Hydrazino-containing compound

Abstract

The invention belongs to the field of medicinal chemistry, provides a hydrazino-containing compound, and particularly relates to a compound shown as a formula I-A, pharmaceutically acceptable salt of the compound, a pharmaceutical composition of the compound or a preparation method of the compound, and application of the compound in preparation of medicines for treating tumors. # imgabs0 #

Description

[0001] This application is a divisional application of the following application: application date January 18, 2023; application number 202380015687.3; invention title: "Compound Containing Hydrazino Group".

[0002] Cross-reference to related applications

[0003] This application claims the priority and benefits of Chinese Patent Application No. 202210092492.6 filed with the State Intellectual Property Office of China on January 26, 2022, Chinese Patent Application No. 202211104139.1 filed with the State Intellectual Property Office of China on September 9, 2022, and Chinese Patent Application No. 202310035797.8 filed with the State Intellectual Property Office of China on January 10, 2023. The entire contents disclosed in all applications are incorporated herein by reference in their entirety. Technical field

[0004] This application belongs to the field of medicinal chemistry, and provides a compound containing a hydrazino group, its pharmaceutically acceptable salt, its pharmaceutical composition, or its preparation method, and relates to its use in the preparation of drugs for treating tumors. Background of the invention

[0006] The ataxia-telangiectasia mutated gene (ATM) is closely related to the body's DNA damage response mechanism (DDR). Patients with ATM gene mutations generally show particular sensitivity to X-rays and a significant decline in DNA repair ability. The ATM gene encodes the ATM protein, which is a serine / threonine protein kinase and belongs to the phosphatidylinositol 3-kinases (PI3K)-related kinase (PIKK) protein family, and has a catalytic domain homologous to PI3K. The ATM kinase is mainly located in the nucleus and microsomes, and it functions at the S / G2 / M cell cycle transition and at the replication fork to initiate cell cycle checkpoints, chromatin modification, HR repair, and pro-survival signal cascades. The ATM kinase is involved in a variety of key cellular functions, such as cell growth, cell proliferation, migration, differentiation, survival, and cell adhesion. In particular, the ATM kinase responds to DNA damage by activating cell cycle arrest and DNA repair programs. That is, when DNA double-strand breaks occur, the ATM kinase is activated within minutes at the earliest, autophosphorylates at Ser1981 and dissociates, and binds to the DNA break point under the regulation of the MRN complex to help the broken DNA complete repair and maintain cell integrity.

[0007] In common anti-cancer treatments, a large number of single-strand or double-strand breaks occur in DNA. After the ATM kinase is activated, the self-repair function of cancer cells is enhanced and they escape from the processes of apoptosis, necrosis or autophagy, resulting in a poor anti-cancer treatment effect. ATM inhibitors can enhance the activity and sensitivity of anti-cancer therapeutic agents. Therefore, based on the role of ATM inhibitors in the treatment of malignant tumors, there is a great clinical need and market value in searching for novel and effective ATM inhibitors. Summary of the Invention

[0008] This application relates to a compound of formula I-A, a pharmaceutically acceptable salt thereof or a stereoisomer thereof,

[0009]

[0010] wherein,

[0011] R 1 is selected from hydrogen, C 1-10 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heteroalkyl, C 3-10 aryl or 3- to 10-membered heteroaryl, and the C 1-10 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heteroalkyl, C 3-10 aryl or 3- to 10-membered heteroaryl is optionally substituted by one or more halogens, hydroxyl groups, amino groups, cyano groups, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylNH-, (C 1-6 alkyl)2N-, C 3-10 cycloalkyl, 3- to 10-membered heteroalkyl, C 3-10 aryl or 3- to 10-membered heteroaryl;

[0012] R 2a and R 2b are each independently selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heteroalkyl, C 3-10 aryl or 3- to 10-membered heteroaryl, or R 2a and R 2b are connected to each other to form a 3- to 12-membered heteroalkyl, and the C 1-6 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heteroalkyl, C 3-10 aryl, 3- to 10-membered heteroaryl or 3- to 12-membered heteroalkyl is optionally substituted by one or more deuterium, halogens, hydroxyl groups, amino groups, cyano groups, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylNH-, (C1-6 (alkyl)2N-, C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 3-10 aryl, 3- to 10-membered heteroaryl, -COC 1-6 alkyl, -COOC 1-6 alkyl, -OCOC 1-6 alkyl, -CONHC 1-6 alkyl, -CON(C 1-6 alkyl)2, -SO2NHC 1-6 alkyl or -SO2N(C 1-6 alkyl)2 substituted;

[0013] R 3 and R 4 are each independently selected from halogen, hydroxy, amino, cyano, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylNH- or (C 1-6 alkyl)2N-, said C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylNH- or (C 1-6 alkyl)2N- is optionally substituted by one or more halogen, hydroxy, amino, cyano, nitro or -COOH;

[0014] p and m are independently selected from 0, 1, 2, 3 or 4;

[0015] Ring A is selected from phenyl or 3- to 10-membered heteroaryl;

[0016] X is selected from a single bond, -NR a -, -O- or -S-;

[0017] Y 1 , Y 2 , Y 3 or Z are each independently selected from N or CH, and Y 1 , Y 2 , Y 3 or Z at least one of which is selected from CH;

[0018] R a is selected from hydrogen or C 1-6 alkyl;

[0019] L is selected from C 1-6 alkylene, C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, -C 1-6 alkylene-C 3-10 cycloalkyl-, -C 1-6 alkylene-3- to 10-membered heterocycloalkyl, -C 3-10Cycloalkyl-C 1-6 Alkylene- or 3- to 10-membered heterocycloalkyl-C 1-6 Alkylene-;

[0020] R 5 and R 6 are each independently selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl or 3- to 10-membered heterocycloalkyl, or R 5 and R 6 are joined to form a 3- to 12-membered heterocycloalkyl, and the C 1-6 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl or 3- to 12-membered heterocycloalkyl is optionally substituted with one or more of the following groups: deuterium, halogen, hydroxy, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylNH-, (C 1-6 alkyl)2N- or C 1-6 alkyl substituted with one or more halogen, hydroxy, amino or cyano.

[0021] This application relates to a compound of formula I, a pharmaceutically acceptable salt thereof or a stereoisomer thereof,

[0022]

[0023] wherein,

[0024] R 1 is selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 3-10 aryl or 3- to 10-membered heteroaryl, and the C 1-6 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 3-10 aryl or 3- to 10-membered heteroaryl is optionally substituted with one or more halogen, hydroxy, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylNH- or (C 1-6 alkyl)2N-;

[0025] R 2a and R 2b are each independently selected from hydrogen or C 1-6 alkyl, or R 2a and R 2b are joined to form a 3- to 10-membered heterocycloalkyl, and the C 1-6 alkyl or 3- to 10-membered heterocycloalkyl is optionally substituted with one or more deuterium, halogen, hydroxy, amino, cyano, C1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylNH- or (C 1-6 alkyl)2N- substituted;

[0026] R 3 and R 4 are each independently selected from halogen, hydroxy, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylNH- or (C 1-6 alkyl)2N-;

[0027] p and m are each independently selected from 0, 1 or 2;

[0028] X 1 、X 2 、X 3 or X 4 are each independently selected from N or CH, and one or more of X 1 、X 2 、X 3 or X 4 are selected from N;

[0029] X is selected from a single bond, -NR a -, -O- or -S-;

[0030] R a is selected from hydrogen or C 1-6 alkyl;

[0031] L is selected from C 1-6 alkylene, C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, -C 1-6 alkylene-C 3-10 cycloalkyl-, -C 1-6 alkylene-3- to 10-membered heterocycloalkyl, -C 3-10 cycloalkyl-C 1-6 alkylene- or -3- to 10-membered heterocycloalkyl-C 1-6 alkylene-;

[0032] R 5 and R 6 are each independently selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl or 3- to 10-membered heterocycloalkyl, or R 5 and R 6 are joined together to form a 3- to 10-membered heterocycloalkyl, and the C 1-6 alkyl, C 3-10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted with one or more deuterium, halogen, hydroxy, amino, cyano, C1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylNH- or (C 1-6 alkyl)2N-substituted.

[0033] In some embodiments, R 1 is selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heteroalkyl, C 3-10 aryl or 3- to 10-membered heteroaryl, wherein the C 1-6 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heteroalkyl, C 3-10 aryl or 3- to 10-membered heteroaryl is optionally substituted with one or more halogen, hydroxy, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylNH- or (C 1-6 alkyl)2N-substituted.

[0034] In some embodiments, R 1 is selected from hydrogen, C 1-4 alkyl, C 3-8 cycloalkyl, 3- to 8-membered heteroalkyl, C 3-8 aryl or 3- to 8-membered heteroaryl, wherein the C 1-4 alkyl, C 3-8 cycloalkyl, 3- to 8-membered heteroalkyl, C 3-8 aryl or 3- to 8-membered heteroaryl is optionally substituted with one or more halogen, hydroxy, amino, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylNH- or (C 1-4 alkyl)2N-substituted.

[0035] In some embodiments, R 1 is selected from hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heteroalkyl, C 3-6 aryl or 3- to 6-membered heteroaryl, wherein the C 1-4 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heteroalkyl, C 3-6 aryl or 3- to 6-membered heteroaryl is optionally substituted with one or more halogen, hydroxy, amino, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylNH- or (C 1-4 alkyl)2N-substituted.

[0036] In some embodiments, R1 Selected from C 1-3 alkyl, C 3-6 cycloalkyl, 5- or 6-membered heterocycloalkyl, C 5-6 aryl or 5- or 6-membered heteroaryl, wherein the C 3-6 cycloalkyl, 5- or 6-membered heteroaryl, C 5-6 aryl or 5- or 6-membered heteroaryl is optionally substituted with one or more halogen, hydroxy, amino, cyano, C 1-3 alkyl or C 1-3 alkoxy.

[0037] In some embodiments, R 1 is selected from C 1-3 alkyl, C 3-5 cycloalkyl, 6-membered heterocycloalkyl, phenyl or 6-membered heteroaryl, wherein the C 3-5 cycloalkyl, 6-membered heterocycloalkyl, phenyl or 6-membered heteroaryl is optionally substituted with one or more halogen or C 1-3 alkoxy.

[0038] In some embodiments, R 1 is selected from propyl, cyclopropyl, cyclobutyl, cyclopentyl, 6-membered oxygen-containing heterocycloalkyl or 6-membered nitrogen-containing heteroaryl, wherein the cyclobutyl, cyclopentyl, 6-membered oxygen-containing heterocycloalkyl or 6-membered nitrogen-containing heteroaryl is optionally substituted with one or more fluorine or methoxy.

[0039] In some embodiments, R 1 is selected from propyl, cyclopropyl, cyclobutyl, cyclopentyl, tetrahydropyranyl or pyridyl, wherein the cyclobutyl, cyclopentyl or pyridyl is optionally substituted with one or more fluorine or methoxy.

[0040] In some embodiments, R 1 is selected from isopropyl,

[0041] In some specific embodiments, R 1 is selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl or 3- to 10-membered heterocycloalkyl, wherein the C 1-6 alkyl, C 3-10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted with one or more halogen, hydroxy, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylNH- or (C 1-6 alkyl)2N-.

[0042] In some specific embodiments, R 1 is selected from C 1-4 alkyl, C 3-8Cycloalkyl or 3-8 membered heteroalkyl, said C 1-6 alkyl, C 3-8 cycloalkyl or 3-8 membered heteroalkyl is optionally substituted with one or more halogens, hydroxy, amino, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylNH- or (C 1-4 alkyl)2N-.

[0043] In some specific embodiments, R 1 is selected from C 1-4 alkyl, C 3-6 cycloalkyl or 3-6 membered heteroalkyl, said C 1-4 alkyl, C 3-6 cycloalkyl or 3-6 membered heteroalkyl is optionally substituted with one or more halogens, hydroxy, amino, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylNH- or (C 1-4 alkyl)2N-.

[0044] In some specific embodiments, R 1 is selected from C 1-3 alkyl, C 3-6 cycloalkyl or 5-6 membered heteroalkyl, said C 1-3 alkyl, C 3-6 cycloalkyl or 5-6 membered heteroalkyl is optionally substituted with one or more halogens, hydroxy, amino, cyano, C 1-3 alkyl or C 1-3 alkoxy.

[0045] In some specific embodiments, R 1 is selected from C 1-3 alkyl, C 3-5 cycloalkyl or 6 membered heteroalkyl, said C 1-3 alkyl, C 3-5 cycloalkyl or 6 membered heteroalkyl is optionally substituted with one or more halogens or C 1-3 alkoxy.

[0046] In some specific embodiments, R 1 is selected from propyl, cyclopropyl, cyclobutyl, cyclopentyl or 6 membered oxygen-containing heteroalkyl, said cyclopropyl, cyclobutyl, cyclopentyl or 6 membered oxygen-containing heteroalkyl is optionally substituted with one or more fluorine or methoxy.

[0047] In some specific embodiments, R 1 is selected from isopropyl,

[0048] In some embodiments, R2a and R 2b are each independently selected from hydrogen or C 1-6 alkyl, or R 2a and R 2b are joined to form a 3- to 10-membered heterocycloalkyl, and the C 1-6 alkyl or 3- to 10-membered heterocycloalkyl is optionally substituted with one or more deuterium, halogen, hydroxy, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylNH- or (C 1-6 alkyl)2N-.

[0049] In some embodiments, R 2a and R 2b are each independently selected from hydrogen or C 1-4 alkyl, or R 2a and R 2b are joined to form a 3- to 8-membered heterocycloalkyl, and the C 1-4 alkyl or 3- to 8-membered heterocycloalkyl is optionally substituted with one or more deuterium, halogen, hydroxy, amino, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylNH- or (C 1-4 alkyl)2N-.

[0050] In some embodiments, R 2a and R 2b are each independently selected from hydrogen or C 1-4 alkyl, or R 2a and R 2b are joined to form a 3- to 6-membered heterocycloalkyl, and the C 1-4 alkyl or 3- to 6-membered heterocycloalkyl is optionally substituted with one or more deuterium, halogen, hydroxy, amino, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylNH- or (C 1-4 alkyl)2N-.

[0051] In some embodiments, R 2a and R 2b are each independently selected from hydrogen or C 1-4 alkyl, or R 2a and R 2b are joined to form a 3- to 4-membered heterocycloalkyl, and the C 1-4 alkyl or 3- to 4-membered heterocycloalkyl is optionally substituted with one or more deuterium, halogen, hydroxy, amino, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4alkyl NH- or (C 1-4 alkyl)2N-substituted.

