalent, trivalent or tetravalent.

"Alkenyl" refers to substituted or unsubstituted straight-chain and branched unsaturated hydrocarbon groups, which have at least 1, usually 1, 2 or 3 carbon-carbon double bonds, and the main chain includes but is not limited to 2 to 10 , 2 to 6 or 2 to 4 carbon atoms, examples of alkenyl include but are not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl , 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl Alkenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1 -Pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl base, 1-nonenyl, 3-nonenyl, 1-decene, 4-decene, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene and 1,4-hexadiene, etc.; the alkenyl group can be monovalent, divalent, trivalent or tetravalent.

"Alkynyl" refers to substituted or unsubstituted straight-chain and branched unsaturated hydrocarbon groups, which have at least 1, usually 1, 2 or 3 carbon-carbon triple bonds, including but not limited to 2 in the main chain. to 10 carbon atoms, 2 to 6 carbon atoms, 2 to 4 carbon atoms, alkynyl examples include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butyl Alkynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl, 2-Methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl base, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1- Octynyl, 3-octynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, 4-decynyl, etc.; the alkynyl group can be monovalent, divalent, trivalent or tetravalent .

"Alkoxy" refers to substituted or unsubstituted -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, cyclopropyloxy Oxygen and cyclobutoxy.

"Carbocyclyl" or "carbocyclic ring" refers to a substituted or unsubstituted saturated or unsaturated aromatic ring or non-aromatic ring. The aromatic ring or non-aromatic ring can be a 3- to 8-membered monocyclic ring or a 4- to 12-membered ring. Bicyclic or 10 to 15-membered tricyclic system, the carbocyclic group can be connected to an aromatic ring or a non-aromatic ring, and the aromatic ring or non-aromatic ring can be optionally a single ring, a bridged ring or a spiro ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclohexane Pentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, benzene ring, naphthalene ring, "Carbocyclyl" or "carbocycle" may be monovalent, divalent, trivalent or tetravalent.

"Heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic ring or non-aromatic ring. The aromatic ring or non-aromatic ring can be a 3- to 8-membered monocyclic ring or a 4- to 12-membered ring. Bicyclic or 10 to 15-membered tricyclic system, and containing 1 or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O or S, selected from the ring of the heterocyclyl group Sexually substituted N and S can be oxidized into various oxidation states. The heterocyclyl group can be connected to a heteroatom or a carbon atom. The heterocyclyl group can be connected to an aromatic ring or a non-aromatic ring. The heterocyclyl group can be connected to a bridged ring or a spiro ring. Non-limiting examples include epoxyethyl. , aziridyl, oxetanyl, azetidinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxanyl, nitrogen Heterocycloheptyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorphyl Phyllinyl, 1,3-dithiyl, dihydrofuryl, dihydropyranyl, dithiopentanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyran base, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothienyl , benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabis Cycl[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptyl alkyl, "Heterocyclyl" or "heterocycle" may be monovalent, divalent, trivalent or tetravalent.

"Spirocyclic" or "spirocyclyl" refers to a polycyclic group in which substituted or unsubstituted monocyclic rings share one atom (called a spiro atom). The number of ring atoms in the spirocyclic system includes but is not limited to 5 to 20, 6 to 14, 6 to 12, 6 to 10, one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds, and any may contain 0 to 5 heteroatoms selected from N, O or S(=O) _n .

"Spiro" or "spiryl" may be monovalent, divalent, trivalent or tetravalent.

"Ring ring" or "ring ring group" refers to a polycyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, in which one or more rings may contain 0 or more ( Including but not limited to 1, 2, 3 or 4) double bonds, and may be substituted or un Each ring in the substituted and combined ring system may contain 0 to 5 heteroatoms or heteroatom-containing groups (including but not limited to selected from N, S(=O) _n or O, n is 0, 1 or 2) . The number of ring atoms in the parallel ring system includes but is not limited to 5 to 20, 5 to 14, 5 to 12, and 5 to 10. Non-limiting examples include: "And ring" or "and ring group" can be monovalent, divalent, trivalent or tetravalent.

"Bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing any two atoms that are not directly connected, and may contain 0 or more double bonds. Any ring in the bridged ring system It may contain 0 to 5 selected from heteroatoms or groups containing heteroatoms (including but not limited to N, S(=O)n or O, where n is 0, 1, 2). The number of ring atoms includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include Cubane, adamantane. The "bridging ring" or "bridging ring base" may be monovalent, divalent, trivalent or tetravalent.

"Carbospirocycle", "spirocarbocyclyl", "spirocarbocyclyl" or "carbospirocyclyl" refers to a "spirocycle" in which the ring system consists only of carbon atoms.

"Carbocyclic ring", "carbocyclic ring radical", "carbocyclic ring radical" or "carbocyclic ring radical" refers to a "carbocyclic ring" in which the ring system only consists of carbon atoms.

"Carbon bridged ring", "bridged carbocyclyl", "bridged carbocyclyl" or "carbon bridged ring" refers to a "bridged ring" in which the ring system consists only of carbon atoms.

"Heteromonocycle", "monocyclic heterocyclyl" or "heteromonocyclyl" refers to a "heterocyclyl" or "heterocycle" of a monocyclic ring system,

"Heterocyclic ring", "heterocyclic ring group", "heterocyclic heterocyclyl group" or "heterocyclic ring radical" refers to a "heterocyclic ring" containing heteroatoms.

"Heterospirocycle", "heterospirocyclyl", "spirocycloheterocyclyl" or "spiroheterocyclyl" refers to a "spirocycle" containing heteroatoms.

"Heterobridged ring", "heterobridged cyclyl", "bridged heterocyclyl" or "bridged heterocyclyl" refers to a "bridged ring" containing heteroatoms.

"Aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group with a monocyclic or fused ring. The number of ring atoms in the aromatic ring includes but is not limited to 6 to 18, 6 to 12 or 6 to 10. carbon atoms. The aryl ring can be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, in which the ring connected to the parent structure is an aryl ring. Non-limiting examples include benzene ring, naphthalene ring, "Aryl" or "aryl ring" may be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the attachment site is on the aryl ring.

"Heteroaryl" or "heteroaryl ring" refers to a substituted or unsubstituted aromatic hydrocarbon group, and contains 1 to 5 optional heteroatoms or heteroatom-containing groups (including but not limited to N, O or S (= O)n, n is 0, 1, 2), the number of ring atoms in the heteroaromatic ring includes but is not limited to 5 to 15, 5 to 10 or 5 to 6. Non-limiting examples of heteroaryl groups include, but are not limited to, pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazole, benzimidazole, benzene Pyridine, pyrrolopyridine, etc. The heteroaryl ring can be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, wherein the ring connected to the parent structure is a heteroaryl ring. Non-limiting examples include Heteroaryl groups appearing herein have the same definition as this definition. Heteroaryl groups may be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the attachment site is on the heteroaryl ring.

"Substituted" or "substituted" means substituted by one or more (including but not limited to 2, 3, 4 or 5) substituents, including but not limited to H, F, Cl, Br, I , alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, mercapto, amino, cyano, isocyanyl, aryl, heteroaryl, heterocyclyl, bridged cyclic group, spiro Cyclic group, cyclic group, hydroxyalkyl group, =O, carbonyl group, aldehyde, carboxylic acid, formate, -(CH ₂ ) _m -C(=O)-R ^a , -O-(CH ₂ ) _m - C(=O)-R ^a , -(CH ₂ ) _m -C(=O)-NR ^b R ^c , -(CH ₂ ) _m S(=O) _n R ^a , -(CH ₂ ) _m -ene Base -R ^a , OR ^d or -(CH ₂ ) _m -alkynyl-R ^a (where m, n is 0, 1 or 2), arylthio, thiocarbonyl, silyl or -NR ^b R ^c and other groups, wherein R ^b and R ^c are independently selected from the group including H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethyl Sulfonyl group, as an option, R ^b and R ^c can form a five- or six-membered cycloalkyl or heterocyclyl group, and R ^a and R ^d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl group, heterocyclic group, carbonyl group, ester group, bridged cyclic group, spirocyclic group or paracyclic group.

"Containing 1 to X heteroatoms selected from O, S, and N" means containing 1, 2, 3...X heteroatoms selected from O, S, and N.

"Substituted by 0 to X substituents selected from..." means substituted by 0, 1, 2, 3... For example, "substituted with 0 to 4 substituents selected from..." means substituted with 0, 1, 2, 3 or 4 substituents selected from... For example, "substituted with 0 to 5 substituents selected from..." means substituted with 0, 1, 2, 3, 4 or 5 substituents selected from... For example, "the hetero-bridged ring is optionally substituted by 1 to 4 substituents selected from H or F" means that the hetero-bridged ring is optionally substituted by 1, 2, 3 or 4 substituents selected from H or F.

Rings of ring. Rings include heterocycles, carbocycles, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocycles, heterocycles, heterospirocycles or heterobridged rings. For example, "497-membered heteromonocyclic ring" refers to a 4-, 5-, 6-, or 7-membered heteromonocyclic ring, and "5910-membered heterocyclic ring" refers to a 5-, 6-, 7-, 8-, or 9-membered heterocyclic ring. 10-membered heterocyclic ring.

"Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that description includes instances where the event or circumstance does or does not occur. For example: "Alkyl optionally substituted by F" means that the alkyl group can but does not have to be substituted by F, including the case where the alkyl group is substituted by F and the case where the alkyl group is not substituted by F.

"Pharmaceutical composition" refers to one or more compounds of the present invention, or their stereoisomers, tautomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or A mixture of cocrystals and other chemical components, where "other chemical components" refers to pharmaceutically acceptable carriers, excipients and/or one or more other therapeutic agents.

