Pyrazole derivative and use thereof in medicine

Abstract

The present invention relates to a pyrazole derivative and a use thereof in medicine, and specifically relates to a compound as shown in general formula (I) or a stereoisomer, racemate, tautomer, and pharmaceutically acceptable salt thereof, an intermediate thereof, and a use thereof in inhibition or degradation of EGFR for treatment of EGFR-associated diseases such as cancer. B-L-K(I).

Description

Pyrazole derivatives and their use in medicine TECHNICAL FIELD

[0001] The present application relates to a compound of general formula (I) or its stereoisomer, racemate, tautomer, pharmaceutically acceptable salt, and intermediates and methods of preparation, and uses in EGFR related diseases such as cancer. BACKGROUND

[0002] Epidermal growth factor receptor (EGFR) is a transmembrane protein tyrosine kinase, which can trigger the EGFR signaling pathway in human epithelial cells as a receptor for EGF family members, 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 EGFR gene in human body leads to abnormal increase of EGFR activity, which can cause the occurrence of 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 (NSCLC) (Cells, 2019, 8, 350-361.).

[0003] PROTAC (proteolysis targeting chimera) molecules are a class of bifunctional compounds that can simultaneously bind to target proteins and E3 ubiquitin ligases. Such compounds can be recognized by the proteasome of the cell, causing degradation of the target protein, and can effectively reduce the content of the target protein in the cell. 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, and this technology has received widespread attention in recent years (ACS Chem. Biol. 2017, 12, 892-898; Drug Discovery Today Technol. 2019, 31, 15-27.).

[0004] Developing new PROTAC drugs that bind to EGFR protein for the treatment of diseases related to EGFR protein will have promising applications. SUMMARY

[0005] The purpose of the present application is to provide a compound with novel structure, good drug efficacy, high bioavailability, safety, and the ability to inhibit or degrade EGFR, for the treatment of diseases related to EGFR such as cancer.

[0006] The present application provides a compound or its stereoisomer, racemate, tautomer, pharmaceutically acceptable salt, wherein the compound is selected from the compounds represented by general formula (I),

[0007] B-L-K (I);

[0008] In some embodiments, the compound of Formula (I) is selected from the group consisting of compounds of Formula (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), (II-7), (II-8), (II-9),

[0009] In some embodiments, the compound of Formula (I) is selected from the group consisting of compounds of Formula (III-1), (III-2), or (III-3),

[0010] In some embodiments, the compound of Formula (I) is selected from the group consisting of compounds of Formula (IV-1), (IV-2), or (IV-3),

[0011] In some embodiments, L is selected from the group consisting of a bond or -C 1-50 hydrocarbyl-, said hydrocarbyl having 1 to 20 methylene units optionally replaced by -Ak- or -Cy-;

[0012] In some embodiments, L is selected from the group consisting of a bond or -C 1-20 hydrocarbyl-, said hydrocarbyl having 1 to 20 methylene units optionally replaced by -Ak- or -Cy-;

[0013] In some embodiments, each -Ak- is independently selected from the group consisting of -(CH2) q -, -(CH2) q -O-, -O-(CH2) q -, -(CH2) q -S-, -S-(CH2) q -, -(CH2) q -NR L -, -NR L -(CH2) q -, -(CH2) q -NR L C(=O)-, -NR L (CH2) q C(=O)-, -(CH2) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH2) q -NR L -, -(C≡C) q -, -CH=CH-, -Si(R L)2-、-Si(OH)(R L )-、-Si(OH)2-、-P(=O)(OR L )-、-P(=O)(R L )-, -S-, -S(=O)-, -S(=O)2- or a bond, wherein the CH, -CH2- is optionally replaced by 1 to 2 R z replace;

[0014] In some embodiments, q is each independently selected from 0, 1, 2, 3, 4, 5, or 6;

[0015] In some embodiments, R L Selected from H, deuterium, C 1-4 Alkyl, C 3-7 Carbocyclic group, 4 to 10 membered heterocyclic group, said alkyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R z replace;

[0016] In some embodiments, R L Selected from H, deuterium or C 1-4 alkyl;

[0017] In some embodiments, R L is selected from H, deuterium, methyl or ethyl;

[0018] In some embodiments, each -Cy- is independently selected from a bond or optionally substituted by 1 to 4 R L2 One of the following substituted groups: 4-8 membered heteromonocyclic group, 4-12 membered heterocyclic group, 5-13 membered heterospirocyclic group, 7-12 membered heterobridged ring group, C 3-7 Monocyclic alkyl, C 4-7 Monocyclic alkenyl, C 4-12 Cycloalkyl, C 5-13 Spiroalkyl, C 5-12 Bridged cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl;

[0019] In some embodiments, Ak is selected from Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, or Ak9;

[0020] In some embodiments, Ak is selected from Ak1, Ak2, Ak3, Ak4, or Ak5;

[0021] In some embodiments, -Cy- is selected from Cy1, Cy2, Cy3, Cy4, or Cy5;

[0022] In some embodiments, -Cy- is selected from Cy1, Cy2, Cy3, or Cy4;

[0023] In some embodiments, L is selected from -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Ak5-, -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Cy4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Ak5-Cy4-, -Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Ak2-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Cy4-Ak3-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Cy2-Cy3-Cy4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Cy3-Cy4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Cy4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Ak5-Cy1-Cy2-Cy3-Cy4-, -Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5- Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Cy4-Ak5-, -Ak1-Cy1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Cy1-Cy2-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Ak1-Cy1-Cy2-Cy3-Ak2-Ak3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Cy1-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Cy1-Cy2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Ak1-Ak2-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Ak3-Cy1-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy2-Ak4-Ak5-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Ak5-Cy3-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Ak5-Cy4-, -Ak1-, -Ak1-Ak2-, -Ak1-Ak2-Ak3-, -Ak1-Ak2-Ak3-Ak4-, -Ak1-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-, -Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-, -Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-, -Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-Ak9-;

[0024] -Cy1-Cy2-Cy3-Cy4-Ak4-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-, -Ak1-Cy2-, -Ak1-Cy2-Cy3-, -Ak1-Ak2-Cy3-, -Ak1-Ak2-Cy3-Cy4-, -Ak1-Cy2-Ak2-Cy3-, -Ak1-Cy2-Cy3-Ak3-Cy4-, -Ak1-Cy2-Cy3-Cy4-Ak4-Cy5-, -Ak1-Cy2-Ak2-, -Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak2-Cy3-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-Ak6-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-Ak9-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-Ak9-Ak10-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-Ak9-Ak10-Ak11-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-Ak9-Ak10-Ak11-Ak12-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-Ak9-Ak10-Ak11-Ak12-Ak13-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-Ak9-Ak10-Ak11-Ak12-Ak13-Ak14-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-Ak9-Ak10-Ak11-Ak12-Ak13-Ak14-Ak15-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-Ak9-Ak10-Ak11-Ak12-Ak13-Ak14-Ak15-Ak16-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-Ak9-Ak10-Ak11-Ak12-Ak13-Ak14-Ak15-Ak16-Ak17-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-Ak9-Ak10-Ak11-Ak12-Ak13-Ak14-Ak15-Ak16-Ak17-Ak18-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-Ak9-Ak10-Ak11-Ak12-Ak13-Ak14-Ak15-Ak16-Ak17-Ak18-Ak19-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-Ak9-Ak10-Ak11-Ak12-Ak13-Ak14-Ak15-Ak16-Ak17-Ak18-Ak19-Ak20-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-Ak9-Ak10-Ak11-Ak12-Ak13-Ak14-Ak15-Ak16-Ak17-Ak18-Ak19-Ak20-Ak21-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-Ak9-Ak10-Ak11-Ak12-Ak13-Ak14-Ak15-Ak16-Ak17-Ak18-Ak19-Ak20-Ak21-Ak22-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-Ak9-Ak10-Ak11-Ak12-Ak13-Ak14-Ak15-Ak16-Ak17-Ak18-Ak19-Ak20-Ak21-Ak22-Ak23-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-Ak9-Ak10-Ak11-Ak12-Ak13-Ak14-Ak15-Ak16-Ak17-Ak18-Ak19-Ak20-Ak21-Ak22-Ak23-Ak24-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-Ak9-Ak10-Ak11-Ak12-Ak13-Ak14-Ak15-Ak16-Ak17-Ak18-Ak19-Ak20-Ak21-Ak22-Ak23-Ak24-Ak25-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-Ak9-Ak10-Ak11-Ak12-Ak13-Ak14-Ak15-Ak16-Ak17-Ak18-Ak19-Ak20-Ak21-Ak22-Ak23-Ak24-Ak25-Ak26-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-Ak9-Ak10-Ak11-Ak12-Ak13-Ak14-Ak15-Ak16-Ak17-Ak18-Ak19-Ak20-Ak21-Ak22-Ak23-Ak24-Ak25-Ak26-Ak27-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-Ak9-Ak10-Ak11-Ak12-Ak13-Ak14-Ak15-Ak16-Ak17-Ak18-Ak19-Ak20-Ak21-Ak22-Ak23-Ak24-Ak25-Ak26-Ak27-Ak28-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-Ak9-Ak10-Ak11-Ak12-Ak13-Ak14-Ak15-Ak16-Ak17-Ak18-Ak19-Ak20-Ak21-Ak22-Ak23-Ak24-Ak25-Ak26-Ak27-Ak28-Ak29-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-Ak9-Ak10-Ak11-Ak12-Ak13-Ak14-Ak15-Ak16-Ak17-Ak18-Ak19-Ak20-Ak21-Ak22-Ak23-Ak24-Ak25-Ak26-Ak27-Ak28-Ak29-Ak30-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-Ak9-Ak10-Ak11-Ak12-Ak13-Ak14-Ak15-Ak16-Ak17-Ak18-Ak19-Ak20-Ak21-Ak22-Ak23-Ak24-Ak25-Ak26-Ak27-Ak28-Ak29-Ak30-Ak31-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-Ak9-Ak10-Ak11-Ak12-Ak13-Ak14-Ak15-Ak16-Ak17-Ak18-Ak19-Ak20-Ak21-Ak22-Ak23-Ak24-Ak25-Ak26-Ak27-Ak28-Ak29-Ak30-Ak31-Ak32-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-Ak9-Ak10-Ak11-Ak12-Ak13-Ak14-Ak15-Ak16-Ak17-Ak18-Ak19-Ak20-Ak21-Ak22-Ak23-Ak24-Ak25-Ak26-Ak27-Ak28-Ak29-Ak30-Ak31-Ak32-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-, -Ak1-Cy 2-Ak2-Ak3-Ak4-Ak5-, -Ak1-Cy2-Ak2-Ak3-Ak4-, -Ak1-Cy2-Ak2-Ak3-;,

[0025] In some embodiments, L is selected from -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-;

[0026] In some embodiments, L is selected from -NHCH2-, -Cy1-, -Cy1-CH2-, -Cy1-C≡C-, -Cy1-Cy2-, -Cy1-CH2-Cy2-, -Cy1-Cy2-Cy3-, -Cy1-CH2-Cy2-Cy3-, -Cy1-Cy2-CH2-Cy3-, -NH-Cy1-, -NH-Cy1-Cy2-, -NH-Cy1-CH2-Cy2, -Cy1-Ak1-;

[0027] In some embodiments, L is selected from -Cy1-, -Cy1-Cy2-, -Cy1-Cy2-Cy3-, -Cy1-Ak2-Cy2-Cy3-, -Cy1-Cy2-Ak3-Cy3-, -Cy1-Ak2-, -Cy1-Ak2-Cy2-, -Ak1-Cy1-Ak2-;

[0028] In some embodiments, La or Lb is selected from -Cy1-, -Cy1-CH2-, -Cy1-Cy2-, -Cy1-CH2-Cy2-;

[0029] In some embodiments, La is selected from -Cy1-, -Cy1-CH2-;

[0030] In some embodiments, Lb is selected from -Cy1-Cy2-, -Cy1-CH2-Cy2-;

[0031] In some embodiments, Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, and Ak9 are each independently selected from -(CH2) q -、-(CH2) q -O-, -O-(CH2) q -、-(CH2) q -S-, -S-(CH2) q -、-(CH2) q -NR L -、-NR L -(CH2) q -、-(CH2)q -NR L C(=O)-, -(CH2) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH2) q -NR L -, -(C≡C) q - or a bond, said -CH2- being optionally substituted with 1 to 2 R z ;

[0032] In some embodiments, Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, Ak9 are each independently selected from a bond, -O-, -S-, -OCH2-, -CH2O-, -OCH2CH2-, -CH2CH2O-, -C≡C-, -C(CH3)2-, -CH2-, -CH2CH2-, -CH2CH2CH2-, -N(CH3)-, -NH-, -CH2N(CH3)-, -CH2NH-, -NHCH2-, -CH2CH2N(CH3)-, -CH2CH2NH-, -NHCH2CH2-, -C(=O)-, -C(=O)CH2NH-, -CH2C(=O)NH-, -C(=O)NH-, or -NHC(=O)-;

[0033] In some embodiments, Ak1, Ak2, Ak3, Ak4, Ak5 are each independently selected from -(CH2) q -, -(CH2) q -O-, -O-(CH2) q -, -(CH2) q -S-, -S-(CH2) q -, -(CH2) q -NR L -, -NR L -(CH2) q -, -(CH2) q -NR L C(=O)-, -(CH2) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH2) q -NR L -, -(C≡C) q - or a bond, said -CH2- being optionally substituted with 1 to 2 R z ;

[0034] In some embodiments, each Ak1, Ak2, Ak3, Ak4, Ak5 is independently selected from a bond, -O-, -S-, -OCH2-, -CH2O-, -OCH2CH2-, -CH2CH2O-, -C≡C-, -C(CH3)2-, -CH2-, -CH2CH2-, -CH2CH2CH2-, -N(CH3)-, -NH-, -CH2N(CH3)-, -CH2NH-, -NHCH2-, -CH2CH2N(CH3)-, -CH2CH2NH-, -NHCH2CH2-, -C(=O)-, -C(=O)CH2NH-, -CH2C(=O)NH-, -C(=O)NH-, or -NHC(=O)-;

[0035] In some embodiments, each Ak1, Ak2, or Ak3 is independently selected from a bond, -O-, -S-, -OCH2-, -CH2O-, -OCH2CH2-, -CH2CH2O-, -C≡C-, -C(CH3)2-, -CH2-, -CH2CH2-, -CH2CH2CH2-, -N(CH3)-, -NH-, -CH2N(CH3)-, -CH2NH-, -NHCH2-, -CH2CH2N(CH3)-, -CH2CH2NH-, -NHCH2CH2-, -C(=O)-, -C(=O)CH2NH-, -CH2C(=O)NH-, -C(=O)NH-, or -NHC(=O)-;

[0036] In some embodiments, each Cy1, Cy2, Cy3, Cy4, or Cy5 is independently selected from a bond or optionally substituted by 1 to 4 R L2 one of the following groups: 4-7 membered nitrogen-containing heteromonocyclic group, 4-12 membered nitrogen-containing heteroannular group, 5-13 membered nitrogen-containing heterospirocyclic group, 7-12 membered nitrogen-containing heterobridged cyclic group, C 3-7 monocyclic alkyl group, C 4-7 monocyclic alkenyl group, C 4-12 annular alkyl group, C 5-13 spirocyclic alkyl group, C 7-12 bridged cyclic alkyl group, 5-10 membered heteroaryl group, or C 6-10 aryl group;

[0037] In some embodiments, the definition of Cy5 is the same as Cy1;

[0038] In some embodiments, each Cy1, Cy2, Cy3, Cy4 is independently selected from a bond or optionally substituted by 1 to 4 R L2 one of the following groups: phenyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, pyridazinyl group, pyrazolyl group, thiazolyl group, oxazolyl group, triazolyl group, In some embodiments, the definition of Cy5 is the same as Cy1; s1, s3, s5 are each independently selected from 0, 1, or 2, s2, s4 are each independently selected from 0 or 1, s6 is selected from 0, 1, 2, or 3, s7 is selected from 1, 2, or 3;

[0039] In some embodiments, Cy1, Cy2, Cy3, Cy4 are each independently selected from a bond or one of the following groups optionally substituted:

[0040] when substituted, substituted with 1 to 4 substituents selected from deuterium, F, CF3, OH, =0, COOH, CN, NH2, hydroxymethyl, methyl, methoxy, cyclopropyl,

[0041] In some embodiments, Cy1, Cy2, Cy3 are each independently selected from a bond or one of the following groups optionally substituted:

[0042] when substituted, substituted with 1 to 4 substituents selected from deuterium, F, CF3, OH, =0, COOH, CN, NH2, hydroxymethyl, methyl, methoxy, cyclopropyl,

[0043] In some embodiments, Cy1or Cy2is selected from each independently one of the following groups optionally substituted: when substituted, substituted with 1 to 4 substituents selected from deuterium, F, CF3, OH, =0, COOH, CN, NH2, hydroxymethyl, methyl, methoxy, cyclopropyl,

[0044] In some embodiments, B is selected from In some embodiments, B is selected from In some embodiments, B is selected from

[0045] In some embodiments, B is selected from

[0046] In some embodiments, X is selected from O, NH, or S;

[0047] In some embodiments, B1is selected from a 5-12 membered heterocyclyl;

[0048] ​​​In some embodiments, B1is selected from 5-6 membered heteroaryl, 9-10 membered heteroaryl;

[0049] In some embodiments, B1is selected from 6 membered heteroaryl, 9 membered heteroaryl, 10 membered heteroaryl;

[0050] In some embodiments, B1is selected from pyridyl, benzothiazolyl, benzothiophenyl, benzimidazolyl, pyrimidinyl, pyridinonyl, pyridazinyl, pyrazinyl,

[0051] In some embodiments, B1is selected from pyridyl, benzothiazolyl, or pyridinonyl;

[0052] In some embodiments, b1is selected from 0, 1, 2, 3, or 4;

[0053] In some embodiments, b1is selected from 0, 1, or 2;

[0054] In some embodiments, b2is selected from 0, 1, 2, or 3;

[0055] In some embodiments, L B is selected from -(CR Lb1 R Lb2 ) m -; 1 to 5 -CR B R Lb1 - in said L Lb2 are optionally replaced with -Akb- or -Cyb-;

[0056] In some embodiments, L B is selected from -(CR Lb1 R Lb2 ) m -; 1 to 3 -CR B R Lb1 - in said L Lb2 are optionally replaced with -Akb- or -Cyb-;

[0057] In some embodiments, L B is selected from -(CR Lb1 R Lb2 ) m -; 1 to 2 -CR B R Lb1 - in said L Lb2 are optionally replaced with -Akb- or -Cyb-;

[0058] In some embodiments, L B is selected from

[0059] In some embodiments, m is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

[0060] In some embodiments, m is selected from 0, 1, 2, 3, 4, 5, 6, 7, or 8;

[0061] In some embodiments, m is selected from 0, 1, 2, 3, 4, 5, or 6;

[0062] In some embodiments, each -Akb- is independently selected from -O-, -S-, -NR Lb3 -, -C(=O)-, -C≡C-, -CR Lb4 =CR Lb5 -, -S(=O)-, or -S(=O)2-;

[0063] In some embodiments, each -Akb- is independently selected from -O-, -S-, -NR Lb3 -, or -C(=O)-;

[0064] In some embodiments, each -Akb- is independently selected from -O-;

[0065] In some embodiments, each -Cyb- is independently selected from one of the following groups optionally substituted with 1 to 4 R L2 4-8 membered heteromonocyclic, 4-12 membered heteroannular, 5-13 membered heterospirocyclic, 7-12 membered heterobicyclic, C 3-7 monocycloalkyl, C 4-7 monocycloalkenyl, C 4-12 annular alkyl, C 5-13 spirocycloalkyl, C 5-12 bicycloalkyl, 5-10 membered heteroaryl, or C 6-10 aryl;

[0066] In some embodiments, each -Cyb- is independently selected from one of the following groups optionally substituted with 1 to 4 R L2 4-7 membered nitrogen-containing heteromonocyclic, 4-12 membered nitrogen-containing heteroannular, 5-13 membered nitrogen-containing heterospirocyclic, 7-12 membered nitrogen-containing heterobicyclic, C 3-7 monocycloalkyl, C 4-7 monocycloalkenyl, C 4-12 annular alkyl, C 5-13 spirocycloalkyl, C 5-12 bicycloalkyl, 5-10 membered heteroaryl, or C 6-10 aryl;

[0067] In some embodiments, each -Cyb- is independently selected from one of the following groups optionally substituted with 1 to 4 R L2 4-7 membered nitrogen-containing heteromonocyclic, or C3-7 monocycloalkyl;

[0068] In some embodiments, each -Cyb- is each independently selected from optionally substituted one of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; L2 monocycloalkyl;

[0069] In some embodiments, each -Cyb- is each independently selected from cyclopropyl;

[0070] In some embodiments, R Lb1 , R Lb2 are each independently selected from H, deuterium, F, Cl, Br, I, OH, =0, NH2, CN, COOH, CONH2, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl, heterocyclyl optionally substituted with 1 to 4 R z ;

[0071] In some embodiments, R Lb1 , R Lb2 are each independently selected from H, deuterium, F, Cl, Br, I, OH, =0, NH2, CN, COOH, CONH2, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl, heterocyclyl optionally substituted with 1 to 4 R z ;

[0072] In some embodiments, R Lb1 , R Lb2 are each independently selected from H, deuterium, F, Cl, Br, I, OH, =0, NH2, CN, COOH, CONH2, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, ethenyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, said methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, ethenyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl optionally substituted with 1 to 4 R z ;

[0073] In some embodiments, R Lb1 , R Lb2each independently selected from H, deuterium, F, Cl, Br, I, OH, =0, NH2, CN, COOH, CONH2, CD3, CF3, OCD3, OCF3, methyl, ethyl, methoxy, ethoxy, or cyclopropyl, said methyl, ethyl, methoxy, ethoxy, or cyclopropyl optionally substituted with 1 to 4 R z substituted;

[0074] In some embodiments, R Lb1 , R Lb2 each independently selected from H, deuterium, F, Cl, Br, I, OH, =0, NH2, CN, COOH, CONH2, CD3, CF3, OCD3, OCF3, methyl, ethyl, methoxy, ethoxy, or cyclopropyl;

[0075] In some embodiments, R Lb3 each independently selected from H, deuterium, F, Cl, Br, I, OH, =0, NH2, CN, COOH, CONH2, C 1-6 alkyl, C 3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, said alkyl, carbocyclyl, heterocyclyl optionally substituted with 1 to 4 R z substituted;

[0076] In some embodiments, R Lb3 each independently selected from H, deuterium, F, Cl, Br, I, OH, =0, NH2, CN, COOH, CONH2, C 1-4 alkyl, C 3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, said alkyl, carbocyclyl, heterocyclyl optionally substituted with 1 to 4 R z substituted;

[0077] In some embodiments, R Lb3 each independently selected from H, deuterium, F, Cl, Br, I, OH, =0, NH2, CN, COOH, CONH2, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, said methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl optionally substituted with 1 to 4 R z substituted;

[0078] In some embodiments, R Lb3 each independently selected from H, deuterium, F, Cl, Br, I, OH, =0, NH2, CN, COOH, CONH2, methyl, ethyl, or cyclopropyl, said methyl, ethyl, or cyclopropyl optionally substituted with 1 to 4 R z substituted;

[0079] In some embodiments, R Lb3each independently selected from H, deuterium, F, CI, Br, I, OH, =0, NH2, CN, COOH, CONH2, CD3, CF3, methyl, ethyl, or cyclopropyl;

[0080] In some embodiments, R Lb4 or R Lb5 each independently selected from H, deuterium, F, C 1-6 alkyl, C 3-6 carbon ring group, or 3- to 6-membered heterocyclyl, said alkyl, carbon ring group, or heterocyclyl optionally substituted with 1 to 4 R z ;

[0081] In some embodiments, R Lb4 or R Lb5 each independently selected from H, deuterium, F, C 1-4 alkyl, C 3-6 carbon ring group, or 3- to 6-membered heterocyclyl, said alkyl, carbon ring group, or heterocyclyl optionally substituted with 1 to 4 R z ;

[0082] In some embodiments, R Lb4 or R Lb5 each independently selected from H, deuterium, F, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, said methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl optionally substituted with 1 to 4 R z ;

[0083] In some embodiments, R b1 , R b2 or R b4 each independently selected from H, deuterium, F, CI, Br, I, OH, =0, NH2, CN, COOH, CONH2, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylene-3- to 6-membered heterocyclyl, C 1-6 alkylene-C 3-6 carbon ring group, C 1-6 alkylene-O-C 3-6 carbon ring group, C 3-6 carbon ring group, or 3- to 6-membered heterocyclyl, said alkyl, alkylene, carbon ring group, or heterocyclyl optionally substituted with 1 to 4 R z ;

[0084] In some embodiments, R b1 , R b2 or R b4each independently selected from the group consisting of H, deuterium, F, Cl, Br, I, OH, =0, NH2, CN, COOH, CONH2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, ethenyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylene-O-cyclopropyl, ethylene-O-cyclopropyl, methylene-cyclopropyl, methylene-cyclobutyl, methylene-azetidinyl, methylene-pyrrolidinyl, methylene-piperidinyl, methylene-piperazinyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxetanyl, oxetanyl, oxetanyl, oxetanyl, oxetanyl, piperazinyl, optionally substituted with 1 to 4 R 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkylene-3- to 6-membered heterocyclyl, C 1-4 alkylene-C 3-6 carbocyclyl, C 3-6 carbocyclyl, C 1-4 alkylene-O-C 3-6 carbocyclyl or 3- to 6-membered heterocyclyl, said alkyl, alkylene, carbocyclyl or heterocyclyl optionally substituted with 1 to 4 R z substituents;

[0085] In some embodiments, R b1 , R b2 or R b4 each independently selected from the group consisting of H, deuterium, F, Cl, Br, I, OH, =0, NH2, CN, COOH, CONH2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, ethenyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylene-O-cyclopropyl, ethylene-O-cyclopropyl, methylene-cyclopropyl, methylene-cyclobutyl, methylene-azetidinyl, methylene-pyrrolidinyl, methylene-piperidinyl, methylene-piperazinyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxetanyl, oxetanyl, oxetanyl, oxetanyl, oxetanyl, piperazinyl, optionally substituted with 1 to 4 R z substituents;

[0086] In some embodiments, R b1 , R b2 or R b4 each independently selected from the group consisting of H, deuterium, F, Cl, Br, I, OH, =0, NH2, CN, COOH, CONH2, methyl, ethyl, propyl, isopropyl, methylene-cyclopropyl, methylene-cyclobutyl, methylene-azetidinyl, methylene-pyrrolidinyl, methylene-piperidinyl, methylene-piperazinyl, azetidinyl, pyrrolidinyl, piperidinyl, methylene-O-cyclopropyl, ethylene-O-cyclopropyl, methoxy, ethoxy or cyclopropyl, said methyl, ethyl, propyl, methylene, ethylene, isopropyl, methoxy, ethoxy, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or cyclopropyl optionally substituted with 1 to 4 R z substituents;

[0087] In some embodiments, R b1 , R b2 , or R b4 is each independently selected from H, deuterium, F, CI, Br, I, OH, =0, NH2, CN, COOH, CONH2, CD3, CHF2, CH2F, CF3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl,

[0088] In some embodiments, R b1 is each independently selected from H, deuterium, OH, NH2, CN, COOH, CONH2, CD3, CHF2, CH2F, CF3, methyl, ethyl, propyl, isopropyl, cyclopropyl,

[0089] In some embodiments, R b3 or R b5 is each independently selected from H, deuterium, F, CI, Br, I, OH, =0, NH2, CN, COOH, CONH2, C 1-6 alkyl, C 3-6 carbocyclyl, C 1-6 alkylene-3- to 6-membered heterocyclyl, C 1-6 alkylene-C 3-6 carbocyclyl, C 1-6 alkylene-O-C 3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, said alkyl, alkylene, carbocyclyl, or heterocyclyl optionally substituted with 1 to 4 R z groups;

[0090] In some embodiments, R b3 or R b5 is each independently selected from H, deuterium, F, CI, Br, I, OH, =0, NH2, CN, COOH, CONH2, C 1-4 alkyl, C 3-6 carbocyclyl, C 1-4 alkylene-3- to 6-membered heterocyclyl, C 1-4 alkylene-C 3-6 carbocyclyl, C 1-4 alkylene-O-C 3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, said alkyl, alkylene, carbocyclyl, or heterocyclyl optionally substituted with 1 to 4 R z groups;

[0091] In some embodiments, R b3or R b5 Each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylene-O-cyclopropyl, ethylene-O-cyclopropyl, methylene-cyclopropyl, methylene-cyclobutyl, methylene-azetidinyl, methylene-pyrrolidinyl, methylene-piperidinyl, methylene-piperazinyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolanyl, oxhexyl, said methyl, ethyl, propyl, methylene, ethylene, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, oxolanyl, oxhexyl, piperazinyl is optionally substituted by 1 to 4 R z replace;

[0092] In some embodiments, R b3 or R b5 each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, methyl, ethyl, propyl, isopropyl, methylene-cyclopropyl, methylene-cyclobutyl, methylene-azetidinyl, methylene-pyrrolidinyl, methylene-piperidinyl, methylene-piperazinyl, azetidinyl, pyrrolidinyl, piperidinyl, methylene-O-cyclopropyl, ethylene-O-cyclopropyl or cyclopropyl, wherein the methyl, ethyl, propyl, methylene, ethylene, isopropyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or cyclopropyl is optionally substituted by 1 to 4 R z replace;

[0093] In some embodiments, R b3 or R b5 Each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, CD3, CHF2, CH2F, CF3, methyl, ethyl, propyl, isopropyl, cyclopropyl,

[0094] In some embodiments, R b5 Each independently selected from H, deuterium, OH, NH2, CN, COOH, CONH2, CD3, CHF2, CH2F, CF3, methyl, ethyl, propyl, isopropyl, cyclopropyl,

[0095] In some embodiments, K is selected from

[0096] In some embodiments, K is selected from

[0097] In some embodiments, is selected from

[0098] In some embodiments, is selected from

[0099] In some embodiments, is selected from

[0100] In some embodiments, G is selected from N, CH, or CD;

[0101] In some embodiments, Q is each independently selected from a bond, -0-, -S-, -CH2-, -NR q -, -CO-, -NR q CO-, -CONR q -;

[0102] In some embodiments, Q and G cannot directly form a nitrogen-nitrogen bond, a nitrogen-oxygen bond, a nitrogen S bond;

[0103] In some embodiments, Q is each independently selected from a bond, CH2, NH, N(CH3), O, S, C(=0), NHC(=0), C(=0)NH, N(CH3)C(=0), C(=0)N(CH3);

[0104] In some embodiments, Q is selected from a bond, NHC(=0), C(=0)NH, N(CH3)C(=0), C(=0)N(CH3);

[0105] In some embodiments, R q is selected from H, deuterium, or C 1-4 alkyl;

[0106] In some embodiments, R q is selected from H, deuterium, methyl, or ethyl;

[0107] In some embodiments, F is each independently selected from phenyl, pyridyl, C 13-20 tricyclic carbocyclyl, or 13-20 membered tricyclic heterocyclyl;

[0108] In some embodiments, F is each independently selected from phenyl, pyridyl, 13-15 membered tricyclic heteroannular cyclyl;

[0109] In some embodiments, F is selected from phenyl, pyridyl, the ring to which it is attached is an aromatic or non-aromatic ring;

[0110] In some embodiments, H1is selected from N, NH, CH, CH2, CHR k1 , NR k1 , CR k1 , C(=O), C(R k1 )2;

[0111] In some embodiments, H1is selected from N, NH, CH, CH2, CHR k1 , NR k1 , CR k1 , C(=O);

[0112] In some embodiments, H2is selected from a bond, O, N, NH, CH, CH2, CHR k1 , NR k1 , CR k1 , or C(R k1 )2;

[0113] In some embodiments, H2is selected from a bond, O, N, NH, CH, CH2, CHR k1 , NR k1 , CR k1 , C(=O);

[0114] In some embodiments, H3is selected from N or CH;

[0115] In some embodiments, H4is selected from C, N or CH;

[0116] In some embodiments, H5, H6, H7are each independently selected from N, CH or CR k1 , and H5, H6, H7contain at most 2 N;

[0117] In some embodiments, H5or H6is selected from N or CR k1 ;

[0118] In some embodiments, R k1 are each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl being optionally substituted with 1 to 4 R z ;

[0119] In some embodiments, Rk2 each independently selected from a bond, -C(=0)-, -S(=0)2-, -S(=0)-, or -C(R k3 )2-;

[0120] In some embodiments, R k3 each independently selected from H, deuterium, F, Cl, Br, I, OH, =0, NH2, CN, COOH, CONH2, C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, or 3- to 8-membered heterocyclyl, said alkyl, alkoxy, cycloalkyl, or heterocyclyl optionally substituted with 1 to 4 R z substituents;

[0121] In some embodiments, two R k3 are directly connected to form a C 3-8 carbocyclyl or 4-8 membered heterocyclyl, said carbocyclyl or heterocyclyl optionally substituted with 1 to 4 R z substituents;

[0122] In some embodiments, R k1 , R k3 each independently selected from H, deuterium, F, Cl, Br, I, OH, =0, NH2, CF3, CN, COOH, CONH2, or optionally substituted with 1 to 4 R z substituents: methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl;

[0123] In some embodiments, R k1 each independently selected from H, deuterium, F, Cl, Br, I, OH, =0, NH2, CF3, CN, COOH, CONH2, CD3, CF3, OCD3, OCF3, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl.

[0124] In some embodiments, R L2 , R z each independently selected from deuterium, F, Cl, Br, I, OH, =0, CF3, SF5, CN, NH2, NO2, COOH, CONH2, NHC 1-4 alkyl, N(C 1-4 alkyl)2, COOH, CONH2, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, -S-C 1-4 alkyl, -C 0-4 alkylene-C 3-6 cycloalkyl, C1-4 alkylene-O-C 1-4 alkyl, the alkyl, alkylene, alkoxy, alkenyl, alkynyl, cycloalkyl are optionally substituted with one to four substituents selected from the group consisting of deuterium, F, Cl, Br, I, OH, CN, C 1-4 alkyl, C 1-4 alkoxy, and the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl are optionally substituted with one to four substituents selected from the group consisting of deuterium, F, Cl, Br, I, OH, CN, C

[0125] In some embodiments, R L2 , R z each independently is selected from the group consisting of deuterium, F, Cl, Br, I, OH, =O, CF3, SF5, CN, NH2, NO2, COOH, CONH2, N(CH3)2, NHCH3, methyl, ethyl, ethylene, ethyne, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, methylene-O-methyl, methylene-O-ethyl, ethylene-O-methyl, ethylene-O-ethyl, the methyl, methylene, ethylene, ethyl, ethylene, ethyne, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally substituted with one to four substituents selected from the group consisting of deuterium, F, Cl, Br, I, OH, CN, C 1-4 alkyl, C 1-4 alkoxy, and the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl are optionally substituted with one to four substituents selected from the group consisting of deuterium, F, Cl, Br, I, OH, CN, C

[0126] In some embodiments, R L2 is selected from the group consisting of deuterium, F, CF3, OH, =O, COOH, CN, NH2, hydroxymethyl, methyl, methoxy, cyclopropyl,

[0127] In some embodiments, R L2 is selected from the group consisting of deuterium, F, CF3, OH, =O, COOH, CN, NH2, hydroxymethyl, methyl, methoxy, cyclopropyl,

[0128] In some embodiments, n1 is selected from 0, 1, 2, or 3;

[0129] In some embodiments, p1 or p2 is each independently selected from 0, 1, 2, 3, 4, or 5;

[0130] In some embodiments, p2 is each independently selected from 0, 1, 2, or 3.

[0131] In some embodiments, p1 is selected from 0, 1, 2, or 3;

[0132] In some embodiments, L is selected from the group of radicals shown in Table L-1, wherein the radical is attached to B on the left side;

[0133] In some embodiments, L is selected from a bond, a group shown in Table L-1 or Table L-2, wherein the group is attached to B on the left side;

[0134] In some embodiments, L is selected from a bond or a group shown in Table L-2, wherein the group is attached to B on the left side;

[0135] Table L-1 L groups

[0136] Table L-2 L groups

[0137] In some embodiments, B is selected from one of the structural fragments described in B-1 ;

[0138] Table B-1

[0139] In some embodiments, K is selected from one of the structural fragments shown in Table K-1 ;

[0140] Table K-1

[0141] Optionally, when is selected from F is not selected from phenyl or pyridyl.