[0052] In some embodiments, R 2a and R 2b are each independently selected from hydrogen or C 1-4 alkyl, or R 2a and R 2b are joined to form a 3- to 4-membered heterocycloalkyl, and the C 1-4 alkyl or 3- to 4-membered heterocycloalkyl is optionally substituted with one or more deuterium, halogen, hydroxy, amino, cyano or C 1-3 alkyl.

[0053] In some embodiments, R 2a and R 2b are each independently selected from hydrogen or C 1-4 alkyl, and the C 1-4 alkyl is optionally substituted with one or more deuterium, halogen, hydroxy, amino or cyano.

[0054] In some embodiments, R 2a and R 2b are each independently selected from hydrogen or C 1-4 alkyl, and the C 1-4 alkyl is optionally substituted with one or more deuterium, fluorine, chlorine or bromine.

[0055] In some embodiments, R 2a and R 2b are each independently selected from hydrogen or C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted with one or more deuterium.

[0056] In some embodiments, R 2a and R 2b are each independently selected from hydrogen or CH3-, and the CH3- is optionally substituted with one or more deuterium.

[0057] In some embodiments, R 2a and R 2b are each independently selected from hydrogen, CH3- or CD3-.

[0058] In some embodiments, R 3 and R 4 are each independently selected from halogen, hydroxy, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl NH- or (C 1-6 alkyl)2N-.

[0059] In some embodiments, R3 and R 4 are each independently selected from halogen, hydroxy, amino, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylNH- or (C 1-3 alkyl)2N-.

[0060] In some embodiments, R 3 and R 4 are each independently selected from halogen or C 1-3 alkoxy.

[0061] In some embodiments, R 3 is selected from fluorine, chlorine, bromine or C 1-3 alkoxy.

[0062] In some embodiments, R 3 is selected from fluorine or methoxy.

[0063] In some embodiments, R 4 is selected from halogen, hydroxy, amino, cyano, methyl or methoxy. In some embodiments, R 4 is selected from halogen, hydroxy, amino or cyano.

[0064] In some embodiments, p and m are independently selected from 0, 1 or 2.

[0065] In some embodiments, p is selected from 0 or 1. In some embodiments, p is selected from 0.

[0066] In some embodiments, m is selected from 0 or 1. In some embodiments, m is selected from 1. In some embodiments, m is selected from 0.

[0067] In some embodiments, ring A is selected from phenyl, 5- or 6-membered heteroaryl or 9- or 10-membered heteroaryl.

[0068] In some embodiments, ring A is selected from 5- or 6-membered heteroaryl. In some embodiments, ring A is selected from 6-membered heteroaryl. In some embodiments, ring A is selected from 5- or 6-membered nitrogen-containing heteroaryl. In some embodiments, ring A is selected from 6-membered nitrogen-containing heteroaryl.

[0069] In some embodiments, ring A is selected from 5- or 6-membered heteroaryl or 9- or 10-membered heteroaryl.

[0070] In some embodiments, ring A is selected from pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, triazolyl, pyrazinyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, triazinyl, benzimidazolyl or imidazopyridinyl. In some embodiments, ring A is selected from pyridyl or pyrimidinyl. In some embodiments, ring A is selected from pyridyl.

[0071] In some embodiments, X 1 , X 2 , X 3 or X 4 is independently selected from N or CH, and one or more of X 1 , X 2 , X 3 or X 4 is selected from N.

[0072] In some embodiments, X 1 , X 2 , X 3 or X 4 is independently selected from N or CH, and one or two of X 1 , X 2 , X 3 or X 4 is selected from N.

[0073] In some embodiments, X 4 is selected from N, and X 1 , X 2 or X 3 is independently selected from N or CH.

[0074] In some embodiments, X 4 is selected from N, and X 3 is selected from N or CH, X 1 , X 2 is selected from CH.

[0075] In some embodiments, X 4 is selected from N, and X 1 , X 2 or X 3 is selected from CH.

[0076] In some embodiments, X 3 , X 4 is selected from N, and X 1 , X 2 is selected from CH.

[0077] In some embodiments, X is selected from -NR a - or -O-. In some embodiments, X is selected from -NH- or -O-. In some embodiments, X is selected from -O-.

[0078] In some embodiments, Y 1 , Y 2 , Y 3 or Z is independently selected from N or CH, and Y 1 , Y 2 , Y3 One, two, three, or four of Y, Z are selected from CH.

[0079] In some embodiments, Y 1 is selected from N, and Y 2 , Y 3 is selected from CH.

[0080] In some embodiments, Y 2 is selected from N, and Y 1 , Y 3 is selected from CH.

[0081] In some embodiments, Y 3 is selected from N, and Y 1 , Y 2 is selected from CH. In some embodiments, Y 1 , Y 2 or Y 3 is selected from CH.

[0082] In some embodiments, Y 1 , Y 2 , Y 3 or Z is selected from CH.

[0083] In some embodiments, Z is selected from N or CH.

[0084] In some embodiments, Z is selected from N. In some embodiments, Z is selected from CH.

[0085] In some embodiments, R a is selected from hydrogen or C 1-6 alkyl.

[0086] In some embodiments, R a is selected from hydrogen or C 1-4 alkyl.

[0087] In some embodiments, R a is selected from hydrogen or C 1-3 alkyl.

[0088] In some embodiments, R a is selected from hydrogen or methyl. In some embodiments, R a is selected from hydrogen.

[0089] In some embodiments, L is selected from C 1-6 alkylene, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, -C 1-6 alkylene-C 3-10 cycloalkyl-, -C 1-6 alkylene-3-10 membered heterocycloalkyl, -C 3-10Cycloalkyl-C 1-6 Alkylene- or 3- to 10-membered heterocycloalkyl-C 1-6 Alkylene-.

[0090] In some embodiments, L is selected from C 1-4 Alkylene, C 3-8 Cycloalkyl, 3- to 8-membered heterocycloalkyl, -C 1-4 Alkylene-C 3-8 Cycloalkyl-, -C 1-4 Alkylene-3- to 8-membered heterocycloalkyl-, -C 3-8 Cycloalkyl-C 1-4 Alkylene- or 3- to 8-membered heterocycloalkyl-C 1-4 Alkylene-.

[0091] In some embodiments, L is selected from C 1-4 Alkylene, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -C 1-4 Alkylene-C 3-6 Cycloalkyl-, -C 1-4 Alkylene-3- to 6-membered heterocycloalkyl-, -C 3-6 Cycloalkyl-C 1-4 Alkylene- or 3- to 6-membered heterocycloalkyl-C 1-4 Alkylene-.

[0092] In some embodiments, L is selected from C 1-4 Alkylene, C 3-6 Cycloalkyl, -C 1-4 Alkylene-C 3-6 Cycloalkyl- or -C 3-6 Cycloalkyl-C 1-4 Alkylene-.

[0093] In some embodiments, L is selected from C 2-4 Alkylene, C 4-6 Cycloalkyl, -C 1-2 Alkylene-C 4-6 Cycloalkyl- or -C 4-6 Cycloalkyl-C 1-2 Alkylene-.

[0094] In some embodiments, L is selected from C 2-3 Alkylene, C 4-6 Cycloalkyl, -CH2-C4 cycloalkyl- or -C4 cycloalkyl-CH2-.

[0095] In some embodiments, L is selected from -CH2CH2-, -CH2CH2CH2-,

[0096] In some embodiments, L is selected from C 1-4 alkylene.

[0097] In some embodiments, L is selected from C 2-3 alkylene.

[0098] In some embodiments, L is selected from -CH2CH2- or -CH2CH2CH2-. In some embodiments, L is selected from -CH2CH2CH2-.

[0099] In some embodiments, R 5 and R 6 are each independently selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, or 3- to 10-membered heterocycloalkyl, or R 5 and R 6 are joined to form a 3- to 10-membered heterocycloalkyl, and the C 1-6 alkyl, C 3-10 cycloalkyl, or 3- to 10-membered heterocycloalkyl is optionally substituted with one or more of the following groups: deuterium, halogen, hydroxy, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylNH-, (C 1-6 alkyl)2N-, C 1-6 alkyl substituted with one or more halogen, hydroxy, amino, or cyano groups.

[0100] In some embodiments, R 5 and R 6 are each independently selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, or 3- to 10-membered heterocycloalkyl, or R 5 and R 6 are joined to form a 3- to 10-membered heterocycloalkyl, and the C 1-6 alkyl, C 3-10 cycloalkyl, or 3- to 10-membered heterocycloalkyl is optionally substituted with one or more of the following groups: deuterium, halogen, hydroxy, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylNH-, (C 1-6 alkyl)2N-, C 1-6 alkyl substituted with one or more halogen groups.

[0101] In some embodiments, R 5 and R 6 are each independently selected from hydrogen, C 1-4 alkyl, C 3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl, or R 5and R 6 are connected to each other to form a 3- to 8-membered heterocycloalkyl group, and the C 1-4 alkyl group, C 3-8 cycloalkyl group or 3- to 8-membered heterocycloalkyl group is optionally substituted by one or more of the following groups: deuterium, halogen, hydroxyl, amino, cyano, C 1-4 alkyl group, C 1-4 alkoxy group, C 1-4 alkyl NH-, (C 1-4 alkyl)2N- or halo C 1-6 alkyl substitution.

[0102] In some embodiments, R 5 and R 6 are each independently selected from C 1-4 alkyl group or C 3-6 cycloalkyl group, or R 5 and R 6 are connected to each other to form a 3- to 7-membered heterocycloalkyl group, and the C 3-6 cycloalkyl group or 3- to 7-membered heterocycloalkyl group is optionally substituted by one or more of the following groups: deuterium, halogen, hydroxyl, amino, cyano, C 1-3 alkyl group, C 1-3 alkoxy group or halo C 1-4 alkyl group.

[0103] In some embodiments, R 5 and R 6 are each independently selected from C 1-4 alkyl group or C 3-6 cycloalkyl group, or R 5 and R 6 are connected to each other to form a 3- to 7-membered heterocycloalkyl group, and the 3- to 7-membered heterocycloalkyl group is optionally substituted by one or more of the following groups: deuterium, halogen, hydroxyl, amino, cyano, C 1-3 alkyl group, C 1-3 alkoxy group or halo C 1-4 alkyl group.

[0104] In some embodiments, R 5 and R 6 are each independently selected from C 1-3 alkyl group or C 3-4 cycloalkyl group, or R 5 and R 6 are connected to each other to form a 4-, 5-, 6- or 7-membered heterocycloalkyl group, and the heterocycloalkyl group is optionally substituted by one or more halogens or halo C 1-3 alkyl substitution.

[0105] In some embodiments, R 5 and R 6 are each independently selected from C 1-3 alkyl group or C3-4 Cycloalkyl. In some embodiments, R 5 and R 6 are connected to each other to form a 4-, 5-, 6- or 7-membered heterocycloalkyl group, and the heterocycloalkyl group is optionally substituted with one or more halogens or halo-C 1-3 alkyl groups.

[0106] In some embodiments, R 5 and R 6 are connected to each other to form a 4-, 5- or 6-membered heterocycloalkyl group, and the heterocycloalkyl group is optionally substituted with one or more halogens or halo-C 1-3 alkyl groups. In some embodiments, R 5 and R 6 are connected to each other to form a 4-membered heterocycloalkyl group, and the heterocycloalkyl group is optionally substituted with one or more halogens or halo-C 1-3 alkyl groups. In some embodiments, R 5 and R 6 are connected to each other to form a 5-membered heterocycloalkyl group, and the heterocycloalkyl group is optionally substituted with one or more halogens or halo-C 1-3 alkyl groups. In some embodiments, R 5 and R 6 are connected to each other to form a 6-membered heterocycloalkyl group, and the heterocycloalkyl group is optionally substituted with one or more halogens or halo-C 1-3 alkyl groups.

[0107] In some embodiments, R 5 and R 6 are each independently selected from methyl or cyclopropyl, or R 5 and R 6 are connected to each other to form azetidine, pyrrolidine, piperidine, azaspiroheptane or azabicycloheptane, and the azetidine or pyrrolidine is optionally substituted with one or more F or -CH2F.

[0108] In some embodiments, R 5 and R 6 are each independently selected from methyl or cyclopropyl, or R 5 and R 6 are connected to each other to form azetidine, pyrrolidine or piperidine, and the azetidine, pyrrolidine or piperidine is optionally substituted with one or more halogens or halo-C 1-3 alkyl groups.

[0109] In some embodiments, R 5 and R 6 are each independently selected from methyl or cyclopropyl, or R 5 and R 6are connected to form azetidinyl, pyrrolidinyl or piperidinyl, and the azetidinyl or pyrrolidinyl is optionally substituted by one or more F or -CH2F.

[0110] In some specific embodiments, R 5 and R 6 are each independently selected from C 1-6 alkyl, or R 5 and R 6 are connected to form a 4- to 6-membered heteroalkyl group, and the C 1-6 alkyl or 4- to 6-membered heteroalkyl group is optionally substituted by one or more of the following groups: halogen, hydroxy, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 alkyl substituted by one or more halogen, hydroxy, amino or cyano groups.

[0111] In some specific embodiments, R 5 and R 6 are each independently selected from C 1-6 alkyl, or R 5 and R 6 are connected to form a 4- to 6-membered heteroalkyl group, and the C 1-6 alkyl or 4- to 6-membered heteroalkyl group is optionally substituted by one or more of the following groups: halogen, hydroxy, amino, cyano, or C 1-6 alkyl optionally substituted by halogen.

[0112] In some specific embodiments, R 5 and R 6 are each independently selected from C 1-3 alkyl, or R 5 and R 6 are connected to form pyrrolidinyl or piperidinyl, and the C 1-3 alkyl, pyrrolidinyl or piperidinyl is optionally substituted by one or more of the following groups: halogen, hydroxy, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 alkyl substituted by one or more halogen, hydroxy, amino or cyano groups.

[0113] In some specific embodiments, R 5 and R 6 are each independently selected from C 1-3 alkyl, or R 5 and R 6 are connected to form pyrrolidinyl or piperidinyl, and the pyrrolidinyl or piperidinyl is optionally substituted by one or more of the following groups: halogen, hydroxy, amino, cyano, or C 1-6 alkyl optionally substituted by halogen.