"Preparation specification" refers to the weight of the main drug contained in each tube, tablet or other unit preparation.

"Prodrug" refers to a compound of the present invention that can be converted into a biologically active compound through metabolism in the body. The prodrugs of the present invention are prepared by modifying the amino group or carboxyl group in the compound of the present invention. The modification can be removed by conventional operations or in vivo to obtain the parent compound. When the prodrug of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free amino or carboxyl group.

"Stereoisomers" refer to isomers produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and conformational isomers.

"Tautomers" refer to functional group isomers produced by rapid movement of an atom in a molecule between two positions, such as ketone- Enol isomerism and amide-iminoalcohol isomerism, etc.

“IC ₅₀ ” is the concentration of a drug or inhibitor required to inhibit half of a specified biological process (or a component in the process such as an enzyme, receptor, cell, etc.).

Detailed ways

For the purposes of the present invention, the compounds used in the reactions described herein were prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and/or compounds described in the chemical literature. "Chemicals" were obtained from standard commercial sources, including Shanghai Aladdin Biochemical Technology Co., Ltd., Shanghai McLean Biochemical Technology Co., Ltd., Sigma-Aldrich, Alfa Aesar (China) Chemical Co., Ltd., TiXIA (Shanghai) ) Chemical Industrial Development Co., Ltd., Anaiji Chemical, Shanghai Titan Technology Co., Ltd., Kelon Chemical, Bailingwei Technology Co., Ltd., etc.

The following examples illustrate the technical solution of the present invention in detail, but the protection scope of the present invention includes but is not limited to these.

The compounds used in the reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and/or compounds described in the chemical literature. "Commercially available chemicals" are obtained from regular commercial sources, and suppliers include: Titan Technology, Anaiji Chemical, Shanghai Demer, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, WuXi AppTec, and Bailingwei Technology, etc. company.

The structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts (δ) are given in units of 10 ^-6 (ppm). NMR was measured using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic instruments, and the measurement solvents were deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), and deuterated methanol (CD ₃ OD ), the internal standard is tetramethylsilane (TMS);

For MS measurement (Agilent 6120B (ESI) and Agilent 6120B (APCI));

HPLC was measured using Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100×4.6mm, 3.5μM);

Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications of silica gel plates used in thin layer chromatography (TLC) are 0.15mm-0.20mm. The specifications used for thin layer chromatography separation and purification products are 0.4mm. -0.5mm;

Column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.

SEM: THP: Boc: tert-butoxycarbonyl; Ms: TBS: MTBE: methyl tert-butyl ether; Bn: DIPEA: N,N-diisopropylethylamine; DMAc: N,N-dimethylacetamide; DMSO: dimethyl sulfoxide; DCM: dichloromethane; Cbz: NMP: N-methylpyrrolidone; PE: petroleum ether.

Example 1: Preparation of Compound 1

Step One: Preparation of Compound 1B

1A (2.86g, 9.99mmol), dimethylphosphine oxide (0.94g, 11.99mmol), Xant-Phos (4,5-bisdiphenylphosphine-9,9-dimethylxanthene, 0.29g , 0.5mmol) and palladium acetate (0.11g, 0.5mmol) were added to 1,4-dioxane (60mL) in sequence, and anhydrous potassium phosphate (2.78g, 13.09mmol) was added under stirring. Replace with nitrogen three times, raise the temperature to 80°C and stir for 6 hours. Cool to room temperature, filter, wash the filter cake with ethyl acetate, and combine the filtrate. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 1B (2.2 g, yield: 93%).

LCMS m/z＝238.1[M+H] ⁺

Step 2: Preparation of Compound 1C

Dissolve 5-bromo-2,4-dichloropyrimidine (2.11g, 9.28mmol) and 1B (1.1g, 4.64mmol) in NMP (15mL), add DIPEA (0.9g, 6.96mmol) dropwise, and raise the temperature to 130°C Stir the reaction for 2 hours. The reaction solution is cooled to room temperature. The reaction solution is diluted with 100 mL of ethyl acetate, washed three times with water and once with saturated brine. The organic phase is dried over anhydrous sodium sulfate, concentrated and then subjected to flash column chromatography (mobile phase: pure Ethyl acetate) to obtain compound 1C, (0.7g, yield: 35%).

LCMS m/z＝428.3[M+H] ⁺

Step 3: Preparation of Compound 1D

Dissolve 4-bromo-5-fluoro-2-nitrophenol (160g, 678mmol) in 2.0L N,N-dimethylformamide, add potassium carbonate (375g, 2.71mol) and methyl iodide (289g, 2.03mol), raise the temperature to 45°C and react for 3 hours. Cool to room temperature, add 5.0L of water to dilute the reaction solution, and filter under reduced pressure. The filter cake is compound 1D (161g, yield: 95%), which is used directly in the next step.

LCMS m/z＝250.0[M+H] ⁺

Step 4: Preparation of Compound 1E

In a 5.0L three-necked flask, add piperazine-1-carboxylic acid tert-butyl ester (207g, 1.11mol) and 4-formylpiperidine-1-carboxylic acid benzyl ester (250g, 1.01mol) and mix them with anhydrous dichloro To methane (2.5L), add acetic acid (60.71g, 1.01mol) and react at room temperature for two hours. After adding sodium triacetoxyborohydride (278.5g, 1.31mol), continue the reaction at room temperature for 4 hours. TLC monitors that the reaction is complete. . join in The sodium hydroxide aqueous solution was used to adjust the pH to about 13, and dichloromethane was extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether ( V/V)=10/1-1/1) to obtain target compound 1E (411 g, yield: 97%).

LCMS m/z＝418.3[M+H] ⁺

Step 5: Preparation of Compound 1F

In a 5.0L reaction flask, add compound 1E (411g, 0.984mol) dissolved in methanol (2L), add palladium on carbon (wt% = 10%, 100g) and glacial acetic acid (40mL), replace with 1 atm hydrogen three times, at room temperature The reaction was stirred overnight at high temperature, filtered through diatomaceous earth, and the filter cake was washed with dichloromethane/methanol (V/V=10/1). The filtrate was concentrated under reduced pressure to obtain crude compound 1F (276g), which was directly used in the next step.

LCMS m/z＝284.2[M+H] ⁺

Step 6: Preparation of Compound 1G

Dissolve compound 1F (276g, 974mmol) and compound 1D (267.83g, 1071.24mmol) in DMSO (1.3L), add potassium carbonate (269.19g, 1.95mol), raise the temperature to 120°C, stir and react for 5-6 hours, and react The liquid was cooled to room temperature, 5.0L of water was added, a yellow solid precipitated, filtered with suction, washed the filter cake 3 times, redissolved the filter cake with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the target compound 1G (400g, collected rate: 80%).

Step 7: Preparation of Compound 1H

Compound 1G (400g, 0.78mol) and 1-methyl-1H-pyrazole-4-boronic acid (158g, 1.24mol) were dissolved in 1,4-dioxane (1.6L) and water (0.4L) and mixed To the solvent, add potassium carbonate (216g, 1.56mol), Pd(dppf)Cl2·DCM (38g, 0.047mol), replace with nitrogen three times, raise the temperature to 90°C and stir the reaction overnight. After the reaction is complete, remove part of the solvent by rotary evaporation under reduced pressure. , then add 500 mL of ethyl acetate to dilute the reaction solution, wash 3 times with water and 1 time with saturated sodium chloride, dry the organic phase with anhydrous sodium sulfate and concentrate under reduced pressure to obtain a crude solid, add PE/EA=3/1 mixed solution ( 1600 mL) and beat for 30 minutes, filtered with suction, and the filter cake was concentrated under reduced pressure to obtain compound 1H (377 g, yield: 94%).

LCMS m/z＝515.3[M+H] ⁺

Step 8: Preparation of Compound 1I

Dissolve compound 1H (377g, 0.73mol) in methanol (600mL), add hydrogen chloride-dioxane solution (4mol/L, 2.5L), stir the reaction at room temperature for 60min, concentrate under reduced pressure to obtain a crude product, add water to the crude product 2.5L and 500mL of concentrated hydrochloric acid, extracted with ethyl acetate (1.5L×2), adjusted the pH of the aqueous phase to 13 with sodium hydroxide solution, extracted with dichloromethane (1.5L×2), combined the organic phases and dried with anhydrous sodium sulfate , filtered with suction, and the filtrate was concentrated under reduced pressure to obtain a viscous solid. Add PE/MTBE mixed solution (v/v=1/1, 1.2L) to beat, filtered with suction, and concentrated the filter cake to dryness under reduced pressure to obtain compound 1I (256g, yield :85%).

LCMS m/z＝415.2[M+H] ⁺

Step 9: Preparation of Compound 1J

The crude compound 1I (120g, 0.29mol) was dissolved in DMSO (600mL), and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3- was added successively. Dione (80g, 0.29mmol) and DIPEA (112g, 0.87mmol) were reacted at 100°C overnight. Add 2.0L water, precipitate the solid, suction filter, dissolve and extract the filter cake with 200mL dichloromethane, dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and purify with silica gel column chromatography (mobile phase: dichloromethane/ Methanol (V/V) = 100/1-10/1) to obtain compound 1J (186 g, yield: 96%).

LCMS m/z＝671.3[M+H] ⁺

Step 10: Preparation of Compound 1K

Compound 1J (80g, 119mmol) was dissolved in a mixture of THF (0.8L) and water (0.25L), and ammonium chloride (44.6g, 835mmol) and zinc powder (54.6g, 835mmol), slowly raise the temperature to 60°C and stir for 1 hour. The reaction solution is cooled to room temperature and filtered. The filter cake is washed with 1L of DCM, the organic phases are combined, and the organic phase is washed with 0.5L ammonia water in turn. The mixture was washed with 0.5 L saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 1K (76 g, yield 99%), which was directly used in the next step.