[0142] As a first embodiment of the present application, the aforementioned compound represented by the general formula (I) or a stereoisomer, a racemate, a tautomer, a pharmaceutically acceptable salt thereof, wherein,

[0143] L is selected from a bond or -C 1-50 hydrocarbyl, said hydrocarbyl having 1 to 20 methylene units optionally replaced by -Ak- or -Cy-;

[0144] each -Ak- is independently selected from -(CH2) q -, -(CH2) q -O-, -O-(CH2)q -S-, -S-(CH2) q -S-, -S-(CH2) q -S-, -S-(CH2) q -NR L -NR L -(CH2) q -(CH2) q -NR L C(=O)-, -NR L (CH2) q C(=O)-, -(CH2) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH2) q -NR L -, -(C≡C) q -, -CH=CH-, -Si(R L )2-, -Si(OH)(R L )-, -Si(OH)2-, -P(=O)(OR L )-, -P(=O)(R L )-, -S-, -S(=O)-, -S(=O)2- or a bond, said CH, -CH2- optionally being substituted with 1 to 2 R z ;

[0145] each q is independently selected from 0, 1, 2, 3, 4, 5 or 6;

[0146] R L is selected from H, deuterium, C 1-4 alkyl, C 3-7 carbocyclyl, 4- to 10-membered heterocyclyl, said alkyl, carbocyclyl or heterocyclyl being optionally substituted with 1 to 4 R z ;

[0147] each -Cy- is independently selected from one of the following groups: a bond or a 4-8 membered heteromonocyclic group, a 4-12 membered heteroannelated cyclic group, a 5-13 membered heterospirocyclic group, a 7-12 membered heterobridged cyclic group, a C L2 monocyclic alkyl group, a C 3-7 monocyclic alkenyl group, a C 4-7 annelated cyclic alkyl group, a C 4-12 annelated cyclic alkyl group, a C 5-13 spirocyclic alkyl group, a C 5-12 bridged cyclic alkyl group, a 5-10 membered heteroaryl group or a C 6-10 aryl group;

[0148] B is selected from

[0149] X is selected from O, NH or S;

[0150] B1is selected from 5-12 membered heterocyclyl;

[0151] b1is selected from 0, 1, 2, 3 or 4;

[0152] b2is selected from 0, 1, 2 or 3;

[0153] L B is selected from -(CR Lb1 R Lb2 ) m -, said L B has 1 to 5 -CR Lb1 R Lb2 - groups optionally replaced by -Akb- or -Cyb-;

[0154] m is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0155] each -Akb- is independently selected from -0-, -S-, -NR Lb3 -, -C(=0)-, -C≡C-, -CR Lb4 =CR Lb5 -, -S(=0)- or -S(=0)2-;

[0156] each -Cyb- is independently selected from one of the following groups optionally substituted with 1 to 4 R L2 : 4-8 membered heteromonocyclyl, 4-12 membered heteroannulenediyl, 5-13 membered heterospirocyclyl, 7-12 membered hetero- bridged cyclyl, C 3-7 monocycloalkyl, C 4-7 monocycloalkenyl, C 4-12 annulenediyl, C 5-13 spirocycloalkyl, C 5-12 bridged cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl;

[0157] R Lb1 , R Lb2 are each independently selected from H, deuterium, F, CI, Br, I, OH, =0, NH2, CN, COOH, CONH2, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocyclyl or 3- to 6-membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl, heterocyclyl being optionally substituted with 1 to 4 R z ;

[0158] R Lb3each independently selected from H, deuterium, F, Cl, Br, I, OH, =0, NH2, CN, COOH, CONH2, C 1-6 alkyl, C 3-6 carbocyclyl or 3- to 6-membered heterocyclyl, said alkyl, carbocyclyl, heterocyclyl being optionally substituted with 1 to 4 R z substituents;

[0159] R Lb4 or R Lb5 each independently selected from H, deuterium, F, C 1-6 alkyl, C 3-6 carbocyclyl or 3- to 6-membered heterocyclyl, said alkyl, carbocyclyl, heterocyclyl being optionally substituted with 1 to 4 R z substituents;

[0160] R b1 , R b2 or R b4 each independently selected from H, deuterium, F, Cl, Br, I, OH, =0, NH2, CN, COOH, CONH2, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylene-3- to 6-membered heterocyclyl, C 1-6 alkylene-C 3-6 carbocyclyl, C 1-6 alkylene-O-C 3-6 carbocyclyl, C 3-6 carbocyclyl or 3- to 6-membered heterocyclyl, said alkyl, alkylene, carbocyclyl or heterocyclyl being optionally substituted with 1 to 4 R z substituents;

[0161] R b3 or R b5 each independently selected from H, deuterium, F, Cl, Br, I, OH, =0, NH2, CN, COOH, CONH2, C 1-6 alkyl, C 3-6 carbocyclyl, C 1-6 alkylene-3- to 6-membered heterocyclyl, C 1-6 alkylene-C 3-6 carbocyclyl, C 1-6 alkylene-O-C 3-6 carbocyclyl or 3- to 6-membered heterocyclyl, said alkyl, alkylene, carbocyclyl or heterocyclyl being optionally substituted with 1 to 4 R z substituents;

[0162] K is selected from

[0163] G is selected from N, CH or CD;

[0164] Q is each independently selected from a bond, -O-, -S-, -CH2-, -NR q -, -CO-, -NR q CO-, -CONR q -;

[0165] Q and G cannot directly form a nitrogen-nitrogen bond, a nitrogen-oxygen bond, a nitrogen S bond;

[0166] R q is selected from H, deuterium or C 1-4 alkyl;

[0167] F is each independently selected from phenyl, pyridyl, C 13-20 tricyclic carbocyclyl or 13-20 membered tricyclic heterocyclyl;

[0168] R k1 is each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 3 to 6 membered heterocycloalkyl, said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl being optionally substituted with 1 to 4 R z ;

[0169] R k2 is each independently selected from a bond, -C(=O)-, -S(=O)2-, -S(=O)- or -C(R k3 )2-;

[0170] R k3 is each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl or 3 to 8 membered heterocyclyl, said alkyl, alkoxy, cycloalkyl or heterocyclyl being optionally substituted with 1 to 4 selected from R z ;

[0171] Alternatively, two R k3 are directly linked to form a C 3-8 carbocyclyl or 4-8 membered heterocyclyl, said carbocyclyl or heterocyclyl being optionally substituted with 1 to 4 selected from R z ;

[0172] R L2 , R zeach independently selected from the group consisting of deuterium, F, Cl, Br, I, OH, =0, CF3, SF5, CN, NH2, NO2, COOH, CONH2, NHC(=0)R 1-4 alkyl, N(C 1-4 alkyl)2, COOH, CONH2, NHC 1-4 alkyl, N(C 2-4 alkyl, N(C 2-4 alkyl, N(C 1-4 alkyl, N(C 1-4 alkyl, N(C 0-4 alkyl, N(C 3-6 alkyl, N(C 1-4 alkyl, N(C 1-4 alkyl, N(C 1-4 alkyl, N(C 1-4 alkyl, N(C

[0173] n1 is selected from 0, 1, 2 or 3;

[0174] each of p1 or p2 is independently selected from 0, 1, 2, 3, 4 or 5;

[0175] provided that when is selected from F is not selected from phenyl or pyridyl.

[0176] As a second embodiment of the present application, the aforementioned compound represented by the general formula (I) or a stereoisomer, a racemate, a tautomer, a pharmaceutically acceptable salt thereof, wherein,

[0177] L is selected from -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-;

[0178] each of Ak1, Ak2, Ak3, Ak4, Ak5 is independently selected from -(CH2) q -, -(CH2) q -O-, -O-(CH2) q -, -(CH2) q -S-, -S-(CH2) q -, -(CH2) q -NR L -, -NR L -(CH2) q -, -(CH2) q -NR L C(=O)-, -(CH2) q -C(=O)NR L-C(=O)-, -C(=O)-(CH2) q -NR L -, -(C≡C) q - or a bond, said -CH2- is optionally substituted with 1 to 2 R z ;

[0179] R L each independently selected from H, deuterium or C 1-4 alkyl;

[0180] Cy1, Cy2, Cy3or Cy4are each independently selected from a bond or one of the following groups optionally substituted with 1 to 4 R L2 4-7 membered nitrogen containing heteromonocyclic, 4-12 membered nitrogen containing heteroannelated cyclic, 5-13 membered nitrogen containing heterospirocyclic, 7-12 membered nitrogen containing heterobridged cyclic, C 3-7 monocyclic alkyl, C 4-7 monocyclic alkenyl, C 4-12 annelated cyclic alkyl, C 5-13 spirocyclic alkyl, C 5-12 bridged cyclic alkyl, 5-10 membered heteroaryl or C 6-10 aryl;

[0181] B1is selected from 5-6 membered heteroaryl, 9-10 membered heteroaryl;

[0182] m is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0183] each -Cyb- is independently selected from one of the following groups optionally substituted with 1 to 4 R L2 4-7 membered nitrogen containing heteromonocyclic, 4-12 membered nitrogen containing heteroannelated cyclic, 5-13 membered nitrogen containing heterospirocyclic, 7-12 membered nitrogen containing heterobridged cyclic, C 3-7 monocyclic alkyl, C 4-7 monocyclic alkenyl, C 4-12 annelated cyclic alkyl, C 5-13 spirocyclic alkyl, C 5-12 bridged cyclic alkyl, 5-10 membered heteroaryl or C 6-10 aryl;

[0184] R Lb1 , R Lb2 each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 carbocyclyl or 3- to 6-membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl, heterocyclyl is optionally substituted with 1 to 4 R zsubstituted;

[0185] R Lb3 each independently selected from H, deuterium, F, Cl, Br, I, OH, =0, NH2, CN, COOH, CONH2, C 1-4 alkyl, C 3-6 carbocyclyl or 3- to 6-membered heterocyclyl, said alkyl, carbocyclyl, heterocyclyl optionally substituted with 1 to 4 R z substituted;

[0186] R Lb4 or R Lb5 each independently selected from H, deuterium, F, C 1-4 alkyl, C 3-6 carbocyclyl or 3- to 6-membered heterocyclyl, said alkyl, carbocyclyl, heterocyclyl optionally substituted with 1 to 4 R z substituted;

[0187] R b1 , R b2 or R b4 each independently selected from H, deuterium, F, Cl, Br, I, OH, =0, NH2, CN, COOH, CONH2, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkylene-3- to 6-membered heterocyclyl, C 1-4 alkylene-C 3-6 carbocyclyl, C 3-6 carbocyclyl, C 1-4 alkylene-O-C 3-6 carbocyclyl or 3- to 6-membered heterocyclyl, said alkyl, alkylene, carbocyclyl or heterocyclyl optionally substituted with 1 to 4 R z substituted;

[0188] R b3 or R b5 each independently selected from H, deuterium, F, Cl, Br, I, OH, =0, NH2, CN, COOH, CONH2, C 1-4 alkyl, C 3-6 carbocyclyl, C 1-4 alkylene-3- to 6-membered heterocyclyl, C 1-4 alkylene-C 3-6 carbocyclyl, C 1-4 alkylene-O-C 3-6 carbocyclyl or 3- to 6-membered heterocyclyl, said alkyl, alkylene, carbocyclyl or heterocyclyl optionally substituted with 1 to 4 R z substituted;

[0189] F are each independently selected from phenyl, pyridyl, 13-15 membered tricyclic heteroannellated ring groups;

[0190] The remaining definitions are the same as in the first embodiment of the present application.

[0191] As a third embodiment of the present application, the aforementioned compound represented by the general formula (I) or a stereoisomer, racemate, tautomer, pharmaceutically acceptable salt thereof, wherein,

[0192] R L is selected from H, deuterium, methyl or ethyl;

[0193] Cy1, Cy2, Cy3, Cy4are each independently selected from a bond or one of the following groups optionally substituted with 1 to 4 R L2 substituted with 1 to 4 R

[0194] s1, s3, s5are each independently selected from 0, 1 or 2;

[0195] s2, s4are each independently selected from 0 or 1;

[0196] s6is selected from 0, 1, 2 or 3;

[0197] s7is selected from 1, 2 or 3;

[0198] B1is selected from a 6-membered heteroaryl, 9-membered heteroaryl, 10-membered heteroaryl;

[0199] L B is selected from -(CR Lb1 R Lb2 ) m -, said L B has 1 to 3 -CR Lb1 R Lb2 - optionally replaced with -Akb- or -Cyb-;

[0200] m is selected from 0, 1, 2, 3, 4, 5 or 6;

[0201] each -Cyb- is independently selected from one of the following groups optionally substituted with 1 to 4 R L2 substituted with 1 to 4 R 3-7 monocyclic alkyl;

[0202] R Lb1 , R Lb2each independently selected from the group consisting of H, deuterium, F, CI, Br, I, OH, =0, NH2, CN, COOH, CONH2, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, ethenyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, said methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, ethenyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl optionally substituted with 1 to 4 R z substituents;

[0203] R Lb3 each independently selected from the group consisting of H, deuterium, F, CI, Br, I, OH, =0, NH2, CN, COOH, CONH2, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, said methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl optionally substituted with 1 to 4 R z substituents;

[0204] R Lb4 or R Lb5 each independently selected from the group consisting of H, deuterium, F, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, said methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl optionally substituted with 1 to 4 R z substituents;

[0205] R b1 , R b2 or R b4 each independently selected from the group consisting of H, deuterium, F, CI, Br, I, OH, =0, NH2, CN, COOH, CONH2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, ethenyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylene-O-cyclopropyl, ethylene-O-cyclopropyl, methylene-cyclopropyl, methylene-cyclobutyl, methylene-azetidinyl, methylene-pyrrolidinyl, methylene-piperidinyl, methylene-piperazinyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxetanyl, oxetanyl, oxetanyl, oxetanyl, piperazinyl, said methyl, ethyl, propyl, methylene, ethylene, isopropyl, methoxy, ethoxy, isopropoxy, ethenyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, oxetanyl, oxetanyl, oxetanyl, oxetanyl, piperazinyl optionally substituted with 1 to 4 R z substituents;

[0206] R b3 or R b5each independently selected from the group consisting of H, deuterium, F, Cl, Br, I, OH, =0, NH2, CN, COOH, CONH2, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylene-O-cyclopropyl, ethylene-O-cyclopropyl, methylene-cyclopropyl, methylene-cyclobutyl, methylene-azetidinyl, methylene-pyrrolidinyl, methylene-piperidinyl, methylene-piperazinyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxetanyl, oxetanyl, oxetanyl, oxetanyl, piperazinyl optionally substituted with 1 to 4 R z substituents;

[0207] selected from

[0208] F is selected from phenyl or pyridyl;

[0209] represents an aromatic or non-aromatic ring;

[0210] H1is selected from N, NH, CH, CH2, CHR k1 , NR k1 , CR k1 , C(=O), C(R k1 )2;

[0211] H2is selected from a bond, O, N, NH, CH, CH2, CHR k1 , NR k1 , CR k1 , or C(R k1 )2;

[0212] H3is selected from N or CH;

[0213] H4is selected from C, N or CH;

[0214] H5, H6, H7are each independently selected from N, CH or CR k1 , and H5, H6, H7contain at most 2 N;

[0215] Q is each independently selected from a bond, CH2, NH, N(CH3), O, S, C(=O), NHC(=O), C(=O)NH, N(CH3)C(=O), C(=O)N(CH3);

[0216] R k1 , R k3each independently selected from the group consisting of H, deuterium, F, Cl, Br, I, OH, =0, NH2, CF3, CN, COOH, CONH2, or optionally substituted with one to four R z substituted with one to four substituents independently selected from the group consisting of H, deuterium, F, Cl, Br, I, OH, =0, NH2, CF3, CN, COOH, CONH2, or optionally substituted with one to four R

[0217] R L2 , R z each independently selected from the group consisting of deuterium, F, Cl, Br, I, OH, =0, CF3, SF5, CN, NH2, NO2, COOH, CONH2, N(CH3)2, NHCH3, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, methylene-O-methyl, methylene-O-ethyl, ethylene-O-methyl, ethylene-O-ethyl, said methyl, methylene, ethylene, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl optionally substituted with one to four substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, OH, CN, C 1-4 alkyl, C 1-4 alkoxy;

[0218] each p2is independently selected from 0, 1, 2, or 3;

[0219] the remaining definitions are the same as in the first or second embodiment of the present application.

[0220] As a fourth embodiment of the present application, the aforementioned compound represented by the general formula (I) or a stereoisomer, a racemate, a tautomer, a pharmaceutically acceptable salt thereof, wherein,

[0221] Ak1, Ak2, Ak3, Ak4, Ak5are each independently selected from a bond, -O-, -S-, -OCH2-, -CH2O-, -OCH2CH2-, -CH2CH2O-, -C≡C-, -C(CH3)2-, -CH2-, -CH2CH2-, -CH2CH2CH2-, -N(CH3)-, -NH-, -CH2N(CH3)-, -CH2NH-, -NHCH2-, -CH2CH2N(CH3)-, -CH2CH2NH-, -NHCH2CH2-, -C(=O)-, -C(=O)CH2NH-, -CH2C(=O)NH-, -C(=O)NH-, or -NHC(=O)-;

[0222] Cy1, Cy2, Cy3, Cy4are each independently selected from a bond or one of the following groups optionally substituted with one to four substituents independently selected from the group consisting of H, deuterium, F, Cl, Br, I, OH, =0, NH2, CF3, CN, COOH, CONH2, or optionally substituted with one to four R when substituted, is substituted with one to four substituents selected from deuterium, F, CF3, OH, =0, COOH, CN, NH2, hydroxymethyl, methyl, methoxy, cyclopropyl, when substituted, is substituted with one to four substituents selected from deuterium, F, CF3, OH, =0, COOH, CN, NH2, hydroxymethyl, methyl, methoxy, cyclopropyl,

[0223] B1is selected from pyridyl, benzothiazolyl, benzothienyl, benzimidazolyl, pyrimidinyl, pyridinonyl, pyridazinyl, pyrazinyl,

[0224] L B selected from -(CR Lb1 R Lb2 ) m -, said L B has one to two -CR Lb1 R Lb2 - groups optionally replaced with -Akb- or -Cyb-;

[0225] each -Akb- is independently selected from -0-, -S-, -NR Lb3 - or -C(=0)-;

[0226] each -Cyb- is independently selected from one of the following groups optionally substituted with one to four R L2 : cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

[0227] R Lb1 , R Lb2 are each independently selected from H, deuterium, F, Cl, Br, I, OH, =0, NH2, CN, COOH, CONH2, methyl, ethyl, methoxy, ethoxy or cyclopropyl, said methyl, ethyl, methoxy, ethoxy or cyclopropyl being optionally substituted with one to four R z ;

[0228] R Lb3 are each independently selected from H, deuterium, F, Cl, Br, I, OH, =0, NH2, CN, COOH, CONH2, methyl, ethyl or cyclopropyl, said methyl, ethyl or cyclopropyl being optionally substituted with one to four R z ;

[0229] R b1 , R b2 or R b4each independently selected from the group consisting of H, deuterium, F, CI, Br, I, OH, =0, NH2, CN, COOH, CONH2, methyl, ethyl, propyl, isopropyl, methylene-cyclopropyl, methylene-cyclobutyl, methylene-azetidinyl, methylene-pyrrolidinyl, methylene-piperidinyl, methylene-piperazinyl, azetidinyl, pyrrolidinyl, piperidinyl, methylene-0-cyclopropyl, ethylene-0-cyclopropyl, methoxy, ethoxy, or cyclopropyl, said methyl, ethyl, propyl, methylene, ethylene, isopropyl, methoxy, ethoxy, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or cyclopropyl being optionally substituted with 1 to 4 R z substituents;

[0230] R b3 or R b5 each independently selected from the group consisting of H, deuterium, F, CI, Br, I, OH, =0, NH2, CN, COOH, CONH2, methyl, ethyl, propyl, isopropyl, methylene-cyclopropyl, methylene-cyclobutyl, methylene-azetidinyl, methylene-pyrrolidinyl, methylene-piperidinyl, methylene-piperazinyl, azetidinyl, pyrrolidinyl, piperidinyl, methylene-0-cyclopropyl, ethylene-0-cyclopropyl, or cyclopropyl, said methyl, ethyl, propyl, methylene, ethylene, isopropyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or cyclopropyl being optionally substituted with 1 to 4 R z substituents;

[0231] the remaining definitions being the same as in the first, second, or third embodiment of the present application.

[0232] As a fifth embodiment of the present application, the aforementioned compound represented by the general formula (I) or a stereoisomer, racemate, tautomer, pharmaceutically acceptable salt thereof, wherein,

[0233] B1is selected from the group consisting of pyridyl, benzothiazolyl, or pyridinonyl;

[0234] L B is selected from the group consisting of

[0235] R b1 , R b2 or R b4 each independently selected from the group consisting of H, deuterium, F, CI, Br, I, OH, =0, NH2, CN, COOH, CONH2, CD3, CHF2, CH2F, CF3, OCD3, OCF3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl,

[0236] Rb3 or R b5 each independently selected from H, deuterium, F, CI, Br, I, OH, =0, NH2, CN, COOH, CONH2, CD3, CHF2, CH2F, CF3, methyl, ethyl, propyl, isopropyl, cyclopropyl,

[0237] L is selected from -Cy1-, -Cy1-Cy2-, -Cy1-Cy2-Cy3-, -Cy1-Ak2-Cy2-Cy3-, -Cy1-Ak2-, -Cy1-Ak2-Cy2-, -Ak1-Cy1-Ak2-;

[0238] each of Cy1, Cy2, Cy3is independently selected from a bond or optionally substituted one of the following groups: when substituted, substituted with 1 to 4 substituents selected from deuterium, F, CF3, OH, =0, COOH, CN, NH2, hydroxymethyl, methyl, methoxy, cyclopropyl, ;

[0239] K is selected from

[0240] Q is selected from a bond, NHC(=0), C(=0)NH, N(CH3)C(=0), C(=0)N(CH3);

[0241] H1is selected from N, NH, CH, CH2, CHR k1 , NR k1 , CR k1 , C(=0);

[0242] H2is selected from a bond, O, N, NH, CH, CH2, CHR k1 , NR k1 , CR k1 , C(=0);

[0243] H5or H6is selected from N or CR k1 ;

[0244] p1is selected from 0, 1, 2 or 3;

[0245] R k1 each independently selected from H, deuterium, F, CI, Br, I, OH, =0, NH2, CF3, CN, COOH, CONH2, CD3, CF3, OCD3, OCF3, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl;

[0246] The remaining definitions are identical with the first, second, third or fourth embodiment of the present application.

[0247] As a sixth embodiment of the present application, the aforementioned compounds of the general formula (I) or a stereoisomer, a racemate, a tautomer, a pharmaceutically acceptable salt thereof, wherein

[0248] B is selected from one of the structural fragments depicted in Table B-1 ;

[0249] L is selected from one of the structural fragments depicted in Table L-2;

[0250] K is selected from one of the structural fragments depicted in Table K-1.

[0251] As a seventh embodiment of the present application, the aforementioned compounds of the general formula (I) or a stereoisomer, a racemate, a tautomer, a pharmaceutically acceptable salt thereof, wherein the compounds of the general formula (I) are selected from the group consisting of the compounds of the general formula (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), (II-7), (II-8), (II-9),

[0252] La or Lb is selected from -Cy1-, -Cy1-CH2-, -Cy1-Cy2-, -Cy1-CH2-Cy2-;

[0253] M is selected from CH or N;

[0254] The remaining definitions are identical with the first, second, third, fourth or fifth embodiment of the present application.

[0255] As an eighth embodiment of the present application, the aforementioned compounds of the general formula (I), (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), (II-7), (II-8), (II-9) or a stereoisomer, a racemate, a tautomer, a pharmaceutically acceptable salt thereof,

[0256] R b1 each independently is selected from the group consisting of H, deuterium, OH, NH2, CN, COOH, CONH2, CD3, CHF2, CH2F, CF3, methyl, ethyl, propyl, isopropyl, cyclopropyl,

[0257] R b5each independently selected from the group consisting of H, deuterium, OH, NH2, CN, COOH, CONH2, CD3, CHF2, CH2F, CF3, methyl, ethyl, propyl, isopropyl, cyclopropyl,

[0258] La is selected from -Cy1-, -Cy1-CH2-;

[0259] Lb is selected from -Cy1-Cy2-, -Cy1-CH2-Cy2-;

[0260] Cy1or Cy2is selected from one of the following groups each independently selected from optionally substituted: when substituted, substituted with 1 to 4 substituents selected from the group consisting of deuterium, F, CF3, OH, =O, COOH, CN, NH2, hydroxymethyl, methyl, methoxy, cyclopropyl,

[0261] R k1 each independently selected from the group consisting of H, deuterium, F, Cl, Br, I, OH, =O, NH2, CF3, CN, COOH, CONH2, CD3, CF3, OCD3, OCF3, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl;

[0262] each p1is independently selected from 0, 1 or 2.

[0263] As a ninth embodiment of the present application, the aforementioned compound represented by the general formula (I) or a stereoisomer, a racemate, a tautomer, a pharmaceutically acceptable salt thereof, wherein the compound represented by the general formula (I) is selected from a compound represented by the general formula (III-1), (III-2) or (III-3),

[0264] the remaining definitions are in accordance with the first, second, third, fourth, fifth, seventh or eighth embodiment of the present application.

[0265] As a ninth embodiment of the present application, the aforementioned compound represented by the general formula (I) or a stereoisomer, a racemate, a tautomer, a pharmaceutically acceptable salt thereof, wherein the compound represented by the general formula (I) is selected from a compound represented by the general formula (IV-1), (IV-2) or (IV-3),

[0266] the remaining definitions are in accordance with the first, second, third, fourth, fifth, seventh or eighth embodiment of the present application.

[0267] ​The present application relates to a compound selected from one of the following structures of Table E below, or a stereoisomer, a racemate, a tautomer, a pharmaceutically acceptable salt thereof:

[0268] Table E

[0269] The present application relates to a pharmaceutical composition comprising a compound as described above, or a stereoisomer, a racemate, a tautomer, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0270] The present application relates to use of a compound as described above, or a stereoisomer, a racemate, a tautomer, a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease associated with EGFR activity or expression.

[0271] The present application relates to use of a compound as described above, or a stereoisomer, a racemate, a tautomer, a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease associated with inhibiting or degrading EGFR.

[0272] In some embodiments, the disease associated with inhibiting or degrading EGFR is cancer, preferably esophageal cancer, glioblastoma, anal cancer, head and neck cancer, breast cancer, lung cancer or pancreatic cancer.

[0273] The present application relates to a pharmaceutical composition or a pharmaceutical preparation comprising a therapeutically effective amount of a compound according to the present application or a stereoisomer, a racemate, a tautomer, a pharmaceutically acceptable salt thereof and a pharmaceutical excipient. The pharmaceutical composition can be in the form of a unit preparation (the amount of the main drug in the unit preparation is also referred to as "the preparation specification").

[0274] The present application also provides a method for treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound according to the present application or a stereoisomer, a racemate, a tautomer, a pharmaceutically acceptable salt or a pharmaceutical composition thereof. In some embodiments, the mammal according to the present application includes a human.

[0275] An "effective amount" or "therapeutically effective amount" as described herein refers to an amount of a compound disclosed herein that, when administered to a subject for treating a disease or condition (e.g., cancer), will alleviate, to some extent, one or more symptoms of the disease or condition being treated. In some embodiments, the result is reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the amount of a compound disclosed herein that will provide clinical benefit, including preventing a disease, alleviating a symptom, or causing regression of the disease.Examples of therapeutically effective amounts include, but are not limited to, 1-1500 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, 5-600 mg, 6-600 mg, 10-600 mg, 20-600 mg, 25-600 mg, 30-600 mg, 40-600 mg, 50-600 mg, 60-600 mg, 70-600 mg, 75-600 mg, 80-600 mg, 90-600 mg, 100-600 mg, 200-600 mg, 1-500 mg, 2-500 mg, 3-500 mg, 4-500 mg, 5-500 mg, 6-500 mg, 10-500 mg, 20-500 mg, 25-500 mg, 30-500 mg, 40-500 mg, 50-500 mg, 60-500 mg, 70-500 mg, 75-500 mg, 80-500 mg, 90-500 mg, 100-500 mg, 125-500 mg, 150-500 mg, 200-500 mg, 250-500 mg, 300-500 mg, 400-500 mg, 5-400 mg, 10-400 mg, 20-400 mg, 25-400 mg, 30-400 mg, 40-400 mg, 50-400 mg, 60-400 mg, 70-400 mg, 75-400 mg, 80-400 mg, 90-400 mg, 100-400 mg, 125-400 mg, 150-400 mg, 200-400 mg, 250-400 mg, 300-400 mg, 1-300 mg, 2-300 mg, 5-300 mg, 10-300 mg, 20-300 mg, 25-300 mg, 30-300 mg, 40-300 mg, 50-300 mg, 60-300 mg, 70-300 mg, 75-300 mg, 80-300 mg, 90-300 mg, 100-300 mg, 125-300 mg, 150-300 mg, 200-300 mg, 250-300 mg, 1-200 mg, 2-200 mg, 5-200 mg, 10-200 mg, 20-200 mg, 25-200 mg, 30-200 mg, 40-200 mg, 50-200 mg, 60-200 mg, 70-200 mg, 75-200 mg, 80-200 mg, 90-200 mg, 100-200 mg, 125-200 mg, 150-200 mg, 80-1500 mg, 80-1000 mg, 80-800 mg.

[0276] In some embodiments, the pharmaceutical composition comprises, but is not limited to, 1-1500 mg, 1-1000 mg, 20-800 mg, 40-800 mg, 40-400 mg, 25-200 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 300 mg, 320 mg, 400 mg, 480 mg, 500 mg, 600 mg, 640 mg, 840 mg, 1000 mg of a compound of the present application or a stereoisomer, racemate, tautomer, pharmaceutically acceptable salt thereof.

[0277] A method for treating a disease in a mammal, the method comprising administering to the subject a therapeutically effective amount of a compound of the present application or a stereoisomer, racemate, tautomer, pharmaceutically acceptable salt thereof, the therapeutically effective amount preferably 1-1500 mg, the disease preferably an autoimmune disease, an inflammatory disease or a cancer.

[0278] A method for treating a disease in a mammal, the method comprising administering to the subject a compound of the present application or a stereoisomer, racemate, tautomer, pharmaceutically acceptable salt thereof in a daily dose of 1-1500 mg per day, the daily dose can be in a single dose or in divided doses, in some embodiments, the daily dose comprises, but is not limited to, 10-1500 mg per day, 10-1000 mg per day, 10-800 mg per day, 25-800 mg per day, 50-800 mg per day, 100-800 mg per day, 200-800 mg per day, 25-400 mg per day, 50-400 mg per day, 100-400 mg per day, 200-400 mg per day, in some embodiments, the daily dose comprises, but is not limited to, 10 mg per day, 20 mg per day, 25 mg per day, 50 mg per day, 80 mg per day, 100 mg per day, 125 mg per day, 150 mg per day, 160 mg per day, 200 mg per day, 300 mg per day, 320 mg per day, 400 mg per day, 480 mg per day, 600 mg per day, 640 mg per day, 800 mg per day, 1000 mg per day, 1500 mg per day.

[0279] The present application relates to a kit which can include a composition in single or multiple dose form, the kit comprising a compound of the present application or a stereoisomer, racemate, tautomer, pharmaceutically acceptable salt thereof, in an amount equivalent to the amount of a compound of the present application or a stereoisomer, racemate, tautomer, pharmaceutically acceptable salt thereof contained in the above pharmaceutical composition.

[0280] The amount of a compound of the present application or a stereoisomer, racemate, tautomer, pharmaceutically acceptable salt thereof in the present application is in each case calculated as the free base.

[0281] The compound of the present application also includes its deuterated compound, solvate, prodrug, metabolite, co-crystal.

[0282] To accomplish the objectives of the present application, the compounds used in the reactions described herein are prepared according to the techniques of organic synthesis known to those skilled in the art, starting from commercially available chemicals and / or compounds described in chemical literature. "Commercially available chemicals" are obtained from standard commercial sources, including Shanghai Aladdin Bio-Chem Technology Co., Ltd., Shanghai Macklin Biochemical Technology Co., Ltd., Sigma-Aldrich, Alfa Aesar (China) Chemical Co., Ltd., TCI (Shanghai) Chemical Industry Development Co., Ltd., Anjieke Chemicals, Shanghai Titan Scientific Co., Ltd., Kelong Chemicals, and Bailingwei Technology Co., Ltd.

[0283] Unless otherwise indicated, the terms used in the specification and claims have the following meanings.

[0284] The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds described in the present application all include their isotopic cases, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds described in the present application are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C, 13 C and 14 C, the isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super-heavy hydrogen), the isotopes of oxygen include 16 O, 17 O and 18 O, the isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, the isotopes of nitrogen include 14 N and 15 N, the isotopes of fluorine include 17 F and 19 F, the isotopes of chlorine include 35 Cl and 37 Cl, the isotopes of bromine include79 Br and 81 Br.

[0285] "CN" means cyano.

[0286] "Halogen" means F, Cl, Br, or I.

[0287] "Halogen substituted" means F, Cl, Br, or I substitution, including but not limited to substitution with 1 to 10, 1 to 6, or 1 to 4 substituents selected from F, Cl, Br, or I. "Halogen substituted" is also referred to as "halo."

[0288] "Alkyl" means a straight or branched chain saturated aliphatic hydrocarbon group, substituted or unsubstituted, including but not limited to alkyl of 1 to 20 carbon atoms, alkyl of 1 to 8 carbon atoms, alkyl of 1 to 6 carbon atoms, alkyl of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, neopentyl, t-butyl, n-pentyl, i-pentyl, neopentyl, n-hexyl, and various branched isomers thereof; alkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0289] "Heteroalkyl" means 1 or more (including but not limited to 2, 3, 4, 5, or 6) carbon atoms in an alkyl group are replaced by a heteroatom (including but not limited to N, O, or S). Non-limiting examples include -X-(CH2)v-X-(CH2)v-X-(CH2)v-H (v is an integer from 1 to 5, and each X is independently selected from a bond or a heteroatom, including but not limited to N, O, or S, and at least one X is selected from a heteroatom, and N or S in the heteroatom can be oxidized to various oxidation states). Heteroalkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0290] "Alkylene" means a straight chain and branched chain divalent saturated hydrocarbon radical, substituted or unsubstituted, including -(CH2) v (v is an integer from 1 to 10), examples of alkylene include but are not limited to methylene, ethylene, propylene, and butylene, etc.

[0291] "Heteroalkylene" means 1 or more (including but not limited to 2, 3, 4, 5, or 6) carbon atoms in an alkylene group are replaced by a heteroatom (including but not limited to N, O, or S). Non-limiting examples include -X-(CH2)v-X-(CH2)v-X-(CH2)v-, v is an integer from 1 to 5, and each X is independently selected from a bond, N, O, or S, and at least one X is selected from N, O, or S.

[0292] "Cycloalkyl" refers to substituted or unsubstituted saturated carbocyclic hydrocarbon groups, typically having from 3 to 12 carbon atoms, and cycloalkyl groups can be monocyclic, fused, bridged, and spirocyclic. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutylcyclobutyl, cyclobutylspirocyclobutyl, adamantyl, and the like. Cycloalkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0293] "Heterocycloalkyl" refers to substituted or unsubstituted saturated heteroatom-containing cyclic hydrocarbon groups, including but not limited to 3 to 12 atoms, 3 to 8 atoms, containing 1 to 3 heteroatoms selected from N, O, or S, and the C, N, S on the ring of the heterocycloalkyl group can be oxidized to various oxidation states. Heterocycloalkyl groups can be monocyclic, fused, bridged, and spirocyclic. Heterocycloalkyl groups can be attached at a heteroatom or carbon atom, and non-limiting examples include oxiranyl, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolanyl, dioxanyl, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazinanyl, morpholinyl, hexahydropyrimidinyl, piperazinyl, Heterocycloalkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0294] "Alkenyl" refers to substituted or unsubstituted straight chain and branched chain unsaturated hydrocarbon groups having at least one, typically one, two, or three carbon-carbon double bonds, and main chains including but not limited to 2 to 10, 2 to 6, or 2 to 4 carbon atoms, and alkenyl examples include but are not limited to ethenyl, 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, 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, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene, and 1,4-hexadiene, and the like; alkenyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0295] "Alkynyl" refers to substituted or unsubstituted straight and branched unsaturated hydrocarbon groups having at least one, typically one, two or three carbon-carbon triple bonds, with a backbone comprising 2 to 10 carbon atoms, including but not limited to 2 to 6 carbon atoms in the backbone, and 2 to 4 carbon atoms in the backbone. Examples of alkynyl groups include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 5-pentynyl, 6-pentynyl, 7-pentynyl, 8-pentynyl, 9-pentynyl, 10-pentynyl, 11-pentynyl, 12-pentynyl, 13-pentynyl, 14-pentynyl, 15-pentynyl, 16-pentynyl, 17-pentynyl, 18-pentynyl, 19-pentynyl, 20-pentynyl, 21-pentynyl, 22-pentynyl, 23-pentynyl, 24-pentynyl, 25-pentynyl, 26-pentynyl, 27-pentynyl, 28-pentynyl, 29-pentynyl, 30-pentynyl, 31-pentynyl, 32-pentynyl, 33-pentynyl, 34-pentynyl, 35-pentynyl, 36-pentynyl, 37-pentynyl, 38-pentynyl, 39-pentynyl, 40-pentynyl, 41-pentynyl, 42-pentynyl, 43-pentynyl, 44-pentynyl, 45-pentynyl, 46-pentynyl, 47-pentynyl, 48-pentyn Alkynyl, 1-methyl-1-butynyl, 2-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 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, and the like; an alkynyl group may be monovalent, divalent, trivalent, or tetravalent.

[0296] "Alkoxy" refers to a substituted or unsubstituted -O-alkyl group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropyloxy, and cyclobutyloxy.

[0297] "Carbocyclyl" or "carbocycle" refers to a substituted or unsubstituted aromatic or non-aromatic ring, which can be a 3-8 membered monocycle, a 4-12 membered bicycle, a 10-15 membered tricycle, or a 12-18 membered quaternary system. The carbocyclyl can be attached to the aromatic or non-aromatic ring, and the ring can be optionally a monocycle, a cyclic ring, a bridged ring, or a spirocycle. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, a benzene ring, a naphthalene ring, "Carbocyclyl" or "carbocycle" can be monovalent, divalent, trivalent, or tetravalent.

[0298] "Heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted aromatic or non-aromatic ring, which can be a 3- to 8-membered monocyclic, 4- to 12-membered bicyclic, or 10- to 15-membered tricyclic, 12- to 18-membered tetracyclic ring system, and contains 1 or more (including, but not limited to, 2, 3, 4, or 5) heteroatoms selected from N, O, S, or Se, and the optionally substituted C, N, S in the ring of the heterocyclyl group can be oxidized in various oxidation states. The heterocyclyl group can be attached to a heteroatom or a carbon atom, the heterocyclyl group can be attached to an aromatic ring or a non-aromatic ring, the heterocyclyl group is optionally monocyclic, bridged, annulated, or spirocyclic, and non-limiting examples include oxiranyl, aziridinyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxananyl, azepanyl, pyridyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, dihydrofuranyl, dihydropyranyl, dihydrothiopyranyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothienyl, benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo[3.2.1]octanyl, azabicyclo[5.2.0]nonanyl, oxatricyclo[5.3.1.1]dodecanyl, azadamantyl, oxaspiro[3.3]heptanyl, "Heterocyclyl" or "heterocycle" can be monovalent, divalent, trivalent, or tetravalent.

[0299] "Spirocycle" or "spirocyclic" refers to a polycyclic group in which two or more rings share a common atom, referred to as a spiro atom. The number of ring atoms in a spirocyclic system includes, but is not limited to, 5 to 20, 6 to 14, 6 to 12, 6 to 10, wherein one or more rings can contain 0 or more (including, but not limited to, 1, 2, 3, or 4) double bonds, and optionally can contain 0 to 5 heteroatoms selected from N, O, S (=O) n or Se (=O) n (n is 0, 1, or 2). Non-limiting examples include: "Spirocycle" or "spirocyclic" can be monovalent, divalent, trivalent, or tetravalent.

[0300] "Parallel ring" or "parallel ring group" refers to a polycyclic group in which each ring in the system shares a pair of adjacent atoms with other rings in the system, wherein 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 unsubstituted, and each ring in the parallel ring system may contain 0 to 5 heteroatoms or groups containing heteroatoms (including but not limited to N, S(=O) n 、Se(=O) n or O, n is 0, 1 or 2). The number of ring atoms in the cyclic system includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, and 5 to 10. Non-limiting examples include: "Bicyclic" or "bicyclic group" can be monovalent, divalent, trivalent or tetravalent.