[0114] In some specific embodiments, R 5 and R 6 are each independently selected from methyl, or R 5 and R 6 are connected to each other to form a 5- or 6-membered heteroalkyl group, and the 5- or 6-membered heteroalkyl group is optionally substituted with one or more -CH2F.

[0115] In some specific embodiments, R 5 and R 6 are each independently selected from methyl, or R 5 and R 6 are connected to each other to form a pyrrolidinyl or piperidinyl group, and the pyrrolidinyl or piperidinyl group is optionally substituted with one or more -CH2F which is optionally substituted with one or more -CH2F.

[0116] In some other embodiments, R 5 and R 6 are each independently selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl or 3- to 10-membered heteroalkyl, or R 5 and R 6 are connected to each other to form a 3- to 10-membered heteroalkyl, and the C 1-6 alkyl, C 3-10 cycloalkyl or 3- to 10-membered heteroalkyl is optionally substituted with one or more deuterium, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylNH- or (C 1-6 alkyl)2N-.

[0117] In some other embodiments, R 5 and R 6 are each independently selected from hydrogen, C 1-4 alkyl, C 3-8 cycloalkyl or 3- to 8-membered heteroalkyl, or R 5 and R 6 are connected to each other to form a 3- to 8-membered heteroalkyl, and the C 1-4 alkyl, C 3-8 cycloalkyl or 3- to 8-membered heteroalkyl is optionally substituted with one or more deuterium, halogen, hydroxyl, amino, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylNH- or (C 1-4 alkyl)2N-.

[0118] In some other embodiments, R 5 and R 6independently selected from C 1-4 alkyl or C 3-6 cycloalkyl, or R 5 and R 6 are connected to each other to form a 3- to 6-membered heterocycloalkyl group, and the C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl group is optionally substituted with one or more deuterium, halogen, hydroxyl, amino, cyano, C 1-3 alkyl or C 1-3 alkoxy groups.

[0119] In some other embodiments, R 5 and R 6 are independently selected from C 1-3 alkyl or C 3-4 cycloalkyl, or are connected to each other to form a 5- to 6-membered heterocycloalkyl group.

[0120] In some other embodiments, R 5 and R 6 are independently selected from methyl or cyclopropyl, or are connected to each other to form pyrrolidinyl or piperidinyl.

[0121] In some embodiments, when m is selected from 1, the connecting position of R 3 is as shown in the figure.

[0122] In some embodiments, the R 4 is connected to X 1 or X 2 is connected.

[0123] In some embodiments, the structural fragment is selected from In some embodiments, the structural fragment is selected from

[0124] In some specific embodiments, the structural fragment is selected from In some specific embodiments, the structural fragment is selected from

[0125] In some embodiments, the structural fragment is selected from

[0126] In some specific embodiments, the structural fragment is selected from

[0127] In some other embodiments, the structural fragment is selected from

[0128] In some embodiments, the structural fragment is selected from In some embodiments, the structural fragment is selected from In some embodiments, the structural fragment is selected from

[0129] In some embodiments, the structural fragment is selected from In some embodiments, the structural fragment is selected from In some embodiments, the structural fragment is selected from In some embodiments, the structural fragment is selected from In some embodiments, the structural fragment is selected from

[0130] In some embodiments, the structural fragment is selected from

[0131] In some other embodiments, the structural fragment is selected from

[0132] In some embodiments, the structural fragment is selected from

[0133] In some specific embodiments, the structural fragment is selected from

[0134] In some embodiments, the structural fragment is selected from

[0135] In some other embodiments, the structural fragment is selected from

[0136]

[0137] In some embodiments, the compound of formula I-A or a pharmaceutically acceptable salt thereof, the compound of formula I or a pharmaceutically acceptable salt thereof according to the present application is selected from the compound of formula II or a pharmaceutically acceptable salt thereof,

[0138]

[0139] wherein, R 1 , R 2a , R 2b , R 3 , R 4 , R 5 , R 6 , X, X 3 are as defined above.

[0140] In some embodiments, the compound of formula I-A or a pharmaceutically acceptable salt thereof, the compound of formula I or a pharmaceutically acceptable salt thereof, the compound of formula II or a pharmaceutically acceptable salt thereof according to the present application is selected from the compound of formula III or formula IV or a pharmaceutically acceptable salt thereof,

[0141]

[0142] wherein, R 1 , R 3 , R 5 , R 6 , m or Z are as defined above.

[0143] In some embodiments, the present application includes the variables and their embodiments defined above, and any combination thereof.

[0144] The heteroatoms in the above-mentioned heterocycloalkyl or heteroaryl are selected from nitrogen (NH or N), oxygen, sulfur (S), boron, Si, S(O) or S(O)2, and the remaining ring atoms are selected from carbon. The heteroatoms in the above-mentioned heterocycloalkyl or heteroaryl are selected from nitrogen (NH or N), oxygen or sulfur (S), and the remaining ring atoms are selected from carbon. In some embodiments, the number of the heteroatoms is selected from 1, 2, 3 or 4. In some embodiments, the number of the heteroatoms is selected from 1, 2 or 3. In some embodiments, the number of the heteroatoms is selected from 1 or 2.

[0145] The present application provides the following compounds, their pharmaceutically acceptable salts or their stereoisomers:

[0146]

[0147]

[0148]

[0149]

[0150] On the other hand, the present application also provides a pharmaceutical composition, which comprises the above-mentioned compound of the present application or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition of the present application further comprises a pharmaceutically acceptable excipient.

[0151] On the other hand, the present application also provides a method for treating various ATM-related diseases, which includes administering to a mammal in need of such treatment, preferably a human, a therapeutically effective amount of the above-mentioned compound of the present application, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0152] On the other hand, the present application also provides the use of the above-mentioned compound of the present application, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for treating various ATM-related diseases.

[0153] On the other hand, the present application also provides the use of the above-mentioned compound of the present application, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the treatment of various ATM-related diseases.

[0154] On the other hand, the present application also provides the above-mentioned compound of the present application, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for treating various ATM-related diseases.

[0155] In some embodiments, the various ATM-related diseases are selected from tumors.

[0156] In some embodiments, the disease or tumor is selected from lung cancer or colon cancer.

[0157] Technical effects

[0158] The compounds of the present application have ATM kinase inhibitory activity and have ATM kinase selectivity compared to ATR and DNA-PK kinases. At the same time, the compounds of the present application have good inhibitory activity against CHK2 phosphorylation in NCI-H2228 cells; and good in vitro and in vivo metabolism data, are stable in in vitro liver microsomes (species: human, monkey, dog, rat, and mouse), and have a low in vitro plasma protein binding rate; based on in vivo drug metabolism data including mice, rats, or dogs, the compounds of the present application have high exposure levels in the brain and plasma of mice and a high brain-blood ratio; based on in vivo efficacy studies, the compounds of the present application can inhibit tumor growth.

[0159] Definitions

[0160] Unless otherwise specified, the following terms used in the present application have the following meanings. A specific term should not be considered uncertain or unclear without a special definition, but should be understood according to the ordinary meaning in the art. When a trade name appears in this article, it is intended to refer to the corresponding product or its active ingredient.

[0161] When a covalent bond in certain structural units or groups in the present application is not connected to a specific atom, it means that the covalent bond can be connected to any atom in the structural unit or group, as long as the valence bond connection rules are not violated.

[0162] The term "substituted" means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, as long as the valence state of the specific atom is normal and the resulting compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced, and oxo does not occur on an aromatic group.

[0163] The term "optionally" or "optionally" means that the subsequently described event or situation may or may not occur, and this description includes the occurrence and non-occurrence of the described event or situation. For example, "optionally" substituted by a halogen for ethyl means that ethyl can be unsubstituted (CH2CH3), monosubstituted (such as CH2CH2F), polysubstituted (such as CHFCH2F, CH2CHF2, etc.) or fully substituted (CF2CF3). Those skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution pattern that is spatially impossible to exist and / or cannot be synthesized will be introduced.

[0164] "One or more" herein refers to an integer within one to ten. For example, "one or more" refers to one, two, three, four, five, six, seven, eight, nine or ten; or, "one or more" refers to one, two, three, four, five or six; or, "one or more" refers to one, two or three.

[0165] C in this article m-n , means that this part has an integer number of carbon atoms within a given range. For example, "C 1-6 " means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms. For example, C 1-3 means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms.

[0166] When any variable (such as R) appears more than once in the composition or structure of a compound, its definition in each case is independent. Therefore, for example, if a group is substituted by 2 Rs, each R has an independent option.

[0167] When the number of a linking group is 0, such as -(CH2)0-, it means that the linking group is a covalent bond.

[0168] When one of the variables is selected from a covalent bond, it means that the two groups it connects are directly connected. For example, when L' in A-L'-Z represents a covalent bond, it means that the structure is actually A-Z.

[0169] When a substituent is cross-linked to two atoms on a ring by a bond, this substituent can be bonded to any atom on this ring. For example, the structural unit indicates that substitution can occur at any position on cyclohexyl or cyclohexadiene. Specifically, for example when m is 1, the position of R 3 can be in the positions of the following groups:

[0170] The term "halogen" or "halogens" refers to fluorine, chlorine, bromine, and iodine.

[0171] The term "alkyl" refers to a hydrocarbon group having the general formula C n H 2n+1 . This alkyl group can be straight-chain or branched-chain. For example, the term "C 1-6 alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Similarly, the alkyl moieties of alkoxy, alkylamino, dialkylamino, alkylhydrazino, alkylsulfonyl, and alkylthio groups (i.e., alkyl) have the same definition as above. Also, for example, the term "C 1-3 alkyl" refers to an alkyl group containing 1 to 3 carbon atoms (such as methyl, ethyl, propyl, and isopropyl).

[0172] The term "alkylene" refers to a divalent group formed by removing one hydrogen from any position of an alkyl group. For example, for example, the term "C 1-6 alkylene" refers to an alkylene group containing 1 to 6 carbon atoms; the term "C 1-4 alkylene" refers to an alkylene group containing 1 to 4 carbon atoms, including but not limited to -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-.

[0173] The term "alkoxy" refers to -O-alkyl.

[0174] The term "cycloalkyl" refers to a carbocyclic group that is completely saturated and can exist as a monocyclic, bridged, or spiro ring. Depending on its position in the compound, it can be a monovalent group or a polyvalent group such as a divalent group. Unless otherwise indicated, this carbocyclic ring is usually a 3- to 15-membered ring, 3- to 12-membered ring, 3- to 10-membered ring, or 3- to 8-membered ring, or 4- to 6-membered ring or 5- to 8-membered ring. Non-limiting examples of cycloalkyl include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, bicyclo[1.1.1]pent-1-yl, etc. For example, C 3-4 cycloalkyl includes cyclopropyl and cyclobutyl.

[0175] The term "heterocycloalkyl" refers to a fully saturated cyclic group that can exist as a monocyclic, bridged (including fused) or spiro ring, and depending on its position in the compound, it can be a monovalent group or a polyvalent group such as a divalent group. Unless otherwise indicated, the heterocycle is usually a 3- to 15-membered ring, 3- to 12-membered ring, 3- to 10-membered ring, 3- to 9-membered ring, 3- to 7-membered ring, 4- to 6-membered ring or 5- to 6-membered ring containing 1 to 3 heteroatoms independently selected from sulfur, oxygen and / or nitrogen (preferably 1 or 2 heteroatoms). Examples of 3-membered heterocycloalkyl include, but are not limited to, oxiranyl, thiiranyl, aziridinyl; non-limiting examples of 4-membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl; examples of 5-membered heterocycloalkyl include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, tetrahydropyrazolyl; examples of 6-membered heterocycloalkyl include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, 1,4-dithianyl; examples of 7-membered heterocycloalkyl include, but are not limited to, azepanyl, oxepanyl, thiepanyl. Preferred is a monocyclic heterocycloalkyl having 5 or 6 ring atoms.

[0176] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π-electron system. For example, an aryl can have 6 - 20 carbon atoms, 6 - 14 carbon atoms or 6 - 12 carbon atoms. Non-limiting examples of aryl include, but are not limited to, phenyl, naphthyl, anthracenyl, 1,2,3,4-tetrahydronaphthalene, etc.

[0177] The term "heteroaryl" refers to a group having a monocyclic or fused polycyclic system containing at least one ring atom selected from N, O, S, for example 1, 2, 3 or 4 ring atoms selected from N, O, S, with the remaining ring atoms being C, and having at least one aromatic ring. Depending on its position in the compound, it can be a monovalent group or a polyvalent group such as a divalent group. Preferred heteroaryl has a single 5- to 8-membered ring or 5- to 6-membered ring, or multiple fused rings containing 6 to 14, especially 6 to 10 ring atoms. Non-limiting examples of heteroaryl include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, benzimidazolyl, imidazopyridyl, indolyl, isoindolyl, etc. For example, in the present application, it indicates that the ring system is heteroaryl.

[0178] For the groups or structural fragments in the present application, such as L and its specific options, the reading order is from left to right, and they are respectively connected to the groups on the left and right sides of the general formula corresponding to this group or fragment. For example, when L is selected from According to the reading order from left to right, the left side of L is connected to the corresponding left-side fragment in the general formula connected, and the right side is connected to the right-side group X, and the formed fragment is When L is selected from According to the reading order from left to right, the left side of L is connected to the corresponding left-side fragment in the general formula connected, and the right side of L is connected to the corresponding right-side group X in the general formula to form a fragment of Other groups are as described above.

[0179] The term "treatment" means administering the compounds, pharmaceutically acceptable salts thereof, pharmaceutical compositions or formulations described in the present application to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0180] (i) inhibiting a disease or disease state, i.e., curbing its development;

[0181] (ii) alleviating a disease or disease state, i.e., causing the disease or disease state to subside.

[0182] The term "prevention" means administering the compounds, pharmaceutically acceptable salts thereof, pharmaceutical compositions or formulations described in the present application to prevent a disease or one or more symptoms associated with the disease, and includes: preventing the occurrence of a disease or disease state in a mammal, especially when such a mammal is susceptible to the disease state but has not been diagnosed as having the disease state.

[0183] The term "therapeutically effective amount" means (i) treating or preventing a specific disease, condition or disorder, (ii) alleviating, improving or eliminating one or more symptoms of a specific disease, condition or disorder, or (iii) preventing or delaying the onset of one or more symptoms of a specific disease, condition or disorder described herein. The amount of the compound of the present application constituting a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and the present disclosure.