LCMS m/z＝641.3[M+H] ⁺

¹ H NMR (400MHz, CD ₃ OD) δ7.98(s,1H),7.89(s,1H),7.68(d,1H),7.36(d,1H),7.22(dd,1H),6.87(s ,1H),6.74(s,1H),5.06(dd,1H),3.90(s,3H),3.85(s,3H),3.53–3.42(m,4H),3.08–2.96(m,2H), 2.91–2.69(m,3H),2.69–2.54(m,6H),2.41–2.28(m,2H),2.15–2.06(m,1H),1.90–1.78(m,2H),1.77–1.61(m ,1H),1.43–1.24(m,2H).

Step 11: Preparation of Compound 1

Compound 1K (350mg, 0.54mmol) and compound 1C (0.23g, 0.54mmol) were dissolved in N,N-dimethylformamide (10mL), and p-toluenesulfonic acid monohydrate (210mg, 1.08mmol) was added. , heated to 100°C under nitrogen protection and stirred for 16 hours. Cool to room temperature, add 20 mL saturated aqueous sodium bicarbonate solution and 50 mL methylene chloride to separate layers, concentrate the organic layer under reduced pressure, and purify the residue by silica gel column chromatography (mobile phase: DCM/MeOH (V/V) = 100/1- 20/1), the crude product continues to be used for preparative HPLC (instrument: waters 2767 preparation liquid phase; chromatographic column: XBridge@Prep C18 (30mm×150mm); mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.1 % trifluoroacetic acid)), and the prepared product was alkalized with saturated sodium bicarbonate aqueous solution to obtain compound 1 (205 mg, yield: 37%).

LCMS m/z＝517.00[(M+2H)/2] ⁺

¹ H NMR (400MHz, CDCl ₃ /CD ₃ OD (v/v) = 1/1) δ8.62 (dd, 1H), 8.22 (s, 1H), 7.98 (s, 1H), 7.91 (s, 1H) ),7.70(d,1H),7.62–7.55(m,1H),7.55–7.51(m,1H),7.37–7.30(m,1H),7.19–7.05(m,2H),6.80(s,1H ),5.06–4.92(m,1H),3.92(s,3H),3.89(s,3H),3.55–3.43(m,4H),3.24–3.12(m,2H),2.87–2.74(m,3H ),2.71–2.58(m,6H),2.38(d,2H),2.21–2.08(m,1H),1.99-1.83(m,8H),1.80-1.66(m,1H),1.45–1.35(m ,2H).

Example 2: Preparation of Compound 2

Step One: Preparation of Compound 2A

Dissolve compound 2,4,5-trichloropyrimidine (1.7g, 9.28mmol) and compound 1B (1.1g, 4.64mmol) in N-methylpyrrolidone (15mL), add DIPEA (0.9g, 6.96mmol) dropwise, The temperature was raised to 130°C and the reaction was stirred for 2 hours. The reaction solution was cooled to room temperature. The reaction solution was diluted with 100 mL of ethyl acetate, washed three times with water and once with saturated brine. The organic phase was washed with anhydrous sodium sulfate, concentrated and then chromatographed by flash column chromatography (mobile Phase: pure ethyl acetate) to obtain compound 2A (1.3 g, yield: 73%).

LCMS m/z＝384.3[M+H] ⁺

Step 2: Preparation of Compound 2

Compound 1K (350 mg, 0.55 mmol) and compound 2A (0.21 g, 0.55 mmol) were dissolved in N,N-dimethylformamide (10 mL), and p-toluenesulfonic acid monohydrate (210 mg, 1.1 mmol) was added. , heated to 100°C under nitrogen protection and stirred for 16 hours. Cool to room temperature, add 20 mL saturated aqueous sodium bicarbonate solution and 50 mL methylene chloride to separate layers, concentrate the organic layer under reduced pressure, and purify the residue by silica gel column chromatography (mobile phase: DCM/MeOH (V/V) = 100/1- 20/1), the crude product continues to be used for preparative HPLC (instrument: waters 2767 preparation liquid phase; chromatographic column: XBridge@Prep C18 (30mm×150mm); mobile phase composition: mobile phase A: Acetonitrile, mobile phase B: water (containing 0.1% trifluoroacetic acid)) was purified, and the prepared product was alkalized with saturated sodium bicarbonate aqueous solution to obtain compound 2 (210 mg, yield: 39%).

LCMS m/z＝495.10[(M+2H)/2] ⁺

¹ H NMR (400MHz, CDCl ₃ /CD ₃ OD (v/v) = 1/1) δ8.71 (dd, 1H), 8.10 (s, 1H), 7.96 (s, 1H), 7.90 (s, 1H) ),7.68(d,1H),7.61(s,1H),7.59–7.52(m,1H),7.35–7.26(m,1H),7.18–7.00(m,2H),6.79(s,1H), 5.04–4.90(m,1H),3.90(s,3H),3.87(s,3H),3.55–3.40(m,4H),3.23–3.09(m,2H),2.85–2.71(m,3H), 2.71–2.56(m,6H),2.36(d,2H),2.18–2.06(m,1H),1.99–1.81(m,8H),1.76–1.66(m,1H),1.43–1.31(m,2H ).

Example 3: Preparation of Compound 3

Step One: Preparation of Compound 3B

Diethylaminosulfur trifluoride (10 mL) was added dropwise to 3-(4-bromophenyl)cyclobutan-1-one (Compound 3A, 1.5 g, 6.66 mmol) in dichloromethane ( 10 mL) solution, stirred at room temperature overnight, added ice water (50 mL) to quench, extracted with dichloromethane (3×20 mL), combined the organic layers, washed once with saturated aqueous sodium bicarbonate solution (20 mL), and used anhydrous sulfuric acid to wash the organic layer After drying over sodium, it was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (V/V) = 1/50-1/20) to obtain 3B (1.4 g, yield: 85%).

¹ H NMR (400MHz, CDCl ₃ ) δ7.48–7.41(m,2H),7.14–7.06(m,2H),3.38-3.29(m,1H),3.13–2.93(m,2H),2.74–2.52 (m,2H).

Step 2: Preparation of compound 3C

Compound 3B (1.2g, 4.86mmol), tert-butyl carbamate (2.85g, 24.3mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4' ,6'-triisopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl)palladium(II) (CAS: 1470372-59-8) (0.44 g, 0.49mmol) was added to 1,4-dioxane (80mL) in sequence, and cesium carbonate (4.75g, 14.58mmol) was added under stirring. Replace with nitrogen three times, raise the temperature to 80°C and stir for 6 hours. Cool to room temperature, filter, wash the filter cake with ethyl acetate, and combine the filtrate. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound 3C (1.1 g, yield: 80%).

Step 3: Preparation of compound 3D

Add compound 3C (1.1g, 3.88mmol) and dichloromethane (10mL) into the reaction flask, stir to dissolve, add trifluoroacetic acid (3mL) dropwise, complete the addition and react at room temperature for 3h, concentrate to dryness under reduced pressure, and add DCM to the residue ( 10mL), adjust the pH to about 12 with 1N sodium hydroxide solution, and let stand to separate layers; the aqueous layer was extracted three times with DCM (10mL), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain compound 3D (0.7 g, yield: 98%).

LCMS m/z＝184.2[M+H] ⁺

Step 4: Preparation of Compound 3E

Compound 3D (0.7g, 3.82mmol), iodine (0.97g, 3.82mmol) and sodium bicarbonate (0.96g, 11.46mmol) were added to a mixture of dichloromethane (20mL) and water (10mL) at room temperature. Stir overnight at high temperature. After the reaction, the organic layer is separated, the aqueous layer is extracted with dichloromethane (3 × 10 mL), the organic layers are combined, and sequentially treated with saturated sodium thiosulfate aqueous solution (2 × 10 mL) and saturated brine. (2 × 10 mL), washed with anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (ethyl acetate/petroleum ether (V/V) = 1/20-1/5) to obtain compound 3E (600 mg, yield :51%).

LCMS m/z＝310.0[M+H] ⁺

Step 5: Preparation of Compound 3F

Compound 3E (0.6g, 1.94mmol), dimethylphosphine oxide (0.15g, 1.94mmol), Xant-Phos (4,5-bisdiphenylphosphine-9,9-dimethylxanthene, 0.11 g, 0.19mmol) and palladium acetate (44mg, 0.19mmol) were added to 1,4-dioxane (60mL) in sequence, and anhydrous potassium phosphate (0.62g, 2.92mmol) was added under stirring. Replace with nitrogen three times, raise the temperature to 80°C and stir for 6 hours. Cool to room temperature, filter, wash the filter cake with ethyl acetate, and combine the filtrate. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound 3F (0.4 g, yield: 80%).

Step 6: Preparation of Compound 3G

Compound 3F (0.2g, 0.77mmol) and 5-bromo-2,4-dichloropyrimidine (0.35g, 1.54mmol) were dissolved in N-methylpyrrolidone (10mL), and DIPEA (0.15g, 1.16mmol) was added , heated to 120°C under nitrogen protection, and stirred at this temperature for 2 hours. Cool to room temperature, add 30 mL of ethyl acetate and 10 mL of water for extraction, and wash the organic layer three times with 10 mL of saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol (V/V) = 1/100-1/20) to obtain 3G (0.3g, yield :86.46%)

LCMS m/z＝450.0[M+H] ⁺

Step 7: Preparation of Compound 3

Compound 3G (0.3g, 0.67mmol) and compound 1K (0.43g, 0.67mmol) were dissolved in N,N-dimethylformamide (10mL), and p-toluenesulfonic acid monohydrate (320mg, 1.68mmol) was added ), raise the temperature to 100°C under nitrogen protection and stir for 16 hours. Cool to room temperature, add 20 mL saturated aqueous sodium bicarbonate solution and 50 mL methylene chloride to separate layers, concentrate the organic layer under reduced pressure, and purify the residue by silica gel column chromatography (mobile phase: DCM/MeOH (V/V) = 100/1- 20/1), the crude product continues to be used for preparative HPLC (instrument: waters2767 preparation liquid phase; chromatographic column: XBridge@Prep C18 (30mm×150mm); mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% Trifluoroacetic acid)) was purified, and the prepared product was basified with saturated sodium bicarbonate aqueous solution to obtain compound 3 (150 mg, yield: 21%).