[0301] "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 zero or more double bonds. Any ring in the bridged ring system may contain zero to five heteroatoms or groups containing heteroatoms (including but not limited to N, S(=O)n, Se(=O) n or O, wherein 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, A "bridged ring" or "bridged ring group" may be monovalent, divalent, trivalent, or tetravalent.

[0302] "Carbospirocycle," "spirocarbocyclyl," "spirocarbocyclyl," or "carbospirocyclyl" refers to a "spirocycle" wherein the ring system consists of only carbon atoms.

[0303] "Carbocyclyl," "carbocyclyl," "carbocyclyl," or "carbocyclyl" refers to a "carbocyclyl" ring system consisting of only carbon atoms.

[0304] "Carbobridged ring," "bridged carbocyclic group," "bridged carbocyclic group," or "carbon-bridged cyclic group" refers to a "bridged ring" in which the ring system consists of only carbon atoms.

[0305] "Heteromonocycle", "monocyclic heterocyclyl" or "heteromonocyclyl" refers to a monocyclic ring system of "heterocyclyl" or "heterocycle",

[0306] "Heterocyclo", "heterocycloalkyl", "cycloheterocyclyl" or "cycloheterocyclyl" refers to a "cyclo" containing a heteroatom.

[0307] "Heterospirocycle," "heterospirocyclyl," "spiroheterocyclyl," or "spiroheterocyclyl" refers to a "spirocycle" containing a heteroatom.

[0308] "Heterobridged ring", "heterobridged cyclic group", "bridged ring heterocyclic group" or "bridged heterocyclic group" refers to a "bridged ring" containing a heteroatom.

[0309] "Aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group having a single ring or a fused ring, wherein 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 may be fused to a saturated or unsaturated carbon ring, wherein the ring connected to the parent structure is the aryl ring, non-limiting examples of which include benzene ring, naphthalene ring, "Aryl" or "aromatic ring" can be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the point of attachment is on the aryl ring.

[0310] "Heteroaryl" or "heteroaromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group containing 1 to 5 heteroatoms or groups containing heteroatoms (including but not limited to N, O, S(=O)n, Se(=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. The atoms C, N, S, and Se on the ring are optionally oxidized (i.e., C(=O), NO, S(=O)n, Se(=O)n, n is 1, 2). Non-limiting examples of heteroaryl include but are not limited to pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazolyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, pyridonyl, etc. The heteroaryl ring can be fused to a saturated or unsaturated carbocyclic ring or heterocyclic ring, wherein the ring connected to the parent structure is an aryl ring. Non-limiting examples include When heteroaryl appears in this document, its definition is consistent with this definition. Heteroaryl can be monovalent, divalent, trivalent or tetravalent. When it is divalent, trivalent or tetravalent, the attachment point is located on the ring with aromaticity.

[0311] "Substituted" or "substituted" refers to substitution 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, isocyano, aryl, heteroaryl, heterocyclic, bridged, spiro, cycloalkyl, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, -(CH2), m -C(=O)-R a 、-O-(CH2) m -C(=O)-R a 、-(CH2) m -C(=O)-NR b R c-(CH2) m S(=O) n R a -(CH2) m -alkenyl-R a OR d -(CH2) m -alkynyl-R a (wherein m, n are 0, 1 or 2), arylthio, thio carbonyl, silyl, or -NR b R c groups, wherein R b and R c are independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethylsulfonyl, and, optionally, R b and R c may form a five or six membered cycloalkyl or heterocyclyl ring, R a and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spirocyclic, or fused ring.

[0312] "1 to X substituents selected from" means 1, 2, 3,... X substituents selected from, X is selected from any integer between 1 and 10. For example, "1 to 4 R k substituents" means 1, 2, 3, or 4 R k substituents. For example, "1 to 5 substituents selected from" means 1, 2, 3, 4, or 5 substituents selected from. For example, "hetero bridged ring is optionally substituted with 1 to 4 substituents selected from H or F" means hetero bridged ring is optionally substituted with 1, 2, 3, or 4 substituents selected from H or F.

[0313] A ring of X-Y members (X, Y are integers, and 3≤X

[0314] C x-y A carbocyclic ring (including aryl, cycloalkyl, monocyclic carbocyclic, spirocarbocyclic, fused carbocyclic, or bridged carbocyclic) includes C x , C x+1 , C x+2 , C x+3 , C x+4 ... C y"ring of x members" (x is an integer, and 3 < x < y, y is selected from any integer between 4 and 20), for example, means a 3-, 4-, 5-, or 6-membered ring. 3-6 "Cycloalkyl" means a C3, C4, C5, or C6cycloalkyl group.

[0315] When a group has one or more available sites for attachment, any one or more of the sites of the group can be attached to other groups by a chemical bond. When the attachment of the chemical bond is not defined, and the available site has a hydrogen atom, the number of H atoms at the site will correspondingly decrease to the valence of the group as the number of chemical bonds attached to the site increases. For example "represents that any available site on the piperidinyl group can be attached to other groups by one chemical bond, at least including The four modes of attachment, even though the H atoms are drawn on the -N-, also include For example "represents that the R group on the piperidinyl group can be on the C or on the N, at least including

[0316] When the listed connecting groups are not specified for their direction of attachment, the direction of attachment includes both left-to-right and right-to-left reading order, for example, A-L-B, L selected from -M-W-, includes A-M-W-B and A-W-M-B.

[0317] "Optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and thus such phrase includes instances where the event or circumstance occurs and instances where it does not. For example, "alkyl optionally substituted with F" means that the alkyl group can or can not be substituted with F, and the description includes instances where the alkyl group is substituted with F and instances where the alkyl group is not substituted with F.

[0318] "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" means a salt of a compound of the application that retains the biological effectiveness and properties of the free acids or free bases, and is obtained by reaction of the free acid with a non-toxic inorganic or organic base, or the free base with a non-toxic inorganic or organic acid.

[0319] "Pharmaceutical composition" means a mixture of one or more compounds of the application, or stereoisomers, racemics, tautomers, pharmaceutically acceptable salts thereof, and other chemical components, wherein the "other chemical components" means pharmaceutically acceptable carriers, excipients, and / or one or more other therapeutic or active agents.

[0320] "Dosage form" means the weight of the active drug contained in each unit of the dosage form, such as each tablet, capsule, or other unit.

[0321] "Carrier" means a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of an administered compound.

[0322] "Prodrug" means a compound that can be converted in vivo to a biologically active compound of the present application. Prodrugs of the present application are prepared by modifying the amino or carboxyl groups of the compounds of the present application in such a way that the modifications can be easily removed in vivo to form the parent compound. When a prodrug of the present application is administered to a mammalian subject, the prodrug is cleaved to form the free amino or carboxyl groups.

[0323] "Co-crystal" means a crystal formed by the combination of an active pharmaceutical ingredient (API) and a co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, wherein the pure state of the API and the CCF are both solid at room temperature, and there is a fixed stoichiometric ratio between the components. Co-crystals are a kind of multi-component crystals, including binary co-crystals formed between two neutral solids, and multi-component co-crystals formed between neutral solids and salts or solvates.

[0324] "Animal" means including mammals, such as humans, companion animals, zoo animals, and farm animals, preferably humans, horses, or dogs.

[0325] "Stereoisomer" means isomers that have the same molecular formula but different structures resulting from the spatial arrangement of atoms. Stereoisomers include enantiomers (mirror image isomers), diastereomers (isomers of a chiral compound that are not mirror image isomers), and conformers (isomers of a non-chiral compound that are not mirror image isomers).

[0326] "Tautomer" means isomers of a molecule that differ only in the position of a proton, such as keto-enol isomers and amide-imine isomers.

[0327] Synthesis Method One:

[0328] R D-1 selected from halogen or OTf, OTs, OMs, preferably from Br, I, OTf;

[0329] R D-2 each independently selected from C 1-6 alkyl or two R D-2 may be linked to form a ring;

[0330] m D-1 selected from 0 or 1;

[0331] the remaining groups are defined in accordance with the specification.

[0332] The compound of general formula (D1-1) is obtained by a coupling reaction or a substitution reaction to obtain a compound of general formula (D1-2);

[0333] The compound of general formula (D1-2) is obtained by removing the protecting group to obtain a compound of general formula (D1-3);

[0334] The compound of formula (D1-3) is reacted with the compound of formula (D1-4) to obtain the compound of formula (D-1) by reductive amination.

[0335] Synthetic Method Two:

[0336] R D-3 is selected from N or CH;

[0337] F D-2 is selected from benzene ring or pyridine;

[0338] The definitions of the remaining groups are consistent with the description.

[0339] The compound of formula (D2-1) is reacted to obtain the compound of formula (D2-2) by coupling reaction or substitution reaction;

[0340] The compound of formula (D2-2) is reacted to obtain the compound of formula (D2-3) by removing the protecting group;

[0341] The compound of formula (D2-3) is reacted with the compound of formula (D2-4) to obtain the compound of formula (D-2) by reductive amination. DETAILED DESCRIPTION

[0342] The following examples illustrate the technical solutions of the present application in detail, but the protection scope of the present application includes but is not limited to the following examples.

[0343] The compounds used in the reactions described herein are prepared according to the organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and / or compounds described in the chemical literature. The “commercially available chemicals” are obtained from regular commercial sources, including suppliers such as Titan Scientific, Anpel Chemical, Shanghai Dema, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, Nanjing Yushi, Pharmaron, and Bailingwei Technology.

[0344] The structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). The NMR shift (δ) is given in units of 10 -6 (ppm). The NMR is measured by a nuclear magnetic instrument (Bruker Avance III 400 and Bruker Avance 300), and the measuring solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and the internal standard is tetramethylsilane (TMS).

[0345] The MS is measured by (Agilent 6120B (ESI) and Agilent 6120B (APCI)).

[0346] The HPLC determination used an Agilent 1260 DAD high pressure liquid chromatograph (Zorbax SB-C18 100 x 4.6 mm, 3.5 μM).

[0347] The thin layer chromatography silica gel plate used Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography was 0.15 mm-0.20 mm. The specification of the thin layer chromatography used for separating and purifying the product was 0.4 mm-0.5 mm.

[0348] Column chromatography generally used Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0349] The * next to the chemical bond represents the chirality of the chiral atom as R or S;

[0350] NBS: N-bromosuccinimide, CAS No.: 128-08-5;

[0351] XANT PHOS (or Xantphos): 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, CAS No.: 161265-03-8;

[0352] Tris(dibenzylidene-BASE acetone) dipalladium: CAS No.: 60748-47-2;

[0353] Sodium triacetoxyborohydride: CAS No.: 56553-60-7.

[0354] Example 1: Preparation of compound 1

[0355] Step 1: Preparation of 1B

[0356] Compound 1A (reference patent WO2023232133 synthesis) (1.145 g, 3.74 mmol), NBS (0.73 g, 4.11 mmol) were added to acetonitrile (30 mL) and reacted at room temperature for 1 h. The reaction solution was diluted with 200 mL of ethyl acetate, washed with water 3 times, and saturated aqueous sodium bicarbonate solution 1 time. The organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by flash column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V) = 0-50%) to obtain 1B (1.30 g, yield: 90%).

[0357] LCMS m / z = 329.0 [M-55] +

[0358] Step 2: Preparation of 1C

[0359] To a solution of 1B (6.29 g, 16.32 mmol), benzophenone imine (4.14 g, 22.85 mmol), cesium carbonate (10.63 g, 32.64 mmol), palladium acetate (0.73 g, 3.26 mmol), XANT PHOS (0.94 g, 1.63 mmol) in dioxane (100 mL) was heated at 105 °C for 16 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature, filtered through celite to remove the solid, the filter cake was washed with dichloromethane, and the organic phase was collected and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (mobile phase: ethyl acetate / petroleum ether (v / v) = 1 / 5) to give 1C (6.94 g, yield: 87%).

[0360] LCMS m / z = 486.2 [M+H] +

[0361] Third step: Preparation of 1D

[0362] To a solution of 1C (6.94 g, 14.29 mmol) in methanol (200 mL) was added palladium on carbon (6.92 g, wt% = 10%), ammonium acetate (6.79 g, 88.03 mmol), and the reaction mixture was stirred at room temperature under hydrogen atmosphere (balloon pressure) for 12 h. The reaction mixture was filtered through celite, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (mobile phase: ethyl acetate / petroleum ether (v / v) = 1 / 1) to give 1D (4.15 g, yield: 90%).

[0363] LCMS m / z = 322.2 [M+H] +

[0364] Fourth step: Preparation of 1E

[0365] To a solution of 1D (4.15 g, 12.91 mmol), ethyl acrylate (3.88 g, 38.73 mmol), and N,N-diisopropylethylamine (5.01 g, 38.73 mmol) in ethanol (60 mL) was heated at 100 °C for 72 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 20) to give 1E (3.91 g, yield: 71%).

[0366] LCMS m / z = 422.3 [M+H] +

[0367] Fifth step: Preparation of 1F

[0368] To a solution of 1E (0.50 g, 1.19 mmol) and N, N-diisopropylethylamine (0.46 g, 3.56 mmol) in tetrahydrofuran (20 mL) was added slowly triphosgene (0.39 g, 1.31 mmol) and stirred at room temperature for 1 h. Ammonia water (5 mL) was added and the reaction was continued at 50 °C for 2 h. The reaction was diluted with 100 mL of ethyl acetate, the organic phase was washed with water for 3 times, saturated sodium chloride for 1 time, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) to give 1F (0.46 g, yield: 83%).

[0369] LCMS m / z = 465.3 [M+H] +

[0370] Sixth step: Preparation of 1G

[0371] To a solution of 1F (0.46 g, 1.00 mmol) in acetonitrile (10 mL) was added benzyltrimethylammonium hydroxide 40% in methanol (1.2 mL) and stirred at 60 °C for 2 h. Appropriate amount of silica gel was added and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) to give 1G (0.21 g, yield: 50%).

[0372] Seventh step: Preparation of 1H

[0373] To a solution of 1G (0.21 g, 0.50 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (5 mL) and stirred at room temperature for 1 h. The trifluoroacetic acid was removed by concentration under reduced pressure. The residue was dissolved in 10 mL of dichloromethane and 1 mL of isopropyl alcohol. The solution was adjusted to basic with aqueous sodium bicarbonate solution and extracted with dichloromethane / isopropyl alcohol (v / v) = 10 / 1 for 3 times. The organic phase was combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1H (0.158 g).

[0374] LCMS m / z = 319.2 [M+H] +

[0375] Eighth step: Preparation of 1J

[0376] To a solution of 1I (1.50 g, 2.94 mmol) and 4-(dimethoxymethyl)-piperidine (0.70 g, 4.41 mmol) in N,N-dimethylacetamide (50 mL) was added tris(dibenzylideneacetone)dipalladium (0.27 g, 0.29 mmol), Xantphos (0.27 g, 0.59 mmol) and sodium tert-butoxide (0.85 g, 8.82 mmol). After the addition was complete, the reaction mixture was purged with nitrogen three times and heated to 100 °C for 16 h. The reaction mixture was diluted with 500 mL of ethyl acetate and washed with water three times, saturated aqueous sodium chloride solution once. The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) to give 1J (1.70 g).

[0377] LCMS m / z = 588.4 [M+H] +

[0378] Ninth step: Preparation of 1K

[0379] To a solution of 1J (1.70 g, 2.89 mmol) in tetrahydrofuran (20 mL) was added 2M sulfuric acid solution (20 mL). After the addition was complete, the reaction mixture was stirred at room temperature for 2 h. Solid sodium bicarbonate was added to the reaction mixture under ice bath. The pH was adjusted to basic and the mixture was extracted with dichloromethane / methanol ((v / v) = 10 / 1)) three times. The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) to give 1K (0.88 g, yield: 56%).

[0380] LCMS m / z = 542.3 [M+H] +

[0381] Tenth step: Preparation of compound 1

[0382] To a solution of 1K (0.13 g, 0.24 mmol), 1H (0.076 g, 0.24 mmol), chloroform (10 mL), glacial acetic acid (0.029 g, 0.48 mmol), anhydrous sodium sulfate (0.068 g, 0.48 mmol) was added under nitrogen. After the addition was complete, the reaction mixture was heated to 50 °C for 1 h. Sodium triacetoxyborohydride (0.25 g, 1.20 mmol) was added and the reaction mixture was heated to 50 °C for another 1 h. Dichloromethane and saturated aqueous sodium bicarbonate solution were added and the mixture was stirred to separate into two layers. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) to give compound 1 (0.091 g, yield: 42%).

[0383] LCMS m / z = 844.4 [M+H] +

[0384] 1 H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 10.33 (s, 1H), 8.42 (s, 1H), 7.92 (s, 1H), 7.55 (s, 1H), 7.36 (d, 1H), 7.12 (s, 1H), 6.96 - 6.85 (m, 2H), 6.72 (d, 1H), 4.43 - 4.30 (m, 1H), 4.20 - 4.08 (m, 1H), 4.04 - 3.89 (m, 2H), 3.80 - 3.63 (m, 6H), 3.60 (t, 2H), 3.05 - 2.96 (m, 1H), 2.91 (d, 2H), 2.85 - 2.57 (m, 8H), 2.55 (s, 3H), 2.21 (d, 3H), 2.12 - 1.67 (m, 8H), 1.67 - 1.54 (m, 1H), 1.52-1.38 (m, 1H), 1.35-1.20 (m, 2H), 0.82 (d, 3H).

[0385] Example 2: Preparation of compound 2

[0386] The compound 2 trifluoroacetate salt (0.038 g) was prepared by the synthesis of Reference Compound 1, using Compound 1I as the starting material, and the final step product was purified by preparative HPLC (Instrument: waters 2767 preparative liquid phase; chromatographic column: XBridge®Prep C18 (30 mm x 150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)), and the preparative liquid was lyophilized.

[0387] LCMS m / z = 415.8 [(M+2H) / 2] +

[0388] 1H NMR (400 MHz, DMSO-d6) δ 12.58 (s, 1H), 10.37 (s, 1H), 9.78 (s, 1H), 8.51 (s, 1H), 8.03 (s, 1H), 7.67 (s, 1H), 7.41 (d, 1H), 7.23 (s, 1H), 7.03 (d, 1H), 6.99-6.89 (m, 2H), 4.43-4.33 (m, 1H), 4.21-4.12 (m, 2H), 4.07-3.97 (m, 2H), 3.96-3.85 (m, 2H), 3.75 (s, 3H), 3.72-3.64 (m, 2H), 3.64-3.57 (m, 2H), 3.50-3.38 (m, 1H), 3.35-3.26 (m, 1H), 3.22-3.11 (m, 1H), 3.09-3.00 (m, 1H), 2.98-2.88 (m, 1H), 2.87-2.65 (m, 7H), 2.62 (s, 3H), 2.28-2.16 (m, 3H), 2.08-1.88 (m, 3H), 1.88-1.75 (m, 2H), 1.74-1.62 (m, 1H), 1.52-1.40 (m, 1H), 0.83 (d, 3H).

[0389] Example 3: Preparation of compound 3

[0390] The synthesis of reference compound 1 was carried out using compound 1K (0.15 g, 0.28 mmol), 3A (0.089 g, 0.28 mmol) as starting materials to obtain compound 3 (0.127 g, yield: 50%).

[0391] LCMS m / z = 422.4 [(M+2H) / 2] +

[0392] 1H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 10.76 (s, 1H), 8.42 (s, 1H), 7.92 (s, 1H), 7.55 (s, 1H), 7.36 (d, 1H), 7.12 (s, 1H), 6.89 (dd, 1H), 6.79 (d, 1H), 6.62 (d, 1H), 4.41-4.32 (m, 1H), 4.18-4.10 (m, 1H), 4.03-3.91 (m, 2H), 3.85-3.77 (m, 1H), 3.75 - 3.61 (m, 6H), 3.02-2.86 (m, 3H), 2.84 - 2.65 (m, 6H), 2.64 - 2.46 (m, 5H), 2.27-2.16 (m, 3H), 2.15 - 1.67 (m, 10H), 1.65 - 1.52 (m, 1H), 1.51-1.38 (m, 1H), 1.35-1.21 (m, 2H), 0.82 (d, 3H).

[0393] Example 4: Preparation of compound 4

[0394] First step: Preparation of 4A

[0395] Under nitrogen atmosphere, 1B (7.00 g, 18.17 mmol) and 70 mL of tetrahydrofuran were added into a reaction flask, then cooled to -78 °C and slowly added 2.5 M n-butyllithium n-hexane solution (14.50 mL, 36.34 mmol). The system was stirred at -78 °C for 1.5 hours, then replaced with carbon dioxide three times, controlled the system temperature below -40 °C and placed in the carbon dioxide balloon atmosphere for 0.5 h. Then the system was restored to room temperature, 20 mL of ethyl acetate was added to the system, the pH was adjusted to 2 using 1M dilute hydrochloric acid, extracted with ethyl acetate (30 mL x 3), the organic phase was combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10:1 to 2:1) to give compound 4A (2.4 g, reaction yield 37%).

[0396] Second step: Preparation of 4B

[0397] To a reaction flask was added 4A (0.15 g, 0.43 mmol), (S)-3-aminopiperidine-2,6-dione hydrochloride (0.071 g, 0.43 mmol,), EDCI (0.16 g, 0.86 mmol), HOBT (0.087 g, 0.65 mmol), and DMF (5 mL), N-methylmorpholine (0.13 g, 1.29 mmol) was added with stirring, the reaction was stirred at room temperature for 3 h, ethyl acetate and saturated aqueous sodium bicarbonate solution was added, stirred, partitioned, the organic layer was washed with saturated aqueous sodium bicarbonate solution once, saturated aqueous sodium chloride solution once, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 4B (0.18 g, yield: 91%).

[0398] Step 3: Preparation of 4C

[0399] To a reaction flask was added 4B (0.15 g, 0.33 mmol), dichloromethane (5 mL), trifluoroacetic acid (5 mL) was added with stirring, the reaction was stirred at room temperature for 2 h, concentrated under reduced pressure, the residue was dissolved in a mixture of dichloromethane / methanol (10 / 1), excess triethylamine was added to adjust to basic, concentrated under reduced pressure to give 4C (0.115 g, yield: 98%).

[0400] LCMS m / z = 361.2 [M+H] +

[0401] Step 4: Preparation of compound 4

[0402] To a reaction flask was added 1K (0.15 g, 0.28 mmol), 4C (0.101 g, 0.28 mmol), dichloromethane (10 mL), glacial acetic acid (0.034 g, 0.56 mmol), anhydrous sodium sulfate (0.08 g, 0.56 mmol), after addition, the temperature was raised to 50 °C for 1 h, then sodium triacetoxyborohydride (0.30 g, 1.40 mmol) was added, and the reaction was continued at 50 °C for 1 h. Dichloromethane and saturated aqueous sodium bicarbonate solution were added, stirred, partitioned, the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated residue was purified by column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) to give compound 4 (0.14 g, yield: 55%).

[0403] LCMS m / z = 443.8 [(M+2H) / 2] +

[0404] 1H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 10.82 (s, 1H), 8.42 (s, 1H), 8.01 - 7.86 (m, 2H), 7.55 (s, 1H), 7.36 (d, 2H), 7.12 (d, 1H), 6.89 (dd, 1H), 6.69 (d, 1H), 4.79 - 4.66 (m, 1H), 4.42 - 4.29 (m, 1H), 4.22 - 4.10 (m, 1H), 4.03 - 3.92 (m, 2H), 3.91 - 3.80 (m, 1H), 3.78 - 3.60 (m, 5H), 3.16 - 3.08 (m, 1H), 2.98 - 2.88 (m, 2H), 2.88 - 2.62 (m, 7H), 2.60 - 2.51 (m, 4H), 2.29 - 2.16 (m, 3H), 2.14 - 1.66 (m, 10H), 1.66 - 1.53 (m, 1H), 1.52 - 1.38 (m, 1H), 1.37 - 1.18 (m, 2H), 0.82 (d, 3H).

[0405] Example 5: Preparation of compound 5

[0406] First step: Preparation of compound 5H

[0407] Compound 5G:

[0408] 1 H NMR (400 MHz, CDCl3 / CD3OD (v / v) = 1 / 1) δ 12.19 - 11.79 (m, 1H), 8.85 (d, 1H), 8.58 (s, 1H), 8.17 (d, 1H), 7.39 (d, 1H), 7.35 (dd, 1H), 7.19 (d, 1H), 4.50 - 4.39 (m, 1H), 4.30 (dd, 1H), 3.88 - 3.80 (m, 1H), 3.78 (s, 3H), 3.69 (s, 3H), 3.60 (dd, 1H), 2.93 - 2.70 (m, 1H), 2.31 - 2.17 (m, 1H), 2.13 - 2.01 (m, 1H), 1.99 - 1.86 (m, 1H), 1.55 - 1.43 (m, 1H), 0.92 (d, 3H).

[0409] Compound 5G (0.6 g, 1.14 mmol, synthesis reference patent WO2024046221) and 4-(dimethoxymethyl)-piperidine (0.54 g, 3.42 mmol) were dissolved in 1,4-dioxane solution (30 mL), and then (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (2'-amino-1,1'-biphenyl-2-yl)palladium(II) (0.31 g, 0.34 mmol), lithium bis(trimethylsilyl)amide (6 mL, 1M in THF) were added. After addition, the reaction was stirred at 60 °C for 16 h under nitrogen protection. The reaction was quenched by adding saturated aqueous ammonium chloride solution, extracted with ethyl acetate (30 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (mobile phase: dichloromethane / methanol (v / v) = 10 / 1) to give compound 5H (0.5 g, yield: 73%).

[0410] LCMS m / z = 604.4 [M+H] +

[0411] Second step: preparation of compound 5I

[0412] Compound 5H (0.5 g, 0.83 mmol) was dissolved in tetrahydrofuran (20 mL), and hydrochloric acid (2N) (50 mL) was added dropwise at room temperature. The reaction was stirred at room temperature for 2 h. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (30 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 5I (0.22 g, yield: 48%).

[0413] Third step: preparation of compound 5

[0414] Compound 5I (0.11 g, 0.2 mmol) and 5F (63 mg, 0.2 mmol) were dissolved in dichloromethane (10 mL), and glacial acetic acid (0.024 g, 0.4 mmol) was added dropwise at room temperature. Then sodium sulfate (0.088 g, 0.62 mmol) and sodium triacetoxyborohydride (0.085 g, 0.4 mmol) were added. After addition, the reaction was stirred at room temperature for 16 h. The reaction was adjusted to basic by adding 1N sodium hydroxide aqueous solution, extracted with dichloromethane three times, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by preparative HPLC (instrument: waters 2767 preparative liquid phase; column: XBridge@Prep C18 (30 mm x 150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)) to give trifluoroacetate of compound 5 (0.055 g).

[0415] LCMS m / z = 859.3 [M+H]+

[0416] 1 H NMR (400 MHz, DMSO-d6) δ 12.39 (s, 1H), 10.79 (s, 1H), 9.57 (s, 1H), 8.80 (d, 1H), 8.35 (s, 1H), 8.27 (d, 1H), 7.39 (d, 1H), 7.21 (s, 1H), 6.94 (d, 1H), 6.89 (d, 1H), 6.80 (d, 1H), 4.40-4.32 (m, 1H), 4.16-4.06 (m, 2H), 3.96–3.83 (m, 2H), 3.78-3.60 (m, 8H), 3.48-3.30 (m, 2H), 3.16–3.05 (m, 4H), 2.93-2.62 (m, 8H), 2.56-2.46 (m, 2H), 2.20-1.85 (m, 9H), 1.70-1.55 (m, 1H), 1.50-1.35 (m, 3H), 0.82 (d, 3H).

[0417] Example 6: Preparation of compound 6

[0418] The compound 6 trifluoroacetate salt (0.068 g) was obtained by synthesis, using compound 5I and 1H as raw materials, according to the preparation of reference compound 5.

[0419] LCMS m / z = 860.3 [M+H] +

[0420] Example 7: Preparation of compound 7

[0421] First step: preparation of 7A

[0422] 7A-0 (5.0 g, 12.98 mmol), benzophenone imine (3.05 mL, 3.29 g, 18.17 mmol), cesium carbonate (9.30 g, 28.56 mmol), palladium acetate (583 mg, 2.6 mmol), XANT PHOS (751 mg, 1.3 mmol) were added to a solution of dioxane (100 mL) and reacted at 100 °C for 16 h under a nitrogen atmosphere. The reaction was cooled to room temperature, and the solid was removed by filtration with diethyl ether. The filter cake was washed with dichloromethane, and the organic phase was collected and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (v / v) = 1 / 5) to obtain 7A (5.6 g, yield: 89%).

[0423] LCMS m / z = 486.3 [M+H] +

[0424] Second Step: Preparation of 7B

[0425] 7A (5.6 g, 11.53 mmol) was added to methanol (200 mL), palladium on carbon (3.0 g, wt% = 10%), ammonium acetate (5.6 g, 72.6 mmol), and the reaction was carried out under a hydrogen atmosphere (balloon pressure) at room temperature for 16 h. The reaction was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (mobile phase: ethyl acetate / petroleum ether (v / v) = 1 / 1) to obtain 7B (3.6 g, yield: 97%).

[0426] LCMS m / z = 322.3 [M+H] +

[0427] Third Step: Preparation of 7C

[0428] 7B (3.6 g, 11.2 mmol), ethyl acrylate (3.36 g, 33.60 mmol), and N,N- diisopropylethylamine (4.34 g, 33.60 mmol) were sequentially added to ethanol (100 mL), and the reaction was carried out at 100 °C for 72 h. The reaction was concentrated under reduced pressure, and the residue was purified by column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 20) to obtain 7C (3.0 g, yield: 64%).

[0429] LCMS m / z = 422.3 [M+H]+

[0430] Fourth Step: Preparation of 7D

[0431] 7C (1.0 g, 2.37 mmol) and N,N-diisopropylethylamine (0.92 g, 7.11 mmol) were added to tetrahydrofuran (30 mL), and then triphosgene (0.77 g, 2.61 mmol) was slowly added and the reaction was carried out at room temperature for 1 h. Ammonia water (9 mL) was added, and the reaction was carried out at 50 °C for 2 h. The reaction was diluted with 100 mL of ethyl acetate, and the organic phase was washed with water 3 times, saturated sodium chloride 1 time, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) to obtain 7D (1.0 g, yield: 91%).

[0432] LCMS m / z = 465.3 [M+H] +

[0433] Fifth Step: Preparation of 7E

[0434] To a solution of 7D (1.0 g, 2.15 mmol) in acetonitrile (20 mL) was added benzyltrimethylammonium hydroxide 40% in methanol (2.5 mL, 6.45 mmol) and the reaction mixture was heated to 60 °C for 2 h. Silica gel was added and the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: methanol / dichloromethane (v / v) = 1 / 15) to give 7E (0.69 g, yield: 77%).

[0435] LCMS m / z = 363.2 [M-55] +

[0436] Step 6: Preparation of 7F

[0437] To a solution of 7E (0.5 g, 1.19 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (5 mL) and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to remove the trifluoroacetic acid. The residue was dissolved in 10 mL of dichloromethane and 1 mL of isopropanol. The solution was made basic with aqueous sodium carbonate solution and extracted with dichloromethane / isopropanol (v / v) = 10 / 1 three times. The organic phase was combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 7F (0.37 g).

[0438] Step 7: Preparation of compound 7

[0439] To a solution of 1K (0.145 g, 0.27 mmol) and 7F (0.095 g, 0.30 mmol) in chloroform (6 mL) was added sodium triacetoxyborohydride (0.086 g, 0.41 mmol) and one drop of acetic acid. The reaction mixture was heated at 50 °C for 1 h and then heated at 60 °C for 2 h. The reaction mixture was cooled to room temperature and dichloromethane and saturated sodium bicarbonate solution were added. The organic phase was separated and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: DCM / CH3OH = 100-0 to 90-10) to give compound 7 (0.12 g, yield: 53%).

[0440] LCMS m / z = 844.6 [M+H] +

[0441] 1H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 10.32 (s, 1H), 8.42 (s, 1H), 7.92 (s, 1H), 7.55 (s, 1H), 7.36 (d, 1H), 7.12 (s, 1H), 6.98 - 6.82 (m, 2H), 6.72 (d, 1H), 4.42 - 4.30 (m, 1H), 4.18 - 4.10 (m, 1H), 4.03 - 3.90 (m, 2H), 3.80 - 3.63 (m, 6H), 3.60 (t, 2H), 3.05 - 2.96 (m, 1H), 2.95 - 2.86 (m, 2H), 2.85 - 2.58 (m, 8H), 2.55 (s, 3H), 2.25 - 2.15 (m, 3H), 2.09 - 1.69 (m, 8H), 1.66 - 1.54 (m, 1H), 1.50 - 1.40 (m, 1H), 1.35 - 1.20 (m, 2H), 0.82 (d, 3H).

[0442] Example 8: Preparation of compound 8

[0443] Compound 8 (0.18 g) was obtained by using compound 5F and 1K as starting materials.

[0444] LCMS m / z = 843.6 [M+H] +

[0445] 1 H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 10.75 (s, 1H), 8.42 (s, 1H), 7.92 (s, 1H), 7.55 (s, 1H), 7.36 (d, 1H), 7.11 (d, 1H), 6.88 (dd, 1H), 6.79 (d, 1H), 6.62 (d, 1H), 4.40 - 4.30 (m, 1H), 4.18 - 4.10 (m, 1H), 4.02 - 3.91 (m, 2H), 3.85 - 3.78 (m, 1H), 3.76 - 3.60 (m, 6H), 3.01 - 2.85 (m, 3H), 2.85 - 2.58 (m, 7H), 2.55 (s, 3H), 2.52 - 2.47 (m, 1H), 2.27 - 2.15 (m, 3H), 2.14 - 1.65 (m, 10H), 1.65 - 1.53 (m, 1H), 1.50 - 1.40 (m, 1H), 1.34 - 1.20 (m, 2H), 0.82 (d, 3H).

[0446] Example 9: Preparation of compound 9

[0447] Referring to the preparation synthesis of compound 5, compound 9 (0.07 g) was obtained using compound 5I and 7F as raw materials.

[0448] LCMS m / z = 430.8 [(M+2H) / 2] +

[0449] 1 H NMR (400 MHz, DMSO-d6) δ 12.33 (s, 1H), 10.32 (s, 1H), 8.79 (d, 1H), 8.35 (s, 1H), 8.25 (d, 1H), 7.35 (d, 1H), 7.09 (s, 1H), 6.93 (d, 1H), 6.86 (dd, 1H), 6.72 (d, 1H), 4.40-4.30 (m, 1H), 4.15-4.03 (m, 1H), 3.99–3.84 (m, 2H), 3.78–3.63 (m, 6H), 3.62–3.57 (m, 5H), 3.04-2.96 (m, 1H), 2.95-2.86 (m, 2H), 2.82–2.56 (m, 8H), 2.26-2.11 (m, 3H), 2.10-2.00 (m, 1H), 1.95–1.54 (m, 8H), 1.48-1.38 (m, 1H), 1.35-1.22 (m, 2H), 0.81 (d, 3H).

[0450] Example 10: Preparation of compound 10

[0451] First step: preparation of 10B

[0452] In a 500 mL single-necked flask, 2-bromo-1,3-difluoro-5-iodobenzene (30 g, 94.08 mmol) and N-Boc-piperazine (17.52 g, 94.08 mmol) were dissolved in 300 mL of dioxane, and then cuprous iodide (2.69 g, 14.11 mmol), L-proline (1.62 g, 14.11 mmol) and potassium phosphate (40 g, 188.16 mmol) were added thereto, and the mixture was replaced with nitrogen three times, and then the temperature was raised to 90°C for 16 h. The reaction solution was cooled to room temperature, filtered with diatomite, and the filtrate was concentrated and purified by flash column chromatography (mobile phase: petroleum ether / ethyl acetate (V / V) = 20 / 1) to obtain 10B (12 g, yield: 34%).

[0453] Second step: preparation of 10C

[0454] To a solution of 10B (12 g, 31.81 mmol), benzophenone imine (6.34 g, 34.99 mmol), cesium carbonate (25.91 g, 79.52 mmol), palladium acetate (0.71 g, 3.18 mmol), XantPhos (1.84 g, 3.18 mmol) in dioxane (200 mL) was heated to 100 °C under nitrogen atmosphere for 16 h. The reaction mixture was cooled to room temperature, filtered through celite to remove the solid, the filter cake was washed with dichloromethane, and the organic phase was collected and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (v / v) = 1 / 10) to give 10C (8.5 g, yield: 56%).

[0455] Third Step: Preparation of 10D

[0456] To a solution of 10C (8.5 g, 17.8 mmol) in methanol (200 mL) was added palladium on carbon (5.0 g, wt% = 10%), ammonium acetate (5.0 g, 64.87 mmol), and the reaction mixture was stirred under hydrogen atmosphere (balloon pressure) at room temperature for 16 h. The reaction mixture was filtered through celite, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (v / v) = 5 / 1) to give 10D (5.5 g, yield: 98%).

[0457] LCMS m / z = 314.2 [M+H] +

[0458] Fourth Step: Preparation of 10E

[0459] To a solution of 10D (5.5 g, 17.55 mmol), ethyl acrylate (5.27 g, 52.65 mmol), and N,N-diisopropylethylamine (6.8 g, 52.65 mmol) in ethanol (60 mL) was heated to 100 °C for 72 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 20) to give a mixture of 10E (6.75 g (containing about 40% of 10D).

[0460] LCMS m / z = 414.3 [M+H] +

[0461] Fifth Step: Preparation of 10F

[0462] The mixture of 10E and 10D (6.75 g) obtained in the previous step and N, N- diisopropylethylamine (6.33 g, 48.99 mmol) were added to tetrahydrofuran (100 mL), then triphosgene (5.33 g, 17.96 mmol) was slowly added under ice bath and the reaction was allowed to proceed at room temperature for 1 h. Ammonia water (40 mL) was slowly added and the reaction was allowed to proceed at 50 °C for 2 h. The reaction solution was diluted with 100 mL of ethyl acetate, the organic phase was washed with water for 3 times, washed with saturated sodium chloride for 1 time, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated and purified by column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 20) to obtain 10F (4.0 g, two-step yield 50%).

[0463] LCMS m / z = 457.3 [M+H] +

[0464] Sixth step: Preparation of 10G

[0465] 10F (4.0 g, 8.76 mmol) was added to acetonitrile (40 mL), then benzyltrimethylammonium hydroxide 40% methanol solution (9.22 mL, 17.52 mmol) was added, and the reaction was allowed to proceed at 60 °C for 15 min. An appropriate amount of silica gel was added, concentrated under reduced pressure, and the residue was separated and purified by column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 20) to obtain 10G (3.3 g, yield: 92%).