[0184] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are within the scope of sound medical judgment, suitable for use in contact with human and animal tissues, without excessive toxicity, irritation, allergic reaction or other problems or complications, and commensurate with a reasonable benefit / risk ratio.

[0185] As pharmaceutically acceptable salts, mention may be made, for example, of metal salts, ammonium salts, salts formed with organic bases, salts formed with inorganic acids, salts formed with organic acids, salts formed with basic or acidic amino acids, etc.

[0186] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or salts thereof and pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compounds of the present application to an organism.

[0187] The term "pharmaceutically acceptable excipients" refers to those excipients that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0188] The word "comprise" or "comprising" and its English variants such as "comprises" or "comprising" should be understood in an open, non-exclusive sense, i.e., "including but not limited to".

[0189] The compounds and intermediates of the present application may also exist in different tautomeric forms, and all such forms are included within the scope of the present application. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also called prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. Specific examples of proton tautomers are imidazole moieties, where the proton can migrate between two ring nitrogens. Valence tautomers include interconversions through the reorganization of some bonding electrons.

[0190] The present application also includes isotopically labeled compounds of the present application that are the same as those described herein, but in which one or more atoms are replaced by atoms having an atomic weight or mass number different from the atomic weight or mass number normally found in nature. Examples of isotopes that can be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F,123 I, 125 I and 36 Cl, etc.

[0191] Certain isotopically labeled compounds of the present application (e.g., those labeled with 3 H and 14 C) can be used in the analysis of the tissue distribution of compounds and / or substrates. Tritium labeling (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron-emitting isotopes, such as 15 O, 13 N, 11 C, and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the present application can generally be prepared by substituting non-isotopically labeled reagents with isotopically labeled reagents through the following procedures similar to those disclosed in the schemes and / or examples below.

[0192] In addition, substitution with heavier isotopes (such as deuterium (i.e., 2 H)) can provide certain therapeutic advantages resulting from higher metabolic stability (e.g., increased in vivo half-life or reduced dose requirements), and may therefore be preferred in certain cases, where deuterium substitution can be partial or complete. Partial deuterium substitution means that at least one hydrogen is replaced by at least one deuterium, and all such forms of the compound are included within the scope of the present application.

[0193] The compounds of the present application can be asymmetric, for example, having one or more stereoisomers. Unless otherwise specified, all stereoisomers are included, such as enantiomers and diastereomers. Compounds of the present application containing asymmetric carbon atoms can be isolated in optically pure form or in racemic form. The optically pure form can be resolved from the racemic mixture or synthesized by using chiral starting materials or chiral reagents.

[0194] The pharmaceutical compositions of the present application can be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, and can be formulated into solid, semi-solid, liquid, or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres, and aerosols, etc.

[0195] Typical routes of administration of the compounds of the present application or their pharmaceutically acceptable salts or their pharmaceutical compositions include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.

[0196] The pharmaceutical compositions of the present application can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, sugarcoating pill methods, grinding methods, emulsification methods, freeze-drying methods, etc.

[0197] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, syrups, suspensions, etc. for oral administration to patients.

[0198] Solid oral compositions can be prepared by conventional mixing, filling or tableting methods. For example, it can be obtained by the following method: mixing the active compound with solid excipients, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain the core of tablets or dragees. Suitable excipients include but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.

[0199] The pharmaceutical composition is also suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.

[0200] The therapeutic dose of the compounds of the present application can depend on, for example: the specific use of the treatment, the manner of administering the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of the compounds of the present application in the pharmaceutical composition may not be fixed and depends on various factors, including the dose, chemical properties (such as hydrophobicity) and the route of administration. For example, the compounds of the present application can be provided by a physiological buffer aqueous solution containing about 0.1 - 10% w / v of the compound for parenteral administration. Some typical dose ranges are about 1 μg / kg - about 1 g / kg body weight per day. In some embodiments, the dose range is about 0.01 mg / kg - about 100 mg / kg body weight per day. The dose is likely to depend on such variables as the type and progression of the disease or disorder, the general health status of the specific patient, the relative biological potency of the selected compound, the excipient formulation and its route of administration. The effective dose can be extrapolated from the dose-response curve derived from in vitro or animal model test systems.

[0201] The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by their combination with other chemical synthesis methods, and the equivalent replacement methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.

[0202] The chemical reactions in the specific embodiments of the present application are completed in a suitable solvent, and the solvent must be suitable for the chemical changes of the present application and the reagents and materials required therefor. In order to obtain the compounds of the present application, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction processes on the basis of the existing embodiments.

[0203] An important consideration in the synthesis route planning in the art is to select a suitable protecting group for the reactive functional group (such as the amino group in the present application). For example, reference can be made to Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc.

[0204] In some embodiments, the general formula compounds of the present application can be prepared by those skilled in the art of organic synthesis through the following routes using general or conventional methods in the art:

[0205]

[0206] wherein, R 1 、R 2a 、R 2b 、R 3 、R 4 、R 5 、R 6 、X, X 3 、m and p are as described above.

[0207] The following abbreviations are used in the present application:

[0208] DMF represents N, N-dimethylformamide; THF represents tetrahydrofuran; EtOH represents ethanol; DIPEA represents N, N-diisopropylethylamine; DCM represents dichloromethane; EA represents ethyl acetate; MeOH represents methanol; DBU represents 1,8-diazabicyclo[5.4.0]undec-7-ene; TBAB represents tetrabutylammonium bromide; DMA represents N, N-dimethylacetamide; CDI represents N, N'-carbonyldiimidazole.

[0209] For clarity, the present application is further illustrated by examples, but the examples do not limit the scope of the present application. All the reagents used in the present application are commercially available and can be used without further purification. Specific Embodiments

[0210] Preparation Example A-3

[0211]

[0212] Step A: Synthesis of Compound A-2

[0213] Add A-1 (10.9 g) and THF (150 mL) to a single-necked flask in sequence. Under N₂ protection, add sodium hydride (5.8 g) with a purity of 60% (mass percentage), and stir at 50 °C for 10 min; then cool to room temperature, and add 5-bromo-2-fluoropyridine (10 g) thereto, and stir at 50 °C for 2 h. After the reaction is completed, slowly pour the reaction solution into a saturated ammonium chloride solution (100 mL) in ice to quench the reaction. Extract with dichloromethane (150 mL × 3), combine the organic phases, wash with saturated sodium chloride (150 mL), dry over anhydrous sodium sulfate, filter by suction, and concentrate under reduced pressure to obtain A-2 (20 g). MS (ESI+, [M+H] + ) m / z: 298.97.

[0214] Step B: Synthesis of compound A-3

[0215] Add A-2 (10.9 g), THF (250 mL), and isopropyl alcohol pinacol borate (13.74 g) to a three-necked flask in sequence. Under N₂ protection, cool to -78 °C, and then slowly add a 2.5 M solution of n-butyllithium in tetrahydrofuran (31 mL). After addition, continue to stir for 1 h, and then restore to room temperature and stir overnight. After the reaction is completed, slowly pour the reaction solution into a saturated ammonium chloride solution (100 mL) in ice, extract with EA (200 mL × 4), wash the organic phase with saturated sodium chloride (200 mL), dry over anhydrous sodium sulfate, filter by suction, and concentrate under reduced pressure to remove the solvent to obtain A-3 (19 g). MS (ESI+, [M+H] + ) m / z: 347.17.

[0216] Preparation example A-6

[0217]

[0218] Step A: Synthesis of compound A-5

[0219] Referring to the synthesis of Preparation example A-3, in the preparation step of A-2, replace A-1 with A-4 to obtain compound A-5. MS (ESI+, [M+H] + ) m / z: 284.94.

[0220] Step B: Synthesis of compound A-6

[0221] Referring to the synthesis of Preparation example A-3, in the preparation step of A-3, replace A-2 with A-5 to obtain compound A-6. MS (ESI+, [M+H] + ) m / z: 333.09.

[0222] Preparation example A-9

[0223]

[0224] Step A: Synthesis of Compound A-8

[0225] Referring to the synthesis of Preparation Example A-3, in the preparation step of A-2, replace A-1 with A-7 to obtain Compound A-8. MS(ESI+, [M+H] + ) m / z: 310.87.

[0226] Step B: Synthesis of Compound A-9

[0227] Referring to the synthesis of Preparation Example A-3, in the preparation step of A-3, replace A-2 with A-8 to obtain Compound A-9. MS(ESI+, [M+H] + ) m / z: 359.12.

[0228] Preparation Example A-12

[0229]

[0230] Step A: Synthesis of Compound A-11

[0231] Referring to the synthesis of Preparation Example A-3, in the preparation step of A-2, replace A-1 with A-10 to obtain Compound A-11. MS(ESI+, [M+H] + ) m / z: 258.90.

[0232] Step B: Synthesis of Compound A-12

[0233] Referring to the synthesis of Preparation Example A-3, in the preparation step of A-3, replace A-2 with A-11 to obtain Compound A-12. MS(ESI+, [M+H] + ) m / z: 307.23.

[0234] Example 1

[0235]

[0236] Reaction process:

[0237]

[0238] Step A: Synthesis of Compound 1-2

[0239] Add 1-1 (10 g), dichloromethane (100 mL), DMF (0.67 g) to a single-necked flask in sequence, and add oxalyl chloride (8.69 g) under an ice bath. Stir the resulting mixture at 0 °C for 1 h. After the reaction is completed, concentrate under reduced pressure to obtain Intermediate 1-2 (10 g), which is directly used for the next step of the reaction.

[0240] Step B: Synthesis of Compound 1-3

[0241] Add 1-2 (10 g), toluene (100 mL), and DIPEA (8.16 mL) into a single-necked flask in sequence. Under N2 protection, add ethyl (E)-3-(dimethylamino)acrylate (6.63 g) dropwise. Stir the resulting solution at 70 °C for 17 h and then cool it to room temperature. Add 4-methoxybenzylamine (5.84 g) and stir at room temperature for 3 h. After the reaction is completed, dilute the reaction solution with DCM (300 mL), wash it with water (3 × 200 mL) and saturated brine (200 mL) in sequence. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to obtain intermediate 1-3 (18 g). MS (ESI+, [M+H] + ) m / z: 436.02.

[0242] Step C: Synthesis of Compound 1-4

[0243] Add 1-3 (18 g) and acetone (200 mL) into a single-necked flask in sequence. Add DBU (6.28 g) at 10 °C. Stir at room temperature for 16 h under N2 protection. After the reaction is completed, filter the reaction system, collect the filter cake, wash the filter cake with petroleum ether (3 × 5 mL), and dry it under reduced pressure in vacuo to obtain intermediate 1-4 (8.0 g). MS (ESI+, [M+H] + ) m / z: 416.06. 1 1H NMR (500 MHz, DMSO-d6) δ 8.92 (s, 1H), 8.30 (d, J = 2.4 Hz, 1H), 7.85 (dd, J = 9.1, 2.5 Hz, 1H), 7.67 (d, J = 9.1 Hz, 1H), 7.26–7.17 (m, 2H), 6.95–6.88 (m, 2H), 5.59 (s, 2H), 4.25 (q, J = 7.1 Hz, 2H), 3.71 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H).

[0244] Step D: Synthesis of Compound 1-5

[0245] Add 1-4 (8.3 g), thionyl chloride (47.4 g), and DMF (0.029 g) into a single-necked flask in sequence. Stir at 70 °C for 3 h under N2 protection. After the reaction is completed, concentrate the reaction solution to dryness. Pulverize the crude product with n-hexane (20 mL) for purification and filter by suction to obtain intermediate 1-5 (5.3 g). MS (ESI+, [M+H] + ) m / z: 313.85.

[0246] Step E: Synthesis of Compound 1-6

[0247] Add 1-5 (2.5 g), DMA (30 mL), isopropylamine (0.705 g), and DIPEA (2.05 g) to a single-necked flask in sequence. Under N2 protection, stir the mixture at 100 °C for 4 h. After the reaction is complete, pour the reaction solution into ice water (150 mL), filter to collect the filter cake, wash the filter cake with water (10 mL × 3), and dry it under vacuum to obtain intermediate 1-6 (2.7 g). MS (ESI+, [M+H] + ) m / z: 336.97.

[0248] Step F: Synthesis of Compound 1-7

[0249] Add 1-6 (2.7 g), THF (30 mL), water (10 mL), and NaOH (1.6 g) to a single-necked flask in sequence. Stir the mixture at 60 °C for 5 h. After the reaction is complete, concentrate the reaction solution, dilute it with water (50 mL), and adjust the pH to 2-3 with 2 M hydrochloric acid. Filter to collect the filter cake, wash the filter cake with water (5 mL × 3), and dry it under vacuum to obtain intermediate 1-7 (2.1 g). MS (ESI+, [M+H] + ) m / z: 308.88.

[0250] Step G: Synthesis of Compound 1-8

[0251] Add 1-7 (1.6 g), DMF (15 mL), and triethylamine (1.571 g) to a single-necked flask in sequence. Under N2 protection, stir at room temperature for 30 min, then add diphenylphosphoryl azide (1.709 g) and stir the reaction solution at room temperature for another 30 min, and then stir at 60 °C for 3 h. After the reaction is complete, pour the reaction solution into ice water (100 mL), filter, collect the filter cake, wash the filter cake with water (5 mL × 3), and dry it under vacuum to obtain intermediate 1-8 (1.5 g). MS (ESI+, [M+H] + ) m / z: 305.88.

[0252] Step H: Synthesis of Compound 1-9

[0253] Add 1-8 (0.10 g), DCM (5 mL), water (2.5 mL), TBAB (10.53 mg), NaOH (21.6 mg), and 2,4-dinitrophenylhydroxylamine (98 mg) to a single-necked flask in sequence. Under nitrogen protection, stir at room temperature for 24 h. After the reaction is complete, concentrate under reduced pressure to remove some solvents, filter to collect the filter cake, slurry the filter cake with 5 mL of acetonitrile, and dry it under vacuum to obtain intermediate 1-9 (95 mg). MS (ESI+, [M+H] + ) m / z: 320.86.