LCMS m/z＝527.8[(M+2H)/2] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.06(s,1H),10.94(s,1H),8.32–8.23(m,1H),8.20(s,1H),8.16(s,1H), 7.98(s,1H),7.86–7.80(m,1H),7.68(d,1H),7.59(s,1H),7.39-7.32(m,2H),7.29-7.22(m,1H),6.89- 6.77(m,2H),5.11-5.02(m,1H),3.82(s,3H),3.79(s,3H),3.20-3.39(m,4H),3.32-3.19(m,1H),3.14- 3.03(m,2H),2.96–2.82(m,3H),2.69–2.44(m,10H),2.33-2.25(m,2H),2.06–1.97(m,1H),1.85-1.72(m,8H ),1.70-1.60(m,1H),1.42–1.26(m,2H).

Example 4: Preparation of Compound 4

Step One: Preparation of Compound 4A

Compound 3F (0.2g, 0.77mmol) and 2,4,5-trichloropyrimidine (0.28g, 1.54mmol) were dissolved in N-methylpyrrolidone (10 mL), add DIPEA (9.91g, 76.71mmol), raise the temperature to 120°C under nitrogen protection, and stir at this temperature for 2 hours. Cool to room temperature, add 30 mL of ethyl acetate and 10 mL of water for extraction, and wash the organic layer three times with 10 mL of saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol (V/V) = 1/100-1/20) to obtain target compound 4A (0.31g, Yield: 99%)

LCMS m/z＝406.0[M+H] ⁺

Step 2: Preparation of Compound 4

Compound 1K (490mg, 0.76mmol) and compound 4A (0.31g, 0.76mmol) were dissolved in N,N-dimethylformamide (10mL), and p-toluenesulfonic acid monohydrate (290mg, 1.53mmol) was added. , heated to 100°C under nitrogen protection and stirred for 16 hours. Cool to room temperature, add 20 mL saturated aqueous sodium bicarbonate solution and 50 mL methylene chloride to separate layers, concentrate the organic layer under reduced pressure, and purify the residue by silica gel column chromatography (mobile phase: DCM/MeOH (V/V) = 100/1- 20/1), the crude product continues to be used for preparative HPLC (instrument: waters 2767 preparation liquid phase; chromatographic column: XBridge@Prep C18 (30mm×150mm); mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.1 % trifluoroacetic acid)), and the prepared product was basified with saturated sodium bicarbonate aqueous solution to obtain compound 4 (200 mg, yield: 26%).

LCMS m/z＝505.9[(M+2H)/2] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.20(s,1H),11.06(s,1H),8.42-8.33(m,1H),8.20(s,1H),8.09(s,1H), 8.00(s,1H),7.85(s,1H),7.68(d,1H),7.63-7.56(m,1H),7.41–7.31(m,2H),7.29-7.21(m,1H),6.90- 6.72(m,2H),5.13-5.01(m,1H),3.82(s,3H),3.80(s,3H),3.50-3.40(m,4H),3.32–3.19(m,1H),3.14- 3.04(m,2H),2.97–2.83(m,3H),2.72–2.44(m,10H),2.34-2.25(m,2H),2.07-1.96m,1H),1.86-1.73(m,8H) ,1.71-1.61(m,1H),1.42-1.27(m,2H).

Example 5: Preparation of Compound 5

Step One: Preparation of Compound 5B

In a 100mL reaction bottle, add 4-bromo-5-fluoro-2-nitrophenol (5.81g, 24.62mmol), sodium difluorochloroacetate (7.51g, 49.24mmol), and sodium carbonate (3.13g, 29.54mmol). ) and N,N-dimethylformamide (45mL), stir and react at 100°C for 4.5 hours after addition. After the reaction solution is cooled to room temperature, dilute hydrochloric acid (40mL, 4N, 160mmol) is slowly added dropwise and stirred at room temperature. Reaction 2h. Water (100 mL) was added to the reaction solution and extracted with ethyl acetate (80 mL × 2). The organic phases were combined and washed with 1N aqueous sodium hydroxide solution (160 mL × 1) and saturated brine (80 mL × 1). The organic layer was washed with Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is separated and purified by medium pressure preparation (PE/EA=9/1-1/1) to obtain compound 5B (0.647g, yield 89%).

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.57(d,1H),7.76(d,1H),7.39(t,1H).

Step 2: Preparation of Compound 5C

In a 50mL reaction bottle, add 5B (1.27g, 4.44mmol), 1-methyl-1H-pyrazole-4-boronic acid (0.73g, 5.77mmol), anhydrous potassium phosphate (2.83g, 13.27mmol), and Pd(dppf)Cl2·DCM (360 mg, 0.44 mmol) and dioxane/water (v/v=4/1, 10 mL) were replaced with nitrogen three times, and the reaction was stirred at 90°C overnight. Water (50 mL) was added to the reaction solution, and then extracted with ethyl acetate (50 mL × 2). The organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by column chromatography (PE/EA =3/1) to obtain 5C (1.03g, yield 80%).

LCMS m/z＝288.1[M+H] ⁺

Step 3: Preparation of Compound 5D

Dissolve compound 1F (1.11g, 3.91mmol) and compound 5C (1.02g, 3.55mmol) in DMSO (10mL), add potassium carbonate (1.47g, 10.65mol), raise the temperature to 90°C, stir and react overnight, and cool the reaction solution to room temperature, add 100 mL of water, a yellow oily substance precipitates, extract with ethyl acetate (50 mL /MeOH: 0%-3%), the crude product obtained was separated and purified through liquid phase preparation (acidic preparation conditions). The obtained preparation solution was adjusted to a pH of about 13 with saturated sodium bicarbonate solution, and extracted and concentrated with ethyl acetate to obtain compound 5D (519 mg, collected rate: 27%).

LCMS m/z＝551.3[M+H]+

Step 4: Preparation of Compound 5E

Compound 5D (0.51g, 0.93mmol) was dissolved in methanol (5mL), hydrogen chloride-dioxane solution (4mol/L, 6mL, 24mmol) was added, the reaction was stirred at room temperature for 60min, and concentrated under reduced pressure to obtain a crude product dissolved in DMSO (10mL), add 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (0.28g, 1.01mmol) and DIPEA (0.6 g, 4.64mmol), react at 90°C overnight. Add 50 mL of water, precipitate the solid, and suction filtrate. The filter cake is dissolved and extracted with 50 mL of dichloromethane. The organic phase is dried with anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (mobile phase: dichloromethane/methanol). (V/V)=100/1-10/1) to obtain compound 5E (0.4g, yield: 61%).

LCMS m/z＝707.3[M+H] ⁺

Step 5: Preparation of Compound 5F

Dissolve 5E (0.50g, 0.71mmol) in a mixture of THF (20mL) and water (5mL), add ammonium chloride (0.50g, 9.35mmol) and zinc powder (0.50g, 7.65mmol), and react at room temperature 1 hour, the reaction solution was filtered through diatomaceous earth, added ammonia (5mL) and extracted with dichloromethane (50mL×2), combined the organic layers and dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and dried over anhydrous sodium sulfate Concentrate under reduced pressure to obtain 5F (0.172g, yield 36%), which was directly used in the next step.

LCMS m/z＝677.9[M+H] ⁺

Step 6: Preparation of compound 5G-2

Combine 4-bromo-2-iodoaniline (5G-1, 0.5g, 1.68mmol), dimethylphosphine oxide (0.13g, 1.68mmol), Xant-Phos (4,5-bisdiphenylphosphine-9, 9-Dimethylxanthene, 49mg, 0.084mmol) and anhydrous potassium phosphate (0.46g, 2.18mmol) were added to 10mL of 1,4-dioxane in sequence, and palladium acetate (19mg, 0.084mmol) was added under stirring. ). Replace with nitrogen three times, raise the temperature to 80°C and stir for 5 hours. Cool to room temperature, filter, wash the filter cake with 20 mL of ethyl acetate, and combine the filtrate. The filtrate was concentrated under reduced pressure, and 5 mL of methyl tert-butyl ether was added to the residue to make a slurry, filtered, and the filter cake was dried to obtain 5G-2 (0.3 g, yield: 72%).

LCMS m/z＝248.1[M+H] ⁺

Step Seven: Preparation of Compound 5G-3

Dissolve 5G-2 (2.3g, 9.27mmol) and cyclopropylboronic acid (2.39g, 27.81mmol) in 20mL dioxane and 4mL water, then add tricyclohexylphosphine (0.52g, 1.85mmol), Palladium acetate (0.21g, 0.93mmol) and potassium phosphate (7.87g, 37.08mmol) were replaced with nitrogen three times, reacted in an oil bath at 100°C for 24 hours, cooled to room temperature, poured the reaction solution into water, and extracted with ethyl acetate three times. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 5G-3 (1.26 g, yield 65%).