[0466] Seventh step: Preparation of 10H

[0467] 10G (3.3 g, 8.04 mmol) was dissolved in 10 mL of dichloromethane, 10 mL of trifluoroacetic acid was added, and the reaction was allowed to proceed at room temperature for 2 h. The reaction solution was concentrated, redissolved in 50 mL of a mixed solvent (dichloromethane: isopropyl alcohol = 10:1), saturated sodium carbonate solution was added and adjusted to basic, the organic phase was separated, the aqueous layer was washed with a mixed solvent (dichloromethane: isopropyl alcohol = 10:1) for several times, the organic phases were combined, dried, and concentrated to obtain compound 10H (2.4 g, yield: 96%)

[0468] LCMS m / z = 311.1 [M+H] +

[0469] Eighth step: Preparation of compound 10

[0470] To a reaction flask were added 5I (0.15 g, 0.27 mmol), 10H (0.084 g, 0.27 mmol), chloroform (10 mL), glacial acetic acid (0.032 g, 0.54 mmol), and anhydrous sodium sulfate (0.077 g, 0.54 mmol). After complete addition, the temperature was raised to 50°C and the reaction was allowed to react for 1 h. Sodium triacetoxyborohydride (0.29 g, 1.35 mmol) was then added and the reaction continued at 50°C for 1 h. Dichloromethane and saturated aqueous sodium bicarbonate were added, and the layers were stirred and separated. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) to afford compound 10 (0.067 g, yield: 28%).

[0471] LCMS m / z=426.8[(M+2H) / 2] +

[0472] 1 H NMR(400MHz,DMSO-d6)δ12.56(s,1H),10.53(s,1H),9.47(s,1H),8.79(d,1H),8.35(s,1H), 8.30-8.10(m,2H),7.50(d,1H),6.91(d,2H),4.40-4.30(m,1H),4.20-4.10(m,1H),4.05-3. 88(m,4H),3.76–3.60(m,11H),3.30-3.10(m,5H),2.85-2.75(m,1H),2.71(t,2H),2.55(t,4 H),2.25-2.13(s,2H),2.06-1.86(m,4H),1.70-1.50(m,2H),1.50-1.38(m,1H),0.83(d,3H).

[0473] Example 11: Preparation of Compound 11

[0474] Referring to the preparation of compound 5, compound 11 (0.087 g, yield: 36%) was obtained using compound 5I (0.15 g, 0.27 mmol) and 3-(2,6-difluoro-4-(piperazin-1-yl)phenyl)piperidine-2,6-dione (CAS: 2957915-78-3) (0.084 g, 0.27 mmol) as raw materials.

[0475] LCMS m / z=426.3[(M+2H) / 2] +

[0476] 1H NMR (400 MHz, DMSO-d6) δ 12.32 (s, 1H), 10.85 (s, 1H), 8.79 (d, 1H), 8.35 (s, 1H), 8.25 (d, 1H), 7.35 (d, 1H), 7.09 (d, 1H), 6.86 (dd, 1H), 6.63 (d, 2H), 4.40-4.30 (s, 1H), 4.15 - 4.00 (m, 2H), 3.97-3.86 (m, 2H), 3.74 - 3.55 (m, 8H), 3.24-3.15 (m, 4H), 2.85 - 2.63 (m, 4H), 2.55-2.44 (m, 5H), 2.26 - 2.04 (m, 4H), 2.00 - 1.78 (m, 5H), 1.75-1.62 (m, 1H), 1.48-1.38 (m, 1H), 1.35-1.21 (m, 2H), 0.81 (d, 3H).

[0477] Example 12: Preparation of compound 12

[0478] First step: Preparation of 12A

[0479] tert-Butyl 2-(hydroxymethyl)-7-azaspiro[3.5]nonane-7-carboxylate (4.20 g, 16.45 mmol) was dissolved in hydrochloric acid 1,4-dioxane solution (50 mL, 4M) and reacted at room temperature for 2 h. The reaction solution was directly concentrated under reduced pressure to obtain compound 12A (3.15 g, yield: 99%).

[0480] LCMS m / z = 156.2 [M+H] +

[0481] Second step: Preparation of 12B

[0482] Compound 12A (1.50 g, 7.83 mmol) was added to a single-neck flask, followed by the addition of imidazole (2.67 g, 39.15 mmol), DMAP (0.019 g, 0.16 mmol) and tert-butyldimethylsilyl chloride (1.77 g, 11.75 mmol) as solvents. The reaction was carried out at room temperature for 1 h. The reaction solution was diluted with 200 mL of dichloromethane, washed with water 3 times, washed with saturated ammonium chloride 1 time, and the organic phase was collected. After drying over anhydrous sodium sulfate, the reaction solution was concentrated under reduced pressure to obtain compound 12B (2.35 g, yield: 89%).

[0483] LCMS m / z = 270.2 [M+H] +

[0484] Third step: Preparation of 12C

[0485] Dissolve 2,4-difluoronitrobenzene (3.00 g, 18.86 mmol) and (R)-5-amino-4- methylpentan-1-ol hydrochloride (3.04 g, 19.80 mmol) in DMF (50 mL), then add potassium carbonate (8.08 g, 58.47 mmol), and react at room temperature for 16 h after completion of the addition. Dilute the reaction solution with 300 mL of ethyl acetate, wash with water 3 times, and wash with saturated brine 1 time. Dry the organic phase over anhydrous sodium sulfate, concentrate, and then perform flash column chromatography (mobile phase: ethyl acetate / petroleum ether (v / v) = 1 / 1) to obtain compound 12C (4.09 g, yield: 85%).

[0486] LCMS m / z = 257.1 [M+H] +

[0487] Fourth step: Preparation of 12D

[0488] Dissolve 12C (2.00 g, 7.80 mmol) and 12B (2.52 g, 9.36 mmol) in DMF (50 mL), then add potassium carbonate (4.31 g, 31.20 mmol), and react at 80°C for 2 h after completion of the addition. Dilute the reaction solution with 300 mL of ethyl acetate, wash with water 3 times, and wash with saturated brine 1 time. Dry the organic phase over anhydrous sodium sulfate, concentrate, and then perform flash column chromatography (mobile phase: ethyl acetate / petroleum ether (v / v) = 1 / 1) to obtain compound 12D (3.90 g, yield: 99%).

[0489] LCMS m / z = 506.3 [M+H] +

[0490] Fifth step: Preparation of 12E

[0491] Dissolve 12D (3.90 g, 7.71 mmol) and triethylamine (2.34 g, 23.13 mmol) in dichloromethane (50 mL), and add methane sulfonic anhydride (2.01 g, 11.56 mmol) under ice bath, and react at room temperature for 0.5 h after completion of the addition. Dilute the reaction solution with 300 mL of dichloromethane, wash with water 3 times, and wash with saturated brine 1 time. Dry the organic phase over anhydrous sodium sulfate, concentrate, and then perform flash column chromatography (mobile phase: ethyl acetate / petroleum ether (v / v) = 1 / 1) to obtain compound 12E (4.50 g, yield: 99%).

[0492] Sixth step: Preparation of 12F

[0493] Compound 12F (4.03 g, 5.48 mmol) was dissolved in tetrahydrofuran (100 mL), then zinc powder (3.58 g, 54.80 mmol) and an aqueous solution of ammonium chloride (2.93 g, 54.80 mmol) (20 mL) were added, and the mixture was stirred at room temperature for 1 h. The reaction solution was extracted with dichloromethane three times, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) to obtain compound 12G (2.00 g, yield: 52%).

[0494] Seventh step: Preparation of 12G

[0495] Compound 12F (4.03 g, 5.48 mmol) was dissolved in tetrahydrofuran (100 mL), then zinc powder (3.58 g, 54.80 mmol) and an aqueous solution of ammonium chloride (2.93 g, 54.80 mmol) (20 mL) were added, and the mixture was stirred at room temperature for 1 h. The reaction solution was extracted with dichloromethane three times, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) to obtain compound 12G (2.00 g, yield: 52%).

[0496] LCMS m / z = 705.5 [M+H] +

[0497] Eighth step: Preparation of 12H

[0498] Compound 12G (2.00 g, 2.84 mmol) was dissolved in dichloromethane (50 mL) and tert-butyl alcohol (10 mL), then bromo cyanide (0.36 g, 3.41 mmol) was added, and the mixture was stirred at room temperature for 16 h. The reaction solution was directly concentrated under reduced pressure, and the residue was purified by flash column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) to obtain compound 12H (1.23 g, yield: 59%).

[0499] LCMS m / z = 730.5 [M+H] +

[0500] Ninth step: Preparation of 12I

[0501] Compound 12H (1.23 g, 1.68 mmol) was dissolved in tetrahydrofuran (30 mL) and water (30 mL), then sodium hydroxide (0.34 g, 8.40 mmol) was added, and the mixture was stirred at room temperature for 1 h. The reaction solution was directly concentrated under reduced pressure to remove most of the tetrahydrofuran, and the pH was adjusted to 5 by dropwise addition of 6N hydrochloric acid solution in an ice bath. The mixture was stirred for 30 min, and then the pH was adjusted to neutral by dropwise addition of sodium bicarbonate solution. The mixture was extracted with dichloromethane / methanol (v / v = 10 / 1), and the organic phase was collected and dried to obtain compound 12I (1.00 g, yield: 99%).

[0502] LCMS m / z = 602.3 [M+H] +

[0503] Step 10: Preparation of 12J

[0504] 12I (1.00 g, 1.66 mmol) was dissolved in 1,4-dioxane (30 mL), HATU (0.95 g, 2.49 mmol) and DIPEA (0.64 g, 4.98 mmol) were added, after the addition, the reaction was heated to 60 °C for 3 h. The reaction solution was directly concentrated under reduced pressure, and flash column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) was used to obtain compound 12J (0.28 g, yield: 29%).

[0505] LCMS m / z = 584.3 [M+H] +

[0506] Step 10: Preparation of 12J

[0507] 12J (0.28 g, 0.48 mmol) was dissolved in dichloromethane (15 mL), Dess-Martin oxidant (0.31 g, 0.72 mmol) was added, after the addition, the reaction was stirred at room temperature for 3 h. The reaction solution was directly concentrated under reduced pressure, and flash column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) was used to obtain compound 12K (0.164 g, yield: 59%).

[0508] Step 12: Preparation of compound 12

[0509] A reaction bottle was added with 12K (0.04 g, 0.069 mmol), 1H (0.022 g, 0.069 mmol), dichloromethane (5 mL), glacial acetic acid (0.0083 g, 0.14 mmol), anhydrous sodium sulfate (0.02 g, 0.14 mmol), after the addition, the reaction was heated to 50 °C for 1 h, then sodium triacetoxyborohydride (0.073 g, 0.35 mmol) was added, and the reaction was continued at 50 °C for 1 h. Dichloromethane and saturated aqueous sodium bicarbonate solution were added, the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the concentrated residue was purified by column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) to obtain the product, which was purified by preparative HPLC (instrument: waters 2767 preparative liquid phase; column: XBridge@Prep C18 (30 mm x 150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)), and the trifluoroacetate salt of compound 12 was obtained by freeze-drying of the preparation liquid (0.021 g).

[0510] LCMS m / z = 442.8 [(M+2H) / 2] +

[0511] 1 H NMR (400 MHz, DMSO-d6) δ 12.59 (s, 1H), 10.35 (s, 1H), 9.74 (s, 1H), 8.50 (s, 1H), 8.02 (s, 1H), 7.66 (s, 1H), 7.41 (d, 1H), 7.26 (s, 1H), 7.04-6.95 (m, 2H), 6.89 (d, 1H), 4.43-4.34 (m, 1H), 4.20-3.94 (m, 4H), 3.75 (s, 3H), 3.60 (t, 2H), 3.55-3.44 (m, 2H), 3.35-3.16 (m, 5H), 3.14 - 3.00 (m, 4H), 2.90-2.65 (m, 7H), 2.61 (s, 3H), 2.28-2.16 (m, 1H), 2.15-2.05 (m, 2H), 2.04-1.89 (m, 3H), 1.85-1.76 (s, 2H), 1.73 - 1.60 (m, 5H), 1.52-1.40 (m, 1H), 0.82 (d, 3H).

[0512] Example 13: Preparation of compound 13

[0513] Compound 13 was synthesized using compound 12K and 3A as starting materials to give compound 13 trifluoroacetate salt (0.026 g).

[0514] LCMS m / z = 442.3 [(M+2H) / 2] +

[0515] 1H NMR (400 MHz, DMSO-d6) δ 12.60 (s, 1H), 10.78 (s, 1H), 9.85 (s, 1H), 8.50 (s, 1H), 8.02 (s, 1H), 7.66 (s, 1H), 7.41 (s, 1H), 7.28 (s, 1H), 7.00 (d, 1H), 6.88 (d, 1H), 6.78 (d, 1H), 4.42-4.33 (m, 1H), 4.20 - 3.95 (m, 5H), 3.87 - 3.81 (m, 1H), 3.75 (s, 3H), 3.56 - 3.43 (m, 2H), 3.33 - 3.18 (m, 5H), 3.15 - 2.95 (m, 4H), 2.90 - 2.64 (m, 6H), 2.61 (s, 3H), 2.27 - 2.18 (m, 1H), 2.16 - 2.05 (m, 3H), 2.04 - 1.88 (m, 4H), 1.85 - 1.76 (m, 2H), 1.72 - 1.55 (m, 5H), 1.52 - 1.40 (m, 1H), 0.82 (d, 3H).

[0516] Example 14: Preparation of compound 14

[0517] Synthesis of reference compound 5, compound 14 trifluoroacetate salt was obtained using compound 5I and 3A as starting materials (0.12 g).

[0518] LCMS m / z = 430.2 [M / 2 + H] +

[0519] 1 H NMR (400 MHz, DMSO-d6) δ 12.40 (s, 1H), 10.78 (s, 1H), 9.62 (s, 1H), 8.79 (s, 1H), 8.35 (s, 1H), 8.27 (s, 1H), 7.40 (d, 1H), 7.23 (s, 1H), 6.96 (d, 1H), 6.88 (d, 1H), 6.80 (d, 1H), 4.40 - 4.31 (m, 1H), 4.16 - 4.06 (m, 2H), 3.97 - 3.90 (m, 2H), 3.89 - 3.81 (m, 2H), 3.78 - 3.58 (m, 8H), 3.40 - 3.30 (m, 1H), 3.18 - 3.05 (m, 4H), 2.93 - 2.60 (m, 8H), 2.24 - 1.82 (m, 10H), 1.70 - 1.58 (m, 1H), 1.50 - 1.36 (m, 3H), 0.82 (d, 3H).

[0520] Example 15: Preparation of compound 15

[0521] Step 1: Preparation of compound 15A

[0522] Compound 5G (0.7 g, 1.33 mmol) and 4-piperidone glycol (0.57 g, 3.99 mmol) were dissolved in 1,4-dioxane (30 mL), and (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (2'-amino-1,1'-biphenyl-2-yl)palladium(II) (0.36 g, 0.4 mmol), lithium bis(trimethylsilyl)amide (7 mL, 1M in THF) were added. After addition, the reaction was stirred at 60 °C under nitrogen protection for 16 h. The reaction was cooled to room temperature, quenched by saturated aqueous ammonium chloride solution, extracted with ethyl acetate (30 mL x 3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (mobile phase: dichloromethane / methanol (v / v) = 10 / 1) to give compound 15A (0.4 g, yield: 51%).

[0523] Step 2: Preparation of compound 15B

[0524] Compound 15A (0.4 g, 0.83 mmol) was dissolved in tetrahydrofuran (20 mL), and hydrochloric acid (8N) (5 mL) was added dropwise at room temperature. The reaction was stirred at room temperature for 12 h. The reaction was quenched by saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (30 mL x 3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 15B (0.3 g, yield: 81%).

[0525] Step 3: Preparation of compound 15

[0526] Compound 15B (0.1 g, 0.18 mmol) was dissolved in a solution of 3-(2,6-difluoro-4- (piperazin-1-yl)phenyl)piperidine-2,6-dione (CAS: 2957915-78-3) (56 mg, 0.18 mmol) in chloroform (10 mL), glacial acetic acid (0.022 g, 0.36 mmol), anhydrous sodium sulfate (0.077 g, 0.54 mmol), after addition, the temperature was raised to 50 °C and reacted for 16 h, then sodium triacetoxyborohydride (0.076 g, 0.36 mmol) was added in batches, and the reaction was continued at 50 °C for 3 h. After cooling to room temperature, dichloromethane and saturated aqueous sodium bicarbonate solution were added, the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated residue was purified by column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) to obtain a crude product. The crude product was purified by preparative HPLC (instrument: waters 2767 preparative liquid phase; column: XBridge@Prep C18 (30 mm x 150 mm); mobile phase composition: acetonitrile, water containing 0.1% trifluoroacetic acid). The trifluoroacetate salt of compound 15 (0.02 g) was obtained by lyophilization of the preparative liquid.

[0527] LCMS m / z = 419.4 [(M+2H) / 2] +

[0528] Preparation of compound 15-1

[0529] First step: preparation of compound 15-1B

[0530] Under nitrogen protection, 1-BOC-piperazine (2.92 g, 15.68 mmol) and 15-1A (5 g, 15.68 mmol) were dissolved in a solution of 1,4-dioxane (150 mL), and tris(dibenzylideneacetone) dipalladium (1.44 g, 1.57 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.81 g, 3.14 mmol) and cesium carbonate (15.33 g, 47.04 mmol) were added. After addition, the temperature was raised to 90 °C under nitrogen protection and stirred for 12 h. After cooling to room temperature, the reaction solution was diluted with 100 mL of ethyl acetate, and the filtrate was filtered with diatomite. The filter cake was washed with ethyl acetate for 3 times, and the combined filtrate was washed with water once and saturated sodium chloride once. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was quickly column chromatographed (mobile phase: dichloromethane / methanol (v / v) = 20 / 1) to obtain compound 15-1B (5.5 g, yield: 93%).

[0531] Second step: preparation of compound 15-1C

[0532] Compound 15-1B (5.5 g, 14.58 mmol), 2,6-dibenzyloxy pyridine-3-boronic acid pinacol ester (7.3 g, 17.5 mmol) were dissolved in 100 mL of DMF and 10 mL of water in a flask under nitrogen protection, then 1,1'-bis (di-tert-butylphosphine) ferrocene palladium (0) dichloride (0.95 g, 1.46 mmol) and cesium fluoride (6.64 g, 43.74 mmol) were added, replaced with nitrogen for three times, heated to 80 °C for 4 h. After the reaction was completed, it was cooled to room temperature, diluted with ethyl acetate (300 mL), washed with saturated brine for 3 times, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to silica gel column chromatography (dichloromethane: methanol (v:v) = 20:1) to obtain compound 15-1C (6.8 g, yield: 79%).

[0533] Third step: preparation of compound 15-1D

[0534] Compound 15-1C (6.8 g, 11.57 mmol), 10% palladium-carbon (10 g) were added to 80 mL of isopropyl alcohol, replaced with hydrogen for three times, and heated to 30 °C for overnight. After cooling to room temperature, it was filtered with diatomite, the filter cake was washed with methanol for three times, the organic phases were combined, dried over anhydrous sodium sulfate, and rotary evaporated under reduced pressure. The residue was slurried with ethyl acetate to obtain compound 15-1D (2.3 g, yield: 49%).

[0535] Fourth step: preparation of compounds 15-1E1 and 15-1E2

[0536] The racemate 15-1D (2.3 g) was subjected to chiral resolution to prepare:

[0537] The analysis method is as follows:

[0538] Instrument: SHIMADZU LC-30AD SFC; chromatographic column: Chiral IG column;

[0539] Mobile phase composition: mobile phase A: CO2; mobile phase B: methanol and acetonitrile (containing 0.05% DEA);

[0540] Isocratic elution: mobile phase B content is 40%; flow rate: 3 mL / min;

[0541] Back pressure: 100 bar; column temperature: 35 °C; wavelength: 220 nm.

[0542] The preparation method is as follows:

[0543] Instrument: Waters 150Prep-SFC; chromatographic column: Chiral IG column;

[0544] Mobile phase composition: mobile phase A: CO2; mobile phase B: methanol and acetonitrile (containing 0.1% NH3H2O);

[0545] Isocratic elution: mobile phase B content 45%; flow rate: 100 mL / min;

[0546] Back pressure: 100 bar; column temperature: room temperature; wavelength: 220 nm; injection cycle time: 5 min;

[0547] Sample solution preparation: dissolved in acetonitrile / methanol to prepare 20 mg / mL.

[0548] Compound 15-1E1: 1.0 g; retention time under analytical method: 1.127 min.

[0549] LCMS m / z = 310.0 [M-99] +

[0550] Compound 15-1E2: 1.03 g; retention time under analytical method: 2.076 min.

[0551] LCMS m / z = 310.0 [M-99] +

[0552] Fifth step: preparation of 15-1F

[0553] Dissolve 15-1E1 (0.6 g, 1.47 mmol) in dichloromethane (8 mL), add trifluoroacetic acid (2 mL), stir at room temperature for 1 h. Concentrate the reaction solution under reduced pressure to remove most of the trifluoroacetic acid, then dissolve the residue in 10 mL of dichloromethane and 1 mL of isopropanol, adjust to basicity with aqueous sodium bicarbonate solution, extract 3 times with dichloromethane / isopropanol (v / v) = 10 / 1, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 15-1F (0.44 g).

[0554] Sixth step: preparation of compound 15-1

[0555] Compound 15B (0.3 g, 0.55 mmol) was dissolved in a solution of compound 15-1F (170 mg, 0.55 mmol) in chloroform (25 mL), acetic acid (0.066 g, 1.1 mmol), anhydrous sodium sulfate (0.14 g, 1 mmol) were added, after addition, the temperature was raised to 50 °C and reacted for 16 h, then sodium triacetoxyborohydride (0.23 g, 1.1 mmol) was added in batches, and the reaction was continued at 50 °C for 3 h. After cooling to room temperature, dichloromethane and saturated aqueous sodium bicarbonate solution were added, and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrated residue was purified by column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) to obtain a crude product, which was purified by preparative HPLC (instrument: waters 2767 preparative liquid phase; column: XBridge@Prep C18(30mm×150mm); mobile phase composition: acetonitrile, water containing 0.1% trifluoroacetic acid) and freeze-dried to obtain the trifluoroacetate salt of compound 15-1 (0.1 g).

[0556] LCMS m / z = 419.2 [(M+2H) / 2] +

[0557] 1 H NMR (400 MHz, CDCl3 / CD3OD (v / v) = 1 / 1) δ 9.07-8.81 (m, 1H), 8.46 (s, 1H), 8.29-8.13 (m, 1H), 7.36 (d, 1H), 7.06-6.88 (m, 2H), 6.60 (d, 2H), 4.55-4.46 (m, 1H), 4.37-4.27 (m, 1H), 4.12-4.02 (m, 1H), 3.98-3.78 (m, 6H), 3.78-3.35 (m, 13H), 2.97-2.81 (m, 3H), 2.80-2.71 (m, 2H), 2.39-2.22 (m, 4H), 2.19-1.91 (m, 5H), 1.60-1.48 (m, 1H), 0.91 (d, 3H).

[0558] Preparation of compound 15-2

[0559] First step: preparation of 15-2A

[0560] Compound 15-2A (0.3 g) was obtained by the reaction of 15-1E2 (0.5 g, 1.22 mmol) with trifluoroacetic acid (2 mL) in dichloromethane (8 mL) at room temperature for 1 h. The reaction solution was concentrated under reduced pressure to remove most of the trifluoroacetic acid, and then 10 mL of dichloromethane and 1 mL of isopropanol were added to dissolve the residue. The solution was adjusted to basic with an aqueous sodium bicarbonate solution, and then extracted three times with dichloromethane / isopropanol (v / v) = 10 / 1. The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 15-2A (0.3 g).

[0561] Step 2: Preparation of compound 15-2

[0562] Compound 15B (0.1 g, 0.18 mmol) and compound 15-2A (56 mg, 0.18 mmol) were dissolved in a solution of chloroform (10 mL), and acetic acid (0.022 g, 0.36 mmol) and anhydrous sodium sulfate (0.077 g, 0.54 mmol) were added. After the addition was completed, the solution was warmed to 50 °C and reacted for 16 h. Then sodium triacetoxyborohydride (0.076 g, 0.36 mmol) was added in portions, and the reaction was continued at 50 °C for 3 h. After the solution was cooled to room temperature, dichloromethane and saturated aqueous sodium bicarbonate solution were added, and the mixture was stirred and then separated into layers. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) to obtain a crude product, which was purified by preparative HPLC (instrument: waters 2767 preparative liquid phase; column: XBridge® Prep C18 (30 mm x 150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)) and then lyophilized to obtain a trifluoroacetate salt of compound 15-2 (0.03 g).

[0563] LCMS m / z = 419.1 [(M+2H) / 2] +

[0564] NMR (400 MHz, CDCl3 / CD3OD (v / v) = 1 / 1) δ 8.97-8.84 (m, 1H), 8.46 (s, 1H), 8.23-8.10 (m, 1H), 7.37 (d, 1H), 7.06-6.89 (m, 2H), 6.66 (d, 2H), 4.57-4.46 (m, 1H), 4.37-4.27 (m, 1H), 4.16-4.08 (m, 1H), 3.99-3.80 (m, 6H), 3.80-3.36 (m, 13H), 2.98-2.81 (m, 3H), 2.81-2.70 (m, 2H), 2.41-2.23 (m, 4H), 2.20-1.93 (m, 5H), 1.62-1.49 (m, 1H), 0.91 (d, 3H).

[0565] Example 16: Preparation of compound 16

[0566] First step: Preparation of compound 16A

[0567] Compound 5G (1.3 g, 2.47 mmol, synthesis reference patent WO2024046221) and 1-Boc-piperazine (1.38 g, 7.41 mmol) were dissolved in 1,4-dioxane solution (60 mL), and added with (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (2'-amino-1,1'-biphenyl-2-yl)palladium(II) (0.67 g, 0.74 mmol), lithium bis(trimethylsilyl)amide (14 mL, 1M in THF). After addition, the reaction was stirred at 60°C under nitrogen protection for 16 h. The reaction was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate (30 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the residue was concentrated under reduced pressure and purified by flash column chromatography (mobile phase: dichloromethane / methanol (v / v) = 10 / 1) to obtain compound 16A (0.8 g, yield: 51%).

[0568] Second step: Preparation of compound 16B

[0569] Compound 16A (0.8 g, 1.27 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (5 mL) was added. The reaction was stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure to remove the trifluoroacetic acid, and 10 mL of dichloromethane and 1 mL of isopropanol were added to dissolve the residue. The solution was adjusted to basic with aqueous sodium carbonate solution, extracted with dichloromethane / isopropanol (v / v) = 10 / 1 three times, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 16B (0.53 g, yield: 79%).

[0570] Third step: Preparation of compound 16

[0571] Compound 16B (0.1 g, 0.19 mmol) was dissolved in a solution of 16C (CAS: 2960325-23-7, 64 mg, 0.19 mmol) in chloroform (10 mL), glacial acetic acid (0.023 g, 0.38 mmol), anhydrous sodium sulfate (0.077 g, 0.54 mmol), after adding, the reaction was carried out at room temperature for 16 h, then sodium triacetoxyborohydride (0.081 g, 0.38 mmol) was added in batches, and the reaction was continued for 3 h. Dichloromethane and saturated aqueous sodium bicarbonate solution were added, stirred, separated into organic and aqueous layers, the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated residue was purified by column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) to obtain a crude product, which was purified by preparative HPLC (instrument: waters 2767 preparative liquid phase; column: XBridge@Prep C18(30mmx150mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)) and freeze-dried to obtain the trifluoroacetate salt of compound 16 (0.08 g).

[0572] LCMS m / z = 426.4 [(M+2H) / 2] +

[0573] 1 H NMR (400 MHz, DMSO-d6) δ 12.41 (s, 1H), 10.85 (s, 1H), 9.40 (s, 1H), 8.80 (d, 1H), 8.35 (s, 1H), 8.27 (d, 1H), 7.42 (d, 1H), 7.23 (s, 1H), 6.93 (dd, 1H), 6.67 (d, 2H), 4.41-4.30 (m, 1H), 4.17-4.09 (m, 1H), 4.08-4.02 (m, 1H), 3.98-3.87 (m, 2H), 3.86-3.75 (m, 4H), 3.71 (s, 3H), 3.70-3.59 (m, 5H), 3.27-3.18 (m, 1H), 3.18-3.06 (m, 4H), 2.87–2.73 (m, 4H), 2.56-2.47 (m, 2H), 2.28-2.02 (m, 3H), 2.01–1.88 (m, 3H), 1.87-1.78 (m, 2H), 1.51–1.38 (m, 1H), 1.37–1.22 (m, 2H), 0.83 (d, 3H).

[0574] Example 17: Preparation of compound 17

[0575] 16B (0.15 g, 0.28 mmol), 16B-1 (0.09 g, 0.28 mmol), chloroform (10 mL), glacial acetic acid (0.034 g, 0.56 mmol), and anhydrous sodium sulfate (0.08 g, 0.56 mmol) were added to the reaction flask. After the addition, the temperature was raised to 50°C and the reaction was allowed to proceed for 1 h. Sodium triacetoxyborohydride (0.30 g, 1.40 mmol) was then added and the reaction was continued at 50°C for 1 h. Dichloromethane and saturated aqueous sodium bicarbonate solution were added, stirred and separated, the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the concentrated residue was purified by column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) to give the product, which was purified by preparative HPLC (instrument: Waters 2767 preparative liquid phase; chromatographic column: XBridge@Prep C18 (30 mm × 150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)). The preparative solution was lyophilized to give the trifluoroacetate salt of compound 17 (0.038 g).

[0576] LCMS m / z=837.3[M+H] +

[0577] Preparation of compound 17-1:

[0578] Step 1: Preparation of 17A-1 and 17A-2

[0579] The racemate 17A (1.00 g, 2.73 mmol) was subjected to chiral resolution to prepare:

[0580] The analysis method is as follows:

[0581] Instrument: SHIMADZU LC-30AD SFC; Column: Chiral WHELK column;

[0582] Mobile phase composition: Mobile phase A: CO2; Mobile phase B: ethanol (containing 0.05% DEA);

[0583] Isocratic elution: mobile phase B content 5-40%; flow rate: 3 mL / min;

[0584] Back pressure: 100 bar; column temperature: 35°C; wavelength: 220 nm.

[0585] The preparation method is as follows:

[0586] Instrument: Waters 150Prep-SFC; Column: Chiral WHELK column;

[0587] Mobile phase composition: Mobile phase A: CO2; Mobile phase B: ethanol (containing 0.1% NH3·H2O);

[0588] Isocratic elution: mobile phase B content 50%; flow rate: 90 mL / min;

[0589] Back pressure: 100 bar; column temperature: room temperature; wavelength: 220 nm; injection cycle time: 7.3 min;

[0590] Sample solution preparation: dissolved in acetonitrile / methanol to make 20 mg / mL.

[0591] Compound 17A-1: 0.369 g; retention time under analytical method: 1.900 min.

[0592] LCMS m / z = 367.1 [M+H] +

[0593] Compound 17A-2: 0.409 g; retention time under analytical method: 2.103 min.

[0594] LCMS m / z = 367.1 [M+H] +

[0595] Second step: preparation of 17B-1

[0596] 17A-1 (0.369 g, 1.01 mmol) was added to a 50 mL single-neck flask, concentrated hydrochloric acid (5 mL) was added, the reaction was stirred at room temperature for 2 h, sodium bicarbonate aqueous solution was added under ice bath to adjust the pH to alkaline, extracted with dichloromethane / methanol (v / v = 10 / 1) for 3 times, the organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, the residue was purified by silica gel column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 10) to obtain 17B-1 (0.188 g, yield: 58%).

[0597] Third step: preparation of compound 17-1

[0598] A reaction vial was charged with 16B (0.20 g, 0.38 mmol), 17B-1 (0.122 g, 0.38 mmol), chloroform (10 mL), glacial acetic acid (0.046 g, 0.76 mmol), and the mixture was warmed to 50 °C for 16 h. Then sodium triacetoxyborohydride (0.402 g, 1.90 mmol) was added and the mixture was stirred at 50 °C for another 3 h. The mixture was cooled to room temperature, diluted with dichloromethane and saturated aqueous sodium bicarbonate solution, and the mixture was stirred for 10 min. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: methanol / dichloromethane (v / v) = 1 / 15) to give the product. The product was purified by preparative HPLC (instrument: waters 2767 preparative liquid phase; column: XBridge® Prep C18 (30 mm x 150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)), and the product was lyophilized to give compound 17-1 trifluoroacetate salt (0.07 g).

[0599] LCMS m / z = 837.4 [M+H] +

[0600] 1 H NMR (400 MHz, CDCl3 / CD3OD (v / v) = 1 / 1) δ 8.97 - 8.86 (m, 1H), 8.46 (s, 1H), 8.28 - 8.18 (m, 1H), 7.40 (d, 1H), 7.05 - 6.88 (m, 2H), 6.54 (d, 2H), 4.54 - 4.48 (m, 1H), 4.37 - 4.28 (m, 1H), 4.08 - 4.01 (m, 1H), 3.98 - 3.87 (m, 3H), 3.79 (s, 3H), 3.78 - 3.35 (m, 13H), 2.99 - 2.80 (m, 3H), 2.79 - 2.70 (m, 2H), 2.40 - 2.21 (m, 4H), 2.19 - 1.86 (m, 5H), 1.60 - 1.48 (m, 1H), 0.91 (d, 3H).

[0601] Preparation of compound 17-2:

[0602] First step: preparation of 17B-2

[0603] Into a 50 mL single neck flask, 17A-2 (0.409 g, 1.12 mmol) was added, concentrated hydrochloric acid (5 mL) was added, the reaction was stirred at room temperature for 2 h, ice bath was used to cool the reaction, sodium bicarbonate aqueous solution was added to adjust the pH to basic, dichloromethane / methanol (v / v = 10 / 1) was used to extract the reaction 3 times, the organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, the residue was purified by silica gel column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 10) to obtain 17B-2 (0.227 g, yield: 63%).

[0604] Step 3: Preparation of compound 17-2

[0605] Into a reaction flask, 16B (0.20 g, 0.38 mmol), 17B-2 (0.122 g, 0.38 mmol), trichloromethane (10 mL), glacial acetic acid (0.046 g, 0.76 mmol) were added, after addition, the temperature was raised to 50 °C and the reaction was carried out for 16 h, then sodium triacetoxyborohydride (0.402 g, 1.90 mmol) was added, the reaction was continued at 50 °C for 3 h. The temperature was lowered to room temperature, dichloromethane and saturated sodium bicarbonate aqueous solution were added, the organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, the residue was purified by column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) to obtain the product, which was purified by preparative HPLC (instrument: waters 2767 preparative liquid phase; column: XBridge@Prep C18 (30 mm x 150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)), and the trifluoroacetate salt of compound 17-2 was obtained by freeze-drying of the preparative liquid (0.065 g).

[0606] LCMS m / z = 837.3 [M+H] +

[0607] 1 H NMR (400 MHz, CDCl3 / CD3OD (v / v) = 1 / 1) δ 8.95-8.86 (m, 1H), 8.46 (s, 1H), 8.25-8.15 (m, 1H), 7.40 (d, 1H), 7.05-6.91 (m, 2H), 6.57 (d, 2H), 4.57-4.47 (m, 1H), 4.39-4.28 (m, 1H), 4.12-4.04 (m, 1H), 4.01-3.88 (m, 3H), 3.80 (s, 3H), 3.79-3.36 (m, 13H), 2.99-2.81 (m, 3H), 2.79-2.70 (m, 2H), 2.40-2.21 (m, 4H), 2.19-1.87 (m, 5H), 1.62-1.48 (m, 1H), 0.91 (d, 3H).

[0608] Example 18: Preparation of compound 18

[0609] Compound 18 trifluoroacetate salt (0.033 g) was synthesized by following the procedure for the preparation of compound 12, using tert-butyl 2-hydroxy-7- azaspiro[3.5]nonane-7-carboxylate as starting material.

[0610] LCMS m / z = 435.8 [(M+2H) / 2] +

[0611] 1 H NMR (400 MHz, DMSO-d6) δ 12.59 (s, 1H), 10.37 (s, 1H), 10.08 (s, 1H), 8.51 (s, 1H), 8.03 (s, 1H), 7.67 (s, 1H), 7.40 (d, 1H), 7.23 (s, 1H), 7.07 - 6.82 (m, 3H), 4.44 - 4.33 (m, 1H), 4.21 - 4.12 (m, 2H), 4.08 - 3.92 (m, 2H), 3.80 - 3.45 (m, 7H), 3.34 - 3.25 (m, 1H), 3.24 - 3.17 (m, 2H), 3.17 - 3.09 (m, 2H), 3.07 - 2.86 (m, 3H), 2.84 - 2.66 (m, 6H), 2.62 (s, 3H), 2.33 - 2.16 (m, 3H), 2.14 - 1.87 (m, 5H), 1.83 - 1.56 (m, 5H), 1.54 - 1.36 (m, 1H), 0.82 (d, 3H).

[0612] Example 19: Preparation of compound 19

[0613] Compound 19 trifluoroacetate salt (0.015 g) was synthesized by following the procedure for the preparation of compound 15, using compound 15B and 10H as starting materials.

[0614] LCMS m / z = 419.8 [(M+2H) / 2] +

[0615] Example 20: Preparation of compound 20

[0616] Compound 20 trifluoroacetate salt (0.015 g) was synthesized by following the procedure for the preparation of compound 12, using compound 12K and 7F as starting materials.

[0617] LCMS m / z = 884.3 [M+H] +

[0618] Example 21: Preparation of compound 21

[0619] Compound 21 was synthesized using compound 18K and 7F as starting materials.

[0620] LCMS m / z = 870.3 [M+H] +

[0621] 1 H NMR (400 MHz, DMSO-d6) δ 12.61 (s, 1H), 10.37 (s, 1H), 10.17 (s, 1H), 8.53 (s, 1H), 8.06 (s, 1H), 7.70 (s, 1H), 7.41 (d, 1H), 7.26 (s, 1H), 7.03 (d, 1H), 6.99 (d, 1H), 6.92 (d, 1H), 4.44 - 4.34 (m, 1H), 4.21 - 4.12 (m, 1H), 4.07 - 3.95 (m, 1H), 3.85-3.77 (m, 1H), 3.76 (s, 3H), 3.61 (t, 2H), 3.54 - 3.46 (m, 2H), 3.35 - 3.08 (m, 6H), 3.06 - 2.97 (m, 1H), 2.97 - 2.86 (m, 1H), 2.85 - 2.66 (m, 6H), 2.63 (s, 3H), 2.30 - 2.18 (m, 3H), 2.16 - 1.84 (m, 6H), 1.82 - 1.70 (m, 4H), 1.69 - 1.59 (m, 1H), 1.52 - 1.42 (m, 1H), 0.82 (d, 3H).