[0254] Step I: Synthesis of Example 1

[0255] To a single-necked flask were successively added 1-9 (95 mg), 1,4-dioxane (5 mL), water (2 mL), A-3 (166 mg), potassium carbonate (123 mg), 3-(di-tert-butylphosphino) propane-1-sulfonic acid (1.587 mg), disodium tetrachloropalladate(IV) (0.870 mg). Under N2 protection, the mixed solution was stirred at 80 °C for 1 h. After the reaction was completed, the reaction solution was concentrated. The residue was dissolved in DCM (50 mL), washed with saturated brine (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was purified by high-pressure preparation (chromatographic column: Polar RP (10 μm, 21.2 × 250 mm); mobile phase: 10 mM ammonium acetate - 0.1% acetic acid aqueous solution: acetonitrile = 60:40) to obtain Example 1 (32.0 mg). MS (ESI+, [M+H] + ) m / z: 461.27. 1 1H NMR (500 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.65 (d, J = 2.6 Hz, 1H), 8.39 (d, J = 2.0 Hz, 1H), 8.18 (dd, J = 8.6, 2.6 Hz, 1H), 8.13 (d, J = 8.8 Hz, 1H), 7.92 (dd, J = 8.8, 1.9 Hz, 1H), 6.97 (d, J = 8.6 Hz, 1H), 5.55 (s, 2H), 5.36 (p, J = 6.8 Hz, 1H), 4.35 (t, J = 6.6 Hz, 2H), 2.43–2.23 (m, 6H), 1.91 (q, J = 6.8 Hz, 2H), 1.68 (d, J = 6.7 Hz, 6H), 1.49 (p, J = 5.5 Hz, 4H), 1.38 (q, J = 5.9 Hz, 2H).

[0256] Example 2

[0257]

[0258] Reaction process:

[0259]

[0260] Step A: Synthesis of Compound 2-2

[0261] To a three-necked flask were successively added 2-1 (50 g), EtOH (500 mL), 1,3-2-(ethoxymethylene) diethyl malonate (62.6 g). Under N2 protection, the mixture was heated to 80 °C and reacted for 4 h. After the reaction was completed, the solvent was removed by concentration under reduced pressure. After standing, it was filtered by suction, and the filter cake was washed with petroleum ether (20 mL × 5). It was dried under reduced pressure to obtain Intermediate 2-2 (90 g). MS (ESI+, [M+H]+ ) m / z: 360.00.

[0262] Step B: Synthesis of Compound 2-3

[0263] Add 2-2 (90 g) and diphenyl ether (600 g) to a three-necked flask in sequence. Under N2 protection, heat the mixture to 240 °C and react for 8 h. After the reaction is completed, cool the reaction solution to room temperature and filter. Wash the filter cake with petroleum ether (20 mL × 5), and dry it under reduced pressure to obtain intermediate 2-3 (40 g). MS (ESI+, [M+H] + ) m / z: 313.82.

[0264] Step C: Synthesis of Compound 2-4

[0265] Add 2-3 (40 g), EtOH (400 mL), water (80 mL), and NaOH (25.5 g) to a single-necked flask in sequence. Under N2 protection, stir the reaction solution at 75 °C for 2 h. After the reaction is completed, cool the reaction solution in an ice bath and adjust the pH to 4 - 5 with 2N hydrochloric acid. Filter, wash the filter cake with water (20 mL × 3), and dry it under vacuum to obtain intermediate 2-4 (35 g). MS (ESI+, [M+H] + ) m / z: 285.82.

[0266] Step D: Synthesis of Compound 2-5

[0267] Add 2-4 (31.6 g), thionyl chloride (120 mL), and DMF (0.16 g) to a single-necked flask in sequence. Under N2 protection, heat the reaction solution to reflux and react for 2 h. After the reaction is completed, cool the reaction solution, concentrate it under reduced pressure, and then add the concentrate to a solution of ammonium hydroxide (63.8 mL) at 0 °C. Stir vigorously at room temperature for 15 minutes, filter, wash the filter cake with water (15 mL × 3), and dry it under vacuum to obtain intermediate 2-5 (30 g). MS (ESI+, [M+H] + ) m / z: 302.86.

[0268] Step E: Synthesis of Compound 2-6

[0269] Add 2-5 (3.0 g), potassium carbonate (2.73 g), acetonitrile (40 mL), and isopropylamine (0.88 g) to a single-necked flask in sequence. Under N2 protection, stir the mixture at 95 °C for 4 h. After the reaction is completed, cool the reaction solution, add 150 mL of water, filter, wash the filter cake with water (5 mL × 4), and dry it under vacuum to obtain intermediate 2-6 (2.8 g). MS (ESI+, [M+H] + ) m / z: 325.89

[0270] Step F: Synthesis of Compound 2-7

[0271] 2 - 6 (2.8 g), DBU (2.61 g), and methanol (30 mL) were successively added to a single - necked flask. At 5 °C, 1,3,5 - trichloro - 1,3,5 - triazine - 2,4,6 - trione (1.00 g) was added. Under N2 protection, the mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was directly filtered. The filter cake was washed with water (10 mL×2) and dried in vacuo to obtain intermediate 2 - 7 (2.4 g). MS (ESI +, [M + H] + ) m / z: 323.86.

[0272] Step G: Synthesis of compound 2 - 8

[0273] 2 - 7 (2.4 g), DCM (30 mL), water (15 mL), TBAB (0.24 g), 2,4 - dinitrophenylhydroxylamine (2.21 g), and NaOH (0.59 g) were successively added to a single - necked flask. Under N2 protection, the mixture was stirred at room temperature for 24 h. After the reaction was completed, most of the solvent was removed by concentration. The mixture was filtered, and the filter cake was slurried with 10 mL of acetonitrile and dried in vacuo to obtain intermediate 2 - 8 (1.8 g). MS (ESI +, [M + H] + ) m / z: 338.88.

[0274] Step H: Synthesis of Example 2

[0275] 2 - 8 (150 mg), 1,4 - dioxane (5 mL), water (2 mL), A - 3 (249 mg), potassium carbonate (183 mg), 3 - (di - tert - butylphosphino) propane - 1 - sulfonic acid (2.37 mg), and disodium tetrachloropalladate(IV) (1.30 mg) were successively added to a single - necked flask. Under N2 protection, the mixed solution was stirred at 80 °C for 1 h. After the reaction was completed, the reaction solution was concentrated. The residue was dissolved in DCM (50 mL), washed with saturated brine (2×10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was slurried with acetonitrile (5 mL) to obtain Example 2 (70.0 mg). MS (ESI +, [M + H] + ) m / z: 479.30. 11H NMR (500 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.53–8.47 (m, 1H), 8.32 (d, J = 8.2 Hz, 1H), 8.04 (dt, J = 8.7, 2.3 Hz, 1H), 7.91 (d, J = 12.0 Hz, 1H), 6.98 (d, J = 8.6 Hz, 1H), 5.55 (s, 2H), 5.35–5.23 (m, 1H), 4.36 (t, J = 6.6 Hz, 2H), 2.39 (t, J = 7.2 Hz, 2H), 2.33 (s, 4H), 1.96–1.85 (m, 2H), 1.64 (d, J = 6.7 Hz, 6H), 1.49 (p, J = 5.6 Hz, 4H), 1.38 (d, J = 6.1 Hz, 2H).

[0276] Example 3

[0277]

[0278] Reaction process:

[0279]

[0280] 2-8 (100 mg), 1,4-dioxane (5 mL), water (2 mL), A-6 (196 mg), potassium carbonate (122 mg), 3-(di-tert-butylphosphino)propane-1-sulfonic acid (1.58 mg), and disodium tetrachloropalladate(IV) (0.87 mg) were successively added to a single-necked flask under N2 protection. The mixed solution was stirred at 80 °C for 1 h. The reaction solution was concentrated, and the residue was dissolved in DCM (50 mL), washed with saturated brine (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was slurried with acetonitrile (5 mL) to obtain Example 3 (25 mg). MS (ESI+, [M+H] + ) m / z: 465.25, 1 1H NMR (500 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.52–8.48 (m, 1H), 8.32 (d, J = 8.2 Hz, 1H), 8.04 (dt, J = 8.6, 2.3 Hz, 1H), 7.91 (d, J = 12.0 Hz, 1H), 6.99 (d, J = 8.6 Hz, 1H), 5.55 (s, 2H), 5.29 (p, J = 6.8 Hz, 1H), 4.38 (t, J = 6.6 Hz, 2H), 2.55 (t, J = 7.1 Hz, 2H), 2.48–2.43 (m, 4H), 1.97–1.89 (m, 2H), 1.71–1.67 (m, 4H), 1.65 (d, J = 6.8 Hz, 6H).

[0281] Example 4

[0282]

[0283] Reaction process:

[0284]

[0285] Add 2-8 (100 mg), 1,4-dioxane (5 mL), water (2 mL), A-9 (211 mg), potassium carbonate (122 mg), 3-(di-tert-butylphosphino) propane-1-sulfonic acid (1.58 mg) and disodium tetrachloropalladate(IV) (0.87 mg) into a single-necked flask in sequence, stir at 80 °C for 1 h under N2 protection. Concentrate the reaction solution, dissolve the residue in DCM (50 mL), wash with saturated brine (2×10 mL), dry with anhydrous sodium sulfate, filter and concentrate to obtain the crude product, which is purified by high-pressure preparation (chromatographic column: Polar RP (10 μm, 21.2×250 mm); mobile phase: 10 mM ammonium acetate - 0.1% acetic acid aqueous solution: acetonitrile = 60:40), to obtain Example 4 (51.6 mg). MS (ESI+, [M+H] + ) m / z: 491.27, 1 1H NMR (500 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.50 (s, 1H), 8.32 (d, J = 8.1 Hz, 1H), 8.04 (dt, J = 8.8, 2.3 Hz, 1H), 7.91 (d, J = 12.0 Hz, 1H), 6.99 (d, J = 8.6 Hz, 1H), 5.55 (s, 2H), 5.35–5.21 (m, 1H), 4.34 (t, J = 6.5 Hz, 2H), 2.82 (t, J = 7.4 Hz, 2H), 2.03 (p, J = 6.8 Hz, 2H), 1.90 (tt, J = 6.8, 3.8 Hz, 2H), 1.64 (d, J = 6.7 Hz, 6H), 0.42 (dt, J = 6.3, 3.1 Hz, 4H), 0.32 (p, J = 4.2 Hz, 4H).

[0286] Example 5

[0287]

[0288] Reaction process:

[0289]

[0290] Step A: Synthesis of Compound 5-1

[0291] Add 2 - 5 (1.0 g), DMF (10 mL), DIPEA (1.28 g), and 4 - aminotetrahydropyran (0.40 g) to a single - necked flask in sequence. Under N₂ protection, heat to 90 °C and react for 1 h. After the reaction is completed, pour the reaction solution into 100 mL of water, filter, wash the filter cake with water (10 mL × 2), and dry it under vacuum to obtain intermediate 5 - 1 (1.1 g). MS (ESI +, [M + H] + ) m / z: 368.95. 1 ¹H NMR (500 MHz, DMSO - d₆) δ 8.71 (d, J = 7.5 Hz, 1H), 8.58 (s, 1H), 8.13 (s, 1H), 8.02 (d, J = 8.5 Hz, 1H), 7.71 (d, J = 10.0 Hz, 1H), 7.62 (s, 1H), 4.08–3.96 (m, 1H), 3.88 (d, J = 11.5 Hz, 2H), 3.36 (d, J = 1.3 Hz, 1H), 3.32 (s, 1H), 1.91 (d, J = 12.3 Hz, 2H), 1.60 (td, J = 14.2, 4.0 Hz, 2H).

[0292] Step B: Synthesis of compound 5 - 2

[0293] Add 5 - 1 (1.0 g), MeOH (30 mL), DBU (0.83 g), and 1,3,5 - trichloro - 1,3,5 - triazine - 2,4,6 - trione (0.31 g) to a single - necked flask in sequence. Under N₂ protection, stir the suspension at room temperature for 1 h. After the reaction is completed, filter directly, wash the filter cake with water (10 mL × 2), and dry it under vacuum to obtain intermediate 5 - 2 (0.85 g). MS (ESI +, [M + H] + ) m / z: 365.92. 1 ¹H NMR (500 MHz, DMSO - d₆) δ 8.67 (s, 1H), 8.54 (d, J = 7.3 Hz, 1H), 7.89 (d, J = 10.2 Hz, 1H), 4.98–4.83 (m, 1H), 4.03 (dd, J = 11.3, 4.2 Hz, 2H), 3.58 (t, J = 11.3 Hz, 3H), 2.76–2.62 (m, 2H), 1.86–1.77 (m, 2H).

[0294] Step C: Synthesis of compound 5 - 3

[0295] 5-2 (0.65 g), THF (10 mL), sodium hydride (60% purity, mass percentage, 0.11 g), and 2,4-dinitrophenylhydroxylamine (0.42 g) were successively added to a single-necked flask. Under N2 protection, the mixture was stirred at room temperature for 24 h. After the reaction was completed, 50 mL of water was added, and the mixture was extracted with EA (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and the obtained crude product was purified by silica gel column chromatography (eluent: DCM / MeOH = 25 / 1) to obtain intermediate 5-3 (0.45 g). MS (ESI+, [M+H] + ) m / z: 381.95.

[0296] Step D: Synthesis of Example 5

[0297] 5-3 (200 mg), 1,4-dioxane (20 mL), A-6 (227 mg), potassium carbonate (218 mg) dissolved in 0.5 mL of water, 3-(di-tert-butylphosphino)propane-1-sulfonic acid (2.8 mg) dissolved in 0.5 mL of water, and disodium tetrachloropalladate(IV) (1.5 mg) were successively added to a single-necked flask. Under N2 protection, the mixture was heated to 80 °C and reacted for 1 h. After the reaction was completed, 50 mL of water was added, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and the obtained crude product was purified by silica gel column chromatography (eluent: DCM / MeOH = 10 / 1) to obtain Example 5 (44 mg). MS (ESI+, [M+H] + ) m / z: 507.28. 1 H NMR (500 MHz, DMSO-d6) δ 8.84 (d, J = 1.7 Hz, 1H), 8.54 (t, J = 2.5 Hz, 1H), 8.34 (d, J = 8.1 Hz, 1H), 8.10 - 8.07 (m, 1H), 7.93 (dd, J = 12.1, 1.6 Hz, 1H), 7.00 (d, J = 8.2 Hz, 1H), 5.58 (s, 2H), 5.09 (ddt, J = 11.8, 8.2, 4.2 Hz, 1H), 4.40–4.37 (m, 2H), 4.03 (dd, J = 11.4, 4.6 Hz, 2H), 3.54 (t, J = 11.9 Hz, 2H), 2.74 - 2.66 (m, 2H), 2.54 (t, J = 7.2 Hz, 2H), 2.46–2.43 (m, 4H), 1.96–1.89 (m, 4H), 1.70–1.67 (m, 4H).