¹ H NMR (400MHz, CDCl ₃ ) δ6.94(d,1H),6.88-6.80(m,1H),6.63-6.57(m,1H),1.82-1.71(m,7H),0.91-0.83(m ,2H),0.59-0.51(m,2H).

Step 8: Preparation of Compound 5G

Dissolve compound 5G-3 (0.26g, 1.24mmol) and 5-bromo-2,4-dichloropyrimidine (0.57g, 2.48mmol) in 5mL NMP, add DIPEA (190mg, 1.49mmol), and stir at 120°C 2h, cool to room temperature, add 8mL of water, filter, dry the filter cake under reduced pressure, and purify with silica gel column chromatography (petroleum ether: ethyl acetate (V/V) = 10/1-0/10), and the residue is The mixture of ethyl acetate/petroleum ether (10 mL, V/V=1/2) was mixed into a slurry, filtered, and the filter cake was dried under reduced pressure to obtain 5G (0.28 g, yield: 56%).

¹ H NMR (400MHz, CDCl ₃ ) δ11.20(s,1H),8.45-8.39(m,1H),8.30(s,1H),7.24-7.19(m,1H),7.06-7.00(m,1H) ),1.93–1.79(m,7H),1.05-0.96(m,2H),0.78-0.65(m,2H).

Step 9: Preparation of Compound 5

Dissolve 5F (0.086g, 0.13mmol) and 5G (0.057g, 0.14mmol) in N,N-dimethylformamide (10mL), add p-toluenesulfonic acid monohydrate (74mg, 0.39mmol), The temperature was raised to 100°C under nitrogen protection and stirred for 16 hours. Cool to room temperature, add 20 mL of saturated sodium bicarbonate aqueous solution, precipitate the solid, filter out the water, dissolve the filter cake with dimethyl sulfoxide, and use preparative HPLC (preparation conditions: instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19 mm × 250 mm); mobile phase A: acetonitrile, mobile phase B: water (containing 5 mmol/L ammonium acetate)) for purification, and the preparation solution was freeze-dried to obtain compound 5 (7 mg, yield: 5%).

LCMS m/z＝520.8[(M+2H)/2] ⁺

¹ H NMR (400MHz, CDCl ₃ /CD ₃ OD (v/v) = 1/1) δ8.19–8.07 (m, 2H), 7.96 (s, 1H), 7.79 (s, 1H), 7.72 (d ,1H),7.67(s,1H),7.63-7.59(m,1H),7.38-7.33(m,1H),7.24-7.15(m,2H),6.97(s,1H),6.83–6.38(m ,2H),5.08-4.94(m,1H),3.92(s,3H),3.62-3.48(m,4H),3.24-3.12(m,2H),2.92–2.70(m,7H),2.64(t ,2H),2.56-2.47(m,2H),2.25-2.10(m,1H),1.98–1.65(m,10H),1.50-1.40(m,1H),1.00–0.92(m,2H),0.55 -0.48(m,2H).

Example 6: Preparation of Compound 6

Step One: Preparation of Compound 6A

Dissolve 5G-3 (10.7g, 51.14mmol) and 2,4,5-trichloropyrimidine (13.96g, 76.71mmol) in NMP (40mL), add DIPEA (9.91g, 76.71mmol), and raise the temperature under nitrogen protection to 120°C and stir for 2 hours at this temperature. Cool to room temperature, add 200 mL of ethyl acetate and 50 mL of water for extraction, and wash the organic layer three times with 50 mL of saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol (V/V) = 1/100-1/20) to obtain 6A (15.6g, yield :86%)

LCMS m/z＝356.1[M+H] ⁺

Step 2: Preparation of compound 6

Dissolve 5F (0.086g, 0.13mmol) and 6A (0.051g, 0.14mmol) in N,N-dimethylformamide (10mL), add p-toluenesulfonic acid monohydrate (74mg, 0.39mmol), The temperature was raised to 100°C under nitrogen protection and stirred for 16 hours. Cool to room temperature, add 20 mL of saturated sodium bicarbonate aqueous solution, precipitate the solid, filter out the water, dissolve the filter cake with dimethyl sulfoxide, and use preparative HPLC (preparation conditions: instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19 mm × 250 mm); mobile phase A: acetonitrile, mobile phase B: water (containing 5 mmol/L ammonium acetate)) for purification, and the preparation solution was freeze-dried to obtain compound 6 (6 mg, yield: 5%).

LCMS m/z＝498.8[M+2H/2] ⁺

¹ H NMR (400MHz, CDCl ₃ /CD ₃ OD (v/v) = 1/1) δ 8.30–8.22 (m, 1H), 8.10–8.05 (m, 1H), 8.01 (s, 1H), 7.82 (s,1H),7.76(d,2H),7.39(s,1H),7.20(d,2H),7.00(s,1H),6.85–6.43(m,2H),5.10–4.98(m,1H ),3.94(s,3H),3.60(s,4H),3.21(d,2H),2.95–2.73(m,7H),2.73–2.56(m,4H),2.21–2.10(m,1H), 1.99–1.78(m,10H),1.53–1.42(m,2H),1.03–0.95(m,2H),0.60–0.49(m,2H).

Example 7: Preparation of Compound 7

Compound 8K (380 mg, 0.58 mmol) and compound 6A (0.21 g, 0.58 mmol) were dissolved in N, N-dimethylformamide (10 mL), and p-toluenesulfonic acid monohydrate (220 mg, 1.15 mmol) was added. , heated to 100°C under nitrogen protection and stirred for 16 hours. Cool to room temperature, add 20 mL saturated aqueous sodium bicarbonate solution and 50 mL methylene chloride to separate layers, concentrate the organic layer under reduced pressure, and purify the residue by silica gel column chromatography (mobile phase: DCM/MeOH (V/V) = 100/1- 20/1), the crude product continues to be used for preparative HPLC (instrument: waters 2767 preparation liquid phase; chromatographic column: XBridge@Prep C18 (30mm×150mm); mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.1 % trifluoroacetic acid)), and the prepared product was basified with saturated sodium bicarbonate aqueous solution to obtain compound 7 (230 mg, yield: 41%).

LCMS m/z＝490.40[(M+2H)/2] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.08(d,2H),8.26(s,1H),8.15(s,1H),8.07(s,1H),8.01(s,1H),7.91( s,1H),7.68(d,1H),7.60(s,1H),7.35(s,1H),7.30–7.16(m,2H),6.84(s,1H),6.45(s,1H),5.14 –4.98(m,1H),3.80(d,6H),3.47(s,4H),3.03–2.78(m,5H),2.75–2.53(m,8H),2.09–1.81(m,6H),1.80 –1.70(m,6H),0.96–0.80(m,2H),0.57–0.47(m,2H).

Example 8: Preparation of Compound 8

Step One: Preparation of 8B

Combine 4-fluoro-2-iodoaniline (8A, 5.00g, 21.10mmol), dimethylphosphine oxide (2.14g, 27.43mmol), potassium phosphate (6.72g, 31.65mmol), and palladium acetate (0.24g, 1.06mmol). ), Xant-Phos (0.61g, 1.06mmol) and anhydrous magnesium sulfate (2.54g, 21.1mmol) were added to 1,4-dioxane (50ml) in sequence, replaced with nitrogen three times, and stirred at 100°C for 8 hours. Cool to room temperature, filter, and the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography (ethyl acetate/petroleum ether (V/V)=1/1~dichloromethane/methanol (V/V)=30/1) to obtain 8B (3g, yield: 76%).

LCMS m/z=188.1[M+H]+.

Step 2: Preparation of Compound 8C

Dissolve 8B (1.50g, 7.97mmol) and 5-bromo-2,4-dichloropyrimidine (3.63g, 15.94mmol) in NMP (10ml), add DIPEA (1.24g, 9.56mmol), and stir at 120°C for 1 hour. Cool to room temperature, add 30 mL of water and 30 mL of ethyl acetate for extraction, and wash the organic layer twice with saturated brine. Concentrate under reduced pressure, and the residue is pulped with 10 mL MTBE, filtered, and dried under reduced pressure to obtain 8C (1.5 g, yield: 50%).

LCMS m/z＝378.0[M+H]+

Step 3: Preparation of Compound 8E

Add 1-tert-butoxycarbonyl-4-fluoro-4-(hydroxymethyl)piperidine (14g, 60.01mmol) and dichloromethane (210mL) into the reaction flask. After stirring and dissolving, add Dai Dai under cooling with ice water. Stir-Martin reagent (80.91g, 190.8mmol), react at room temperature for about 3 hours, add saturated sodium bicarbonate aqueous solution (300mL), stir for 5 minutes, spread an appropriate amount of diatomaceous earth, filter, and wash the filter cake with dichloromethane (100mL×2) , dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and the residue was purified by column chromatography (eluent PE/EA=1/1) to obtain 8E (5g, yield: 36.03%).

Step 4: Preparation of 8F

Add 8E (5g, 21.62mmol), benzyl-1-piperazine carbonate (4.76g, 21.62mmol) and dichloromethane (100mL) into the reaction flask, add glacial acetic acid (2.59g, 43.24mmol) and stirring Sodium triacetoxyborohydride (11.45g, 54.05mmol), react at room temperature overnight for about 18h, add water (100mL), stir for 5min, leave to separate, and wash the organic layer with saturated aqueous sodium bicarbonate solution (100mL×1). Dry over anhydrous sodium sulfate, filter, and concentrate to dryness under reduced pressure. The residue is purified by column chromatography (eluent PE/EA=2/1) to obtain 8F (6.2g, yield: 66%).