[0622] Example 22: Preparation of compound 22

[0623] Compound 22 was synthesized using compound 12K and 5F as starting materials.

[0624] LCMS m / z = 883.5 [M+H] +

[0625] Example 23: Preparation of compound 23

[0626] Compound 23 was synthesized using compound 18K and 5F as starting materials.

[0627] LCMS m / z = 869.4 [M+H] +

[0628] 1H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 10.76 (s, 1H), 8.42 (s, 1H), 7.92 (s, 1H), 7.55 (s, 1H), 7.35 (d, 1H), 7.13 (s, 1H), 6.89 (d, 1H), 6.79 (d, 1H), 6.62 (d, 1H), 4.42 - 4.28 (m, 1H), 4.17 - 4.08 (m, 1H), 4.03 - 3.91 (m, 2H), 3.86 - 3.78 (m, 1H), 3.78 - 3.74 (m, 1H), 3.73 (s, 3H), 3.20 - 3.10 (m, 2H), 3.09 - 3.01 (m, 2H), 2.98 - 2.78 (m, 4H), 2.76 - 2.64 (m, 4H), 2.64 - 2.58 (m, 1H), 2.54 (s, 3H), 2.50 - 2.44 (m, 1H), 2.28 - 2.07 (m, 2H), 2.04 - 1.84 (m, 7H), 1.76 - 1.69 (m, 2H), 1.68 - 1.53 (m, 6H), 1.51 - 1.38 (m, 1H), 0.82 (d, 3H).

[0629] Example 24: Preparation of compound 24

[0630] First step: Preparation of compound 24A

[0631] Into a reaction bottle was added 24A-1 (0.15 g, 0.54 mmol, synthesis reference patent WO2023109471), dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added under stirring, and the reaction was stirred at room temperature for 1 hour after completion. Dryness was performed under reduced pressure, dichloromethane was added, triethylamine (82 mg, 0.81 mmol) was added dropwise, and dryness was performed under reduced pressure again. Compound 5G (0.14 g, 0.27 mmol), methane sulfonic acid (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (50 mg, 0.054 mmol) and 1,4-dioxane solution (10 mL) were added to the residue, and lithium bis(trimethylsilyl)amide (2.7 mL, 1M in THF) was added dropwise under nitrogen protection at room temperature. After completion of the addition, the reaction was stirred at 60°C for 16 hours. Saturated aqueous ammonium chloride solution was added for quenching, and extraction was performed with ethyl acetate (30 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the residue was concentrated under reduced pressure. Compound 24A (0.12 g, yield: 72%) was obtained by flash column chromatography (mobile phase: dichloromethane / methanol (v / v) = 10 / 1).

[0632] LCMS m / z = 628.3 [M+H] +

[0633] Second Step: Preparation of compound 24B

[0634] Compound 24A (0.12 g, 0.15 mmol) was dissolved in tetrahydrofuran (3 mL), hydrochloric acid (8 N) (2 mL) was added dropwise at room temperature, and the reaction was stirred at 60 °C for 2 h. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (20 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 24B (80 mg).

[0635] LCMS m / z = 584.4 [M+H] +

[0636] Third Step: Preparation of compound 24

[0637] Compound 24B (80 mg) and 3-(2,6-difluoro-4-(piperazin-1-yl)phenyl)piperidine-2,6- dione (CAS: 2957915-78-3) (48 mg, 0.15 mmol) were dissolved in chloroform (10 mL), glacial acetic acid (0.022 g, 0.36 mmol) was added dropwise, and after the addition was complete, the reaction was warmed to 70 °C overnight. Sodium triacetoxyborohydride (89 mg, 0.42 mmol) was added in portions, and after the addition was complete, the reaction was stirred at 70 °C overnight. Dichloromethane and saturated aqueous sodium bicarbonate solution were added, the phases were separated with stirring, the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated residue was purified by column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) to obtain the product, which was purified by preparative HPLC (instrument: waters 2767 preparative liquid phase; column: XBridge® Prep C18 (30 mm x 150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)), and the preparative liquid was lyophilized to obtain the trifluoroacetate salt of compound 24 (12 mg).

[0638] LCMS m / z = 877.3 [M+H] +

[0639] 1H NMR (400 MHz, DMSO-d6) δ 12.37 (s, 1H), 10.89 (s, 1H), 9.93 (s, 1H), 8.80 (d, 1H), 8.35 (s, 1H), 8.26 (d, 1H), 7.37 (d, 1H), 7.17 (s, 1H), 6.91 (d, 1H), 6.80 (d, 2H), 4.40 - 4.29 (m, 1H), 4.14 - 4.06 (m, 2H), 4.05 - 3.78 (m, 6H), 3.71 (s, 3H), 3.61 (s, 3H), 3.21 - 3.16 (m, 2H), 3.13 - 3.08 (m, 2H), 3.07 - 2.91 (m, 4H), 2.85 - 2.74 (m, 2H), 2.56 - 2.52 (m, 1H), 2.27 - 1.87 (m, 10H), 1.77 - 1.67 (m, 4H), 1.50 - 1.39 (m, 1H), 0.81 (d, 3H).

[0640] Example 25: Preparation of compound 25

[0641] Compound 25 was synthesized using compound 24B and 10H as starting materials to give trifluoroacetate salt of compound 25 (10 mg).

[0642] LCMS m / z = 878.4 [M+H] +

[0643] 1 H NMR (400 MHz, DMSO-d6) δ 12.37 (s, 1H), 10.53 (s, 1H), 9.91 (s, 1H), 8.80 (d, 1H), 8.35 (s, 1H), 8.26 (d, 1H), 7.37 (d, 1H), 7.17 (s, 1H), 6.90 (d, 3H), 4.40 - 4.29 (m, 1H), 4.14 - 4.07 (m, 1H), 4.04 - 3.80 (m, 6H), 3.71 (s, 3H), 3.64 - 3.59 (m, 4H), 3.23 - 3.05 (m, 8H), 3.01 - 2.92 (m, 2H), 2.85 - 2.74 (m, 1H), 2.71 (t, 2H), 2.30 - 2.15 (m, 3H), 2.09 - 2.01 (m, 2H), 1.97 - 1.87 (m, 2H), 1.77 - 1.69 (m, 4H), 1.49 - 1.40 (m, 1H), 0.81 (d, 3H).

[0644] Example 26: Preparation of compound 26

[0645] Reference compound 16 was synthesized according to the procedure described in the preparation of compound 16. Using compound 16B (0.105 g, 0.20 mmol), 3-(2-fluoro-4-(4-oxopiperidin-1-yl)phenyl)piperidine-2,6-dione (CAS: 3042837-41-9) as starting material to obtain trifluoroacetate salt of compound 26 (0.034 g).

[0646] LCMS m / z = 819.4 [M+H] +

[0647] 1 H NMR (400 MHz, DMSO-d6) δ 12.41 (s, 1H), 10.79 (s, 1H), 9.50 (s, 1H), 8.80 (d, 1H), 8.35 (s, 1H), 8.27 (d, 1H), 7.41 (d, 1H), 7.25 (d, 1H), 7.12 (t, 1H), 6.92 (dd, 1H), 6.86 - 6.76 (m, 2H), 4.40 - 4.33 (m, 1H), 4.15 - 4.07 (m, 1H), 3.99 - 3.82 (m, 6H), 3.73-3.64 (m, 5H), 3.62 (s, 3H), 3.56 - 3.48 (m, 1H), 3.30 - 3.20 (m, 2H), 3.01 (t, 2H), 2.85 - 2.75 (m, 3H), 2.74 - 2.66 (m, 1H), 2.56 - 2.45 (m, 2H), 2.23 - 2.11 (m, 4H), 2.00 - 1.90 (m, 3H), 1.78 - 1.66 (m, 2H), 1.49 - 1.39 (m, 1H), 0.81 (d, 3H).

[0648] Example 27: Preparation of compound 27

[0649] First step: Preparation of 27B

[0650] 27A (7.0 g, 29.75 mmol), ethyl acrylate (4.47 g, 44.63 mmol) and N,N- diisopropylethylamine (11.53 g, 89.25 mmol) were added into ethanol (50 mL) sequentially, and the reaction was heated to 100 °C for 72 h. Concentration under reduced pressure, the residue was purified by column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 20) to give 27B (5.0 g, yield 50%).

[0651] LCMS m / z = 336.3 [M+H] +

[0652] Second step: Preparation of 27C

[0653] To a solution of 27B (5.0 g, 14.91 mmol) and N, N-diisopropylethylamine (5.78 g, 44.73 mmol) in tetrahydrofuran (100 mL) was added triphosgene (4.87 g, 16.4 mmol) slowly under ice-bath and stirred at room temperature for 1 h. Ammonia water (40 mL) was added slowly and the reaction was continued at 50 °C for 2 h. The reaction was diluted with 100 mL of ethyl acetate and the organic phase was washed with water for 3 times, saturated sodium chloride for 1 time, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 20) to give 27C (4.3 g, yield 76%).

[0654] LCMS m / z = 379.1 [M+H] +

[0655] Third step: Preparation of 27D

[0656] To a solution of 27C (4.3 g, 11.36 mmol) in acetonitrile (40 mL) was added benzyltrimethylammonium hydroxide 40% in methanol (13 mL, 32.93 mmol) and the reaction was continued at 60 °C for 15 min. Appropriate amount of silica gel was added and the reaction was concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 20) to give 27D (3.5 g, yield: 93%).

[0657] LCMS m / z = 333.1 [M+H] +

[0658] Fourth step: Preparation of 27E

[0659] To a solution of 27D (1.0 g, 3.01 mmol) in 6 mL of tetrahydrofuran was added 6N hydrochloric acid (5 mL) slowly and the reaction was continued at 60 °C for 2 h. The reaction was cooled to room temperature and sodium carbonate aqueous solution was added under ice-bath to adjust the pH to basic. The reaction was extracted with dichloromethane / methanol (v / v = 10 / 1) for 3 times and the organic phase was collected, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 27E (0.6 g, yield: 69%).

[0660] LCMS m / z = 289.1 [M+H] +

[0661] Fifth step: Preparation of compound 27

[0662] A reaction vial was charged with 16B (0.15 g, 0.28 mmol), 27E (0.08 g, 0.28 mmol), chloroform (10 mL), glacial acetic acid (0.034 g, 0.56 mmol), after addition, the temperature was raised to 70 °C for 16 h, then sodium triacetoxyborohydride (0.30 g, 1.40 mmol) was added, and the reaction was continued at 70 °C for 4 h. Dichloromethane and saturated aqueous sodium bicarbonate solution were added, the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated residue was purified by column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) to obtain a crude product, which was purified by preparative HPLC (instrument: waters 2767 preparative liquid phase; column: XBridge®Prep C18(30 mm x 150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)), and the trifluoroacetate salt of compound 27 (0.038 g) was obtained by freeze-drying of the preparative liquid.

[0663] LCMS m / z = 803.4 [M+H] +

[0664] 1 H NMR (400 MHz, DMSO-d6) δ 12.41 (s, 1H), 10.39 (s, 1H), 9.62 (s, 1H), 8.80 (d, 1H), 8.35 (s, 1H), 8.27 (d, 1H), 8.15 (d, 1H), 7.57 - 7.47 (m, 2H), 7.42 (d, 1H), 7.25 (d, 1H), 6.93 (dd, 1H), 4.39 - 4.30 (m, 1H), 4.15 - 4.07 (m, 1H), 3.99 - 3.83 (m, 8H), 3.73-3.64 (m, 5H), 3.62 (s, 3H), 3.56 - 3.46 (m, 1H), 3.33 - 3.20 (m, 2H), 3.03 (t, 2H), 2.79 (t, 3H), 2.68 (t, 2H), 2.25 - 2.45 (m, 3H), 1.98 - 1.86 (m, 2H), 1.85 - 1.73 (m, 2H), 1.49 - 1.39 (m, 1H), 0.81 (d, 3H).

[0665] Example 28: Preparation of compound 28

[0666] The trifluoroacetate salt of compound 28 (30 mg) was obtained by synthesizing, using compound 15B and 3-(2-fluoro-4-(piperazin-1-yl)phenyl)piperidine-2,6-dione (synthesis reference patent: WO2022228547) as raw materials.

[0667] LCMS m / z = 410.2 [(M+2H) / 2] +

[0668] 1 H NMR (400 MHz, DMSO-d6) δ 12.37 (s, 1H), 10.82 (s, 1H), 9.58 (s, 1H), 8.80 (d, 1H), 8.35 (s, 1H), 8.26 (d, 1H), 7.38 (d, 1H), 7.18 (t, 2H), 6.94 - 6.79 (m, 3H), 4.42 - 4.29 (m, 1H), 4.01 - 3.86 (m, 1H), 4.00 - 3.82 (m, 6H), 3.75 - 3.56 (m, 8H), 3.52 - 3.15 (m, 5H), 3.09 - 2.95 (m, 2H), 2.81 - 2.64 (m, 4H), 2.27 - 2.11 (m, 4H), 2.01 - 1.72 (m, 5H), 1.52 - 1.38 (m, 1H), 0.83 (t, 3H).

[0669] Example 29: Preparation of compound 29

[0670] First step: Preparation of 29B

[0671] 29A (20 g, 86.20 mmol) was dissolved in DMF (50 mL), potassium carbonate (14.3 g, 103.44 mmol) and deuterated iodomethane (14.99 g, 103.44 mmol) were added, stirred at room temperature overnight, after adding 150 mL water to the reaction solution, solid was precipitated, stirred at room temperature for 30 min, filtered, the filter cake was washed with water and dried to obtain 29B (20 g).

[0672] Second step: Preparation of 29C

[0673] A single-neck flask was charged with 29B (20 g, 80.3 mmol), bis(pinacolato)diboron (26.51 g, 104.39 mmol), potassium acetate (23.64 g, 240.9 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride dichloromethane complex (6.56 g, 8.03 mmol) and 1,4-dioxane (400 mL), and after addition was complete, the flask was purged with nitrogen three times and the reaction was heated to 80 °C overnight. To the reaction mixture after overnight, 80 mL of water, 29B-1 (25.6 g, 72.25 mmol), potassium carbonate (33.29 g, 240.84 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride dichloromethane complex (6.56 g, 8.03 mmol) were added, and after addition was complete, the flask was purged with nitrogen three times and the reaction was heated to 80 °C for 2 h. The reaction was cooled to room temperature, filtered through celite, and the filter cake was washed with 300 mL of ethyl acetate, which was discarded. The filtrate was separated into layers, and the organic layer was collected. The organic layer was washed with saturated brine once, dried over anhydrous sodium sulfate, concentrated, and purified by flash column chromatography (mobile phase: dichloromethane / methanol (v / v) = 20 / 1) to give compound 29C (25 g, yield: 79%).

[0674] LCMS m / z = 397.2 [M+H] +

[0675] Third Step: Preparation of 29D

[0676] 29C (25 g, 63.05 mmol) was dissolved in trifluoroacetic acid (50 mL) and stirred at room temperature for 4 h. The reaction was concentrated, 300 mL of dichloromethane and potassium carbonate (33.29 g, 240.84 mmol) were added, and after addition was complete, the reaction was stirred at room temperature for 30 min. The reaction was filtered through celite, and the filtrate was concentrated. The resulting product was slurried with methyl tert-butyl ether to give 29D (12 g).

[0677] LCMS m / z = 267.2 [M+H] +

[0678] Fourth Step: Preparation of 29F

[0679] Triphenylphosphine (2.46 g, 9.38 mmol) and diisopropyl azodicarboxylate (1.90 g, 9.38 mmol) were dissolved in tetrahydrofuran (30 mL) and stirred under nitrogen for 10 min. 29D (1.25 g, 4.69 mmol) and 29E (1.49 g, 4.69 mmol) were added to the reaction mixture, which was stirred at room temperature for 4 h under nitrogen. The reaction was directly concentrated, and the resulting product was purified by flash column chromatography (mobile phase: ethyl acetate / petroleum ether (v / v) = 1 / 1) to give compound 29F (1.4 g, yield: 53%).

[0680] LCMS m / z = 565.2 [M+H] +

[0681] Step 5: Preparation of 29G

[0682] 29F (1.4 g, 2.48 mmol) was dissolved in tetrahydrofuran (12 mL), then zinc powder (1.2 g, 18.35 mmol) and aqueous ammonium chloride (1.2 g, 22.43 mmol) (3 mL) were added, and the reaction was allowed to proceed at room temperature for 0.5 h. The reaction solution was passed through celite overnight, and the filtrate was extracted with ethyl acetate three times. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and flash column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) was performed to obtain compound 29G (1.2 g, yield: 90%).

[0683] Step 6: Preparation of 29H

[0684] 29G (1.2 g, 2.24 mmol) was dissolved in dichloromethane (20 mL), and brominated nitrile (0.59 g, 5.60 mmol) was added, and the reaction was allowed to proceed at room temperature for 16 h. The reaction solution was directly concentrated under reduced pressure, and flash column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) was performed to obtain compound 29H (1.1 g, yield: 87%).

[0685] LCMS m / z = 560.2 [M+H] +

[0686] Step 7: Preparation of 29I

[0687] 29H (1.0 g, 1.78 mmol) was dissolved in tetrahydrofuran (30 mL), and lithium bis(trimethylsilyl)amide (1.0 mmol / mL, 5.4 mL, 5.4 mmol) was slowly added dropwise at room temperature, and the reaction was allowed to proceed at room temperature for 2 h. The reaction solution was directly concentrated under reduced pressure, and flash column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) was performed to obtain compound 29I (0.5 g, yield: 53%).

[0688] LCMS m / z = 528.2 [M+H] +

[0689] Step 8: Preparation of compound 29J

[0690] Compound 29I (250 mg, 0.47 mmol) and 4-piperidone acetal (202 mg, 1.41 mmol) were dissolved in 1,4-dioxane (10 mL), and added with (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (2'-amino-1,1'-biphenyl-2-yl)palladium(II) (128 mg, 0.14 mmol), lithium bis(trimethylsilyl)amide (2.82 mL, 1 M in THF). After addition, the reaction was stirred at 60 °C for 16 h under nitrogen protection. The reaction was quenched by adding saturated aqueous ammonium chloride solution, extracted with ethyl acetate (10 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the residue was concentrated under reduced pressure and purified by flash column chromatography (mobile phase: dichloromethane / methanol (v / v) = 10 / 1) to give compound 29J (190 mg, yield: 68%).

[0691] LCMS m / z = 591.2 [M+H] +

[0692] Ninth step: Preparation of compound 29K

[0693] Compound 29J (190 mg, 0.32 mmol) was dissolved in tetrahydrofuran (2 mL), and sulfuric acid (4 N) (2 mL) was added dropwise at room temperature. The reaction was stirred at 60 °C for 2 h. After cooling to room temperature, the reaction was quenched by adding saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (10 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 29K (100 mg, yield: 57%).

[0694] LCMS m / z = 547.1 [M+H] +

[0695] Tenth step: Preparation of compound 29

[0696] Compound 29k (0.23 g, 0.42 mmol) was dissolved in a solution of compound 15-1F (130 mg, 0.42 mmol) in chloroform (10 mL), and titanium (IV) isopropoxide (0.36 g, 1.26 mmol) was added. After the addition was completed, the reaction was warmed to 50 °C for 24 h, and sodium triacetoxyborohydride (0.23 g, 1.1 mmol) was added in portions. The reaction was continued at 50 °C for 3 h. Dichloromethane and saturated aqueous sodium bicarbonate solution were added, and the mixture was stirred to separate the layers. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated residue was purified by column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) to obtain a crude product. The crude product was purified by preparative HPLC (instrument: waters 2767 preparative liquid phase; column: XBridge® Prep C18 (30 mm x 150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)), and the preparation was lyophilized to obtain the trifluoroacetate salt of compound 29 (0.06 g).

[0697] LCMS m / z = 420.4 [(M+2H) / 2] +

[0698] 1 H NMR (400 MHz, CDCl3 / CD3OD (v / v) = 1 / 1) δ 8.99-8.88 (m, 1H), 8.46 (s, 1H), 8.29-8.17 (m, 1H), 7.42-7.36 (m, 1H), 7.06-6.94 (m, 2H), 6.74-6.58 (m, 2H), 4.56-4.47 (m, 1H), 4.38-4.28 (m, 1H), 4.17-4.08 (m, 1H), 3.99-3.92 (m, 1H), 3.91-3.39 (m, 15H), 2.97-2.81 (m, 3H), 2.81-2.70 (m, 2H), 2.42-2.24 (m, 4H), 2.18-1.96 (m, 5H), 1.58-1.49 (m, 1H), 0.91 (d, 3H).

[0699] Example 30: Preparation of compound 30

[0700] The trifluoroacetate salt of compound 30 (0.14 g) was synthesized using compound 12C as the starting material.

[0701] LCMS m / z = 437.4 [(M+2H) / 2] +

[0702] 1H NMR (400 MHz, CDC13 / CD3OD (v / v) = 1 / 1) δ 8.88 (d, 1H), 8.38 (s, 1H), 8.30 (d, 1H), 7.96 (s, 0.25H), 7.81 (s, 0.5H), 7.66 (s, 0.25H), 7.47 - 7.29 (m, 1H), 7.02 (d, 2H), 6.60 (d, 2H), 4.52 - 4.47 (m, 1H), 4.31 (d, 1H), 4.13 - 4.04 (m, 1H), 3.99 - 3.89 (m, 1H), 3.88 - 3.37 (m, 15H), 2.98 (t, 2H), 2.90 - 2.70 (m, 3H), 2.41 - 2.19 (m, 4H), 2.18 - 1.92 (m, 5H), 1.55 (d, 1H), 0.91 (d, 3H).

[0703] Example 31: Preparation of compound 31

[0704] First step: Preparation of compound 31A

[0705] Compound 29I (600 mg, 1.14 mmol) and piperazine-1-carboxylic acid tert-butyl ester (320 mg, 1.71 mmol) were dissolved in 1,4-dioxane solution (20 mL), and (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (300 mg, 0.34 mmol), 2'-amino-1,1'-biphenyl-2-yl)palladium(II) (300 mg, 0.34 mmol), lithium bis(trimethylsilyl)amide (6.84 mL, 6.84 mmol, 1M in THF) were added. After addition, the reaction was stirred at 60 °C under nitrogen protection for 16 h. The reaction was quenched by saturated aqueous ammonium chloride solution, extracted with ethyl acetate (20 mL x 3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered and the residue was concentrated under reduced pressure. The residue was purified by flash column chromatography (mobile phase: dichloromethane / methanol (v / v) = 10 / 1) to give compound 31A (300 mg, yield: 42%).

[0706] LCMS m / z = 634.5 [M+H] +

[0707] Second step: Preparation of compound 31B

[0708] Compound 31A (0.2 g, 0.47 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 1 h. The reaction solution was concentrated under reduced pressure to remove the trifluoroacetic acid, 10 mL of dichloromethane was added to dissolve the residue, and the mixture was adjusted to be alkaline by adding an aqueous ammonia solution, concentrated, and purified by flash column chromatography (mobile phase: dichloromethane / methanol (v / v) = 10 / 1) to obtain compound 31B (220 mg, yield: 87%).

[0709] LCMS m / z = 534.3 [M+H] +

[0710] Third step: preparation of compound 31

[0711] Compound 31B (200 mg, 0.37 mmol) and 17B-1 (179 mg, 0.55 mmol) were dissolved in chloroform (10 mL), and tetraisopropyl titanate (315 mg, 1.11 mmol) was added. The mixture was stirred at 60°C for 48 h, and sodium triacetoxyborohydride (235 mg, 1.11 mmol) was added in portions. The reaction was continued for 2 h. The reaction solution was concentrated, and the residue was purified by column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) to obtain a crude product. The crude product was purified by preparative HPLC (instrument: waters 2767 preparative liquid phase; column: XBridge@Prep C18 (30 mm x 150 mm); mobile phase composition: acetonitrile, water containing 0.1% trifluoroacetic acid), and the prepared liquid was lyophilized to obtain a trifluoroacetate salt of compound 31.

[0712] Example 32: preparation of compound 32

[0713] First step: preparation of 32A

[0714] 29A (20 g, 86.20 mmol) was dissolved in DMF (80 mL), potassium carbonate (47.65 g, 344.8 mmol) and sodium difluoro(chloro)acetate (26.28 g, 172.4 mmol) were added, and the mixture was stirred at 100°C for 4 h. 200 mL of water was added to the reaction solution, and a solid was precipitated. The mixture was stirred at room temperature for 30 min, filtered, and the filter cake was washed with water and dried to obtain 32A (19.0 g, yield: 78%).

[0715] Second step: preparation of 32B

[0716] A single-neck flask was charged with 32A (19.0 g, 67.37 mmol), bis(pinacolato)diboron (22.24 g, 87.58 mmol), potassium acetate (19.84 g, 202.1 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride dichloromethane complex (5.50 g, 6.74 mmol) and 1,4-dioxane (400 mL), and after addition was complete, the flask was purged with nitrogen three times and the reaction was heated to 80 °C overnight. To the reaction mixture after overnight, 80 mL of water, 29B-1 (21.48 g, 60.64 mmol), potassium carbonate (27.94 g, 202.1 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride dichloromethane complex (5.50 g, 6.74 mmol) were added, and after addition was complete, the flask was purged with nitrogen three times and the reaction was heated to 80 °C for 2 h. The reaction mixture was filtered through celite, and the filter cake was washed with 300 mL of ethyl acetate, and the filtrate was separated into layers. The organic layer was washed with saturated brine once, dried over anhydrous sodium sulfate, concentrated, and purified by flash column chromatography (mobile phase: dichloromethane / methanol (v / v) = 20 / 1) to give compound 32B (19.0 g, yield: 65%).

[0717] LCMS m / z = 430.2 [M+H] +

[0718] Step 3: Preparation of 32C

[0719] 32B (19.0 g, 44.27 mmol) was dissolved in trifluoroacetic acid (50 mL) and stirred at room temperature for 4 h. The reaction mixture was concentrated, 300 mL of dichloromethane and potassium carbonate (33.29 g, 240.84 mmol) were added, and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was filtered through celite, and the filtrate was concentrated. The reaction mixture was filtered by slurry with methyl tert-butyl ether to give 32C (12.0 g).

[0720] LCMS m / z = 300.0 [M+H] +

[0721] Step 4: Preparation of 32D

[0722] 12C (1.0 g, 3.90 mmol) and tert-butyl piperazine-1-carboxylate (0.87 g, 4.68 mmol) were dissolved in DMF (10 mL), and potassium carbonate (1.62 g, 11.70 mmol) was added. The reaction mixture was heated to 80 °C for 2 h. The reaction mixture was diluted with 30 mL of ethyl acetate, washed with water three times, and washed with saturated brine once. The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by flash column chromatography (mobile phase: ethyl acetate / petroleum ether (v / v) = 1 / 1) to give compound 32D (1.0 g, yield: 61%).

[0723] LCMS m / z = 423.3 [M+H] +

[0724] Step 5: Preparation of 32E

[0725] Dissolve 32D (1.0 g, 2.37 mmol) in dichloromethane (30 mL), add triethylamine (0.49 mL, 3.56 mmol), methane sulfonic anhydride (0.62 g, 3.56 mmol), stir at room temperature for 30 min. Dilute the reaction solution with 30 mL dichloromethane, wash with water for 3 times, collect the organic phase, dry, concentrate, dissolve the obtained crude product in 10 mL DMF, add potassium carbonate (0.81 g, 5.85 mmol) and 32C (0.7 g, 2.34 mmol), after addition, warm to 60 °C for 4 h. After cooling to room temperature, dilute the reaction solution with 30 mL ethyl acetate, wash with water for 3 times, wash with saturated brine for 1 time, dry the organic phase over anhydrous sodium sulfate, concentrate, and then perform flash column chromatography (mobile phase: ethyl acetate / petroleum ether (v / v) = 1 / 1) to obtain compound 32E (830 mg, yield: 63%).

[0726] LCMS m / z = 704.4 [M+H] +

[0727] Step 6: Preparation of 32F

[0728] Dissolve 32E (830 mg, 1.18 mmol) in tetrahydrofuran (12 mL), then add zinc powder (0.6 g, 9.17 mmol) and an aqueous solution of ammonium chloride (500 mg, 9.35 mmol) (4 mL), after addition, react at room temperature for 0.5 h. Pass the reaction solution through diatomite overnight, add ethyl acetate to the filtrate for extraction 3 times, dry the organic phase over anhydrous sodium sulfate, and then concentrate under reduced pressure, and then perform flash column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) to obtain compound 32F (700 mg, yield: 88%).

[0729] LCMS m / z = 674.5 [M+H] +

[0730] Step 7: Preparation of 32G

[0731] Dissolve 32F (0.6 g, 0.89 mmol) in dichloromethane (20 mL), add cyanogen bromide (0.28 g, 2.67 mmol), after addition, react at room temperature for 16 h. Directly concentrate the reaction solution under reduced pressure, and then perform flash column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) to obtain compound 32G (0.5 g, yield: 80%).

[0732] LCMS m / z = 699.5 [M+H] +

[0733] Step 8: Preparation of 32H

[0734] Dissolve 32G (1.0 g, 1.43 mmol) in tetrahydrofuran (8 mL), add 2 mL of methanol and 2 mL of 4N sodium hydroxide aqueous solution, stir at room temperature for 4 hours, slowly drop 2N hydrochloric acid to the reaction solution under ice water bath until PH = 6-7, concentrate under reduced pressure to obtain 32H crude product.

[0735] LCMS m / z = 685.4 [M+H] +

[0736] Step 9: Preparation of compound 32I

[0737] Dissolve the crude product of 32H in 1,4-dioxane (20 mL), add N,N- diisopropylethylamine (0.71 mL, 4.29 mmol) and HATU (800 mg, 2.1 mmol), after adding, warm to 60°C for 3h. After cooling to room temperature, dilute the reaction solution with 30 mL of ethyl acetate, wash with water 3 times, and saturated brine 1 time, dry the organic phase with anhydrous sodium sulfate, concentrate and quickly column chromatograph (mobile phase: ethyl acetate / petroleum ether (v / v) = 1 / 1) to obtain compound 32I (0.5 g, yield 52%).

[0738] LCMS m / z = 667.3 [M+H] +

[0739] Step 10: Preparation of compound 32J

[0740] Dissolve compound 32I (0.5 g, 0.75 mmol) in dichloromethane (2 mL), drop trifluoroacetic acid (2 mL) at room temperature, stir the reaction at room temperature for 2h. Quench with saturated sodium carbonate aqueous solution, extract with dichloromethane / isopropanol (V / V = 10:1) three times, combine the organic phase, dry with anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain compound 32J (140 mg, yield: 33%).

[0741] LCMS m / z = 567.3 [M+H] +

[0742] Step 11: Preparation of compound 32

[0743] Compound 32J (100 mg, 0.18 mmol) was dissolved in chloroform (10 mL) with 17B-1 (70 mg, 0.22 mmol), tetraisopropyl titanate (154 mg, 0.54 mmol) was added, the reaction was stirred at 60 °C for 48 h, sodium triacetoxyborohydride (114 mg, 0.54 mmol) was added in batches, and the reaction was continued for 2 h. The reaction was concentrated, and the residue was purified by column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) to obtain a crude product. The crude product was purified by preparative HPLC (instrument: waters 2767 preparative liquid phase; chromatographic column: XBridge@Prep C18 (30 mm x 150 mm); mobile phase composition: acetonitrile, water containing 0.1% trifluoroacetic acid), and the trifluoroacetate salt of compound 32 (25 mg) was obtained by freeze-drying of the preparative liquid.

[0744] LCMS m / z = 873.3 [M+H] +

[0745] 1 H NMR (400 MHz, CD3OD) δ 8.89 (d, 1H), 8.35 (s, 1H), 8.25 (s, 1H), 8.01 (s, 0.25H), 7.86 (s, 0.5H), 7.71 (s, 0.25H), 7.39 (d, 1H), 7.06 (s, 1H), 7.00 (d, 1H), 6.64 (d, 2H), 4.53-4.43 (m, 1H), 4.33-4.25 (m, 1H), 4.15-4.07 (m, 1H), 4.03–3.66 (m, 11H), 3.60-3.35 (m, 3H), 3.20-3.02 (m, 2H), 2.97–2.63 (m, 5H), 2.35-2.20 (m, 4H), 2.14–1.94 (m, 3H), 1.93–1.79 (m, 2H), 1.58-1.46 (m, 1H), 0.86 (d, 3H).

[0746] Example 33: Preparation of compound 33

[0747] First step: preparation of 33B

[0748] Diisopropyl azodicarboxylate (5.78 g, 28.56 mmol) was added dropwise to a solution of triphenylphosphine (7.49 g, 28.56 mmol) in tetrahydrofuran (200 mL), and then 33A (3 g, 9.52 mmol) and 33A-1 (2.51 g, 9.52 mmol) were added to the reaction system, which was stirred at room temperature overnight. Ethyl acetate and saturated aqueous sodium bicarbonate solution were added, and the mixture was stirred to separate the layers. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 20) to obtain 33B (3.1 g, yield: 58%).

[0749] LCMS m / z = 560.2 [M+H] +

[0750] Second step: Preparation of 33C

[0751] 33B (3.1 g, 5.53 mmol) was dissolved in tetrahydrofuran (120 mL), and then zinc powder (1.09 g, 16.59 mmol) and an aqueous solution of ammonium chloride (0.89 g, 16.59 mmol) (30 mL) were added. After the addition was complete, the reaction was allowed to proceed at room temperature for 1 h. The reaction solution was extracted three times with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated and purified by flash column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) to obtain compound 33C (2.8 g, yield: 95%).

[0752] Third step: Preparation of 33D

[0753] 33C (2.8 g, 2.58 mmol) was dissolved in dichloromethane (50 mL), and then nitrile bromide (0.55 g, 5.16 mmol) was added. After the addition was complete, the reaction was allowed to proceed at room temperature for 16 h. The reaction solution was directly concentrated under reduced pressure, and the residue was separated and purified by flash column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) to obtain compound 33D (2.6 g, yield: 89%).

[0754] Fourth step: Preparation of 33E

[0755] 33D (2.6 g, 4.68 mmol) was dissolved in tetrahydrofuran (50 mL), and then lithium bis(trimethylsilyl)amide (14 mL, 1M in THF) was added. After the addition was complete, the reaction was allowed to proceed at room temperature for 1 h. The reaction was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane / methanol (v / v = 10 / 1), and the organic phase was concentrated under reduced pressure. The residue was separated and purified by flash column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) to obtain compound 33E (1.1 g, yield: 45%).

[0756] Fifth step: Preparation of 33F

[0757] Compound 33E (1.1 g, 2.1 mmol) and 4-piperidone ethylene glycol (0.9 g, 6.3 mmol) were dissolved in 1,4-dioxane solution (20 mL), and added with methane sulfonic acid (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (2'-amino-1,1'-biphenyl-2-yl)palladium(II) (190 mg, 0.21 mmol), lithium bis(trimethylsilyl)amide (12.6 mL, 1M in THF). After addition, the reaction was stirred at 60°C for 16 h under nitrogen protection. After cooling to room temperature, saturated aqueous ammonium chloride solution was added to quench the reaction, and extracted with ethyl acetate (30 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the residue was concentrated under reduced pressure and purified by flash column chromatography (mobile phase: dichloromethane / methanol (v / v) = 10 / 1) to obtain compound 33F (500 mg, yield: 41%).

[0758] LCMS m / z = 586.3 [M+H] +

[0759] Sixth step: preparation of 33G

[0760] Compound 33F (0.5 g, 0.70 mmol) was dissolved in 8N hydrochloric acid (15 mL) and reacted at room temperature for 16 h. Solid sodium bicarbonate was added to the reaction solution in an ice bath to adjust the pH to basic, and extracted with dichloromethane / methanol ((v / v) = 10 / 1)) three times, and the combined organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by flash column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) to obtain 33G (0.35 g, yield: 78%).

[0761] LCMS m / z = 542.3 [M+H] +

[0762] Seventh step: preparation of compound 33

[0763] Compound 33G (13.2 mg, 0.024 mmol), compound 15-1F (9.7 mg, 0.031 mmol), chloroform (2 mL), glacial acetic acid (20 mg, 0.38 mmol) were added to a reaction bottle, and after addition, the reaction was heated to 60°C overnight, and then sodium triacetoxyborohydride (0.20 g, 0.95 mmol) was added to dissolve, and the reaction was continued at 60°C for 3 h. After cooling to room temperature, dichloromethane and saturated aqueous sodium bicarbonate solution were added, and the organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) to obtain compound 33 (5.8 mg, yield 29%).

[0764] LCMS m / z = 418.3 [(M+2H) / 2] +

[0765] To the reaction bottle was added 33G (100 mg, 0.18 mmol), compound 15-1F (67 mg, 0.22 mmol), chloroform (5 mL), glacial acetic acid (110 mg, 1.8 mmol), after adding, the temperature was raised to 60 °C and reacted overnight, then sodium triacetoxyborohydride (76 mg, 0.36 mmol) was added after redissolving in chloroform (3 mL), and the reaction was continued at 60 °C for 3 h. Dichloromethane and saturated aqueous sodium bicarbonate solution were added, stirred, separated, the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated residue was purified by column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) to obtain the crude product, which was purified by preparative HPLC (instrument: waters 2767 preparative liquid phase; column: XBridge@Prep C18 (30 mm x 150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)) to obtain the trifluoroacetate salt of compound 33 (50 mg) after lyophilization.

[0766] LCMS m / z = 835.1 [M+1] +

[0767] 1H NMR (400 MHz, CDCl3 / CD3OD (v / v) = 1 / 1) δ 9.27-9.16 (m, 1H), 8.37 (s, 1H), 8.22-8.11 (m, 1H), 7.36 (d, 1H), 7.04-6.83 (m, 2H), 6.60 (d, 2H), 4.54-4.20 (m, 4H), 4.09-4.03 (m, 1H), 3.87-3.81 (m, 2H), 3.78 (s, 3H), 3.71 (s, 3H), 3.67-3.37 (m, 9H), 2.97-2.86 (m, 4H), 2.78-2.71 (m, 2H), 2.66-2.10 (m, 8H), 2.10-1.95 (m, 2H).

[0768] Example 34: Preparation of compound 34

[0769] Referring to the preparation of compound 33, compound 34 was synthesized using compound 33G and compound 15-2A as raw materials (yield: 2 mg, 13%).