[0298] Example 6

[0299]

[0300] Reaction process:

[0301]

[0302] Add 5-3 (200 mg), 1,4-dioxane (20 mL), A-9 (244 mg), potassium carbonate (218 mg) dissolved in 0.5 mL of water, 3-(di-tert-butylphosphino)propane-1-sulfonic acid (2.8 mg) dissolved in 0.5 mL of water, and sodium tetrachloropalladate (1.5 mg) into a single-necked flask in sequence. Under N2 protection, heat to 80 °C and react for 1 h. After the reaction is completed, add 50 mL of water, extract with dichloromethane (50 mL × 3), combine the organic phases, wash with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure to dryness. The obtained crude product is subjected to silica gel column chromatography (eluent: DCM / MeOH = 10 / 1) to obtain Example 6 (94 mg). MS (ESI+, [M+H] + ) m / z: 533.34. 1 1H NMR (500 MHz, DMSO-d6) δ 8.83 (s, 1H), 8.54 (s, 1H), 8.34 (d, J = 7.9 Hz, 1H), 8.08 (d, J = 7.0 Hz, 1H), 7.93 (d, J = 12.1 Hz, 1H), 7.00 (d, J = 8.6 Hz, 1H), 5.58 (s, 2H), 5.09 (t, J = 11.6 Hz, 1H), 4.38 (t, J = 6.5 Hz, 2H), 4.10–4.00 (m, 2H), 3.54 (t, J = 11.8 Hz, 2H), 2.70 (dt, J = 20.1, 10.0 Hz, 2H), 2.01 (qd, J = 11.9, 4.4 Hz, 2H), 2.08–2.01 (m, 4H), 1.89 (tt, J = 6.8, 3.8 Hz, 2H), 0.42 (dd, J = 6.6, 2.2 Hz, 4H), 0.32 (dd, J = 3.7, 2.3 Hz, 4H).

[0303] Example 7

[0304]

[0305] Reaction process:

[0306]

[0307] Step A: Synthesis of Compound 7-1

[0308] Add 2 - 8 (100 mg), DMF (5 mL), NaOH (35.4 mg), and CH3I (62.8 mg) to a single - necked flask in sequence. React at room temperature for 14 h under N2 protection. After the reaction is completed, add 50 mL of water to the system, filter, wash the filter cake with water (5 mL×2), and dry under reduced pressure to obtain intermediate 7 - 1 (100 mg). MS (ESI +, [M + H] + ) m / z: 352.92.

[0309] Step B: Synthesis of Example 7

[0310] Add 7 - 1 (100 mg), 1,4 - dioxane (5 mL), water (2 mL), A - 3 (159 mg), potassium carbonate (117 mg), 3 - (di - tert - butylphosphino) propane - 1 - sulfonic acid (1.52 mg), and disodium tetrachloropalladate(IV) (0.83 mg) to a single - necked flask in sequence. Stir the mixed solution at 80 °C for 1 h under N2 protection. Concentrate the reaction solution, dissolve the residue in DCM (50 mL), wash with saturated brine (2×10 mL), dry with anhydrous sodium sulfate, filter, and concentrate to obtain the crude product. Purify by high - pressure preparation (chromatographic column: Polar RP (10 μm, 21.2×250 mm); mobile phase: 10 mM ammonium acetate - 0.1% acetic acid aqueous solution: acetonitrile = 60:40) to obtain Example 7 (24 mg). MS (ESI +, [M + H] + ) m / z: 493.27. 1 1H NMR (500 MHz, DMSO - d6) δ8.81 (s, 1H), 8.50 (t, J = 1.8 Hz, 1H), 8.32 (d, J = 8.1 Hz, 1H), 8.04 (dt, J = 8.6, 2.3 Hz, 1H), 7.92 (d, J = 11.9 Hz, 1H), 6.98 (d, J = 8.6 Hz, 1H), 6.27 (d, J = 5.6 Hz, 1H), 5.28 (p, J = 6.8 Hz, 1H), 4.36 (t, J = 6.6 Hz, 2H), 2.77 (d, J = 5.4 Hz, 3H), 2.39 (t, J = 7.2 Hz, 2H), 2.38–2.28 (m, 4H), 1.95–1.86 (m, 2H), 1.65 (d, J = 6.7 Hz, 6H), 1.54–1.45 (m, 4H), 1.42–1.35 (m, 2H).

[0311] Example 8

[0312]

[0313] Reaction process:

[0314]

[0315] Step A: Synthesis of Compound 8-1

[0316] Add 2-8 (50 mg), DMF (5 mL), NaOH (17.7 mg) and CD3I (31.2 mg) into a single-neck flask in sequence. React at room temperature for 14 h under N2 protection. After the reaction is completed, add 50 mL of water, filter, wash the filter cake with water (5 mL×2), and dry under reduced pressure to obtain intermediate 8-1 (45 mg). MS (ESI+, [M+H] + ) m / z: 356.01.

[0317] Step B: Synthesis of Example 8

[0318] Add 8-1 (45 mg), 1,4-dioxane (5 mL), water (2 mL), A-3 (71.1 mg), potassium carbonate (52.4 mg), 3-(di-tert-butylphosphino) propane-1-sulfonic acid (0.68 mg) and disodium tetrachloropalladate(IV) (0.37 mg) into a single-neck flask in sequence. Stir the mixed solution at 80 °C for 1 h under N2 protection. Concentrate the reaction solution, dissolve the residue in DCM (50 mL), wash with saturated brine (2×10 mL), dry with anhydrous sodium sulfate, filter, and concentrate to obtain the crude product. Purify by high-pressure preparation (chromatographic column: Polar RP (10 μm, 21.2×250 mm); mobile phase: 10 mM ammonium acetate-0.1% acetic acid aqueous solution: acetonitrile = 60:40) to obtain Example 8 (15 mg). MS (ESI+, [M+H] + ) m / z: 496.29. 1 H NMR (500 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.58–8.50 (m, 1H), 8.32 (d, J = 8.1 Hz, 1H), 8.09 (dt, J = 8.6, 2.2 Hz, 1H), 7.93 (d, J = 11.9 Hz, 1H), 7.01 (d, J = 8.6 Hz, 1H), 6.25 (s, 1H), 5.28 (h, J = 6.7 Hz, 1H), 4.43 (t, J = 6.1 Hz, 2H), 3.47 (d, J = 11.9 Hz, 2H), 3.24–3.11 (m, 2H), 2.96–2.79 (m, 2H), 2.31–2.17 (m, 2H), 1.86–1.74 (m, 4H), 1.74–1.68 (m, 2H), 1.65 (d, J = 6.7 Hz, 6H).

[0319] Example 9

[0320]

[0321] Reaction process:

[0322]

[0323] Step A: Synthesis of Compound 9-1

[0324] Add 2-8 (100 mg), DMF (5 mL), sodium hydride (35.4 mg, 60% purity, mass percentage) to a single-necked flask in sequence. Stir at room temperature for 10 min under N2 protection, add CD3I (107 mg), and react at room temperature for 14 h. After the reaction is completed, add 50 mL of ice water to quench, filter, wash the filter cake with water (5 mL×2), and dry under reduced pressure to obtain intermediate 9-1 (70 mg). MS (ESI+, [M+H] + ) m / z: 372.99.

[0325] Step B: Synthesis of Example 9

[0326] Add 9-1 (70 mg), 1,4-dioxane (5 mL), water (2 mL), A-3 (106 mg), potassium carbonate (78 mg), 3-(di-tert-butylphosphino) propane-1-sulfonic acid (1.0 mg) and disodium tetrachloropalladate(IV) (0.55 mg) to a single-necked flask in sequence. Stir the mixed solution at 80 °C for 1 h under N2 protection. Concentrate the reaction solution, dissolve the residue in DCM (50 mL), wash with saturated brine (2×10 mL), dry with anhydrous sodium sulfate, filter, and concentrate to obtain the crude product. Purify by high-pressure preparation (chromatographic column: Polar RP (10 μm, 21.2×250 mm); mobile phase: 10 mM ammonium acetate-0.1% acetic acid aqueous solution: acetonitrile = 60:40) to obtain Example 9 (14.4 mg). MS (ESI+, [M+H] + ) m / z: 513.33. 1 1H NMR (500 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.52 (t, J = 1.9 Hz, 1H), 8.30 (d, J = 8.2 Hz, 1H), 8.08 (dt, J = 8.7, 2.2 Hz, 1H), 7.94 (d, J = 11.9 Hz, 1H), 7.01 (d, J = 8.6 Hz, 1H), 5.28–5.18 (m, 1H), 4.42 (t, J = 6.2 Hz, 2H), 3.53–3.39 (m, 2H), 3.24–3.07 (m, 2H), 2.96–2.75 (m, 2H), 2.27–2.13 (m, 2H), 1.86–1.69 (m, 6H), 1.64 (d, J = 6.8 Hz, 6H).

[0327] Example 10

[0328]

[0329] Reaction process:

[0330]

[0331] Step A: Synthesis of Compound 10-2

[0332] Add cyclopropylamine (0.27 g) and THF (10 mL) to a single-necked flask in sequence. Under N2 protection, add 60% (purity, mass percentage) sodium hydride (0.38 g) at 0 °C, stir for 10 min, then add 10-1 (1.0 g), and stir the mixture at room temperature for 1 h. After the reaction is completed, pour the reaction solution into 50 mL of ice water, stir for 30 min, filter, collect the filter cake, wash the filter cake with water (5 mL × 3), and then wash it with petroleum ether (5 mL × 4) to obtain intermediate 10-2 (1.06 g). MS (ESI+, [M+H] + ) m / z: 337.84. 1 1H NMR (500 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.99 (s, 1H), 8.95 (s, 1H), 7.38 (s, 1H), 4.00 (s, 3H), 3.02 (s, 1H), 0.84–0.80 (m, 2H), 0.68–0.65 (m, 2H).

[0333] Step B: Synthesis of Compound 10-3

[0334] Add 10-2 (0.27 g), MeOH (60 mL), a 15 mL aqueous solution of ammonium chloride (1.5 g), and iron powder (0.8 g) to a single-necked flask in sequence. Under N2 protection, heat the mixture to 65 °C and react for 1 h. After the reaction is completed, filter, wash the filter cake with dichloromethane (10 mL × 3), concentrate the filtrate to dryness under reduced pressure, add water (50 mL) to the obtained crude product for pulping, and filter to obtain intermediate 10-3 (883 mg). MS (ESI+, [M+H] + ) m / z: 307.83.

[0335] Step C: Synthesis of Compound 10-4

[0336] Add 10-3 (0.78 g), THF (20 mL), N,N-diisopropylethylamine (1.6 g), and N,N'-carbonyldiimidazole (2 g) to a single-necked flask in sequence. Under N2 protection, stir the mixture at room temperature for 4 h. After the reaction is completed, pour the reaction solution into 100 mL of ice water, stir for 30 min, filter, collect the filter cake, wash the filter cake with water (5 mL × 3), and then wash it with petroleum ether (5 mL × 4) to obtain intermediate 10-4 (784 mg). MS (ESI+, [M+H]+ ) m / z: 333.82.

[0337] Step D: Synthesis of Compound 10-5

[0338] Add 10-4 (0.68 g), DCM (20 mL), 2,4-dinitrophenylhydroxylamine (0.6 g), tetrabutylammonium bromide (65 mg), and a 10 mL aqueous solution of sodium hydroxide (160 mg) to a single-necked flask in sequence. Stir the mixture at room temperature overnight. After the reaction is completed, directly concentrate the reaction solution to remove the organic phase, add acetonitrile (10 mL), stir for 5 min, filter, collect the filter cake, and wash the filter cake with water (5 mL × 3) and acetonitrile (5 mL × 3) in sequence to obtain intermediate 10-5 (515 mg). MS (ESI+, [M+H] + ) m / z: 349.02.

[0339] Step E: Synthesis of Example 10

[0340] Add 10-5 (100 mg), 1,4-dioxane (6 mL), A-3 (143 mg), a solution of potassium carbonate (119 mg) in water (0.5 mL), a solution of 3-(di-tert-butylphosphino)propane-1-sulfonic acid (7.69 mg) in water (0.5 mL), and disodium tetrachloropalladate(IV) (4.21 mg) to a single-necked flask in sequence. Protect with N2, heat the mixture to 80 °C and stir for 1 h. After the reaction is completed, add 50 mL of water, extract with dichloromethane (50 mL × 3), combine the organic phases, wash with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure to dryness, and purify the obtained crude product by silica gel column chromatography to obtain Example 10 (101 mg). MS (ESI+, [M+H] + ) m / z: 489.31. 1 1H NMR (500 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.62 (s, 1H), 8.41 (d, J = 2.4 Hz, 1H), 7.97 (dd, J = 8.6, 2.5 Hz, 1H), 7.55 (s, 1H), 6.91 (d, J = 8.6 Hz, 1H), 5.47 (s, 2H), 4.33 (t, J = 6.6 Hz, 2H), 3.93 (s, 3H), 3.49 (tt, J = 7.0, 3.7 Hz, 1H), 2.39 (t, J = 7.2 Hz, 2H), 2.33 (s, 4H), 1.89 (p, J = 6.8 Hz, 2H), 1.49 (p, J = 5.6 Hz, 4H), 1.40 - 1.38 (m, 2H), 1.23 – 1.19 (m, 2H), 1.12 - 1.09 (m, 2H).

[0341] Example 11

[0342]

[0343] Reaction process:

[0344]

[0345] Step A: Synthesis of Example 11

[0346] Add 10-5 (100 mg), 1,4-dioxane (6 mL), A-6 (143 mg), potassium carbonate (119 mg) aqueous solution (0.5 mL), 3-(di-tert-butylphosphino) propane-1-sulfonic acid (7.69 mg) aqueous solution (0.5 mL) and disodium tetrachloropalladate(IV) (4.21 mg) into a single-necked flask in sequence. Under N2 protection, heat the mixture to 80 °C and stir for 1 h. After the reaction is completed, add 50 mL of water, extract with dichloromethane (50 mL × 3), combine the organic phases, wash with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure to dryness, and purify the obtained crude product by silica gel column chromatography to obtain Example 11 (74 mg). MS (ESI+, [M+H] + ) m / z: 475.32. 1 1H NMR (500 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.61 (s, 1H), 8.40 (d, J = 2.5 Hz, 1H), 7.97 (dd, J = 8.6, 2.5 Hz, 1H), 7.55 (s, 1H), 6.91 (d, J = 8.6 Hz, 1H), 5.47 (s, 2H), 4.35 (t, J = 6.6 Hz, 2H), 3.93 (s, 3H), 3.48 (tt, J = 6.9, 3.7 Hz, 1H), 2.53 (t, J = 7.2 Hz, 2H), 2.46–2.42 (m, 4H), 1.92 (p, J = 6.8 Hz, 2H), 1.71–1.66 (m, 4H), 1.23–1.19 (m, 2H), 1.12 - 1.09 (m, 2H).