Step 5: Preparation of 8G

Add 8F (6.2g, 14.24mmol) and dichloromethane (30mL) into the reaction flask, stir to dissolve, add trifluoroacetic acid (12mL) dropwise, complete the reaction at room temperature for 3 hours, concentrate to dryness under reduced pressure, and add DCM (50mL) to the residue ), adjust the pH to about 12 with 1N sodium hydroxide aqueous solution. Let stand and separate layers; extract the aqueous layer once with DCM (30 mL), combine the organic layers, wash with saturated sodium chloride solution (60 mL × 1), dry over anhydrous sodium sulfate, filter, and concentrate to dryness under reduced pressure to obtain 8G (4.2 g, collected rate: 88%).

Step 6: Preparation of 8H

8G (4.2g, 12.52mmol), 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene (1D, 3.13g, 12.52mmol), potassium carbonate (3.46g, 25.04mmol) and DMSO (40mL) into the reaction bottle, react at 100°C for about 3 hours, cool to room temperature, add ethyl acetate (100mL) and water (100mL), stir, let stand and separate into layers, the organic layer is saturated sodium chloride aqueous solution (50mL×2) Wash, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography (eluent PE/EA=PE to 5/1 to 3/1 to 2/1) to obtain 8H (5g, yield :71%).

Step 7: Preparation of Compound 8I

8H (5g, 8.84mmol), 1-methyl-1H-pyrazole-4-boronic acid (1.67g, 13.26mmol), Pd(dppf)Cl2·DCM (1.07g, 1.33mmol), potassium carbonate (2.44g , 17.68mmol) and 1,4-dioxane (50mL), water (20mL) were added to the reaction bottle, nitrogen was exchanged three times, the reaction was carried out at 100°C for about 3h, cooled in a water bath, and ethyl acetate (100mL) and water ( 50mL), stir and separate layers, wash the organic layer with saturated sodium chloride solution (50mL×2), dry with anhydrous sodium sulfate, filter, concentrate to dryness under reduced pressure, and purify the residue by column chromatography, eluent: DCM/CH3OH=DCM From 50/1 to 30/1, 8I (4.1g, yield: 81.85%) was obtained.

Step 8: Preparation of Compound 8J

Add 8I (0.5g, 0.88mmol), palladium on carbon (10wt%, 0.1g), methanol (5mL) and glacial acetic acid (1mL) into the reaction flask, ventilate with hydrogen three times, hydrogenate at room temperature for about 20h, and spread an appropriate amount of diatoms Soil, filter, wash the filter cake with a small amount of methanol, and concentrate the filtrate to dryness under reduced pressure to obtain 8J, which is directly used in the next step.

Step 9: Preparation of 8K

8J (0.35g, 0.88mmol), 2-(2,6-dioxo-piperidin-3-yl)-5-fluoro-isoindole-1,3-dione (0.24g, 0.88mmol) , DIPEA (0.17g, 1.32mmol) and DMSO (5mL) were added to the reaction bottle, reacted at 100°C for 3h, cooled with ice water, added ethyl acetate (30mL) and water (20mL), stirred for 5min, left to separate, organic The layer was washed with saturated sodium chloride solution (10mL×2), dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and the residue was purified by column chromatography (eluent: DCM/CH3OH=DCM to 50/1 to 30/1 ), 8K (0.10g, yield: 17%) was obtained.

Step 10: Preparation of Compound 8

Dissolve 8K (380 mg, 0.58 mmol) and 8C (0.22 g, 0.58 mmol) in DMF (10 mL), add p-toluenesulfonic acid monohydrate (220 mg, 1.15 mmol), and raise the temperature to 100°C under nitrogen protection and stir for 16 hours. Cool to room temperature, add 20 mL saturated aqueous sodium bicarbonate solution and 50 mL methylene chloride to separate layers, concentrate the organic layer under reduced pressure, and purify the residue by silica gel column chromatography (mobile phase: DCM/MeOH (V/V) = 100/1- 20/1), the crude product continues to be used for preparative HPLC (instrument: waters 2767 preparation liquid phase; chromatographic column: XBridge@Prep C18 (30mm×150mm); mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.1 % trifluoroacetic acid)), and the prepared product was basified with saturated sodium bicarbonate aqueous solution to obtain compound 8 (190 mg, yield: 32.73%).

LCMS m/z＝500.7[(M+2H)/2] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.07(s,1H),10.78(s,1H),8.37–8.23(m,1H),8.18(s,2H),8.00(s,1H), 7.84(s,1H),7.68(d,1H),7.61(s,1H),7.46–7.31(m,2H),7.30–7.20(m,1H),6.83(s,1H),6.76–6.57( m,1H),5.07(dd,1H),3.85(s,3H),3.81(s,3H),3.55–3.39(m,4H),3.00–2.79(m,5H),2.76–2.51(m, 8H),2.05–1.82(m,5H),1.79(s,3H),1.76(s,3H).

Example 9: Preparation of Compound 9

Step One: Preparation of Compound 9A

Dissolve 8B (1.50g, 7.97mmol) and 2,4,5-trichloropyrimidine (3.63g, 15.94mmol) in NMP (10ml), add DIPEA (1.24g, 9.56mmol), and stir at 120°C for 1 hour. Cool to room temperature, add 30 mL of water and 30 mL of ethyl acetate for extraction, and wash the organic layer twice with saturated brine. Concentrate under reduced pressure, and the residue is pulped with 10 mL MTBE, filtered, and dried under reduced pressure to obtain 9A (1.5 g, yield: 50%).

Step 2: Preparation of Compound 9

Dissolve 8K (380 mg, 0.58 mmol) and 9A (0.19 g, 0.58 mmol) in DMF (10 mL), add p-toluenesulfonic acid monohydrate (210 mg, 1.08 mmol), and raise the temperature to 100°C under nitrogen protection and stir for 16 hours. Cool to room temperature, add 20 mL saturated aqueous sodium bicarbonate solution and 50 mL methylene chloride to separate layers, concentrate the organic layer under reduced pressure, and purify the residue by silica gel column chromatography (mobile phase: DCM/MeOH (V/V) = 100/1- 20/1), the crude product continues to be used for preparative HPLC (instrument: waters 2767 preparation liquid phase; chromatographic column: XBridge@Prep C18 (30mm×150mm); mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.1 % trifluoroacetic acid)), and the prepared product was alkalized with saturated sodium bicarbonate aqueous solution to obtain compound 9 (220 mg, yield: 39.66%).

LCMS m/z＝479.10[(M+2H)/2] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.13–11.01(m,2H),8.57–8.26(m,1H),8.19(s,1H),8.10(s,1H),8.02(s,1H ),7.85(s,1H),7.68(d,1H),7.62(s,1H),7.48–7.20(m,3H),6.84(s,1H),6.75–6.52(m,1H),5.07( dd,1H),3.85(s,3H),3.81(s,3H),3.54–3.36(m,4H),2.99–2.80(m,5H),2.77–2.52(m,8H),2.06–1.82( m,5H),1.80(s,3H),1.77(s,3H).

Biological test examples

Test Example 1: Proliferation inhibitory activity against NCI-H1975 (EGFR-L858R-T790M) and A431 (EGFR-WT) cells

NCI-H1975 (EGFR-L858R-T790M) and A431 (EGFR-WT) cells were purchased from ATCC. The culture media were RPMI1640+10%FBS and DMEM+10%FBS respectively, in a 37°C, 5% CO ₂ incubator. nourish. On the first day, NCI-H1975 (EGFR-L858R-T790M) and A431 (EGFR-WT) cells in the exponential growth phase were collected, and viable cells were counted using an automatic cell analyzer (countstar). Adjust the cell suspension with culture medium and then plate it into a 96-well cell culture plate, with 1,000 NCI-H1975 (EGFR-L858R-T790M) cells per well and 3,000 A431 cells per well. The next day, the culture medium was aspirated, and 90 μL of fresh culture medium and 10 μL of compounds of different concentrations were added to each well. The final concentration of DMSO in each well was 0.1%. Incubate in a 37°C, 5% _CO2 incubator for 72 hours. After 72 hours of drug treatment, add 50 μL of CTG solution (promega, G7572) that was pre-melted and equilibrated to room temperature into each well, mix with a microplate shaker for 2 minutes, leave it at room temperature for 10 minutes, and then use a microplate reader (PHERAstar FSX) Measure the fluorescence signal value.

Cell viability was calculated using the formula V _sample /V _{vehicle control} x100%. Where V _sample is the reading of the drug treatment group, and V _vehicle _control is the average value of the solvent control group. Using origin9.2 software, a nonlinear regression model was used to draw a S-type dose-survival rate curve and calculate the IC ₅₀ value.

Table 1 Results of the proliferation inhibitory activity of test compounds on NCI-H1975 (EGFR-L858R-T790M) cells

Note: A＜0.2μM in Table 1

Table 2 Results of the proliferation inhibitory activity of test compounds on A431 (EGFR-WT) cells

Note: 10μM≤C in Table 2

Conclusion: The compounds of the present invention, such as the compounds in the examples, have good proliferation inhibitory activity on NCI-H1975 (EGFR-L858R-T790M) cells; they have poor inhibitory activity on A431 (EGFR-WT) cells and have good selectivity.

Test Example 2: Mouse Pharmacokinetic Test

Purpose of the experiment: In this experiment, the test substance was administered intravenously and intragastrically to ICR mice in a single dose, to measure the concentration of the test substance in the plasma of the mice, and to evaluate the pharmacokinetic characteristics and bioavailability of the test substance in the mice.

Experimental animals: male ICR mice, 20 to 25 g. Purchased from Beijing Huafukang Biotechnology Co., Ltd., experimental animal production license number: SCXK (Beijing) 2019-0008; or Chengdu Dashuo Experimental Animal Co., Ltd. (SCXK (Sichuan) 2020-030); or Hunan Slack King Da Experimental Animal Co., Ltd. (SCXK (Hunan) 2019-0004).