[0770] LCMS m / z = 418.2 [(M+2H) / 2] +

[0771] Example 35: Preparation of compound 35

[0772] Step 1: Preparation of compound 35A

[0773] Compound 33E (0.87 g, 1.66 mmol) and tert-butyl piperazine-1-carboxylate (0.93 g, 4.98 mmol) were dissolved in 1,4-dioxane (30 mL), then BrettPhos-G3-Pd (0.45 g, 0.50 mmol) and lithium bis(trimethylsilyl)amide (9.96 mL, 9.96 mmol, 1 M) were added. The reaction was protected by nitrogen and heated to 60 °C for 16 h. The reaction was cooled to room temperature and quenched with water. The mixture was extracted with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate and directly concentrated under reduced pressure. The residue was purified by flash column chromatography (mobile phase: dichloromethane / methanol (V / V) = 0-5%) to give compound 35A (0.5 g, yield: 48%).

[0774] LCMS m / z = 629.4 [M+H] +

[0775] Step 2: Preparation of compound 35B

[0776] Compound 35A (0.6 g, 0.95 mmol) was dissolved in dichloromethane (10 mL), then trifluoroacetic acid (10 mL) was added. The reaction was stirred at room temperature for 1 h. The reaction was directly concentrated under reduced pressure. The residue was extracted with dichloromethane / methanol (V / V) = 10 / 1) for 3 times after alkalization with sodium bicarbonate aqueous solution. The organic phase was collected, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (mobile phase: dichloromethane / methanol (V / V) = 0-10%) to give compound 35B (0.4 g, yield: 79%).

[0777] LCMS m / z = 529.3 [M+H] +

[0778] Step 3: Preparation of compound 35

[0779] Compound 35B (0.2 g, 0.38 mmol) and compound 17B-1 (0.12 g, 0.38 mmol) were dissolved in chloroform (10 mL), and tetraisopropyl titanate (0.32 g, 1.14 mmol) was added. The reaction was heated to 50 °C for 30 h, and then sodium triacetoxyborohydride (0.16 g, 0.76 mmol) was added. The reaction was continued to react at 50 °C for 8 h. The reaction was cooled to room temperature, diluted with dichloromethane, and extracted with aqueous sodium bicarbonate solution (dichloromethane / methanol (V / V) = 10 / 1) for 3 times. The organic phase was combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (mobile phase: dichloromethane / methanol (V / V) = 0-10%) to obtain the crude product. The crude product was purified by preparative HPLC (instrument: waters 2767 preparative liquid phase; column: XBridge® Prep C18 (30 mm x 150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)), and the product was lyophilized to obtain the trifluoroacetate salt of compound 35 (0.045 g).

[0780] LCMS m / z = 835.4 [M+H] +

[0781] 1 H NMR (400 MHz, CDCl3 / CD3OD (v / v) = 1 / 1) δ 9.24-9.15 (m, 1H), 8.38 (s, 1H), 8.19-8.13 (m, 1H), 7.37 (d, 1H), 7.02-6.83 (m, 2H), 6.51 (d, 2H), 4.41-4.14 (m, 4H), 4.02 (dd, 1H), 3.95-3.87 (m, 2H), 3.77 (s, 3H), 3.74-3.39 (m, 12H), 2.99-2.86 (m, 4H), 2.79-2.71 (m, 2H), 2.63-2.09 (m, 8H), 2.00-1.86 (m, 2H).

[0782] Example 36: Preparation of compound 36

[0783] Compound 36 was synthesized by referring to the preparation of compound 35, using compound 35B and compound 17B-2 as raw materials to obtain the trifluoroacetate salt of compound 36.

[0784] LCMS m / z = 418.2 [(M+2H) / 2] +

[0785] Example 37: Preparation of compound 37

[0786] First step: preparation of compound 37A

[0787] Compound 5G (200 mg, 0.38 mmol) and (S)-4-N-tert-butoxycarbonyl-2- methylpiperazine (99 mg, 0.49 mmol) were dissolved in 1,4-dioxane solution (6 mL), and tris(dibenzylideneacetone)dipalladium (35 mg, 0.038 mmol), 2- dicyclohexylphosphino-2',4',6'-triisopropyl biphenyl (36 mg, 0.076 mmol), sodium tert-butoxide (183 mg, 1.90 mmol) were added. After addition, the reaction was heated to 90 °C under nitrogen protection and stirred for 16 h. After cooling to room temperature, saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the residue was concentrated under reduced pressure and purified by flash column chromatography (mobile phase: dichloromethane / methanol (v / v) = 10 / 1) to give compound 37A (180 mg, yield: 73%).

[0788] LCMS m / z = 645.4 [M+H] +

[0789] Second Step: Preparation of compound 37B

[0790] Compound 37A (180 mg, 0.2 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added. The reaction was stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure to remove the trifluoroacetic acid, and 10 mL of dichloromethane and 2 mL of isopropanol were added to dissolve the residue. The solution was adjusted to basic with aqueous sodium carbonate solution, and extracted with dichloromethane / isopropanol (v / v) = 10 / 1 three times. The organic phase was combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 37B (80 mg, yield: 75%).

[0791] Third Step: Preparation of compound 37

[0792] Compound 37B (80 mg, 0.15 mmol) was dissolved in a solution of 17B-1 (60 mg, 0.19 mmol) in chloroform (10 mL), glacial acetic acid (9 mg, 0.15 mmol) was added, the temperature was raised to 85 °C for 16 h, then the temperature was lowered to 70 °C, sodium triacetoxyborohydride (64 mg, 0.30 mmol) was added in batches, and the reaction was continued for 3 h. After being lowered to room temperature, dichloromethane and saturated aqueous sodium bicarbonate solution were added, the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated residue was purified by column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) to obtain a crude product, which was purified by preparative HPLC (instrument: waters 2767 preparative liquid phase; column: XBridge@Prep C18 (30 mm x 150 mm); mobile phase composition: acetonitrile, water containing 0.1% trifluoroacetic acid) and freeze-dried to obtain the trifluoroacetate salt of compound 37 (5 mg).

[0793] LCMS m / z = 426.2 [(M+2H) / 2] +

[0794] 1 H NMR (400 MHz, CDCl3 / CD3OD (v / v) = 1 / 1) δ 8.95 (s, 1H), 8.43 (s, 1H), 8.27 (s, 1H), 7.52-7.41 (m, 1H), 7.34-7.06 (m, 2H), 6.67-6.48 (m, 2H), 4.55-4.45 (m, 1H), 4.39-4.29 (m, 1H), 4.08 (dd, 1H), 4.03-3.90 (m, 3H), 3.86-3.74 (m, 4H), 3.70 (s, 3H), 3.68-3.34 (m, 8H), 2.99-2.82 (m, 3H), 2.80-2.66 (m, 2H), 2.39-2.21 (m, 4H), 2.17-1.84 (m, 5H), 1.60-1.49 (m, 1H), 1.03-0.87 (m, 6H).

[0795] Preparation of compound 37-2:

[0796] Compound 37-2 was synthesized according to the preparation of compound 37, using compound 37B and 17B-2 as starting materials.

[0797] LCMS m / z = 426.2 [(M+2H) / 2] +

[0798] Example 38: Preparation of compound 38

[0799] First Step: Preparation of 38B

[0800] Compound 38A (5.0 g, 55.49 mmol) and triethylamine (8.42 g, 83.23 mmol) were dissolved in dichloromethane (200 mL), and methanesulfonic anhydride (11.60 g, 66.59 mmol) was added dropwise after ice-bath for 10 minutes. The reaction was warmed to room temperature for 2 hours. The reaction solution was added to water (100 mL) and dichloromethane (100 mL) and extracted three times. The organic phase was combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 38B (9.3 g).

[0801] Second Step: Preparation of 38C

[0802] Compound 38B (8.0 g, 47.57 mmol) and hydrazine hydrate (23.81 g, 475.7 mmol) were dissolved in ethanol (100 mL) and warmed to 100°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by medium pressure preparation (PE / EA: 0-10-25%) to obtain the product. After stirring overnight with 2N hydrochloric acid in methanol, the solution was concentrated under reduced pressure to obtain the hydrochloride salt of compound 38C (6.4 g).

[0803] Third Step: Preparation of 38D

[0804] Compound 38C (6.0 g, 33.89 mmol), dimethyl methoxymethylene maleate (7.33 g, 33.90 mmol), potassium carbonate (9.37 g, 67.80 mmol), ethanol (60 mL), and water (60 mL) were added to a sealed tube, and the reaction was warmed to 100°C for 16 hours. The reaction solution was cooled to room temperature, 2N dilute hydrochloric acid was added to adjust the pH to about 3, dichloromethane (150 mL x 3) was added to extract, the organic phase was combined, and an appropriate amount of silica gel was added and concentrated under reduced pressure. The residue was separated and purified by medium pressure preparation (PE / EA: 0-10-25%) to obtain compound 38D (6.3 g, yield: 81%).

[0805] LCMS m / z = 229.1 [M+H] +

[0806] Fourth Step: Preparation of 38E

[0807] Compound 38D (6.3 g, 27.60 mmol) and sodium hydroxide (16.56 g, 414 mmol) were dissolved in water (80 mL) and heated to 100 °C for 16 h. After the reaction solution was cooled to room temperature, concentrated hydrochloric acid was added to adjust the pH to about 3, and then heated to 100 °C for 3 h. After the reaction solution was cooled to room temperature and concentrated under reduced pressure, the residue was separated and purified by medium pressure preparation (DCM / MeOH: 0%-6%) to obtain the product. The product was added to 2N hydrochloric acid in methanol and stirred overnight. The solution was concentrated under reduced pressure to obtain compound 38E (3.45 g).

[0808] LCMS m / z = 157.2 [M+H] +

[0809] Fifth step: Preparation of 38F

[0810] Compound 38E (3.45 g, 22.09 mmol) was dissolved in acetonitrile (60 mL), and potassium carbonate (7.63 g, 55.21 mmol) was added. After being cooled in an ice bath for ten minutes, 2-(trimethylsilyl)ethoxymethyl chloride (5.52 g, 33.11 mmol) was added dropwise, and the mixture was stirred at 20 °C for 3 h. The reaction solution was diluted with ethyl acetate (80 mL) and washed with water (100 mL) three times. The organic phase was dried over anhydrous sodium sulfate and separated and purified by medium pressure preparation (DCM / MeOH: 0%-6%) to obtain compound 38F (0.9 g, yield: 14%).

[0811] LCMS m / z = 287.2 [M+H] +

[0812] 1 H NMR (400 MHz, DMSO-d6) δ 7.96 (d, 1H), 5.35 (d, 1H), 5.10 (s, 2H), 4.18 (d, 2H), 3.51-3.39 (m, 2H), 1.03-0.92 (m, 2H), 0.88-0.77 (m, 4H), -0.04 (s, 9H).

[0813] Sixth step: Preparation of 38G

[0814] Compound 38F (0.9 g, 3.14 mmol) was dissolved in acetonitrile (20 mL), and N-iodosuccinimide (0.78 g, 3.45 mmol) was added portionwise while being cooled in an ice bath for ten minutes. After the addition was completed, the mixture was stirred at 0 °C for 1 h. The reaction solution was extracted with water (60 mL) and ethyl acetate (80 mL) three times. The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated and purified by medium pressure preparation (DCM / MeOH: 0%-6%) to obtain compound 38G (1.26 g).

[0815] Step 7: Preparation of 38H

[0816] A single-necked flask was charged with 5-bromo-l-methyl-6-oxo-l,6- dihydropyridine-3-carboxylic acid methyl ester (0.98 g, 3.98 mmol), bis(pinacolato)diboron (1.01 g, 3.98 mmol), potassium acetate (1.17 g, 11.93 mmol), [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.32 g, 0.40 mmol) and 1,4-dioxane (30 mL), and after addition, the mixture was purged with nitrogen three times and warmed to 80 °C overnight. The reaction solution was continued to be added with 10 mL of water, 38G (1.26 g, 3.06 mmol), potassium carbonate (1.27 g, 9.18 mmol), [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.16 g, 0.20 mmol), and after addition, the mixture was purged with nitrogen three times and warmed to 80 °C for 2 h. The mixture was cooled to room temperature, filtered through celite, and the filter cake was washed with 60 mL of ethyl acetate and discarded. The filtrate was separated into layers, and the organic phase was washed with saturated brine once, dried over anhydrous sodium sulfate, and concentrated. The residue was subjected to flash column chromatography (mobile phase: dichloromethane / methanol (v / v) = 20 / 1) to give compound 38H (0.84 g, yield: 61%).

[0817] Step 8: Preparation of 38I

[0818] A single-necked flask was charged with 38H (0.84 g, 1.86 mmol) and trifluoroacetic acid (10 mL), and after addition, the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the pH was adjusted to ~9 with saturated sodium bicarbonate solution (60 mL). The mixture was extracted with dichloromethane (60 mL x 3), and the combined organic phase was concentrated under reduced pressure to give a residue. The residue was stirred in methyl tert-butyl ether (60 mL) for 10 min, suction filtered, and the filter cake was washed with methyl tert-butyl ether and dried under vacuum to give compound 38I (315 mg, yield: 52%).

[0819] LCMS m / z = 322.1 [M+H] +

[0820] Step 9: Preparation of 38J

[0821] Triphenylphosphine (640 mg, 2.45 mmol) and diisopropyl azodicarboxylate (400 mg, 1.96 mmol) were dissolved in tetrahydrofuran (30 mL) and stirred for 10 min under nitrogen. 38I (315 mg, 0.98 mmol) and 29E (340 g, 1.08 mmol) were added to the reaction solution, which was stirred at room temperature for 4 h under nitrogen. The reaction solution was directly concentrated to give a residue, which was subjected to column chromatography (mobile phase: ethyl acetate / petroleum ether: 50%-75%-DCM / MeOH: 0-6%) to give compound 38J (1.1 g).

[0822] LCMS m / z = 620.1 [M+H] +

[0823] Tenth step: Preparation of 38K

[0824] Compound 38J (1.1 g) was dissolved in tetrahydrofuran (20 mL), and an aqueous solution of zinc powder (608 mg, 9.30 mmol) and ammonium chloride (608 mg, 11.37 mmol) (10 mL) was added. After the addition was completed, the reaction was stirred at room temperature for 0.5 h. The reaction solution was passed through diatomite overnight, and the filtrate was extracted with ethyl acetate three times. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography (mobile phase: ethyl acetate / petroleum ether: 50%-75%-100%) to give compound 38K (450 mg, yield: 78%).

[0825] Eleventh step: Preparation of 38L

[0826] Compound 38K (450 g, 0.76 mmol) was dissolved in dichloromethane (10 mL), and brominated nitrile (240 mg, 2.28 mmol) was added. The reaction was stirred at room temperature for 16 h. The reaction solution was directly concentrated under reduced pressure, and the residue was subjected to column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) to give compound 38L (470 mg).

[0827] LCMS m / z = 615.2 / 617.2 [M+H] +

[0828] Twelfth step: Preparation of 38M

[0829] Compound 38L (470 mg, 0.76 mmol) was dissolved in tetrahydrofuran (15 mL), and an aqueous solution of lithium hydroxide monohydrate (100 mg, 2.43 mmol) (5 mL) was added. The reaction was stirred at room temperature for 16 h. 2N dilute hydrochloric acid was added to the reaction solution to adjust the pH to about 3, and the reaction solution was concentrated under reduced pressure to give compound 38M (0.49 g).

[0830] LCMS m / z = 601.2 [M+H] +

[0831] Thirteenth step: Preparation of 38N

[0832] Compound 38M (450 mg, 0.75 mmol) was dissolved in 1,4-dioxane (20 mL), N,N- diisopropylethylamine (0.37 mL, 2.25 mmol) and HATU (430 mg, 1.13 mmol) were added, and after the addition was completed, the reaction was warmed to 60 °C overnight. After being cooled to room temperature, the reaction was diluted with 30 mL of ethyl acetate, washed with water 3 times, and saturated brine 1 time. The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography (mobile phase: ethyl acetate / petroleum ether (v / v) = 1 / 1) to give compound 38N (248 mg, yield 57%).

[0833] LCMS m / z = 583.2 / 585.2 [M+H] +

[0834] Fourteenth step: Preparation of 38O

[0835] Compound 38N (0.22 g, 0.38 mmol) and 4-piperidone glycol (163 mg, 1.14 mmol) were dissolved in 1,4-dioxane (30 mL), and Pd2dba3 (35 mg, 0.038 mmol), 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (36 mg, 0.076 mmol) and sodium tert- butoxide (220 mg, 2.28 mmol) were added. The reaction was protected by nitrogen, and warmed to 90 °C for 16 h. The reaction was cooled to room temperature, quenched with water, extracted with dichloromethane, and the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography (mobile phase: dichloromethane / methanol (V / V) = 0-5%) to give compound 38O (165 mg, yield: 68%).

[0836] LCMS m / z = 646.3 [M+H] +

[0837] Fifteenth step: Preparation of 38P

[0838] Compound 38O (165 mg, 0.26 mmol) was dissolved in tetrahydrofuran (10 mL), and sulfuric acid (2N) (45 mL) was added dropwise at room temperature. The reaction was stirred at 60 °C for 12 h. Saturated aqueous sodium bicarbonate solution was added to quench the reaction, and the reaction was extracted with ethyl acetate (30 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 38P (95 mg, yield: 62%).

[0839] LCMS m / z = 602.2 [M+H] +

[0840] Step 16: Preparation of compound 38

[0841] Compound 38P (95 mg, 0.16 mmol) and compound 15-1F (59 mg, 0.19 mmol) were dissolved in chloroform (10 mL), glacial acetic acid (19 mg, 0.32 mmol) was added, and the reaction was heated to 85 °C for 16 h, then sodium triacetoxyborohydride (68 mg, 0.32 mmol) was added, and the reaction was continued at 50 °C for 4 h. The reaction was cooled to room temperature, diluted with dichloromethane, and extracted with aqueous sodium bicarbonate solution (3 times, dichloromethane / methanol (V / V) = 10 / 1). The organic phase was combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography (mobile phase: dichloromethane / methanol (V / V) = 0-10%) to obtain a crude product, which was purified by preparative HPLC (instrument: waters 2767 preparative liquid phase; column: XBridge® Prep C18 (30 mm x 150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)), and then lyophilized to obtain the trifluoroacetate salt of compound 38 (4 mg).

[0842] LCMS m / z = 448.3 [(M+2H) / 2] +

[0843] 1 H NMR (400 MHz, CDCl3 / CD3OD (v / v) = 1 / 1) δ 8.99-8.69 (m, 1H), 8.60-8.37 (m, 1H), 8.33-7.85 (m, 1H), 7.55-7.17 (m, 1H), 7.06-6.89 (m, 1H), 6.87-6.77 (m, 1H), 6.76-6.59 (m, 2H), 4.65-4.46 (m, 2H), 4.43-4.22 (m, 2H), 4.17-4.10 (m, 1H), 4.04-3.31 (m, 16H), 2.91-2.63 (m, 5H), 2.42-2.16 (m, 4H), 2.15-1.79 (m, 5H), 1.55-1.42 (m, 1H), 1.23-0.95 (m, 4H), 0.92-0.69 (m, 3H).

[0844] Preparation of compound 38-2:

[0845] Compound 38-2 was synthesized according to the preparation of compound 38, using compound 38P and 15-2A as starting materials.

[0846] LCMS m / z = 448.3 [(M+2H) / 2] +

[0847] Example 39: Preparation of compound 39

[0848] First Step: Preparation of 39B

[0849] Dissolve 39A (10 g, 40.43 mmol) in 20 mL of HCl (4 N in dioxane), stir at room temperature for 4 h, concentrate the reaction solution to obtain the hydrochloride salt of 39B.

[0850] Second Step: Preparation of 39C

[0851] Dissolve the crude hydrochloride salt of 39B (40.43 mmol) in DMF (50 mL), add potassium carbonate (22.35 g, 161.72 mmol) and 2,4-difluoronitrobenzene (6.43 g, 40.43 mmol), after addition, warm to 80 °C and react for 3 h. Dilute the reaction solution with 150 mL of ethyl acetate, wash with water 3 times, wash with saturated brine once, dry the organic phase over anhydrous sodium sulfate, concentrate, and then perform flash column chromatography (mobile phase: ethyl acetate / petroleum ether (v / v) = 1 / 1) to obtain compound 39C (7.0 g, yield 61%).

[0852] LCMS m / z = 283.1 [M+H] +

[0853] Third Step: Preparation of 39D

[0854] Dissolve 39C (7.0 g, 24.8 mmol) in tetrahydrofuran (50 mL), protect under nitrogen, slowly add a solution of lithium aluminum hydride (2.5 M in THF, 19.8 mL, 49.6 mmol) dropwise under a dry ice bath, stir at -70 °C for 1 h, add 200 mL of a solution of ammonium chloride, extract with ethyl acetate three times, collect the organic phase, dry over anhydrous sodium sulfate, concentrate, and then perform flash column chromatography (mobile phase: ethyl acetate / petroleum ether (v / v) = 1 / 1) to obtain compound 39D (5.2 g, yield 82%).

[0855] LCMS m / z = 255.1 [M+H] +

[0856] Fourth Step: Preparation of 39E

[0857] Compound 39E (3.2 g, yield: 77%) was obtained by dissolving 39D (2.5 g, 9.76 mmol) and tert-butyl piperazine-1-carboxylate (2.75 g, 14.75 mmol) in DMF (10 mL), then adding potassium carbonate (4.08 g, 29.28 mmol), and heating to 80°C for 2 h. The reaction solution was diluted with 30 mL of ethyl acetate, washed with water 3 times, and saturated brine 1 time. The organic phase was dried over anhydrous sodium sulfate, concentrated, and then column chromatographed (mobile phase: ethyl acetate / petroleum ether (v / v) = 1 / 1) to obtain compound 39E (3.2 g, yield: 77%).

[0858] LCMS m / z = 421.3 [M+H] +

[0859] Fifth step: Preparation of 39F

[0860] Compound 39F (4.8 g, yield: 89%) was obtained by dissolving triphenylphosphine (4.03 g, 15.38 mmol) and diisopropyl azodicarboxylate (3.11 g, 15.38 mmol) in tetrahydrofuran (50 mL), stirring for 10 min under nitrogen protection, adding 32C (2.3 g, 7.69 mmol) and 39E (3.2 g, 7.61 mmol) to the reaction solution, and then reacting at room temperature for 4 h under nitrogen protection. The reaction solution was directly concentrated, and the obtained crude product was column chromatographed (mobile phase: ethyl acetate / petroleum ether (v / v) = 1 / 1) to obtain compound 39F (4.8 g, yield: 89%).

[0861] LCMS m / z = 702.2 [M+H] +

[0862] Sixth step: Preparation of 39G

[0863] Compound 39G (4.0 g, yield: 87%) was obtained by dissolving 39F (4.8 g, 6.84 mmol) in tetrahydrofuran (50 mL), then adding zinc powder (4.47 g, 68.4 mmol) and an aqueous solution (10 mL) of ammonium chloride (68.4 g, 3.66 mmol), and reacting at room temperature for 0.5 h. The reaction solution was passed through diatomite overnight, and the filtrate was extracted with ethyl acetate 3 times. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then column chromatographed (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) to obtain compound 39G (4.0 g, yield: 87%).

[0864] Seventh step: Preparation of 39H

[0865] Compound 39G (4.0 g, 5.95 mmol) was dissolved in dichloromethane (50 mL), and brominated nitrile (1.58 g, 14.88 mmol) was added. After the addition was completed, the reaction was allowed to react at room temperature for 16 h. The reaction solution was directly concentrated under reduced pressure, and flash column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) was performed to obtain compound 39H (3.5 g, yield: 84%).

[0866] LCMS m / z = 697.4 [M+H] +

[0867] Eighth step: Preparation of compound 39I

[0868] Compound 39H (1.0 g, 1.44 mmol) was dissolved in tetrahydrofuran (8 mL), 2 mL of methanol and 2 mL of 4N sodium hydroxide solution were added, and stirring was performed at room temperature for 4 h. 2N hydrochloric acid solution was slowly added dropwise to the reaction solution in an ice water bath to adjust the pH to 5-6. Dichloromethane / isopropyl alcohol (V / V = 10:1) was added to extract three times, the organic phase was collected, dried, and concentrated to obtain an intermediate. The obtained intermediate was dissolved in 1,4-dioxane (20 mL), N,N-diisopropylethylamine (0.71 mL, 4.32 mmol) and HATU (820 mg, 2.16 mmol) were added, and after the addition was completed, the reaction was allowed to react at 60°C overnight. The reaction solution was diluted with 30 mL of ethyl acetate, washed with water three times, and saturated brine once. The organic phase was dried over anhydrous sodium sulfate, concentrated, and flash column chromatography (mobile phase: ethyl acetate / petroleum ether (v / v) = 1 / 1) was performed to obtain compound 39I (0.4 g, yield 42%).

[0869] LCMS m / z = 665.3 [M+H] +

[0870] Ninth step: Preparation of compound 39J

[0871] Compound 39I (0.4 g, 0.6 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (2 mL) was added dropwise at room temperature. The reaction was allowed to react at room temperature for 2 h. Saturated sodium carbonate aqueous solution was added to quench, and dichloromethane / isopropyl alcohol (V / V = 10:1) was added to extract three times. The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 39J (200 mg).

[0872] LCMS m / z = 565.3 [M+H] +

[0873] Tenth step: Preparation of compound 39

[0874] Compound 39J (130 mg, 0.23 mmol) was dissolved in chloroform (20 mL) with 17B-1 (89 mg, 0.28 mmol), tetraisopropyl titanate (196 mg, 0.69 mmol) was added, the reaction was stirred at 60 °C for 48 h, sodium triacetoxyborohydride (146 mg, 0.69 mmol) was added in batches, and the reaction was continued for 2 h. The reaction was concentrated, and the residue was purified by column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) to obtain compound 39 (25 mg, yield: 13%).

[0875] LCMS m / z = 871.6 [M+H] +

[0876] Example 40: Preparation of compound 40

[0877] First step: Preparation of compound 40A

[0878] Compound 5G (0.5 g, 0.95 mmol) and (S)-3-(methoxymethyl)piperazine-1-carboxylic acid tert-butyl ester (0.66 g, 2.85 mmol) were dissolved in 1,4-dioxane solution (30 mL), and (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (2'-amino-1,1'-biphenyl-2-yl)palladium(II) (0.26 g, 0.28 mmol), lithium bis(trimethylsilyl)amide (6 mL, 1M in THF) were added. After addition, the reaction was stirred at 60 °C for 16 h under nitrogen protection. After cooling to room temperature, saturated aqueous ammonium chloride solution was added to quench, and ethyl acetate (30 mL x 3) was used for extraction, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the residue was concentrated under reduced pressure and purified by flash column chromatography (mobile phase: dichloromethane / methanol (v / v) = 10 / 1) to obtain compound 40A (0.3 g, yield: 47%).

[0879] LCMS m / z = 675.5 [M+H] +

[0880] Second step: Preparation of compound 40B

[0881] Compound 40A (0.3 g, 0.6 mmol) was dissolved in dichloromethane (6 mL), and trifluoroacetic acid (2 mL) was added dropwise at room temperature. The reaction was stirred at room temperature for 2 h. Saturated aqueous sodium carbonate solution was added to quench, and dichloromethane / isopropanol (V / V = 10:1) was used for extraction three times, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (mobile phase: dichloromethane / ammonia methanol (v / v) = 10 / 1) to obtain compound 40B ((0.13 g, yield: 51%).

[0882] LCMS m / z = 575.2 [M+H] +

[0883] Step 3: Preparation of compound 40

[0884] Into a reaction vial was placed 40B (100 mg, 0.17 mmol), 17B-1 (60 mg, 0.19 mmol), chloroform (2 mL), glacial acetic acid (20 mg, 0.34 mmol), after addition, the temperature was raised to 60 °C overnight, then sodium triacetoxyborohydride (0.072 g, 0.34 mmol) was added, and the reaction was continued at 60 °C for 3 h. The temperature was lowered to room temperature, dichloromethane and saturated aqueous sodium bicarbonate solution were added, the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 50 mg of crude product. The crude product was purified by preparative HPLC (instrument: waters 2767 preparative liquid phase; column: XBridge® Prep C18 (30 mm x 150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)), and the trifluoroacetate salt of compound 40 (13 mg) was obtained by lyophilization of the preparative liquid.

[0885] LCMS m / z = 441.3 [(M+2H) / 2] +

[0886] 1 H NMR (400 MHz, CDCl3 / CD3OD (v / v) = 1 / 1) δ 8.98 - 8.88 (m, 1H), 8.46 (s, 1H), 8.24 (s, 1H), 7.43 (d, 1H), 7.30 - 6.99 (m, 2H), 6.61 - 6.44 (m, 2H), 4.53 - 4.45 (m, 1H), 4.40 - 4.28 (m, 1H), 4.04 (dd, 1H), 3.98 - 3.87 (m, 3H), 3.83 - 3.36 (m, 15H), 3.32 - 3.15 (m, 5H), 3.00 - 2.80 (m, 3H), 2.78 - 2.69 (m, 2H), 2.41 - 2.21 (m, 4H), 2.19 - 1.89 (m, 5H), 1.61 - 1.48 (m, 1H), 0.91 (d, 3H).

[0887] Preparation of compound 40-2:

[0888] Compound 40-2 was synthesized according to the preparation of compound 40, using compound 40B and 17B-2 as starting materials.

[0889] LCMS m / z = 441.3 [(M+2H) / 2] +

[0890] Example 41: Preparation of compound 41

[0891] First step: Preparation of compound 41C

[0892] Compound 41A (3.0 g, 13.87 mmol) and 41B (1.47 g, 13.87 mmol) were dissolved in a solution of chloroform (0 mL), and glacial acetic acid (2.5 g, 41.61 mmol) was added. After the addition was complete, the reaction was carried out at 70 °C for 3 h, and then the temperature was lowered to room temperature. Then, 20 mL of chloroform was added, and sodium triacetoxyborohydride (5.88 g, 27.74 mmol) was added. The reaction was carried out at 70 °C for 3 h. Dichloromethane and saturated aqueous sodium bicarbonate solution were added, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the concentrated residue was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate (v / v) = 1 / 1) to obtain compound 41C (3 g, yield: 71%).

[0893] LCMS m / z = 307.2 [M+H] +

[0894] Second step: Preparation of compound 41E

[0895] Compound 41C (2.6 g, 8.49 mmol) and 41D (1.42 g, 10.19 mmol) were dissolved in a solution of xylene (200 mL), and tetrabutylammonium bromide (0.27 g, 0.85 mmol) and potassium hydroxide (1.43 g, 25.47 mmol) were added. After the addition was complete, the reaction was carried out at 30 °C for 30 h, and then the temperature was lowered to room temperature. Xylene was removed by concentration under reduced pressure, and the residue was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate (v / v) = 1 / 1) to obtain compound 41E (0.6 g, yield: 19.4%).

[0896] LCMS m / z = 365.3 [M+H] +

[0897] Third step: Preparation of compound 41F

[0898] Compound 41E (0.6 g, 1.65 mmol) was dissolved in a solution of isopropanol (10 mL), and palladium on carbon (0.1 g) was added. After the addition was complete, the reaction was carried out at room temperature for 16 h. The palladium on carbon was removed by filtration through diatomite, and the filter cake was washed with dichloromethane three times. The combined organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (mobile phase: dichloromethane / methanol (v / v) = 10 / 1) to obtain compound 41F (0.4 g, yield: 89%).

[0899] LCMS m / z = 275.2 [M+H] +

[0900] Step 4: Preparation of compound 41G

[0901] Compound 5G (0.38 g, 0.72 mmol) and 41F (0.4 g, 1.44 mmol) were dissolved in 1,4-dioxane solution (20 mL), and (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (2'-amino-1,1'-biphenyl-2-yl)palladium(II) (0.2 g, 0.22 mmol), lithium bis(trimethylsilyl)amide (4.5 mL, 1M in THF) were added. After addition, the reaction was stirred at 60 °C under nitrogen protection for 16 h. After cooling to room temperature, saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the residue was concentrated under reduced pressure. The residue was purified by flash column chromatography (mobile phase: dichloromethane / methanol (v / v) = 10 / 1) to give compound 41G (0.2 g, yield: 38%).

[0902] LCMS m / z = 719.4 [M+H] +

[0903] Step 5: Preparation of compound 41H

[0904] Compound 41G (0.2 g, 0.28 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1 mL) was added. The reaction was stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure to remove the trifluoroacetic acid, and 10 mL of dichloromethane and 1 mL of isopropanol were added to dissolve the residue. The solution was adjusted to basic with aqueous sodium carbonate solution, and extracted with dichloromethane / isopropanol (v / v) = 10 / 1 three times. The combined organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by flash column chromatography (mobile phase: dichloromethane / methanol (v / v) = 10 / 1) to give 41H (0.065 g, yield: 38%).

[0905] LCMS m / z = 619.5 [M+H] +

[0906] Step 6: Preparation of compound 41

[0907] Into a reaction vial was added 41H (50 mg, 0.17 mmol), 17B-1 (29 mg, 0.089 mmol), chloroform (2 mL), glacial acetic acid (9.7 mg, 0.16 mmol), after addition, warmed to 60 °C overnight, then added chloroform (1 mL) to dissolve, sodium triacetoxyborohydride (0.034 g, 0.16 mmol), continued to react at 60 °C for 3 h. Cooled to room temperature, added dichloromethane and saturated aqueous sodium bicarbonate solution, stirred to separate layers, the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 25 mg of crude product, the crude product was purified by preparative HPLC (instrument: waters 2767 preparative liquid phase; column: XBridge@Prep C18(30 mm x 150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)), and the trifluoroacetate salt of compound 41 (3 mg) was obtained by freeze-drying of the preparative liquid.

[0908] LCMS m / z = 463.3 [(M+2H) / 2] +

[0909] 1 H NMR (400 MHz, CDCl3 / CD3OD (v / v) = 1 / 1) δ 8.88-8.81 (m, 1H), 8.36 (s, 1H), 8.18-8.12 (m, 1H), 7.39-7.27 (m, 1H), 6.87-6.73 (m, 2H), 6.51-6.40 (m, 2H), 4.45-4.38 (m, 1H), 4.28-4.18 (m, 1H), 4.00-3.92 (m, 1H), 3.90-3.81 (m, 3H), 3.73-3.25 (m, 24H), 2.89-2.73 (m, 3H), 2.68-2.61 (m, 2H), 2.25-2.15 (m, 4H), 2.07-1.82 (m, 5H), 1.55-1.48 (m, 1H), 0.94-0.87 (m, 3H).

[0910] Preparation of compound 41-2

[0911] Compound 41-2 was synthesized by using compound 41H and 17B-2 as starting materials according to the preparation of reference compound 41.

[0912] LCMS m / z = 463.3 [(M+2H) / 2] +

[0913] Example 42: Preparation of compound 42

[0914] First step: preparation of 42C

[0915] A single-neck flask was charged with 42B (5.37 g, 21.83 mmol), bis(pinacolato)diboron (6.4 g, 25.18 mmol), potassium acetate (4.94 g, 50.37 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride dichloromethane complex (1.37 g, 1.68 mmol) and 1,4-dioxane (200 mL), and after addition was complete, the flask was purged with nitrogen three times and the reaction was heated to 80 °C overnight. To the reaction mixture after overnight, 60 mL of water, 42A (6 g, 16.79 mmol), potassium acetate (4.94 g, 50.37 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride dichloromethane complex (0.69 g, 0.84 mmol) were added, and after addition was complete, the flask was purged with nitrogen three times and the reaction was heated to 80 °C for 2 h. The reaction was cooled to room temperature, filtered through celite, and the filter cake was washed with 300 mL of ethyl acetate, which was discarded. The filtrate was separated into layers, and the organic layer was washed with saturated brine once. The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by flash column chromatography (mobile phase: dichloromethane / methanol (v / v) = 20 / 1) to give compound 42C (6.1 g, yield: 92%).

[0916] LCMS m / z = 397.2 [M+H] +

[0917] Second Step: Preparation of 42D

[0918] 42C (6 g, 15.13 mmol) was dissolved in trifluoroacetic acid (100 mL) and stirred at room temperature for 4 h. The reaction was concentrated, 200 mL of dichloromethane and saturated aqueous sodium bicarbonate solution were added, and the organic phase was concentrated under reduced pressure. The residue was filtered by slurry with methyl tert-butyl ether to give 42D (2 g, yield: 50%).

[0919] LCMS m / z = 267.1 [M+H] +

[0920] Third Step: Preparation of 42F

[0921] Triphenylphosphine (2.96 g, 11.27 mmol) and diisopropyl azodicarboxylate (2.28 g, 11.27 mmol) were dissolved in tetrahydrofuran (100 mL) and stirred under nitrogen for 10 min. 42D (1.2 g, 4.51 mmol) and 42E (1.43 g, 4.51 mmol) were added to the reaction mixture, which was stirred at room temperature for 4 h under nitrogen. The reaction mixture was directly concentrated, and the residue was purified by flash column chromatography (mobile phase: ethyl acetate / petroleum ether (v / v) = 1 / 0) to give compound 42F (2.1 g, yield: 82%).

[0922] LCMS m / z = 565.1 [M+H]+

[0923] Step 4: Preparation of 42G

[0924] 42F (2.1 g, 3.71 mmol) was dissolved in tetrahydrofuran (100 mL), then zinc powder (2.1 g, 32.11 mmol) and aqueous solution of ammonium chloride (2.1 g, 39.26 mmol) (30 mL) were added, and the reaction was allowed to proceed at room temperature for 0.5 h. The reaction solution was passed through celite overnight, and the filtrate was extracted with ethyl acetate three times. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then fast column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) was performed to obtain compound 42G (1.99 g).

[0925] LCMS m / z = 535.2 [M+H] +

[0926] Step 5: Preparation of 42H

[0927] 42G (1.99 g, 3.72 mmol) was dissolved in dichloromethane (100 mL), and brominated nitrile (1.18 g, 11.16 mmol) was added. The reaction was allowed to proceed at room temperature for 16 h. The reaction solution was directly concentrated under reduced pressure, and fast column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) was performed to obtain compound 42H (2 g).

[0928] Step 6: Preparation of 42I

[0929] 42H (1.4 g, 2.5 mmol) was dissolved in tetrahydrofuran (50 mL), and lithium bis(trimethylsilyl)amide (5 mL, 1M in THF) was added. The reaction was allowed to proceed at room temperature for 1 h. The reaction solution was quenched with saturated aqueous sodium carbonate solution, and extracted with ethyl acetate three times. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Fast column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) was performed to obtain compound 42I (0.7 g).