[0347] Example 12

[0348]

[0349] Reaction process:

[0350]

[0351] Step A: Synthesis of Compound 12-2

[0352] To a two-necked flask, add 12-1 (0.27 g) and DMF (30 mL) successively. Under N₂ protection, add 60% sodium hydride (0.3 g) at 0 °C, stir for 30 min, then add methyl iodide (1.0 g), and stir the mixture at room temperature for 3 h. After the reaction is completed, slowly pour the reaction solution into 50 mL of ice water, stir for 10 min, extract with ethyl acetate (50 mL × 3), combine the organic phases, wash with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure to dryness, and obtain intermediate 12-2 (1 g).

[0353] Step B: Synthesis of compound 12-3

[0354] To a single-necked flask, add 12-2 (1 g) and 4 M hydrogen chloride-dioxane solution (10 mL) successively. Stir the mixture at room temperature for 1 h. After the reaction is completed, concentrate the reaction solution under reduced pressure to dryness to obtain intermediate 12-3 (690 mg).

[0355] Step C: Synthesis of compound 12-4

[0356] To a single-necked flask, add 2-5 (1 g), N,N-diisopropylethylamine (2.4 g) and 12-3 (0.5 g) successively. Under N₂ protection, heat the mixture to 95 °C and stir for 2 h. After the reaction is completed, pour the reaction solution into 100 mL of water, stir for 5 min, filter, collect the filter cake, wash the filter cake with water (5 mL × 3), and then wash with petroleum ether (5 mL × 4) to obtain intermediate 12-4 (889 mg). MS (ESI+, [M+H] + ) m / z: 381.94.

[0357] Step D: Synthesis of compound 12-5

[0358] To a single-necked flask, add 12-4 (600 mg), DBU (478 mg), and methanol (12 mL) successively. Add 1,3,5-trichloro-1,3,5-triazine-2,4,6-trione (182 mg) at 5 °C. Under N₂ protection, stir the mixture at room temperature for 1 h. After the reaction is completed, directly filter the reaction solution, wash the filter cake with water (10 mL × 2), and dry in vacuo to obtain intermediate 12-5 (589 mg). MS (ESI+, [M+H] + ) m / z: 379.93.

[0359] Step E: Synthesis of compound 12-6

[0360] Add 12-5 (515 mg), DCM (20 mL), 2,4-dinitrophenylhydroxylamine (405 mg), tetrabutylammonium bromide (43 mg), and a 10 mL aqueous solution of sodium hydroxide (108 mg) to a single-necked flask in sequence, and stir the mixture at room temperature overnight. After the reaction is completed, concentrate the reaction solution to remove the organic phase, add acetonitrile (10 mL), stir at room temperature for 10 min, filter, collect the filter cake, wash the filter cake with water (5 mL × 3), and then wash with acetonitrile (5 mL × 3) to obtain intermediate 12-6 (268 mg). MS (ESI+, [M+H] + ) m / z: 394.97.

[0361] Step F: Synthesis of Example 12

[0362] Add 12-6 (88 mg), 1,4-dioxane (6 mL), A-3 (115 mg), a solution of potassium carbonate (92 mg) in water (0.5 mL), a solution of 3-(di-tert-butylphosphino) propane-1-sulfonic acid (5.97 mg) in water (0.5 mL), and disodium tetrachloropalladate(IV) (3.28 mg) to a single-necked flask in sequence, protect with N2, and heat the mixture to 80 °C and stir for 1 h. After the reaction is completed, add 50 mL of water, extract with dichloromethane (50 mL × 3), combine the organic phases, wash with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure to dryness, and subject the obtained crude product to silica gel column chromatography (eluent: DCM / MeOH = 10 / 1) to obtain Example 12 (86 mg). MS (ESI+, [M+H] + ) m / z: 535.33. 1 1H NMR (500 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.47–8.46 (m, 1H), 8.41 (d, J = 8.2 Hz, 1H), 8.03 - 8.00 (m, 1H), 7.91 (d, J = 11.9 Hz, 1H), 6.97 (d, J = 8.6 Hz, 1H), 5.59 (s, 2H), 5.33 (p, J = 9.3 Hz, 1H), 4.36 (t, J = 6.6 Hz, 2H), 3.91 (p, J = 6.0 Hz, 1H), 3.05 (s, 3H), 2.48–2.28 (m, 9H), 2.05 - 1.98 (m, 1H), 1.97–1.88 (m, 4H), 1.49 (p, J = 5.6 Hz, 4H), 1.38 (q, J = 5.9 Hz, 2H).

[0363] Example 13

[0364]

[0365] Reaction process:

[0366]

[0367] Step A: Synthesis of Example 13

[0368] Add 12-6 (88 mg), 1,4-dioxane (6 mL), A-6 (111 mg), potassium carbonate (92 mg) in aqueous solution (0.5 mL), 3-(di-tert-butylphosphino) propane-1-sulfonic acid (5.97 mg) in aqueous solution (0.5 mL), and disodium tetrachloropalladate(IV) (3.28 mg) successively into a single-necked flask. Under N2 protection, heat the mixture to 80 °C and stir for 1 h. After the reaction is completed, add 50 mL of water, extract with dichloromethane (50 mL × 3), combine the organic phases, wash with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure to dryness, and subject the obtained crude product to silica gel column chromatography (eluent: DCM / MeOH = 10 / 1) to obtain Example 13 (84 mg). MS (ESI+, [M+H] + ) m / z: 521.25. 1 H NMR (500 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.46 (t, J = 1.7 Hz, 1H), 8.41 (d, J = 8.1 Hz, 1H), 8.01 (dt, J = 8.7, 2.3 Hz, 1H), 7.91 (d, J = 12.0 Hz, 1H), 6.97 (d, J = 8.5 Hz, 1H), 5.59 (s, 2H), 5.33 (p, J = 9.3 Hz, 1H), 4.38 (t, J = 6.6 Hz, 2H), 3.91 (p, J = 6.0 Hz, 1H), 3.05 (s, 3H), 2.54 (t, J = 7.2 Hz, 2H), 2.48–2.39 (m, 6H), 2.37 - 2.29 (m, 1H), 2.05 - 1.98 (m, 1H), 1.97–1.90 (m, 4H), 1.72 - 1.66 (m, 4H).

[0369] Example 14

[0370]

[0371] Reaction process:

[0372]

[0373] Step A: Synthesis of Example 14

[0374] 12-6 (88 mg), 1,4-dioxane (6 mL), A-12 (111 mg), potassium carbonate (92 mg) in aqueous solution (0.5 mL), 3-(di-tert-butylphosphino) propane-1-sulfonic acid (5.97 mg) in aqueous solution (0.5 mL), and disodium tetrachloropalladate(IV) (3.28 mg) were successively added to a single-necked flask. Under N2 protection, the mixture was heated to 80 °C and stirred for 1 h. After the reaction was completed, 50 mL of water was added, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and the resulting crude product was purified by silica gel column chromatography to obtain Example 14 (91 mg). MS (ESI+, [M+H] + ) m / z: 495.33. 1 1H NMR (500 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.46 (d, J = 2.3 Hz, 1H), 8.42 (dd, J = 8.4, 2.7 Hz, 1H), 8.01 (dt, J = 8.6, 2.3 Hz, 1H), 7.91 (dd, J = 11.9, 2.7 Hz, 1H), 6.97 (dd, J = 8.6, 2.5 Hz, 1H), 5.59 (s, 2H), 5.33 (p, J = 9.4 Hz, 1H), 4.37 (td, J = 6.6, 2.4 Hz, 2H), 3.91 (p, J = 5.9 Hz, 1H), 3.05 (s, 3H), 2.48–2.41 (m, 2H), 2.39–2.35 (m, 2H), 2.34 - 2.28 (m, 1H), 2.15 (s, 6H), 2.05–2.00 (m, 1H), 1.98 - 1.94 (m, 2H), 1.92 - 1.86 (m, 2H).

[0375] Example 15

[0376]

[0377] Reaction procedure:

[0378]

[0379] Step A: Synthesis of Example 15

[0380] Add 5-3 (130 mg), 1,4-dioxane (10 mL), A-3 (177 mg), potassium carbonate (141 mg) aqueous solution (0.5 mL), 3-(di-tert-butylphosphino) propane-1-sulfonic acid (9.15 mg) aqueous solution (0.5 mL), and disodium tetrachloropalladate(IV) (5.02 mg) into a single-necked flask in sequence. Under N2 protection, heat the mixture to 80 °C and stir for 1 h. After the reaction is completed, add 50 mL of water, extract with dichloromethane (50 mL × 3), combine the organic phases, wash with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure to dryness, and purify the obtained crude product by silica gel column chromatography to obtain Example 15 (158 mg). MS (ESI+, [M+H] + ) m / z: 521.29. 1 1H NMR (500 MHz, DMSO-d6) δ 8.83 (s, 1H), 8.54 (t, J = 2.0 Hz, 1H), 8.33 (d, J = 8.2 Hz, 1H), 8.08 (dt, J = 8.6, 2.2 Hz, 1H), 7.93 (d, J = 12.1 Hz, 1H), 7.00 (d, J = 8.6 Hz, 1H), 5.58 (s, 2H), 5.09 (tt, J = 11.8, 4.3 Hz, 1H), 4.36 (t, J = 6.6 Hz, 2H), 4.03 (dd, J = 11.3, 4.6 Hz, 2H), 3.54 (td, J = 12.0, 1.9 Hz, 2H), 2.70 (qd, J = 12.5, 4.7 Hz, 2H), 2.41–2.34 (m, 6H), 1.93–1.89 (m, 4H), 1.52-1.47 (m, 4H), 1.40-1.37 (m, 2H).

[0381] Example 16

[0382]

[0383] Reaction process:

[0384]

[0385] Step A: Synthesis of Compound 16-1

[0386] Add isopropylamine (167.4 mg) and THF (15 mL) into a single-necked flask in sequence. Under nitrogen protection at 0 °C, add sodium hydride (228 mg), stir for 5 min, and then add 10-1 (600 mg). Stir at room temperature for 15 min. After the reaction is completed, add 50 mL of water, filter, collect the filter cake, and wash the filter cake with water (5 mL × 3) and petroleum ether (5 mL × 2) in sequence to obtain Intermediate 16-1 (500 mg). MS (ESI+, [M+H] +)m / z: 339.92.

[0387] Step B: Synthesis of Compound 16-2

[0388] Add 16-1 (500 mg), DCM (20 mL), acetic acid (10 mL), and iron powder (410 mg) into a single-neck flask in sequence. Under nitrogen protection, react at room temperature for 1 h. After the reaction is completed, filter, concentrate the filtrate to dryness, adjust the pH of the residue to 8-9 with saturated sodium bicarbonate solution, extract with DCM (20 mL × 5), combine the organic phases, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain Intermediate 16-2 (400 mg). MS (ESI+, [M+H] + )m / z: 309.90.

[0389] Step C: Synthesis of Compound 16-3

[0390] Add 16-2 (0.3 g), THF (10 mL), DIPEA (0.625 g), and CDI (0.784 g) into a single-neck flask in sequence. Under nitrogen protection, react at room temperature for 12 h. After the reaction is completed, add ice water (100 ml), filter, collect the filter cake, and wash the filter cake with water (5 mL × 3) and petroleum ether (5 mL × 2) in sequence to obtain Intermediate 16-3 (0.23 g). MS (ESI+, [M+H] + )m / z: 335.83.

[0391] Step D: Synthesis of Compound 16-4

[0392] Add 16-3 (180 mg), DCM (5 mL), water (2 mL), TBAB (17.26 mg), 2,4-dinitrophenylhydroxylamine (160 mg), and NaOH (0.59 mg) into a single-neck flask in sequence. Stir at room temperature for 24 h under N2 protection. After the reaction is completed, concentrate to remove most of the solvent, filter, slurry the filter cake with acetonitrile (10 mL), and dry in vacuo to obtain Intermediate 16-4 (118 mg). MS (ESI+, [M+H] + )m / z: 350.88.

[0393] Step E: Synthesis of Example 16

[0394] To a single-necked flask, 16-4 (50 mg), 1,4-dioxane (5 mL), water (2 mL), A-3 (64.1 mg), potassium carbonate (59 mg), 3-(di-tert-butylphosphino)propane-1-sulfonic acid (1.0 mg), and disodium tetrachloropalladate(IV) (0.5 mg) were added successively. Under nitrogen protection, the mixed solution was stirred at 80 °C for 1 h. After the reaction was completed, the reaction solution was concentrated, and the residue was dissolved in DCM (50 mL), washed with saturated brine (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain Example 16 (38.6 mg). MS (ESI+, [M+H] + ) m / z: 491.28. 1 1H NMR (500 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.39 (d, J = 2.4 Hz, 1H), 8.11 (s, 1H), 7.96 (dd, J = 8.5, 2.6 Hz, 1H), 7.57 (s, 1H), 6.91 (d, J = 8.5 Hz, 1H), 5.50 (s, 2H), 5.22 (p, J = 6.7 Hz, 1H), 4.34 (t, J = 6.6 Hz, 2H), 3.92 (s, 3H), 2.39 (t, J = 7.2 Hz, 2H), 2.36–2.32 (m, 4H), 1.90 (p, J = 6.7 Hz, 2H), 1.62 (d, J = 6.7 Hz, 6H), 1.53–1.46 (m, 4H), 1.41–1.33 (m, 2H).