Test method: On the day of the test, ICR mice were randomly divided into groups according to body weight. The patient was fasted for 12 to 14 hours on the day before administration and resumed food 4 hours after administration.

^* The dosage is based on free base, and the dosage for intravenous administration is either 2.5 mg/kg or 1 mg/kg;

Sampling: Before and after administration, blood was collected through the orbit under isoflurane anesthesia and placed in EDTAK ₂ centrifuge tubes. Centrifuge at 5000 rpm and 4°C for 10 min to collect plasma.

Time points for collecting plasma in G1&G2 group: 0, 5min, 15min, 30min, 1, 2, 4, 7, 24h;

Time points for plasma collection in group G3: 0, 5min, 15min, 30min, 1, 2, 4, 7, 24h;

Before analysis and testing, all samples were stored below -60°C. Samples were quantitatively analyzed using LC-MS/MS.

Table 3 Mouse PK data of test compounds (administration method ig (10mg/kg))

*Note: Compounds were administered i.g. (gavage).

Conclusion: The compounds synthesized using the technology of the present invention, such as the example compounds, have better oral absorption performance in mice, and the oral performance is better than that of control compounds A and B.

Test Example 3: Rat Pharmacokinetic Test

Test animals: male SD rats, about 220g, 6 to 8 weeks old. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

Experimental design: On the day of the experiment, SD rats were randomly divided into groups according to body weight. No food and water for 12 to 14 hours one day before administration, and food 4 hours after administration.

Note: Intravenous administration vehicle: 5% DMA+5% Solutol+90% Saline;

Intragastric administration vehicle: 5% DMSO+5% Solutol+30% PEG400+60% (20% SBE-CD)

(DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: physiological saline; MC: methylcellulose)

Before and after administration, 0.15 ml of blood was taken from the orbit under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, centrifuged at 5000 rpm, 4°C for 10 min, and plasma was collected. The blood collection time points for both the intravenous group and the intragastric group were: 0, 5, 15, 30min, 1, 2, 4, 6, 8, and 24h. Before analysis and testing, all samples were stored below -60°C. Samples were quantitatively analyzed using LC-MS/MS.

Conclusion: The compounds synthesized using the technology of the present invention, such as the example compounds, have certain oral absorption properties in rats.

Test Example 4: hERG potassium ion channel function test

Experimental platform: electrophysiology manual patch clamp system

Cell line: Chinese hamster ovary (CHO) cell line stably expressing hERG potassium channel

Experimental method: CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channels were used to record hERG potassium channel currents at room temperature using whole-cell patch clamp technology. The glass microelectrode is drawn from a glass electrode blank (BF150-86-10, Sutter) by a drawing instrument. The tip resistance after infusion of the electrode liquid is about 2-5MΩ. The glass microelectrode can be connected by inserting it into the amplifier probe. to the patch clamp amplifier. Clamp voltage and data recording were controlled and recorded via computer using pClamp 10 software, with a sampling frequency of 10kHz and a filtering frequency of 2kHz. After obtaining the whole-cell recording, the cells were clamped at -80mV, and the step voltage of induced hERG potassium current (I _hERG ) was given a 2s depolarization voltage from -80mV to +20mV, and then repolarization to -50mV for 1s. then returns to -80mV. This voltage stimulation was given every 10 s, and the administration process was started after confirming that the hERG potassium current was stable (at least 1 minute). Compounds were administered for at least 1 min at each concentration tested, and at least 2 cells were tested at each concentration (n ≥ 2).

Data processing: pClamp 10, GraphPad Prism 5 and Excel software were used for data analysis and processing. The degree of inhibition of hERG potassium current (peak hERG tail current induced at -50mV) at different compound concentrations was calculated using the following formula:
Inhibition%＝[1–(I/Io)]×100%

Among them, Inhibition% represents the inhibition percentage of the hERG potassium current by the compound, and I and Io represent the amplitude of the hERG potassium current after and before the addition of the drug, respectively.

Compound IC ₅₀ was calculated by fitting the following equation using GraphPad Prism 5 software:
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))

Among them, X is the Log value of the detection concentration of the test product, Y is the inhibition percentage at the corresponding concentration, Bottom

and Top are the minimum and maximum inhibition percentages, respectively.

Conclusion: The compounds of the present invention, such as the example compounds, have poor inhibitory activity on hERG potassium ion channels.

Test Example 5: Liver Microsome Stability Test

The experiment used five types of hepatic microsomes from humans, dogs, rats and mice as in vitro models to evaluate the metabolic stability of the test substances.

At 37°C, 1 μM of the test substance was incubated with microsomal protein and coenzyme NADPH. After the reaction reached a certain time (5, 10, 20, 30, 60 min), ice-cold acetonitrile containing an internal standard was added to terminate the reaction. LC-MS/ The MS method detects the concentration of the test substance in the sample, and calculates T _1/2 based on the ln value of the remaining rate of the drug in the incubation system and the incubation time, and further calculates the liver microsome intrinsic clearance rate CL _{int (mic)} and the liver intrinsic clearance rate CL _int(Liver) .

Conclusion: The compounds of the present invention, such as the example compounds, have good liver microsome stability.

Test Example 6: CYP450 Enzyme Inhibition Test

The purpose of this study is to apply an in vitro test system to evaluate the effect of test substances on the activity of five isoenzymes of human liver microsomal cytochrome P450 (CYP) (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4). The specific probe substrates of CYP450 isoenzymes were incubated with human liver microsomes and test substances of different concentrations, and reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to start the reaction. After the reaction, By processing the sample and using liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to quantitatively detect the metabolites produced by the specific substrate, determine the changes in CYP enzyme activity, calculate the IC ₅₀ value, and evaluate the effect of the test substance on each Inhibitory potential of CYP enzyme isoforms.

Experimental results: Under test conditions, when the incubation concentration is 0~50/100μM, the IC ₅₀ value of each test compound for CYP enzyme inhibition

Conclusion: The compounds of the present invention, such as the example compounds, have weak CYP inhibitory activity.

Test Example 7: EGFR protein degradation activity in cells H1975-EGFR-T790M-L858R-C797S

method one:

Protein sample preparation: Cells NCI-H1975EGFR-L858R-T790M-C797S were cultured in a 37°C, 5% CO ₂ incubator, and the culture medium was RPMI1640+10% FBS+100 μg/mL hygromycin. Collect cells in the exponential growth phase, adjust the cell suspension to an appropriate concentration with hygromycin-free culture medium, and then plate it into a 6-well plate with a plating density of 200,000 cells/well and a plating volume of 2 mL. Cultivate overnight at 37°C and 5 % _CO2 incubator. The next day, add different concentrations of compounds and set up DMSO control wells to ensure that the DMSO concentration in all wells is 0.1%. Place the 6-well plate in a 37°C, 5% _CO2 incubator for 72 hours, add 30 μL of RIPA lysis buffer (Beyotime, Cat.P0013B) containing protease inhibitor (Beyotime, Cat.P0013B), and lyse on ice. 30 minutes. Centrifuge at 13,000 rpm for 20 min at 4°C, collect the protein supernatant samples, use the BCA method for protein quantification, and prepare Western Blot detection samples.

Western detection: Add 20 μg protein sample to each well, perform polyacrylamide gel electrophoresis and transfer to membrane. After transfer, add diluted anti-EGFR (CST, Cat. 4267S) and NADPH (Kangchen, Cat. KC-5G4) antibodies and incubate at 4°C overnight. After washing the membrane, add diluted goat anti-rabbit (Licor, Cat. 926-32211) and goat anti-mouse (Licor, Cat. 926-68070) antibodies and incubate in the dark for 45 minutes. A far-infrared imaging system (Odyssey) was used to scan and detect at wavelengths of 700 nm and 800 nm.

Calculate the expression of EGFR protein in cells relative to the DMSO control group after incubation with compounds of different concentrations according to formula (7-1). Among them, EGFR _compound is the fluorescence value of EGFR protein after incubation with the compound, and EGFR _vehicle is the fluorescence value of EGFR protein in the DMSO control group. Use Origin9.2 software to calculate the drug concentration DC ₅₀ value when the expression level of EGFR protein is 50% relative to the DMSO control group.
EGFR%=EGFR _compound /EGFR _vehicle ×100% Formula (7-1)

Method Two:

Protein sample preparation: Cells NCI-H1975EGFR-L858R-T790M-C797S were cultured in a 37°C, 5% CO ₂ incubator, and the culture medium was RPMI1640+10% FBS+100 μg/mL hygromycin. Collect cells in the exponential growth phase, adjust the cell suspension to an appropriate concentration with hygromycin-free culture medium, and then plate it into a 6-well plate with a plating density of 350,000 cells/well and a plating volume of 2 mL. Cultivate overnight at 37°C and 5 % _CO2 incubator. The next day, add different concentrations of compounds and set up DMSO control wells to ensure that the DMSO concentration in all wells is 0.1%. Place the 6-well plate in a 37°C, 5% _CO2 incubator for 48 hours, add 30 μL of RIPA lysis buffer (Beyotime, Cat.P0013B) containing protease inhibitor (Beyotime, Cat.P0013B), and lyse on ice. 30 minutes. Centrifuge at 13,000 rpm for 20 minutes at 4°C, collect protein supernatant samples, and perform protein quantification using the BCA method. Prepare samples for Western Blot testing.

Calculate the expression of EGFR protein in cells relative to the DMSO control group after incubation with compounds of different concentrations according to formula (7-1). Among them, EGFR _compound is the fluorescence value of EGFR protein after incubation with the compound, and EGFR _vehicle is the fluorescence value of EGFR protein in the DMSO control group. Use Origin9.2 software to calculate the drug concentration DC ₅₀ value when the expression level of EGFR protein is 50% relative to the DMSO control group.