[0930] Step 7: Preparation of compound 42J

[0931] Compound 42I (0.7 g, 1.32 mmol) and 4-piperidone acetal (0.57 g, 3.96 mmol) were dissolved in 1,4-dioxane (60 mL), and (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (2'-amino-1,1'-biphenyl-2-yl)palladium(II) (0.31 g, 0.34 mmol), lithium bis(trimethylsilyl)amide (8 mL, 1M in THF) were added. After addition, the reaction was stirred at 60 °C under nitrogen protection for 16 h. After cooling to room temperature, the reaction was quenched by saturated aqueous ammonium chloride solution, extracted with ethyl acetate (50 mL x 3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the residue was concentrated under reduced pressure. The residue was purified by flash column chromatography (mobile phase: dichloromethane / methanol (v / v) = 10 / 1) to give compound 42J (0.25 g, yield: 32%).

[0932] LCMS m / z = 591.3 [M+H] +

[0933] Eighth step: Preparation of compound 42K

[0934] Compound 42J (0.25 g, 0.42 mmol) was dissolved in tetrahydrofuran (20 mL), and hydrochloric acid (8N) (20 mL) was added dropwise at room temperature. The reaction was stirred at room temperature for 12 h. The reaction was quenched by saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (30 mL x 3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 42K (0.16 g, yield: 69%).

[0935] LCMS m / z = 547.2 [M+H] +

[0936] Ninth step: Preparation of compound 42

[0937] Compound 42K (0.1 g, 0.18 mmol) was dissolved in a solution of compound 15-1F (67 mg, 0.22 mmol) in chloroform (5 mL), and tetraisopropyl titanate (0.15 g, 0.54 mmol) was added. After the addition was completed, the reaction was warmed to 50 °C for 48 h, and sodium triacetoxyborohydride (0.076 g, 0.36 mmol) was added in portions. The reaction was continued at 50 °C for 3 h. After being cooled to room temperature, dichloromethane and saturated aqueous sodium bicarbonate solution were added, and the mixture was stirred to separate the layers. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated residue was purified by column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) to obtain a crude product, which was purified by preparative HPLC (instrument: waters 2767 preparative liquid phase; column: XBridge® Prep C18 (30 mm x 150 mm); mobile phase composition: acetonitrile, water) and lyophilized to obtain compound 42 (7 mg, yield: 5%).

[0938] LCMS m / z = 420.9 [(M+2H) / 2] +

[0939] 1 H NMR (400 MHz, CDCl3 / CD3OD (v / v) = 1 / 1) δ 8.99-8.86 (m, 1H), 8.53-8.42 (m, 1H), 8.31-8.15 (m, 1H), 7.39-7.27 (m, 1H), 7.04-6.88 (m, 2H), 6.56-6.38 (m, 2H), 4.51-4.47 (m, 1H), 4.36-4.29 (m, 1H), 4.06-3.99 (m, 1H), 3.96-3.87 (m, 1H), 3.79-3.62 (m, 6H), 3.31-3.22 (m, 4H), 2.89-2.62 (m, 9H), 2.56-2.42 (m, 1H), 2.35-2.23 (m, 2H), 2.16-1.96 (m, 5H), 1.87-1.72 (m, 2H), 1.59-1.50 (m, 1H), 0.93 (d, 3H).

[0940] Example 43: Preparation of compound 43

[0941] First step: Preparation of compound 43B

[0942] Compound 5G (0.5 g, 0.95 mmol) and 43A (0.66 g, 2.85 mmol) were dissolved in 1,4-dioxane solution (50 mL), and (2-dicyclohexylphosphino)-3,6- dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (2'-amino-1,1'-biphenyl-2-yl)palladium(II) (0.26 g, 0.28 mmol), lithium bis(trimethylsilyl)amide (5.7 mL, 1M in THF) were added. After addition, the reaction was stirred at 60 °C under nitrogen protection for 16 h. After cooling to room temperature, saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the residue was concentrated under reduced pressure and purified by flash column chromatography (mobile phase: dichloromethane / methanol (v / v) = 10 / 1) to give compound 43B (0.6 g, yield: 93%).

[0943] LCMS m / z = 675.4 [M+H] +

[0944] Second Step: Preparation of compound 43C

[0945] Compound 43B (0.7 g, 1.04 mmol) was dissolved in dichloromethane (15 mL), and trifluoroacetic acid (15 mL) was added. The reaction was stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure to remove the trifluoroacetic acid, and 10 mL of dichloromethane and 1 mL of isopropanol were added to dissolve the residue. The solution was adjusted to basic with aqueous sodium carbonate solution, and extracted with dichloromethane / isopropanol (v / v) = 10 / 1 three times. The combined organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by flash column chromatography (mobile phase: dichloromethane / methanol (v / v) = 10 / 1) to give 43C (0.06 g, yield: 10%).

[0946] LCMS m / z = 575.4 [M+H] +

[0947] Third Step: Preparation of compound 43

[0948] Compound 43C (0.1 g, 0.17 mmol) was dissolved in a solution of 17B-1 (0.055 g, 0.17 mmol) in chloroform (10 mL), and glacial acetic acid (0.02 g, 0.34 mmol) was added. After the addition was complete, the reaction was stirred at 70 °C for 3 h. The solvent was evaporated, and the temperature was reduced to room temperature. Then, 10 mL of chloroform was added, and sodium triacetoxyborohydride (0.072 g, 0.34 mmol) was added. The reaction was stirred at 70 °C for 3 h. The temperature was reduced to room temperature, and dichloromethane and saturated aqueous sodium bicarbonate were added. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) to obtain a crude product. The crude product was purified by preparative HPLC (instrument: waters 2767 preparative liquid phase; column: XBridge® Prep C18 (30 mm x 150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)) and lyophilized to obtain the trifluoroacetate salt of compound 43 (9 mg).

[0949] LCMS m / z = 881.4 [M+H] +

[0950] 1 H NMR (400 MHz, CDC13 / CD3OD (v / v) = 1 / 1) δ 8.92 (s, 1H), 8.47 (s, 1H), 8.31-8.09 (m, 1H), 7.46-7.32 (m, 1H), 7.06-6.89 (m, 2H), 6.62-6.44 (m, 2H), 4.54-4.48 (m, 1H), 4.38-4.27 (m, 1H), 4.04 (dd, 1H), 3.99-3.41 (m, 23H), 3.02-2.84 (m, 3H), 2.79-2.69 (m, 2H), 2.34-1.89 (m, 9H), 1.60-1.47 (m, 1H), 0.91 (d, 3H).

[0951] Preparation of compound 43-2:

[0952] Compound 43-2 was synthesized according to the preparation of compound 43, using compound 43C and 17B-2 as starting materials.

[0953] LCMS m / z = 881.4 [M+H] +

[0954] Example 44: Preparation of compound 44

[0955] First step: preparation of compound 44C

[0956] Compound 44A (3.0 g, 13.87 mmol) and 44B (1.47 g, 13.87 mmol) were dissolved in chloroform (10 mL), glacial acetic acid (2.5 g, 41.61 mmol) was added, and after the addition was complete, the reaction was carried out at 70 °C for 3 h with the mouth open, and then the temperature was lowered to room temperature. Then 20 mL of chloroform was added, sodium triacetoxyborohydride (5.88 g, 27.74 mmol) was added, and the reaction was carried out at 70 °C for 3 h. The temperature was lowered to room temperature, dichloromethane and saturated aqueous sodium bicarbonate solution were added, the organic layer was dried over anhydrous sodium sulfate, and after filtration, the concentrated residue was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate (v / v) = 1 / 1) to obtain compound 44C (2.6 g, yield: 80%).

[0957] Second step: preparation of compound 44E

[0958] Compound 44C (3.4 g, 11.10 mmol) and 44D (2.31 g, 16.65 mmol) were dissolved in xylene (340 mL), tetrabutylammonium bromide (0.36 g, 1.11 mmol) and potassium hydroxide (1.25 g, 22.20 mmol) were added, and after the addition was complete, the reaction was carried out at 30 °C for 30 h. The temperature was lowered to room temperature, xylene was removed by concentration under reduced pressure, and the residue was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate (v / v) = 1 / 1) to obtain compound 44E (0.85 g, yield: 21%).

[0959] Third step: preparation of compound 44F

[0960] Compound 44E (1.07 g, 2.94 mmol) was dissolved in isopropanol (20 mL), palladium on carbon (0.11 g) was added, and after the addition was complete, the reaction was carried out at room temperature for 16 h. The palladium on carbon was removed by filtration over diatomaceous earth, the filter cake was washed with dichloromethane three times, the combined organic phases were concentrated under reduced pressure, and the residue was purified by column chromatography (mobile phase: dichloromethane / methanol (v / v) = 10 / 1) to obtain compound 44F (0.625 g, yield: 78%).

[0961] Fourth step: preparation of compound 44G

[0962] Compound 5G (0.5 g, 0.95 mmol) and 44F (0.39 g, 1.42 mmol) were dissolved in 1,4-dioxane solution (35 mL), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.091 g, 0.19 mmol), tris(dibenzylideneacetone)dipalladium (0.087 g, 0.095 mmol) and sodium tert-butoxide (0.73 g, 7.60 mmol) were added, and the reaction was stirred at 90 °C under nitrogen protection for 3 h. Water was added to quench the reaction, and ethyl acetate (30 mL x 3) was used for extraction. The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the residue was concentrated under reduced pressure and purified by flash column chromatography (mobile phase: dichloromethane / methanol (v / v) = 10 / 1) to obtain compound 44G (0.6 g, yield: 88%).

[0963] LCMS m / z = 719.3 [M+H] +

[0964] Fifth step: Preparation of compound 44H

[0965] Compound 44G (0.6 g, 0.83 mmol) was dissolved in dichloromethane (15 mL), and trifluoroacetic acid (15 mL) was added. The reaction was stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure to remove the trifluoroacetic acid, and 10 mL of dichloromethane and 1 mL of isopropanol were added to dissolve the residue. The solution was adjusted to basic with an aqueous sodium carbonate solution, and dichloromethane / isopropanol (v / v) = 10 / 1 was used for extraction 3 times. The organic phase was combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by flash column chromatography (mobile phase: dichloromethane / methanol (v / v) = 10 / 1) to obtain 44H (0.25 g, yield: 48%).

[0966] LCMS m / z = 619.3 [M+H] +

[0967] Sixth step: Preparation of compound 44

[0968] Compound 44H (0.2 g, 0.32 mmol) was dissolved in toluene (10 mL) with 17B-1 (0.1 g, 0.32 mmol), and glacial acetic acid (0.038 g, 0.64 mmol) was added. After the addition was complete, the reaction was refluxed at 130 °C for 3 h, cooled to room temperature, and concentrated under reduced pressure to remove toluene. Then 10 mL of chloroform was added, and sodium triacetoxyborohydride (0.14 g, 0.64 mmol) was added. The reaction was stirred at 70 °C for 3 h, cooled to room temperature, and dichloromethane and saturated aqueous sodium bicarbonate solution were added. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: methanol / dichloromethane (v / v) = 1 / 15) to obtain a crude product. The crude product was purified by preparative HPLC (instrument: waters 2767 preparative liquid; column: XBridge® Prep C18 (30 mm x 150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)), and the trifluoroacetate salt of compound 44 was obtained by lyophilization (0.013 g).

[0969] LCMS m / z = 925.4 [M+H] +

[0970] 1 H NMR (400 MHz, CDCl3 / CD3OD (v / v) = 1 / 1) δ 9.02-8.86 (m, 1H), 8.47 (s, 1H), 8.29-8.17 (m, 1H), 7.48-7.37 (m, 1H), 7.28-6.90 (m, 2H), 6.62-6.45 (m, 2H), 4.55-4.46 (m, 1H), 4.38-4.28 (m, 1H), 4.04 (dd, 1H), 3.99-3.87 (m, 3H), 3.79 (s, 3H), 3.77-3.35 (m, 21H), 3.00-2.81 (m, 3H), 2.79-2.71 (m, 2H), 2.39-2.20 (m, 4H), 2.20-2.04 (m, 2H), 2.04-1.85 (m, 3H), 1.61-1.48 (m, 1H), 0.91 (d, 3H).

[0971] Preparation of compound 44-2:

[0972] Compound 44-2 was synthesized according to the preparation of compound 44, using compound 44H and 17B-2 as starting materials.

[0973] LCMS m / z = 925.4 [M+H] +

[0974] Example 45: Preparation of compound 45

[0975] First Step: Preparation of 45B

[0976] Compound 5G (400 mg, 0.76 mmol) and 45A (513.66 mg, 2.28 mmol) were dissolved in 1,4-dioxane (10 mL), tris(dibenzylideneacetone)dipalladium (69.59 mg, 0.076 mmol), Xphos (72.46 mg, 0.15 mmol) and sodium tert-butoxide (365.18 mg, 3.8 mmol) were added, replaced with nitrogen for three times, and heated to 90 °C overnight under nitrogen protection. After cooling to room temperature, dichloromethane and water were added, and the mixture was extracted with dichloromethane for three times. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol (V / V) = 0 / 10-10 / 1) to obtain compound 45B (500 mg).

[0977] LCMS m / z = 670.3 [M+H] +

[0978] Second Step: Preparation of 45C

[0979] Compound 45B (500 mg) was dissolved in DCM (5 mL), 5 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1 h. After concentration under reduced pressure, the residue was dissolved in dichloromethane, and saturated aqueous sodium bicarbonate solution was added. The mixture was stirred, extracted with dichloromethane for three times, and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol (V / V) = 0 / 10-5 / 1) to obtain compound 45C (200 mg, yield: 47%).

[0980] LCMS m / z = 570.3 [M+H] +

[0981] Third Step: Preparation of Compound 45

[0982] Compound 45-2 was prepared according to the procedure described in the preparation of compound 45, using compound 45C and 17B-2 as starting materials.

[0983] LCMS m / z = 876.6 [M+H] +

[0984] 1 H NMR (400 MHz, CDCl3 / CD3OD (v / v) = 1 / 1) δ 8.99-8.88 (m, 1H), 8.46 (s, 1H), 8.27-8.17 (m, 1H), 7.40 (d, 1H), 7.09-6.92 (m, 2H), 6.58-6.42 (m, 2H), 4.54-4.48 (m, 1H), 4.35-4.30 (m, 1H), 4.14-3.98 (m, 3H), 3.97-3.88 (m, 1H), 3.86-3.74 (m, 6H), 3.72 (s, 3H), 3.31-2.98 (m, 5H), 2.96-2.81 (m, 5H), 2.79-2.69 (m, 2H), 2.67-2.55 (m, 1H), 2.35-1.98 (m, 7H), 1.80-1.62 (m, 2H), 1.61-1.50 (m, 1H), 0.93 (d, 3H).

[0985] Compound 45-2 was prepared according to the procedure described in the preparation of compound 45, using compound 45C and 17B-2 as starting materials.

[0986] Compound 45-2 was prepared according to the procedure described in the preparation of compound 45, using compound 45C and 17B-2 as starting materials.

[0987] LCMS m / z = 438.9 [(M+2H) / 2] +

[0988] Reference Compound 1: Reference Compound 2:

[0989] Reference Compound 1 and Reference Compound 2 are diastereomers of each other,

[0990] one of the structures is the other is

[0991] Biological Test Example

[0992] Test Example 1: Proliferation inhibition activity of NCI-H1975 (EGFR-L858R-T790M) and A431 (EGFR-WT) cells

[0993] NCI-H1975 (EGFR-L858R-T790M) and A431 (EGFR-WT) cells were purchased from ATCC, and the culture medium was RPMI1640 + 10% FBS and DMEM + 10% FBS, respectively, and cultured in a 37°C, 5% CO2 incubator. On the first day, NCI-H1975 (EGFR-L858R-T790M) and A431 (EGFR-WT) cells in the exponential growth phase were collected, and the viable cell count was performed using an automatic cell analyzer (countstar). After adjusting the cell suspension with the culture medium, 1000 NCI-H1975 (EGFR-L858R-T790M) cells and 3000 A431 cells were plated in each well of a 96-well cell culture plate. On the second day, the culture medium was removed, and 90 μL of fresh culture medium and 10 μL of different concentrations of compounds were added to each well, with a final DMSO concentration of 0.1% per well. Incubate at 37°C, 5% CO2 incubator for 72 hours. After 72 hours of drug treatment, 50 μL of pre-melted and room temperature equilibrated CTG solution (promega, G7572) was added to each well, mixed for 2 min with a microplate shaker, and the fluorescence signal value was measured with a microplate reader (PHERAstar FSX) after incubation at room temperature for 10 min.

[0994] Cell survival rate was calculated using the formula V sample / V vehicle control x 100%. Where V sample is the reading of the drug treatment group, V vehicle control is the average value of the solvent control group. Using origin 9.2 software, a non-linear regression model was used to draw an S-shaped dose-survival curve and calculate the IC 50Values.

[0995] Conclusion: The compound of the application has good proliferation inhibition activity on NCI-H1975 (EGFR-L858R-T790M) cells; has poor proliferation inhibition activity on A431 (EGFR-WT) cells, and has good selectivity.

[0996] Test Example 2: Proliferation inhibition activity of Ba / F3-EGFR-Del19-C797S cells

[0997] Ba / F3 cells with high expression of EGFR-Del19-C797S double mutation (Ba / F3-EGFR-Del19-C797S) were constructed by Hefei Zhongke Puerui Biological Medicine Technology Co., Ltd. The cells were placed in RPMI1640 medium (containing 10% fetal bovine serum) and cultured at 37℃, 5% CO2. Cells in the exponential growth phase were collected, and the viable cell count was performed using a cell counter (Countstar). After adjusting the cell suspension to the appropriate density with medium, 95μL / well volume was inoculated in a 96-well cell culture plate (2000 cells / well), and 5μL of medium containing different concentrations of compounds was added to each well, and the final DMSO concentration in each well was 0.1%. Continue to incubate at 37℃, 5% CO2 for 72 hours. Then, add 50μL of pre-equilibrated CTG solution (Promega, Catalog No. G7572) to each well, mix well with a microplate shaker for 2 minutes, and detect the luminescence signal on a SpectraMax Paradigm plate reader after 10 minutes at room temperature. Inhibition rate = 100-(RLU Drug -RLU Min ) / (RLU Max -RLU Min )*100; wherein RLU Drug is the reading of the drug treatment group, RLU Max is the average of the solvent control group, and RLU Min is the average of the blank control group. The Graphpad Prism software is used to fit and calculate the IC 50 value using the four-parameter fitting method.

[0998] Table 2-1 Proliferation inhibition activity of test compounds on Ba / F3-EGFR-Del19-C797S cells Note: In Table 2-1, A < 20nM, 20nM ≤ B < 50nM, 50nM ≤ C < 200nM.

[0999] Conclusion: The compound of the application, for example, the compound of the example, has good proliferation inhibition activity on Ba / F3-EGFR-Del19-C797S cells.

[1000] Test Example 3: Proliferation inhibition activity of Ba / F3-WT cells

[1001] Ba / F3 cells were provided by Hefei Zhongke Puruisheng Biopharmaceutical Technology Co., Ltd. The cells were placed in RPMI1640 medium (containing 10% fetal bovine serum, 1ng / mL IL-3) and cultured at 37°C and 5% CO2. Cells in the exponential growth phase were collected and viable cells were counted using a cell counter (Countstar). The cell suspension was adjusted to an appropriate density with culture medium and then seeded into a 96-well cell culture plate at a volume of 95μL / well (2000 cells / well). 5μL of culture medium containing different concentrations of compounds was added to each well, and the final DMSO concentration in each well was 0.1%. The cells were incubated for 72 hours at 37°C and 5% CO2. Then, 50μL of CTG solution (Promega, catalog number G7572) pre-equilibrated to room temperature was added to each well, mixed for 2 minutes using a microplate shaker, and the luminescence signal was detected on a SpectraMax Paradigm plate reader after standing at room temperature for 10 minutes. Inhibition rate = 100-(RLU Drug -RLU Min ) / (RLU Max -RLU Min )*100; where RLU Drug The readings for the drug-treated groups, RLU Max is the average value of the solvent control group, RLU Min The IC values ​​were calculated using the four-parameter fitting method using Graphpad Prism software. 50 value.

[1002] Table 3-1 Results of the inhibitory activity of test compounds on Ba / F3-WT cells Note: In Table 3-1, A<1uM, 1uM≤B≤10uM, 10uM<C.

[1003] Conclusion: The compounds of the present invention, such as the compounds in the examples, have poor inhibitory activity against Ba / F3-WT cell proliferation and have good selectivity.

[1004] Test Example 4: EGFR-Del19-C797S enzyme activity inhibition test

[1005] The compound was prepared into a 10 mM stock solution using DMSO, and then diluted 10-fold with DMSO as the starting concentration of the compound test, and then diluted 10 times in a 5-fold gradient. SYSTEM, Beckman) to a 384 reaction plate (Greiner, Cat# 784075). Prepare 2X kinase solution with 1X kinase reaction buffer (1X Enzyme Buffer, 5mM MgCl2, 1mM DTT, and 1mM MnCl2), transfer 5μL of EGFR-Del19-C797S enzyme solution (final concentration 0.004ng / μL, Signalchem, Cat# E10-122TG-10) to the 384 reaction plate. Centrifuge at 1000rpm for 60 seconds, incubate at 25℃ for 10 minutes. Prepare 2X mixture of substrate (final concentration 1μM) and ATP (final concentration 1mM) with kinase reaction buffer, add 5μL of substrate-ATP mixture to the reaction plate, centrifuge at 1000rpm for 60 seconds. Seal the plate with sealing membrane, incubate at 25℃ for 60 minutes. Add 5μL of kinase detection reagent to each well of the reaction plate, centrifuge at 1000rpm for 1 minute, incubate at 25℃ for 60 minutes. Read the fluorescence signal value at 615nm (Cryptate) and 665nm (XL665) with BMG Clarity™ HTS Multimode Plate Reader. Inhibition = (Data 阴性对照 -Data 化合物 ) / (Data 阴性对照 -Data 阳性对照 )*100; where Data 化合物 is the reading of the drug-treated group, Data 阴性对照 is the average of the negative control group (1% DMSO), and Data 阳性对照 is the average of the positive control group (reaction system replaced with buffer solution instead of EGFR-Del19-C797S enzyme). Analyze the data with GraphPad Prism software, and obtain the IC 50 (half-inhibitory concentration) of the compound using the non-linear fitting formula.

[1006] Table 4-1 Results of the inhibition activity of test compounds on EGFR-Del19-C797S enzyme activity Note: In Table 4-1, A < 10nM, 10nM≤B<50nM, 50nM≤C<200nM.

[1007] Conclusion: The compounds of the present application, such as the example compounds, have good inhibitory activity on EGFR-Del19-C797S enzyme activity.

[1008] 5. CYP450 enzyme inhibition test

[1009] The purpose of this study is to evaluate the effects of the test substances on the activities of five isozymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) of human liver microsomal cytochrome P450 (CYP) by using in vitro test system. The specific probe substrates of CYP450 isozymes were incubated with human liver microsomes and different concentrations of test substances, respectively, and the reaction was initiated by adding reduced nicotinamide adenine dinucleotide phosphate (NADPH). After the reaction was completed, the changes in CYP enzyme activity were determined by treating the samples and quantitatively detecting the metabolites produced by the specific substrates using liquid chromatography-tandem mass spectrometry (LC-MS / MS) method, and the IC 50 values were calculated to evaluate the inhibition potential of the test substances on each CYP enzyme subtype.

[1010] Table 5-1 Results of the inhibition activities of the test compounds on CYP enzyme subtypes

[1011] Conclusion: The compounds of the present application, such as the example compounds, have no significant inhibitory effect on CYP450 enzymes.

[1012] 6. Proliferation inhibition activity of HCC827 (Del19) cells

[1013] HCC827 (Del19) was provided by Hefei Zhongke Puerui Biological Medicine Technology Co., Ltd. The cells were cultured in RPMI1640 medium containing 10% fetal bovine serum at 37℃ and 5% CO2. Cells in the logarithmic growth phase were collected and counted using a cell counter (Countstar). After adjusting the cell suspension to the appropriate density with medium, 90μL / well was inoculated in a 96-well cell culture plate (3000 cells / well), and incubated at 37℃ and 5% CO2 for 24 hours. After 24 hours, the test compounds were prepared into a stock solution with DMSO, and diluted with DMSO at five times gradient to obtain nine concentration gradients, with 2.5mM (250X) as the highest concentration. The test compounds were diluted 25 times with medium, and then 10μL of medium containing different concentrations of compounds was added to each well, with a final DMSO concentration of 0.4% in each well. Incubation was continued at 37℃ and 5% CO2 for 3 days. Then, 50μL of pre-equilibrated CTG solution (Promega, Catalog No. G7572) at room temperature was added to each well, mixed well with a microplate shaker for 2 minutes, and then placed at room temperature for 10 minutes before detecting the luminescence signal on a SpectraMax Paradigm plate reader. Inhibition Rate (Inh%) = 100- (RLU Drug -RLU Min ) / (RLU Max -RLU Min )*100%; wherein RLUDrug RLU for drug treated group Max RLU for average of solvent control group Min RLU for average of blank control group. IC50values were calculated using Graphpad Prism software with a four parameter fit. 50

[1014] Table 6-1 Results of the proliferation inhibition activity of test compounds on HCC827 (Del19) cells

[1015] Conclusion: The compounds of the present application, such as the example compounds, have good proliferation inhibition activity on HCC827 (Del19) cells.

[1016] 7. Proliferation inhibition activity of Ba / F3-EGFR-WT cells

[1017] Ba / F3-EGFR-WT cells were constructed by Hefei Zhongke Puerui Biological Medicine Technology Co., Ltd. The cells were cultured in RPMI1640 medium (containing 10% fetal bovine serum, EGF) at 37℃, 5% CO2. Cells in the exponential growth phase were collected, and the viable cell count was performed using a cell counter (Countstar). After adjusting the cell suspension to the appropriate density with medium, 95μL / well volume was inoculated in a 96-well cell culture plate (2000 cells / well), and then 5μL of medium containing different concentrations of compounds was added to each well, and the final concentration of DMSO in each well was 0.1%. Incubate at 37℃, 5% CO2 for 72 hours. Then, 50μL of pre-equilibrated CTG solution (Promega, Catalog No. G7572) at room temperature was added to each well, mixed well with a microplate shaker for 2 minutes, and then the luminescence signal was detected on a SpectraMax Paradigm plate reader after 10 minutes at room temperature. Inhibition rate = 100-(RLU Drug -RLU Min ) / (RLU Max -RLU Min )*100; wherein RLU Drug RLU for drug treated group Max RLU for average of solvent control group Min RLU for average of blank control group. IC50values were calculated using Graphpad Prism software with a four parameter fit. 50

[1018] 8. Proliferation inhibition activity of Ba / F3-FL-EGFR-Del19 cells

[1019] ​​Ba / F3-FL-EGFR-Del19 cells were constructed by Hefei Zhongke Puerui Biology and Medicine Technology Co., Ltd. The cells were placed in RPMI1640 medium (containing 10% fetal bovine serum) and cultured at 37℃, 5% CO2. Cells in the exponential growth phase were collected, and the viable cell count was performed using a cell counter (Countstar). The cell suspension was adjusted to the appropriate density with the culture medium, and then inoculated in a 96-well cell culture plate at 95μL / well (2000 cells / well). The test compound was prepared into a stock solution with DMSO, and diluted with DMSO in a five-fold gradient to obtain nine concentration gradients, with 10mM (1000X) as the highest concentration. The test compound was diluted 50 times with the culture medium, and then 5μL of the culture medium containing different concentrations of the compound was added to each well, and the final DMSO concentration in each well was 0.1%. Incubation was continued at 37℃, 5% CO2 for 3 days. Then, 50μL of pre-equilibrated CTG solution (Promega, item number G7572) at room temperature was added to each well, mixed with a microplate shaker for 2 minutes, and then placed at room temperature for 10 minutes before detecting the luminescence signal on a SpectraMax Paradigm plate reader. Inhibition Rate (Inh%) = 100-(RLU Drug -RLU Min ) / (RLU Max -RLU Min )*100; wherein RLU Drug is the reading of the drug treatment group, RLU Max is the average of the solvent control group, and RLU Min is the average of the blank control group. The IC 50 value was calculated using four-parameter fitting method by using Graphpad Prism software.

[1020] Table 8-1 Results of the proliferation inhibition activity of the test compounds on Ba / F3-FL-EGFR-Del19 cells Note: In the table, A < 10nM, 10nM ≤ B < 50nM, 50nM ≤ C < 200nM.

[1021] Conclusion: The compounds of the present application, such as the example compounds, have good proliferation inhibition activity on Ba / F3-FL-EGFR-Del19 cells.

[1022] 9. Proliferation inhibition activity of NCI-H1975 (L858R-T790M) cells

[1023] NCI-H1975 (L858R-T790M) was constructed by Hefei ZK-Puris Biomedicine Co., Ltd. Cells were placed in RPMI1640 medium (containing 10% fetal bovine serum) and cultured at 37°C, 5% CO2. Cells in the logarithmic growth phase were collected, and the viable cell count was performed using a cell counter (Countstar). After adjusting the cell suspension to the appropriate density with medium, 90 μL / well was inoculated in a 96-well cell culture plate (3000 / well), and incubated at 37°C, 5% CO2 for 24 hours. After 24 hours, the test compound was prepared into a stock solution with DMSO, and diluted with DMSO in five gradients with 2.5 mM (250X) as the highest concentration, to obtain 9 concentration gradients; the test compound was diluted 25 times with medium, then 10 μL of medium containing different concentrations of compound was added to each well, and the final concentration of DMSO in each well was 0.4%. Incubate at 37°C, 5% CO2 for 3 days. Then, 50 μL of pre-equilibrated CTG solution (Promega, Cat. No. G7572) at room temperature was added to each well, mixed with a microplate shaker for 2 minutes, and the luminescence signal was detected on a SpectraMax Paradigm plate reader after 10 minutes at room temperature. Inhibition Rate (Inh%) = 100- (RLU Drug -RLU Min ) / (RLU Max -RLU Min )*100; wherein RLU Drug is the reading of the drug treatment group, RLU Max is the average of the solvent control group, and RLU Min is the average of the blank control group. The IC 50 value was calculated using four-parameter fitting method by Graphpad Prism software.

[1024] 10. HCC827 cell protein degradation test:

[1025] HCC827 cells were provided by Hefei Zhongke Puruisheng Biopharmaceutical Technology Co., Ltd. The cells were placed in RPMI1640 medium (containing 10% fetal bovine serum) and cultured at 37°C and 5% CO2. Cells in the logarithmic growth phase were collected and viable cells were counted using a cell counter (Countstar). The cell suspension was adjusted to an appropriate density with culture medium and then seeded into a 6-well cell culture plate at 1998 μL / well (5E5 cells / well) and cultured overnight at 37°C and 5% CO2. After the cells adhered overnight, the test compound was prepared into a stock solution with DMSO. With 1 mM (1000X) as the highest concentration, 10-fold gradient dilution was performed with DMSO to obtain 6 concentration gradients. Then, 2 μL of a solution containing different concentrations of the compound was added to each well, and the final DMSO concentration in each well was 0.1%. Incubation was continued for 18 hours at 37°C and 5% CO2. After drug incubation, cells from each well were collected into a 1.5 mL centrifuge tube. RIPA lysis buffer was added to each well and cells were lysed on ice for 30 minutes, with the centrifuge tubes vortexed every 10 minutes. After lysis, the BCA protein concentration assay kit was used to determine the concentration of each sample and quantify the protein concentration. 5X protein loading buffer was added, heated at 95 degrees for 10 minutes, and then cooled on ice. The obtained protein samples were subjected to Western blotting analysis. After transfer, the PVDF membrane was blocked and washed, and then incubated with EGFR antibody (1:1000 dilution, CST, 4267S) at 4 degrees overnight. The next day, the membrane was washed three times with TBST, and the PVDF membrane was incubated with secondary antibody at room temperature for 1 hour. The membrane was then washed three times with TBST and exposed to a chemiluminescence imager (Tanon, 5200) and the image was saved. The grayscale value of the EGFR and ACTIN bands in the Western blot results was analyzed using Image J software.

[1026] Degradation Rate (%) = 100 - (Gray Value Drug / Gray Value DMSO) * 100%. Gray Value Drug represents the band signal value in the drug-treated group, and Gray Value DMSO represents the band signal value in the solvent control group. DC50 values ​​were calculated using Graphpad Prism software using a four-parameter fitting method.

[1027] Table 10-1 Results of EGFR protein degradation in HCC827 cells by test compounds Note: In the table, A<1nM, 1nM≤B<10nM, 10nM≤C<100nM.

[1028] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good degradation activity on the EGFR protein in HCC827 cells.

[1029] 11. Ba / F3-FL-EGFR-Del19-C797S cell protein degradation test:

[1030] The Ba / F3-FL-EGFR-Del19-C797S cells were provided by Hefei Zhongke Puresyn Biomedicine Technology Co., Ltd. The cells were placed in RPMI1640 medium (containing 10% fetal bovine serum) and cultured at 37°C, 5% CO2. Cells in the logarithmic growth phase were collected, and the viable cell count was performed using a cell counter (Countstar). After adjusting the cell suspension to the appropriate density with the culture medium, 1998 μL / well was inoculated in a 6-well cell culture plate (2E6 cells / well), and the test compound was prepared into a stock solution with DMSO, with 1 mM (1000X) as the highest concentration, 10-fold gradient dilution with DMSO, to obtain 5 concentration gradients, then 2 μL of compound solution with different concentrations was added to each well, and the final DMSO concentration in each well was 0.1%. Incubate Ba / F3-FL-EGFR-Del19-C797S cells at 37°C, 5% CO2 for 12 hours. After drug incubation, collect cells in each well into a 1.5 mL centrifuge tube, add RIPA lysis buffer to each well, lyse the cells on ice for 30 minutes, and shake the centrifuge tube once every 10 minutes. After lysis, use the BCA protein concentration determination kit to determine the concentration of each sample, then adjust the protein concentration to the same amount, add 5X protein loading buffer, heat at 95°C for 10 min, then cool on ice, and analyze the obtained protein samples by WB. After transferring the membrane, block and wash the PVDF membrane, then incubate the EGFR antibody (1:1000 dilution, CST, 4267S) overnight at 4°C, the next day wash the membrane with TBST 3 times, then incubate the PVDF membrane with the secondary antibody at room temperature for 1 h, then wash the membrane with TBST 3 times, and expose the membrane to a chemiluminescence imager (Tanon, 5200) for imaging, and save the picture. Use Image J software to analyze the gray value of the EGFR and ACTIN bands in the Western Blot result graph.

[1031] Degradation Rate (%) = 100 - (gray valueDrug / gray valueDMSO)*100%. Wherein gray valueDrugis the band signal value of the drug treatment group, and gray valueDMSOis the band signal value of the solvent control group. Use Graphpad Prism software to calculate the DC50 value using four-parameter fitting method.

[1032] Table 11-1 EGFR protein degradation results of test compounds on Ba / F3-FL-EGFR-Del19-C797S cells Note: In the table, A < 5 nM, 5 nM ≤ B < 50 nM, 50 nM ≤ C < 200 nM.

[1033] Conclusion: The compounds of the present application, such as the example compounds, have good degradation activity on the EGFR protein of Ba / F3-FL-EGFR-Del19-C797S cells.

[1034] 12. Ba / F3-FL-EGFR-WT+EGF cell protein degradation test:

[1035] Ba / F3-FL-EGFR-WT+EGF cells were provided by Hefei Zhongke Puerui Biomedicine Technology Co., Ltd. The cells were cultured in RPMI1640 medium (containing 10% fetal bovine serum) at 37°C, 5% CO2. Cells in the logarithmic growth phase were collected, and the viable cell count was performed using a cell counter (Countstar). After adjusting the cell suspension to the appropriate density with the culture medium, 1998 μL / well was inoculated in a 6-well cell culture plate (2E6 cells / well), and the test compound was prepared into a stock solution with DMSO, with 1 mM (1000X) as the highest concentration, 10-fold gradient dilution with DMSO, to obtain 5 concentration gradients, then 2 μL of solution containing different concentrations of compound was added to each well, and the final concentration of DMSO in each well was 0.1%. Under the condition of 37°C, 5% CO2, Ba / F3-FL-EGFR-WT+EGF cells were incubated for 18 hours. After drug incubation, the cells in each well were collected into a 1.5 mL centrifuge tube, RIPA lysis buffer was added to each well, and the cells were lysed on ice for 30 minutes, with vortexing once every 10 minutes. After lysis, the BCA protein concentration determination kit was used to determine the concentration of each sample, and the protein concentration was uniformly quantified, 5X protein loading buffer was added, heated at 95°C for 10 min, then cooled on ice, and the obtained protein sample was subjected to WB analysis. After transferring the membrane, the PVDF membrane was blocked and washed, then incubated with EGFR antibody (1:1000 dilution, CST, 4267S) at 4°C overnight, the next day the membrane was washed with TBST for 3 times, then the PVDF membrane was incubated with secondary antibody at room temperature for 1 h, then washed with TBST for 3 times, and the membrane was exposed to a chemiluminescence imager (Tanon, 5200) for imaging, and the picture was saved. The gray value of the EGFR and ACTIN bands in the Western Blot result image was analyzed using Image J software.

[1036] Degradation Rate (%) = 100-(gray valueDrug / gray valueDMSO)*100%. Wherein gray valueDrugis the band signal value of the drug treatment group, and gray valueDMSOis the band signal value of the solvent control group. The DC50value was calculated using four-parameter fitting method by Graphpad Prism software.

[1037] Table 12-1 Test compound EGFR protein degradation results on Ba / F3-FL-EGFR-WT+EGF cells

[1038] Conclusion: The compound of the present application, for example, the compound of the example, has poor EGFR protein degradation activity on Ba / F3-FL-EGFR-WT+EGF cells, and has good degradation selectivity.

[1039] Test Example 13: Mouse pharmacokinetic test

[1040] Purpose of the experiment: This experiment measures the concentration of the test substance in the plasma and brain of mice by single-dose intravenous and gavage administration of the test substance to ICR mice, and evaluates the pharmacokinetic characteristics and bioavailability of the test substance in mice.

[1041] Test animals: Male ICR mice, 25-40 g. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[1042] Test method: On the test day, ICR mice were randomly divided by weight. Fasting overnight before administration, without water, and food was restored 4 hours after administration. * Dose in free form; Note: Intravenous administration vehicle: 5% DMA + 5% Solutol + 90% Saline or 10% DMA + 10% Solutol + 80% Saline; Gavage administration vehicle: 5% DMSO + 5% Solutol + 10% PEG 400 + 80% (20% SBE-β-CD)

[1043] Sampling: Groups G1, G2, G3, G4, and G6 were taken at the specified time points by orbital blood collection into EDTA K2 centrifuge tubes. Centrifuged at 5000 rpm for 10 min, and the plasma was collected.

[1044] G5, G7 group at the designated time point animals after isoflurane anesthesia by pillow hole needle 2-3 mm directly extracted cerebrospinal fluid, placed in the corresponding centrifuge tube, put into the sample box with label -80℃ refrigerator storage for testing; After the cerebrospinal fluid is extracted, the abdominal aorta is fully bled, the occipital bone and the first cervical vertebra are disconnected, the scalp is cut along the sagittal line, the skull and the meninges are separated along the sagittal suture, the brain tissue is exposed, the brain nerves are gently disconnected, and the brain is taken out; The removed brain tissue is placed in physiological saline and washed, and the surface hair and residual blood are wiped off with a cotton ball, then the surface water is absorbed with paper, the prepared brain tissue is accurately weighed and transferred to a homogenate tube, the weight is recorded, and 50% methanol water is added according to the homogenate ratio 1:4; The sample added with the homogenate is homogenized by using a homogenizer, and the mode 7500 rpm, 10-15 s, 4 DEG C is selected until the sample is homogenized to be visually uniform and without tissue blocks. The sample is placed in a sample box and labeled, and stored in a refrigerator below -40 DEG C.

[1045] G1, G2, G3 group blood plasma collection time points: 0, 5min, 15min, 30min, 1, 2, 4, 7, 24h;

[1046] G4, G6 group blood plasma collection time points: 0, 5min, 15min, 30min, 1, 2, 4, 7, 24h;

[1047] G5, G7 group collection time points: 0.5h; 4h; 24h;

[1048] Before analysis and detection, all samples are stored below -60 DEG C. The samples are quantitatively analyzed by using LC-MS / MS.

[1049] Table 13-1 mouse PK data of test compounds *Note: i.g. (intragastric administration) of the compound.

[1050] Conclusion: The compound of the present application, for example, the compound of the examples, has good oral absorption performance in mice and has brain entry effect.

[1051] Test Example 14: Rat pharmacokinetic test

[1052] Test animals: male SD rats, 160-200g. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[1053] Test design: On the test day, the SD rats were randomly divided into groups according to weight. Fasting overnight, not water-restricted, food was restored 4h after administration. Note: Intravenous administration vehicle: 5% DMA + 5% Solutol + 90% Saline or 10% DMA + 10% Solutol + 80% Saline; Intragastric administration vehicle: 5% DMSO + 5% Solutol + 10% PEG 400 + 80% (20% SBE-β-CD)

[1054] Sampling: G1, G2, G3, G4, G6 group at the designated time point through the orbit, placed in EDTAK2 centrifuge tube. 5000 rpm centrifugation for 10 min, collection of plasma.

[1055] G5, G7 group at the designated time point, the animals were anesthetized by isoflurane, and then the cerebrospinal fluid was directly extracted by 2-3 mm needle from foramen magnum, placed in the corresponding centrifuge tube, and stored in the sample box with label in the-80℃ refrigerator for detection; After the cerebrospinal fluid was extracted, the abdominal aorta was fully bled, the occipital bone was separated from the first cervical vertebra, the scalp was cut along the sagittal line, the skull and meninges were separated along the sagittal suture, the brain tissue was exposed, the brain nerves were gently separated, and the brain was taken out; The removed brain tissue was placed in physiological saline for washing, and the surface hair and residual blood were wiped off with cotton balls, then the surface water was absorbed with paper, the prepared brain tissue was accurately weighed, and then transferred to a homogenate tube, the weight was recorded, and the homogenate solution 50% methanol water was added according to the homogenate ratio 1:4; The sample added with the homogenate solution was homogenized by using a homogenizer, and the mode 7500 rpm, 10-15 s, 4℃ was selected, until the sample was homogenized to be visually uniform, and there was no tissue block. The sample was placed in a sample box and labeled, and stored in a refrigerator below-40℃.

[1056] G1, G2, G3 group blood plasma collection time points: 0, 5min, 15min, 30min, 1, 2, 4, 6, 8, 24h;

[1057] G4, G6 group blood plasma collection time points: 0, 5min, 15min, 30min, 1, 2, 4, 6, 8, 24h;

[1058] G5, G7 group collection time points: 0.5h; 4h; 24h;

[1059] Before analysis and detection, all samples were stored below-60℃. The samples were quantitatively analyzed by using LC-MS / MS.

[1060] *Note: i.g. (intragastric) administration of compounds.

[1061] Conclusion: The compound of the present application, for example, the compound of the example, has good oral absorption performance in rats.

[1062] 15. hERG potassium ion channel effect test

[1063] Experimental platform: manual patch-clamp system

[1064] Cell line: Chinese hamster ovary (CHO) cell line stably expressing hERG potassium ion channel

[1065] Experimental method: hERG potassium channel currents were recorded in CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channel at room temperature using whole-cell patch-clamp technique. Glass microelectrodes were pulled from glass electrode capillary (BF150-86-10, Sutter) using a micropipette puller, and the tip resistance was about 2-5 MΩ after filling the electrode with internal solution. The glass microelectrode was inserted into the amplifier probe to connect to the patch-clamp amplifier. The clamping voltage and data recording were controlled and recorded by computer through pClamp 10 software, with a sampling frequency of 10 kHz and a filter frequency of 2 kHz. After obtaining the whole-cell recording, the cell was clamped at -80 mV, and the step voltage to induce hERG potassium current (I hERG ) was given from -80 mV to a 2s depolarization voltage to +20 mV, and then repolarized to -50 mV for 1s, and then returned to -80 mV. This voltage stimulation was given every 10s, and after the hERG potassium current was determined to be stable (at least 1 minute), the drug administration process was started. Each test concentration of the compound was given for at least 1 minute, and at least 2 cells were tested for each concentration (n≥2).

[1066] Data processing: pClamp 10, GraphPad Prism 5 and Excel software were used for data analysis and processing. The inhibition degree of different compound concentrations on hERG potassium current (peak value of hERG tail current induced at -50 mV) was calculated using the following formula: Inhibition% = [1–(I / Io)]×100%

[1067] where Inhibition% represents the inhibition percentage of the compound on hERG potassium current, and I and Io represent the amplitude of hERG potassium current after and before drug administration, respectively.

[1068] Compound IC 50 The following equation was used to calculate the IC using GraphPad Prism 5 software: Y = Bottom + (Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope))

[1069] where X is the Log value of the test concentration of the test product, Y is the inhibition percentage at the corresponding concentration, and Bottom

[1070] and Top are the minimum and maximum inhibition percentages, respectively.

[1071] Conclusion: The compound of the present application, such as the compound of the example, has no significant inhibition effect on hERG potassium ion channel.

[1072] 16. Beagle pharmacokinetic test

[1073] Test animals: male beagles, 8-10 kg.

[1074] Test method: On the test day, the beagles were randomly divided according to body weight. Fasting but not water restriction for 14-18 h before administration, and feeding 4 h after administration. Note: Intravenous administration vehicle: 5% DMA + 5% Solutol + 90% Saline; gavage administration vehicle: 5% Solutol + 5% TPGS + 30% PEG400 + 60% (20% SBE-b-CD).

[1075] 1 ml of blood was taken from the jugular vein or limb vein before and after administration, and placed in an EDTAK2 centrifuge tube. 5000 rpm, 4℃ centrifugation for 10 min, and collection of plasma. The blood sampling time points of the intravenous group and the gavage group of G1, G2 and G3 groups were: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 10, 12, 24, 48 h. Before analysis, all samples were stored below -60℃, and the samples were quantitatively analyzed by LC-MS / MS.

[1076] Conclusion: The compound of the present application, such as the compound of the example, has good pharmacokinetic performance in beagles.

[1077] 17. Monkey pharmacokinetic test

[1078] Test animals: male cynomolgus monkeys, 3-5 kg, 3-6 years old, 4-6 monkeys per compound.

[1079] Test method: On the test day, 4-6 monkeys per compound were randomly divided according to body weight. Fasting but not water restriction for 14-18 h before administration, and feeding 4 h after administration. Note: Intravenous administration vehicle: 5% DMA + 5% Solutol + 90% Saline; gavage administration vehicle: 5% Solutol + 5% TPGS + 30% PEG400 + 60% (20% SBE-b-CD). (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: normal saline.)

[1080] Blood collection: 1.0 mL of blood was collected from the vena cubitalis before and after administration and placed in EDTA K2 tubes. Centrifugation was performed at 5000 rpm for 10 min at 4°C, and the plasma was collected. The blood collection time points for the intravenous group and the gavage group were: 0, 5 min, 15 min, 30 min, 1, 2, 4, 6, 8, 10, 12, 24 h. Before analysis, all samples were stored at -80°C, and the samples were quantitatively analyzed by LC-MS / MS.

[1081] Conclusion: The compound of the present application, for example, the compound of the examples has good oral absorption performance in monkeys.

[1082] 18. Caco2 permeability test

[1083] The test uses single-layer Caco-2 cells, and three parallel incubations are performed in 96-well Transwell plates. Transport buffer solution (HBSS, 10 mM HEPES, pH 7.4±0.05) containing the compound of the present application (5 μM) is added to the dosing end hole on the top side or the bottom side. The receiving end hole is added with DMSO-containing transport buffer solution. After incubation at 37±1°C for 2 hours, the cell plate is taken out and an appropriate amount of sample is taken from the top and bottom to a new 96-well plate. Then, add acetonitrile containing an internal standard to precipitate the protein. The samples are analyzed by LC MS / MS, and the concentrations of the compound of the present application and the control compound are determined. The concentration data are used to calculate the apparent permeability coefficient of the transport from the top side to the bottom side of the single-layer cells, and the efflux rate is calculated. The integrity of the single-layer cells after 2 hours of incubation is evaluated by the leakage of fluorescein.

[1084] Conclusion: The compound of the present application, for example, the compound of the examples has good Caco2 permeability.

[1085] 19. CYP3A4 induction activity test (PXR activation)

[1086] Objective: The purpose of this study is to evaluate the potential of the test compound to induce the activity of drug metabolizing enzymes by activating PXR in vitro.

[1087] 1. Cell inoculation

[1088] 1) DPX2 cells were cultured in growth medium containing 10% fetal bovine serum.

[1089] 2) DPX2 cells were cultured in T-75 flasks in an incubator at 37°C, 5% CO2, 95% relative humidity, and the cells were digested when they grew to 80-90% of the bottom of the flask.

[1090] 3) Wash the T-75 cultured cell monolayer with 10 mL PBS, aspirate PBS and add 3-5 mL trypsin, incubate at 37°C for 5 minutes or until the cells are detached and in suspension, terminate trypsinization by adding excess media containing fetal bovine serum.

[1091] 4) Transfer the cell suspension to a conical bottom centrifuge tube and centrifuge at 150 g for 5 minutes at room temperature, carefully aspirate the supernatant and resuspend the cells in assay media and adjust the concentration to 3.2 x 105cells / mL (incubation time 24 hours, seeding density 4.0 x 105cells / mL). Add 25 μL of the cell suspension to each well of a 384 well cell culture plate. Place the cell plate in an incubator at 95% humidity, 37°C and 5% CO2for 24 hours.

[1092] 2. Compound Preparation

[1093] 1) Prepare 1000x stock solutions of test compounds, positive control (rifampicin) and negative control (propranolol) in DMSO. The final concentration of the positive control (rifampicin) is 1 μM and 10 μM, the final concentration of the negative control (propranolol) is 10 μM. The final concentration of the test compounds is 10, 1, 0.1 uM or EC50(30, 10, 3, 1, 0.3, 0.1 uM). The final concentration of DMSO is 0.1%.

[1094] 2) Remove the cell plate from the incubator and add 25 nL of the positive, negative control or test compound stock solution directly to the cells using the Echo, with three replicates for each concentration. Place the cell plate back in the incubator for an additional 48 hours (24 hours) of incubation.

[1095] 3) Check the cell morphology and monolayer integrity prior to starting the assay with substrate to ensure that the monolayer is of acceptable quality for the study.

[1096] 3. Quantitative PXR activation assay

[1097] 1) After 48 hours (24 hours) of drug treatment, the cultures can be assayed for PXR activation.

[1098] 2) Add CellTiter-Fluor TM CellTiter-Fluor Cell Viability Kit and One-Glo Luciferase Reagent to room temperature. Prepare the GF-AFC substrate (10 μL) in 2X Assay Buffer (10 ml) and then dilute to IX Reagent with 10 ml PBS. Prepare the ONE-Glo Luciferase substrate in ONE-Glo Luciferase Assay Buffer.

[1099] 3) Take the plates out of the incubator, discard the medium and add 1X CellTiter-Fluor TM Reagent is poured into the sample well, 25 μL reagent is added to each well in the plate using the pipetting station, and the plate is placed in the incubator for 30 minutes.

[1100] 4) Take the cell culture plates out of the incubator, cool slightly to room temperature, and measure the fluorescence value using a full-automatic quantitative enzyme marker, with excitation light of 400 nm and emission light of 505 nm.

[1101] 5) Pour the ONE-Glo reagent into the sample well, add 25 μL to each well, mix the plate gently, incubate at room temperature for 5 minutes, and measure the luminescence value.

[1102] 4, Data analysis

[1103] All data are calculated using Microsoft Excel.

[1104] 1) The luciferase activity is represented by RFU / RLU, RLU is the average luminescence intensity value of three parallels of each compound at each concentration, and RFU is the average fluorescence intensity value of three parallels of each compound at each concentration.

[1105] The fold activation of mRNA is calculated using the following formula: Fold activation = (RLU test / RFU test) / (RLU vehicle / RFU vehicle)

[1106] 2) The percentage of cell viability of the compound is calculated according to the following formula: Cell Viability % = (RFU test / RFU vehicle) x 100

[1107] 3) The percentage relative to the positive control is calculated according to the following formula: Percent of positive control (%) = (Fold activation test / Fold activation Positive control) x 100

[1108] Conclusion: The compound of the present application, such as the example compound, has no obvious induction effect on CYP3A4.

[1109] 20. CYP3A4 induction activity test (enzyme activity and mRNA)

[1110] The purpose of this research project is to evaluate the influence of the test substance on the enzyme activity and gene expression level of cytochrome P450 isozyme CYP1A2, CYP2B6 and CYP3A4 through in vitro liver cell induction experiments.

[1111] Three donor-derived cryopreserved human hepatocytes were incubated with different concentrations (≥ 5 concentration points) of test article at 37°C for 48 hours, with fresh medium prepared every 24 hours. The lactate dehydrogenase release in the medium after 24 and 48 hours of incubation was measured to evaluate the possible cytotoxic effect of the test article. The concentration of the test article in the medium after 0, 5 and 24 hours of incubation after the second dose was determined to evaluate the concentration of the test article in the medium in human hepatocytes. After 48 hours of incubation of the cryopreserved human hepatocytes from three donors with the test article, the cell culture medium was removed and the cells were washed with Hank's Balanced Salt Solution (HBSS) pre-warmed to 37°C, and then the enzyme-specific substrate was added for incubation at 37°C for 30 minutes. The amount of metabolite of each substrate was quantitatively analyzed by liquid chromatography-tandem mass spectrometry. The expression level of genes in the cells was evaluated by fluorescence real-time quantitative PCR.

[1112] Conclusion: The compound of the present application, such as the compound of the example, has no obvious induction effect on CYP3A4.

[1113] 21. P-gp transporter inhibition test

[1114] In this project, MDR1-MDCK II monolayer cell model was used to evaluate the inhibition effect of the test article on the activity of P-glycoprotein transporter.

[1115] In the experiment, MDR1-MDCK II cells were seeded into a 96-well cell plate and cultured continuously for 7 days for transport experiment. Digoxin, a known P-gp substrate, was given bidirectionally with and without the test article, and incubated with different concentrations (0-30 μM) of the test article. After 150 minutes of incubation, the receiving end sample was collected, and the content of digoxin in the sample was detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS). By calculating the efflux ratio (ER) of digoxin with and without the test article, the percentage of P-gp transport activity of MDR1-MDCK II cells under the action of different concentrations of the test article was obtained (% VC (Vehicle Control, solvent control), the percentage of P-gp transport activity with and without the test article), and the half-inhibitory concentration (IC 50 ) was calculated.

[1116] Conclusion: The compound of the present application, such as the compound of the example, has no obvious inhibition effect on P-gp transporter.

[1117] 22. BCRP transporter inhibition

[1118] The purpose of this study is to evaluate the inhibition effect of the test article on the activity of breast cancer resistance protein transporter by using Caco-2 monolayer cell model.

[1119] Caco-2 cells were seeded in 96-well cell plates and cultured for 22 days before the transport experiment. 5.00 μΜ estrone 3-sulfate, a substrate of BCRP, was co-administered in both directions in the presence or absence of the test substance. The test substance was incubated at different concentrations (0-30 μΜ). After 120 min of incubation, the samples at the receiving end were collected, and the content of estrone 3-sulfate in the samples was detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS). The efflux ratio (ER) of estrone 3-sulfate in the presence and absence of the test substance was calculated to obtain the percentage of BCRP transport activity under the action of the test substance at different concentrations (% VC (Vehicle Control, solvent control), the percentage of BCRP transport activity in the presence and absence of the test substance), and the half-inhibitory concentration (IC 50 ) was calculated.

[1120] Conclusion: The compound of the present application, for example, the compound of the examples, has no obvious inhibitory effect on the BCRP transporter.

[1121] 23. SLC transporter inhibition

[1122] The purpose of this study is to evaluate the inhibitory effect of the test substance on the activity of transporters OATP1B1, OATP1B3, OAT1, OAT3, OCT, MATE1 and MATE2-K.

[1123] HEK293-OATP1B1, OATP1B3, OAT1, OAT3, OCT, MATE1 and MATE2-K cells were incubated in the presence and absence of the test substance (0-30 μΜ) for a corresponding time, and then the samples were collected. The content of the substrate in the samples was detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS). The transport activity of the transporter in the presence and absence of the test substance was calculated to obtain the percentage of transporter activity under the action of the test substance at different concentrations (% VC (Vehicle Control, solvent control), the percentage of transporter activity in the presence and absence of the test substance), and the half-inhibitory concentration (IC 50 ) was calculated.

[1124] Conclusion: The compound of the present application, for example, the compound of the examples, has no obvious inhibitory effect on the SLC transporter.

Claims

1. A compound or its stereoisomer, racemate, tautomer, or pharmaceutically acceptable salt, wherein: The compound is selected from the compounds represented by general formula (I), BLK (I); L is selected from a bond or -C 1-50 Hydrocarbyl-, wherein 1 to 20 methylene units are optionally replaced by -Ak- or -Cy-; Each -Ak- is independently selected from -(CH2) q -、-(CH2) q -O-, -O-(CH2) q -、-(CH2) q -S-, -S-(CH2) q -、-(CH2) q -NR L -、-NR L -(CH2) q -、-(CH2) q -NR L C(=O)-、-NR L (CH2) q C(=O)-、-(CH2) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH2) q -NR L -、-(C≡C) q -、-CH=CH-、-Si(R L )2-、-Si(OH)(R L )-、-Si(OH)2-、-P(=O)(OR L )-、-P(=O)(R L )-, -S-, -S(=O)-, -S(=O)2- or a bond, wherein the CH, -CH2- is optionally replaced by 1 to 2 R z replace; q is each independently selected from 0, 1, 2, 3, 4, 5 or 6; R L Selected from H, deuterium, C 1-4 Alkyl, C 3-7 Carbocyclic group, 4 to 10 membered heterocyclic group, said alkyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R z replace; Each -Cy- is independently selected from a bond or optionally substituted by 1 to 4 R L2 One of the following substituted groups: 4-8 membered heteromonocyclic group, 4-12 membered heterocyclic group, 5-13 membered heterospirocyclic group, 7-12 membered heterobridged ring group, C 3-7 Monocyclic alkyl, C 4-7 Monocyclic alkenyl, C 4-12 Cycloalkyl, C 5-13 Spiroalkyl, C 5-12 Bridged cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl; B is selected from X is selected from O, NH or S; B1 is selected from 5-12 membered heterocyclic groups; b1 is selected from 0, 1, 2, 3 or 4; b2 is selected from 0, 1, 2 or 3; L B Selected from -(CR Lb1 R Lb2 ) m -, the L B 1 to 5 - CR Lb1 R Lb2 -optionally replaced by -Akb- or -Cyb-; m is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; Each -Akb- is independently selected from -O-, -S-, -NR Lb3 -, -C(=O)-, -C≡C-, -CR Lb4 =CR Lb5 -, -S(=O)- or -S(=O)2-; Each -Cyb- is independently selected from optionally substituted by 1 to 4 R L2 One of the following substituted groups: 4-8 membered heteromonocyclic group, 4-12 membered heterocyclic group, 5-13 membered heterospirocyclic group, 7-12 membered heterobridged ring group, C 3-7 Monocyclic alkyl, C 4-7 Monocyclic alkenyl, C 4-12 Cycloalkyl, C 5-13 Spiroalkyl, C 5-12 Bridged cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl; R Lb1 、R Lb2 Each independently selected from H, deuterium, F, Cl, Br, I, OH, ═O, NH 2 , CN, COOH, CONH 2 , C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Carbocyclic group or 3 to 6 membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, alkoxy, carbocyclic group, heterocyclic group is optionally substituted by 1 to 4 R z replace; R Lb3 Each independently selected from H, deuterium, F, Cl, Br, I, OH, ═O, NH 2 , CN, COOH, CONH 2 , C 1-6 Alkyl, C 3-6 Carbocyclic group or 3 to 6 membered heterocyclic group, wherein the alkyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R z replace; R Lb4 or R Lb5 Each independently selected from H, deuterium, F, C 1-6 Alkyl, C 3-6 Carbocyclic group or 3 to 6 membered heterocyclic group, wherein the alkyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R z replace; R b1 、R b2 or R b4 Each independently selected from H, deuterium, F, Cl, Br, I, OH, ═O, NH 2 , CN, COOH, CONH 2 , C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylene-3 to 6 membered heterocyclic group, C 1-6 Alkylene-C 3-6 Carbocyclic group, C 1-6 Alkylene-OC 3-6 Carbocyclic group, C 3-6 Carbocyclic group or 3 to 6 membered heterocyclic group, wherein the alkyl, alkylene, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 groups selected from R z replace; R b3 or R b5 Each independently selected from H, deuterium, F, Cl, Br, I, OH, ═O, NH 2 , CN, COOH, CONH 2 , C 1-6 Alkyl, C 3-6 Carbocyclic group, C 1-6 Alkylene-3 to 6 membered heterocyclic group, C 1-6 Alkylene-C 3-6 Carbocyclic group, C 1-6 Alkylene-OC 3-6 Carbocyclic group or 3 to 6 membered heterocyclic group, wherein the alkyl, alkylene, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 groups selected from R z replace; K is selected from G is selected from N, CH or CD; Q is independently selected from a bond, -O-, -S-, -CH2-, -NR q -、-CO-、-NR q CO-、-CONR q -; Q and G cannot directly form nitrogen-nitrogen bonds, nitrogen-oxygen bonds, or nitrogen-S bonds; R q Selected from H, deuterium or C 1-4 alkyl; F are each independently selected from phenyl, pyridyl, C 13-20 tricyclic carbocyclyl or 13-20 membered tricyclic heterocyclyl; R k1 Each independently selected from H, deuterium, F, Cl, Br, I, OH, ═O, NH 2 , CN, COOH, CONH 2 , C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 3 to 6 membered heterocycloalkyl, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl are optionally substituted by 1 to 4 R z replace; R k2 Each independently selected from a bond, -C(=O)-, -S(=O)2-, -S(=O)- or -C(R k3 )2-; R k3 Each independently selected from H, deuterium, F, Cl, Br, I, OH, ═O, NH 2 , CN, COOH, CONH 2 , C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl or 3 to 8 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl or heterocyclic group is optionally substituted by 1 to 4 groups selected from R z replace; Alternatively, two R k3 Direct connection to form C 3-8 Carbocyclic or 4-8 membered heterocyclic, said carbocyclic or heterocyclic group is optionally substituted by 1 to 4 groups selected from R z replace; R L2 、R z Each independently selected from deuterium, F, Cl, Br, I, OH, =O, CF3, SF5, CN, NH2, NO2, COOH, CONH2, NHC 1-4 Alkyl, N(C 1-4 alkyl)2, COOH, CONH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -SC 1-4 Alkyl, -C 0-4 Alkylene-C 3-6 Cycloalkyl, C 1-4 Alkylene-OC 1-4 Alkyl, wherein the alkyl, alkylene, alkoxy, alkenyl, alkynyl, cycloalkyl is optionally substituted by 1 to 4 deuterium, F, Cl, Br, I, OH, CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent; n1 is 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 that when Selected from When F is not selected from phenyl or pyridyl.

2. The compound according to claim 1 or its stereoisomer, racemate, tautomer, or pharmaceutically acceptable salt, wherein: L is selected from -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-; Ak1, Ak2, Ak3, Ak4, Ak5 are each independently selected from -(CH2) q -、-(CH2) q -O-, -O-(CH2) q -、-(CH2) q -S-, -S-(CH2) q -、-(CH2) q -NR L -、-NR L -(CH2) q -、-(CH2) q -NR L C(=O)-、-(CH2) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH2) q -NR L -、-(C≡C) q - or bond, wherein the -CH2- is optionally replaced by 1 to 2 R z replace; R L Each independently selected from H, deuterium, or C 1-4 alkyl; Cy1, Cy2, Cy3 or Cy4 are each independently selected from a bond or optionally substituted by 1 to 4 R L2 One of the following groups substituted: 4-7 membered nitrogen-containing heteromonocyclic group, 4-12 membered nitrogen-containing heterocyclic group, 5-13 membered nitrogen-containing heterospirocyclic group, 7-12 membered nitrogen-containing heterobridged ring group, C 3-7 Monocyclic alkyl, C 4-7 Monocyclic alkenyl, C 4-12 Cycloalkyl, C 5-13 Spiroalkyl, C 5-12 Bridged cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl; B1 is selected from 5-6 membered heteroaryl, 9-10 membered heteroaryl; m is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8; Each -Cyb- is independently selected from optionally substituted by 1 to 4 R L2 One of the following groups substituted: 4-7 membered nitrogen-containing heteromonocyclic group, 4-12 membered nitrogen-containing heterocyclic group, 5-13 membered nitrogen-containing heterospirocyclic group, 7-12 membered nitrogen-containing heterobridged ring group, C 3-7 Monocyclic alkyl, C 4-7 Monocyclic alkenyl, C 4-12 Cycloalkyl, C 5-13 Spiroalkyl, C 5-12 Bridged cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl; R Lb1 、R Lb2 Each independently selected from H, deuterium, F, Cl, Br, I, OH, ═O, NH 2 , CN, COOH, CONH 2 , C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Carbocyclic group or 3 to 6 membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, alkoxy, carbocyclic group, heterocyclic group is optionally substituted by 1 to 4 R z replace; R Lb3 Each independently selected from H, deuterium, F, Cl, Br, I, OH, ═O, NH 2 , CN, COOH, CONH 2 , C 1-4 Alkyl, C 3-6 Carbocyclic group or 3 to 6 membered heterocyclic group, wherein the alkyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R z replace; R Lb4 or R Lb5 Each independently selected from H, deuterium, F, C 1-4 Alkyl, C 3-6 Carbocyclic group or 3 to 6 membered heterocyclic group, wherein the alkyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R z replace; R b1 、R b2 or R b4 Each independently selected from H, deuterium, F, Cl, Br, I, OH, ═O, NH 2 , CN, COOH, CONH 2 , C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkylene-3 to 6 membered heterocyclic group, C 1-4 Alkylene-C 3-6 Carbocyclic group, C 3-6 Carbocyclic group, C 1-4 Alkylene-OC 3-6 Carbocyclic group or 3 to 6 membered heterocyclic group, wherein the alkyl, alkylene, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 groups selected from R z replace; R b3 or R b5 Each independently selected from H, deuterium, F, Cl, Br, I, OH, ═O, NH 2 , CN, COOH, CONH 2 , C 1-4 Alkyl, C 3-6 Carbocyclic group, C 1-4 Alkylene-3 to 6 membered heterocyclic group, C 1-4 Alkylene-C 3-6 Carbocyclic group, C 1-4 Alkylene-OC 3-6 Carbocyclic group or 3 to 6 membered heterocyclic group, wherein the alkyl, alkylene, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 groups selected from R z replace; F is independently selected from phenyl, pyridyl, and 13-15 membered tricyclic heterocyclic group.

3. The compound according to claim 2 or its stereoisomer, racemate, tautomer, or pharmaceutically acceptable salt, wherein: R L is selected from H, deuterium, methyl or ethyl; Cy1, Cy2, Cy3, and Cy4 are each independently selected from a bond or optionally substituted by 1 to 4 R L2 One of the following substituted groups: phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, s1, s3, and s5 are each independently selected from 0, 1, or 2; s2 and s4 are each independently selected from 0 or 1; s6 is selected from 0, 1, 2 or 3; s7 is selected from 1, 2 or 3; B1 is selected from 6-membered heteroaryl, 9-membered heteroaryl, and 10-membered heteroaryl; L B Selected from -(CR Lb1 R Lb2 ) m -, the L B 1 to 3 - CR Lb1 R Lb2 -optionally replaced by -Akb- or -Cyb-; m is selected from 0, 1, 2, 3, 4, 5 or 6; Each -Cyb- is independently selected from optionally substituted by 1 to 4 R L2 One of the following substituted groups: 4-7 membered nitrogen-containing heteromonocyclic group or C 3-7 Monocyclic alkyl; R Lb1 、R Lb2 Each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, wherein the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl is optionally replaced by 1 to 4 R z replace; R Lb3 Each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, wherein the methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl is optionally substituted by 1 to 4 R z replace; R Lb4 or R Lb5 Each independently selected from H, deuterium, F, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, wherein the methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl is optionally substituted by 1 to 4 R z replace; R b1 、R b2 or R b4 each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylene-O-cyclopropyl, ethylene-O-cyclopropyl, methylene-cyclopropyl, methylene-cyclobutyl, methylene-azetidinyl, methylene-pyrrolidinyl, methylene- Piperidinyl, methylene-piperazinyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolanyl, oxhexyl, the methyl, ethyl, propyl, methylene, ethylene, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, oxolanyl, oxhexyl, piperazinyl optionally substituted by 1 to 4 R z replace; R b3 or R b5 Each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylene-O-cyclopropyl, ethylene-O-cyclopropyl, methylene-cyclopropyl, methylene-cyclobutyl, methylene-azetidinyl, methylene-pyrrolidinyl, methylene-piperidinyl, methylene-piperazinyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolanyl, oxhexyl, said methyl, ethyl, propyl, methylene, ethylene, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, oxolanyl, oxhexyl, piperazinyl is optionally substituted by 1 to 4 R z replace; Selected from F is selected from phenyl or pyridyl; The ring where the representative is located is an aromatic ring or a non-aromatic ring; H1 is selected from N, NH, CH, CH2, CHR k1 NR k1 , CR k1 、C(=O)、C(R k1 )2; H2 is selected from a bond, O, N, NH, CH, CH2, CHR k1 NR k1 , CR k1 or C(R k1 )2; H3 is selected from N or CH; H4 is selected from C, N or CH; H5, H6, and H7 are each independently selected from N, CH, or CR k1 , and H5, H6, and H7 contain at most 2 Ns; Each Q is independently selected from a bond, CH2, NH, N(CH3), O, S, C(=O), NHC(=O), C(=O)NH, N(CH3)C(=O), C(=O)N(CH3); R k1 、R k3 Each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH2, CF3, CN, COOH, CONH2 or optionally substituted by 1 to 4 R z Substituted groups such as: methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl; R L2 、R z Each independently selected from deuterium, F, Cl, Br, I, OH, =O, CF3, SF5, CN, NH2, NO2, COOH, CONH2, N(CH3)2, NHCH3, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, methylene-O-methyl, methylene-O-ethyl, ethylene-O-methyl, ethylene-O-ethyl, said methyl, methylene, ethylene, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally substituted by 1 to 4 selected from deuterium, F, Cl, Br, I, OH, CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent; p2 is independently selected from 0, 1, 2 or 3.

4. The compound according to claim 3 or its stereoisomer, racemate, tautomer, or pharmaceutically acceptable salt, wherein: Ak1, Ak2, Ak3, Ak4, Ak5 are each independently selected from a bond, -O-, -S-, -OCH2-, -CH2O-, -OCH2CH2-, -CH2CH2O-, -C≡C-, -C(CH3)2-, -CH2-, -CH2CH2-, -CH2CH2CH2-, -N(CH3)-, -NH-, -CH2N(CH3)-, -CH2NH-, -NHCH2-, -CH2CH2N(CH3)-, -CH2CH2NH-, -NHCH2CH2-, -C(=O)-, -C(=O)CH2NH-, -CH2C(=O)NH-, -C(=O)NH- or -NHC(=O)-; Cy1, Cy2, Cy3, and Cy4 are each independently selected from a bond or one of the following optionally substituted groups: When substituted, it is replaced by 1 to 4 groups selected from deuterium, F, CF3, OH, =O, COOH, CN, NH2, hydroxymethyl, methyl, methoxy, cyclopropyl, substituted by a substituent; B1 is selected from pyridyl, benzothiazolyl, benzothiophenyl, benzimidazolyl, pyrimidinyl, pyridonyl, pyridazinyl, pyrazinyl, L B Selected from -(CR Lb1 R Lb2 ) m -, the L B 1 to 2 CR Lb1 R Lb2 -optionally replaced by -Akb- or -Cyb-; Each -Akb- is independently selected from -O-, -S-, -NR Lb3 - or -C(=O)-; Each -Cyb- is independently selected from optionally substituted by 1 to 4 R L2 Substituted one of the following groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; R Lb1 、R Lb2 Each is independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, methyl, ethyl, methoxy, ethoxy or cyclopropyl, wherein the methyl, ethyl, methoxy, ethoxy or cyclopropyl is optionally substituted by 1 to 4 R z replace; R Lb3 Each is independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, methyl, ethyl or cyclopropyl, wherein the methyl, ethyl or cyclopropyl group is optionally substituted by 1 to 4 R z replace; R b1 、R b2 or R b4 each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, methyl, ethyl, propyl, isopropyl, methylene-cyclopropyl, methylene-cyclobutyl, methylene-azetidinyl, methylene-pyrrolidinyl, methylene-piperidinyl, methylene-piperazinyl, azetidinyl, pyrrolidinyl, piperidinyl, methylene-O-cyclopropyl, ethylene-O-cyclopropyl, methoxy, ethoxy or cyclopropyl, wherein the methyl, ethyl, propyl, methylene, ethylene, isopropyl, methoxy, ethoxy, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or cyclopropyl is optionally substituted by 1 to 4 R z replace; R b3 or R b5 each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, methyl, ethylpropyl, isopropyl, methylene-cyclopropyl, methylene-cyclobutyl, methylene-azetidinyl, methylene-pyrrolidinyl, methylene-piperidinyl, methylene-piperazinyl, azetidinyl, pyrrolidinyl, piperidinyl, methylene-O-cyclopropyl, ethylene-O-cyclopropyl or cyclopropyl, wherein the methyl, ethyl, propyl, methylene, ethylene, isopropyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or cyclopropyl is optionally substituted by 1 to 4 R z replace.

5. The compound according to claim 4 or its stereoisomer, racemate, tautomer, or pharmaceutically acceptable salt, wherein: B1 is selected from pyridyl, benzothiazolyl, or pyridone; L B Selected from R b1 、R b2 or R b4 Each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, CD3, CHF2, CH2F, CF3, OCD3, OCF3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, R b3 or R b5 Each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, CD3, CHF2, CH2F, CF3, methyl, ethyl, propyl, isopropyl, cyclopropyl, L is selected from -Cy1-, -Cy1-Cy2-, -Cy1-Cy2-Cy3-, -Cy1-Ak2-Cy2-Cy3-, -Cy1-Cy2-Ak3-Cy3-, -Cy1-Ak2-, -Cy1-Ak2-Cy2-, -Ak1-Cy1-Ak2-; Cy1, Cy2, and Cy3 are each independently selected from a bond or one of the following optionally substituted groups: When substituted, it is replaced by 1 to 4 groups selected from deuterium, F, CF3, OH, =O, COOH, CN, NH2, hydroxymethyl, methyl, methoxy, cyclopropyl, substituted by a substituent; K is selected from Q is selected from a bond, NHC(=O), C(=O)NH, N(CH3)C(=O), C(=O)N(CH3); H1 is selected from N, NH, CH, CH2, CHR k1 NR k1 , CR k1 , C(=O); H2 is selected from a bond, O, N, NH, CH, CH2, CHR k1 NR k1 , CR k1 , C(=O); H5 or H6 is selected from N or CR k1 ; p1 is selected from 0, 1, 2 or 3; R k1 Each is independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH2, CF3, CN, COOH, CONH2, CD3, CF3, OCD3, OCF3, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, and cyclopropyl.

6. The compound according to claim 1 or its stereoisomer, racemate, tautomer, or pharmaceutically acceptable salt, wherein: B is selected from one of the structural fragments shown in Table B-1; L is selected from one of the structural fragments shown in Table L-2; K is selected from one of the structural fragments shown in Table K-1.

7. The compound according to claim 1 or its stereoisomer, racemate, tautomer, or pharmaceutically acceptable salt, wherein the compound is selected from one of the structures shown in Table E.

8. A pharmaceutical composition comprising the compound according to any one of claims 1 to 7 or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier. Preferably, the pharmaceutical composition contains 1 to 1500 mg of the compound according to any one of claims 1 to 7 or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts.

9. Use of the compound according to any one of claims 1 to 7 or its stereoisomers, racemates, tautomers, pharmaceutically acceptable salts, or the pharmaceutical composition according to claim 8 in the preparation of a medicament for treating diseases associated with EGFR activity or expression.

10. Use of the compound according to any one of claims 1 to 7 or its stereoisomers, racemates, tautomers, pharmaceutically acceptable salts, or the pharmaceutical composition according to claim 8 in the preparation of a medicament for treating diseases associated with the inhibition or degradation of EGFR.

11. The use according to claim 10, characterized in that The disease is selected from cancer, preferably esophageal cancer, glioblastoma, anal cancer, head and neck cancer, breast cancer, lung cancer or pancreatic cancer.

12. A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of a compound according to any one of claims 1 to 7, or a stereoisomer, racemate, tautomer, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 8, wherein the therapeutically effective amount is preferably 1 to 1500 mg, and the disease is preferably selected from cancer (such as esophageal cancer, glioblastoma, anal cancer, head and neck cancer, breast cancer, lung cancer, or pancreatic cancer).

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