Conclusion: The compounds of the present invention, such as the example compounds, have good EGFR degradation activity.

Claims

A compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from the group consisting of compounds represented by general formula (I),

Z is selected from -C(=O)- or -CH 2 -;

R b1 is each independently selected from halogen, OH, CN, C 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 3 to 6-membered heterocycloalkyl The alkyl group, alkynyl group, alkoxy group, cycloalkyl group and heterocycloalkyl group are optionally substituted by 1 to 4 selected from halogen, OH, =O, NH 2 , CN, COOH, C 1-4 Substituted with a substituent of alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl, the heterocycloalkyl contains 1 to 3 heteroatoms selected from O, S, and N;

R b2 is selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, and the alkyl or alkoxy group is optionally substituted by 1 to 4 selected from halogen, CN, OH, C 1-4 alkyl Substituted with substituents of base, C 1-4 alkoxy group, and C 3-6 cycloalkyl group;

R b3 is selected from H, halogen, C 1-4 alkyl, C 1-4 alkoxy, and the alkyl or alkoxy group optionally has 1 to 4 selected from halogen, CN, OH, C 1- Substituted with substituents of 4 alkyl, C 1-4 alkoxy, and C 3-6 cycloalkyl;

R b4 is selected from H, halogen, CN, OH, C 1-4 alkyl, C 1-4 alkoxy or 5 to 6-membered heteroaryl, and the alkyl, alkoxy or heteroaryl is optional Substituted by 1 to 4 substituents selected from halogen, CN, OH, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl , the heteroaryl group contains 1 to 3 heteroatoms selected from O, S, and N;

R b5 is each independently selected from H, halogen, CN, OH, C 1-4 alkyl, C 1-4 alkoxy, and the alkyl and alkoxy groups are optionally substituted by 1 to 4 selected from halogen, Substituted with substituents of CN, OH, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl;

R a and R b are each independently selected from H, halogen, and C 1-4 alkyl;

Cy1 and Cy2 are each independently selected from the group consisting of 4-7 membered nitrogen-containing heteromonocyclic rings, 4-10-membered nitrogen-containing heterocyclic rings, and 5-12-membered nitrogen-containing heterospirocyclic rings. The ring is optionally substituted by 1 to 4 atoms selected from halogen, OH, COOH, CN, NH 2 , =O, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, and hydroxyl-substituted C 1-4 alkyl. Or substituted by a C 1-4 alkoxy substituent, the heteromonocyclic ring, heterocyclic ring, heterobridged ring, heterospirocyclic ring or heteroaryl group contains 1 to 4 heterocyclic groups selected from O, S, N atom;

R k1 is each independently selected from H, halogen, OH, NH 2 , CN, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, the alkyl, alkoxy , cycloalkyl is optionally substituted by 1 to 4 substituents selected from halogen, OH, CN, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl;

Alternatively, two R k1 and the atoms to which they are connected together form a C 3-6 carbocyclic ring or a 4 to 7-membered heterocyclic ring, and the said carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 atoms selected from H, halogen, OH, =O, NH 2 , CN, C 1-4 alkyl or C 1-4 alkoxy substituents substituted, the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, N;

Rk2 is each independently selected from H, halogen, OH, CN, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, the alkyl, alkoxy, cycloalkyl The base is optionally substituted by 1 to 4 substituents selected from halogen, OH, CN, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl;

Or two R k2 and the carbon atoms or ring skeleton directly connected to the two together form a C 3-6 carbocyclic ring or a 3-8 membered heterocyclic ring, and the carbocyclic ring or heterocyclic ring is optionally selected from 1 to 4 halogens. , OH, =O, NH 2 , CN, C 1-4 alkyl or C 1-4 alkoxy substituents, the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, N ;

b1 and b5 are each independently selected from 0, 1, 2 or 3;

p1 or p2 are each independently selected from 0, 1, 2, 3, 4 or 5,

The condition is when Selected from When, at least one of R b2 , R b3 , R b4 , Cy1 and Cy2 contains F;

And the compound does not have the following structure:
The compound according to claim 1 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein,

R b1 is each independently selected from F, Cl, Br, I, OH, CN, methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, the The methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl groups are optionally replaced by 1 to 4 selected from halogen, OH, =O, NH 2 , CN, Substituted with substituents of COOH, C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl;

R b2 is selected from H, F, Cl, Br, I, methyl, and ethyl, and the methyl or ethyl group is optionally substituted by 1 to 4 selected from halogen, CN, OH, C 1-4 alkyl, Substituted with substituents of C 1-4 alkoxy and C 3-6 cycloalkyl;

R b3 is selected from H, F, Cl, Br, I, methyl, ethyl, methoxy or ethoxy, and the methyl, ethyl, methoxy or ethoxy is optionally replaced by 1 to 4 Substituted with a substituent selected from halogen, CN, OH, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl;

R b4 is selected from pyrazolyl, imidazolyl, pyrrolyl, and triazolyl, and the pyrazolyl, imidazolyl, pyrrolyl, and triazolyl are optionally substituted by 1 to 4 selected from halogen, CN, OH , C 1-4 alkyl, halogen-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl substituents;

R b5 is each independently selected from H, F, Cl, Br, I, OH, methyl, ethyl, methoxy or ethoxy, and the methyl, ethyl, methoxy or ethoxy is any Substituted by 1 to 4 substituents selected from halogen, CN, OH, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl;

R a and R b are each independently selected from H or F;

Cy1 and Cy2 are each independently selected from piperazinyl, piperidinyl, azetidinyl, azetipentyl, cyclobutylspiroazetihexyl, azetidinylspiroazetihexyl, cyclobutyl Basespiroazetidinyl, azetidinylspiroazetidinyl, azetidinylspiro Azepanyl, cyclohexylspiroazepanyl, cyclopentyl azepanyl, azepanyl azepanyl, the Cy1 and Cy2 are optionally selected from 1 to 4 halogens , OH, NH 2 , COOH, CN, =O, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl or C 1-4 alkoxy substituents replaced;

R k1 is each independently selected from H, F, Cl, Br, I, CF 3 , CHF 2 , CH 2 F, methyl, and ethyl;

p2 is 0.
The compound according to claim 2 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein,

R b1 is each independently selected from F, Cl, Br, I, OH, CN, methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, the The methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl groups are optionally replaced by 1 to 4 selected from F, Cl, Br, I, OH, CN, Substituted by methyl and ethyl substituents;

R b2 is selected from H, F, Cl, Br, I, methyl, and ethyl. The methyl or ethyl group is optionally substituted by 1 to 4 selected from F, Cl, Br, I, CN, OH, methane, etc. Substituted with ethyl or ethyl substituents;

R b3 is selected from H, F, Cl, Br, I, methyl, ethyl, methoxy or ethoxy, and the methyl, ethyl, methoxy or ethoxy is optionally replaced by 1 to 4 Substituted with a substituent selected from F, Cl, Br, I, CN, OH, methyl or ethyl;

R b4 is selected from pyrazolyl, imidazolyl, pyrrolyl, and triazolyl, and the pyrazolyl, imidazolyl, pyrrolyl, and triazolyl are optionally substituted by 1 to 4 selected from F, Cl, Br , I, CN, OH, CH 2 F, CHF 2 , CF 3 , methyl, ethyl substituents;

R b5 is each independently selected from H, F, Cl, Br, I, OH, methyl, ethyl, methoxy or ethoxy, and the methyl, ethyl, methoxy or ethoxy is any Replaced by 1 to 4 substituents selected from F, Cl, Br, I, CN, OH, methyl, and ethyl;

Cy1 and Cy2 are each independently selected from piperazinyl, piperidinyl, and azetidinyl, and Cy1 and Cy2 are optionally substituted by 1 to 4 selected from F, CF 3 , methyl, =O, and hydroxymethyl Substituted with , OH, COOH, CN or NH 2 substituents.
The compound according to claim 3 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein,

Z is selected from -C(=O)-;

R b1 is each independently selected from F, Cl, Br, I, CF 3 , cyclopropyl, cyclobutyl,

R b2 is selected from F, Cl, Br, I, CF 3 , CHF 2 , CH 2 F, methyl, and ethyl;

R b3 is selected from methoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy;

R b4 is selected from

Cy1 and Cy2 are each independently selected from

R a and R b are selected from H;

R k1 is selected from F, Cl, Br;

b1 is selected from 0, 1 or 2;

b5 is selected from 0 and 1;

p1 is chosen from 0 or 1.
The compound according to claim 1 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from one of the structures in Table E-1.
A pharmaceutical composition, comprising the compound of any one of claims 1 to 5 or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, and a pharmaceutical an acceptable carrier, preferably, the pharmaceutical composition contains 1-1500 mg of the compound according to any one of claims 1-5 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutical Acceptable salts or eutectics.
The compound described in any one of claims 1 to 5 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal or the drug and combination described in claim 6 The application of the substance in the preparation of drugs for treating diseases related to EGFR activity or expression.
The compound described in any one of claims 1 to 5 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal or the drug and combination described in claim 6 The application of substances in the preparation of drugs for treating diseases related to inhibition or degradation of EGFR.
The application according to claim 7 or 8, characterized in that the disease is selected from cancer.
A method for treating diseases in mammals, the method comprising administering to a subject a therapeutically effective amount of the compound of any one of claims 1-5 or its stereoisomers, deuterated products, solvates, or protoplasts. Drug, metabolite, pharmaceutically acceptable salt or co-crystal, the therapeutically effective dose is preferably 1-1500 mg, and the disease is cancer.