[0395] Example 17

[0396]

[0397] Reaction process:

[0398]

[0399] To a single-necked flask, 16-4 (50 mg), 1,4-dioxane (5 mL), water (2 mL), A-6 (82 mg), potassium carbonate (59 mg), 3-(di-tert-butylphosphino)propane-1-sulfonic acid (1.0 mg), and disodium tetrachloropalladate(IV) (0.5 mg) were added successively. Under nitrogen protection, the mixed solution was stirred at 80 °C for 1 h. After the reaction was completed, the reaction solution was concentrated, and the residue was dissolved in DCM (50 mL), washed with saturated brine (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain Example 17 (10.3 mg). MS (ESI+, [M+H] + ) m / z: 477.26. 11H NMR (500 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.39 (d, J = 2.6 Hz, 1H), 8.11 (s, 1H), 7.96 (dd, J = 8.5, 2.6 Hz, 1H), 7.57 (s, 1H), 6.91 (d, J = 8.5 Hz, 1H), 5.50 (s, 2H), 5.27–5.15 (m, 1H), 4.36 (t, J = 6.6 Hz, 2H), 3.92 (s, 3H), 2.65–2.55 (m, 4H), 2.04–1.86 (m, 2H), 1.77–1.66 (m, 4H), 1.62 (d, J = 6.9 Hz, 6H), 1.28–1.22 (m, 2H).

[0400] Example 18

[0401]

[0402] Reaction process:

[0403]

[0404] Step A: Synthesis of compound 18-1

[0405] Add 2-5 (1.0 g), potassium carbonate (1.37 g), acetonitrile (40 mL), and cyclopropylamine (0.28 g) to a single-necked flask in sequence. Under N2 protection, stir the mixture at 95 °C for 4 h. After the reaction is completed, cool the reaction solution, add 150 mL of water, filter, wash the filter cake with water (5 mL × 4), and dry it under vacuum to obtain intermediate 18-1 (985 mg). MS (ESI+, [M+H] + ) m / z: 323.85

[0406] Step B: Synthesis of compound 18-2

[0407] Add 18-1 (750 mg), iodobenzene diacetate (745 mg), acetonitrile (10 mL), ethyl acetate (10 mL), water (10 mL), and KOH (260 mg) to a single-necked flask in sequence. Stir the reaction at room temperature overnight. After the reaction is completed, filter the reaction solution directly, wash the filter cake with water (10 mL × 2), and dry it under vacuum to obtain intermediate 18-2 (700 mg). MS (ESI+, [M+H] + ) m / z: 321.92.

[0408] Step C: Synthesis of compound 18-3

[0409] To a single-necked flask, add 18-2 (700 mg), DCM (20 mL), water (10 mL), TBAB (70 mg), 2,4-dinitrophenylhydroxylamine (650 mg), and NaOH (175 mg) in sequence, and stir the reaction overnight at room temperature. After the reaction is completed, concentrate to remove most of the solvent, filter, and slurry the filter cake with 5 mL of acetonitrile, then dry it under vacuum to obtain intermediate 18-3 (350 mg). MS (ESI+, [M+H] + ) m / z: 336.98.

[0410] Step D: Synthesis of Example 18

[0411] To a single-necked flask, add 18-3 (150 mg), 1,4-dioxane (5 mL), water (2 mL), A-3 (249 mg), potassium carbonate (183 mg), 3-(di-tert-butylphosphino) propane-1-sulfonic acid (2.37 mg), and disodium tetrachloropalladate(IV) (1.30 mg) in sequence. Under N2 protection, stir the mixed solution at 80 °C for 1 h. After the reaction is completed, concentrate the reaction solution, dissolve the residue in DCM (50 mL), wash it with saturated brine (2×10 mL), dry it with anhydrous sodium sulfate, filter and concentrate to obtain the crude product, and slurry it with acetonitrile (5 mL) to obtain Example 18 (80 mg). MS (ESI+, [M+H] + ) m / z: 477.27. 1 1H NMR (500 MHz, DMSO-d6) δ 8.91–8.77 (m, 2H), 8.61 (s, 1H), 8.13–7.99 (m, 1H), 7.89 (d, J = 12.3 Hz, 1H), 6.99 (d, J = 8.6 Hz, 1H), 5.53 (s, 2H), 4.36 (t, J = 6.6 Hz, 2H), 3.69–3.43 (m, 1H), 2.50–2.28 (m, 6H), 1.99–1.78 (m, 2H), 1.58–1.45 (m, 4H), 1.45–1.33 (m, 2H), 1.33–1.21 (m, 2H), 1.17–1.10 (m, 2H).

[0412] Example 19

[0413]

[0414] Reaction process:

[0415]

[0416] To a single-necked flask were successively added 18-3 (150 mg), 1,4-dioxane (5 mL), water (2 mL), A-6 (249 mg), potassium carbonate (183 mg), 3-(di-tert-butylphosphino)propane-1-sulfonic acid (2.37 mg), and disodium tetrachloropalladate(IV) (1.30 mg). Under N2 protection, the mixed solution was stirred at 80 °C for 1 h. After the reaction was completed, the reaction solution was concentrated. The residue was dissolved in DCM (50 mL), washed with saturated brine (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was slurried with acetonitrile (5 mL) to obtain Example 19 (60 mg). MS (ESI+, [M+H] + ) m / z: 463.37. 1 1H NMR (500 MHz, DMSO-d6) δ 9.00–8.75 (m, 2H), 8.50 (s, 1H), 8.05 (dt, J = 8.6, 2.2 Hz, 1H), 7.89 (d, J = 12.3 Hz, 1H), 6.99 (d, J = 8.5 Hz, 1H), 5.53 (s, 2H), 4.37 (t, J = 6.6 Hz, 2H), 3.59–3.51 (m, 1H), 2.55 (t, J = 7.2 Hz, 2H), 2.49–2.38 (m, 4H), 1.99–1.80 (m, 2H), 1.82–1.64 (m, 4H), 1.30–1.20 (m, 2H), 1.17–1.09 (m, 2H).

[0417] Example 20

[0418]

[0419] Reaction process:

[0420]

[0421] Step A: Synthesis of Compound 20-1

[0422] To a single-necked flask were successively added 2-5 (1.0 g), potassium carbonate (1.37 g), acetonitrile (40 mL), and 3-methoxycyclobutanamine hydrochloride (0.46 g). Under N2 protection, the mixture was stirred at 95 °C for 4 h. After the reaction was completed, the reaction solution was cooled, 150 mL of water was added, and the mixture was filtered. The filter cake was washed with water (5 mL × 4) and dried in vacuo to obtain Intermediate 20-1 (1.06 g). MS (ESI+, [M+H] + ) m / z: 367.95.

[0423] Step B: Synthesis of Compound 20-2

[0424] Add 20-1 (500 mg), DBU (413 mg), and methanol (30 mL) to a single-necked flask in sequence. At 5 °C, add 1,3,5-trichloro-1,3,5-triazine-2,4,6-trione (158 mg). Under N2 protection, stir at room temperature for 1 h. After the reaction is completed, directly filter the reaction solution. Wash the filter cake with water (10 mL × 2), and dry it under vacuum to obtain intermediate 20-2 (350 mg). MS (ESI+, [M+H] + ) m / z: 366.94.

[0425] Step C: Synthesis of Compound 20-3

[0426] Add 20-2 (350 mg), DCM (20 mL), water (10 mL), TBAB (31 mg), 2,4-dinitrophenylhydroxylamine (285 mg), and NaOH (76 mg) to a single-necked flask in sequence. Stir the reaction at room temperature overnight. After the reaction is completed, concentrate to remove most of the solvent, filter, and slurry the filter cake with 5 mL of acetonitrile, and dry it under vacuum to obtain intermediate 20-3 (240 mg). MS (ESI+, [M+H] + ) m / z: 380.97.

[0427] Step D: Synthesis of Example 20

[0428] Add 20-3 (150 mg), 1,4-dioxane (5 mL), water (2 mL), A-3 (249 mg), potassium carbonate (183 mg), 3-(di-tert-butylphosphino)propane-1-sulfonic acid (2.37 mg), and disodium tetrachloropalladate(IV) (1.30 mg) to a single-necked flask in sequence. Under N2 protection, stir the mixed solution at 80 °C for 1 h. After the reaction is completed, concentrate the reaction solution, dissolve the residue in DCM (50 mL), wash it with saturated brine (2 × 10 mL), dry it with anhydrous sodium sulfate, filter and concentrate to obtain the crude product, and slurry it with acetonitrile (5 mL) to obtain Example 20 (80 mg). MS (ESI+, [M+H] + ) m / z: 521.31. 11H NMR (500 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.56–8.47 (m, 1H), 8.37 (d, J = 8.1 Hz, 1H), 8.09–7.99 (m, 1H), 7.90 (d, J = 12.0 Hz, 1H), 6.98 (d, J = 8.5 Hz, 1H), 5.55 (s, 2H), 5.21–5.02 (m, 1H), 4.36 (t, J = 6.6 Hz, 2H), 3.90–3.76 (m, 1H), 3.18 (s, 3H), 3.05–2.93 (m, 2H), 2.86–2.74 (m, 2H), 2.43–2.22 (m, 6H), 1.97–1.86 (m, 2H), 1.54–1.45 (m, 4H), 1.46–1.33 (m, 2H).

[0429] Example 21

[0430]

[0431] Reaction process:

[0432]

[0433] 20-3 (150 mg), 1,4-dioxane (5 mL), water (2 mL), A-12 (249 mg), potassium carbonate (183 mg), 3-(di-tert-butylphosphino) propane-1-sulfonic acid (2.37 mg) and disodium tetrachloropalladate(IV) (1.30 mg) were successively added to a single-necked flask. Under N2 protection, the mixed solution was stirred at 80 °C for 1 h. After the reaction was completed, the reaction solution was concentrated, and the residue was dissolved in DCM (50 mL), washed with saturated brine (2 × 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product, which was slurried with acetonitrile (5 mL) to obtain Example 21 (95 mg). MS (ESI+, [M+H] + ) m / z: 481.31. 1 1H NMR (500 MHz, DMSO-d6) δ 8.91–8.77 (m, 1H), 8.51 (s, 1H), 8.38 (s, 1H), 8.15–8.00 (m, 1H), 8.00–7.86 (m, 1H), 6.99 (s, 1H), 5.55 (s, 2H), 5.10 (s, 1H), 4.49–4.30 (m, 2H), 3.90–3.75 (m, 1H), 3.18 (s, 3H), 3.09–2.93 (m, 2H), 2.90–2.75 (m, 2H), 2.42–2.35 (m, 2H), 2.16 (s, 6H), 2.01–1.86 (m, 2H).

[0434] Example 22

[0435]

[0436] Reaction process:

[0437]

[0438] Step A: Synthesis of compound 22-1

[0439] Add 2-8 (100 mg), 1,4-dioxane (3 mL), 2-fluoropyrimidine-5-boronic acid pinacol ester (100 mg), potassium carbonate (122 mg) dissolved in 0.5 mL of water, 3-(di-tert-butylphosphino)propane-1-sulfonic acid (3.96 mg) dissolved in 0.5 mL of water, and disodium tetrachloropalladate(IV) (2.17 mg) into a single-necked flask in sequence. Under N2 protection, heat the mixture to 80 °C and stir for 1 h. After the reaction is completed, add 10 mL of water, extract with dichloromethane, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure to dryness. The obtained crude product is purified by silica gel column chromatography (eluent: DCM / MeOH) to obtain intermediate 22-1 (105 mg). MS (ESI+, [M+H] + ) m / z: 356.05. 1 1H NMR (500 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.60 (t, J = 1.7 Hz, 1H), 8.39 (d, J = 8.1 Hz, 1H), 8.35 (tt, J = 8.1, 2.1 Hz, 1H), 7.96 (d, J = 12.0 Hz, 1H), 7.40 (dd, J = 8.5, 2.8 Hz, 1H), 5.56 (s, 2H), 5.31 (p, J = 6.7 Hz, 1H), 1.64 (d, J = 6.7 Hz, 6H).

[0440] Step B: Synthesis of compound 22-3

[0441] Add 22-2 (1 g), ethanol (100 mL), pyrrolidine (555 mg), and 10% (purity, mass percentage) Pd / C (0.831 g) into a single-necked flask in sequence. Stir the mixture at room temperature overnight under a H2 atmosphere. After the reaction is completed, filter through diatomaceous earth, and concentrate the filtrate under reduced pressure to dryness to obtain intermediate 22-3 (1.4 g).

[0442] Step C: Synthesis of compound 22-4

[0443] To a single-necked flask, 22-3 (200 mg) and tetrahydrofuran (5 mL) were added successively. At 0 °C, 2.5 M lithium aluminum hydride-tetrahydrofuran solution (1.31 mL) was added. Under N2 protection, the mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was poured into 2 mL of water, stirred for 5 min, filtered through diatomaceous earth, and the filtrate was concentrated to dryness under reduced pressure to obtain intermediate 22-4 (150 mg).

[0444] Step D: Synthesis of Example 22

[0445] To a single-necked flask, 22-4 (131 mg) and tetrahydrofuran (5 mL) were added successively. Under N2 protection, 60 wt% sodium hydride (56 mg) was added at 0 °C. The mixture was heated to 50 °C and stirred for 20 min, then 22-1 (100 mg) was added and stirred for 2 h. After the reaction was completed, the reaction solution was slowly poured into 10 mL of ice water, stirred for 10 min, extracted with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: DCM / MeOH) to obtain Example 22 (66 mg). MS (ESI+, [M+H] + ) m / z: 491.25. 1 H NMR (500 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.49 (s, 1H), 8.32 (d, J = 8.1 Hz, 1H), 8.04 (dt, J = 8.6, 2.3 Hz, 1H), 7.91 (d, J = 12.0 Hz, 1H), 6.98 (d, J = 8.6 Hz, 1H), 5.55 (s, 2H), 5.33 - 5.25 (m, 1H), 4.30 (d, J = 6.5 Hz, 2H), 2.80 (p, J = 7.8 Hz, 1H), 2.44 (q, J = 8.0 Hz, 1H), 2.37 (d, J = 5.8 Hz, 4H), 2.18 - 2.13 (m, 2H), 1.75 - 1.71 (m, 2H), 1.69 - 1.66 (m, 4H), 1.64 (d, J = 6.7 Hz, 6H).

[0446] Example 23

[0447]

[0448] Reaction process:

[0449]

[0450] Step A: Synthesis of Compound 23-2

[0451] Add 3-bromopropanol (20 g), DCM (150 mL) and imidazole (17.14 g) to a single-necked flask in sequence. Under N2 protection, add tert-butyldimethylchlorosilane (21.69 g) at 0 °C, stir for 15 min, and stir the mixture at room temperature for 1 h. After the reaction is completed, add 50 mL of DCM and 50 mL of saturated brine to the reaction solution. After liquid separation, the aqueous phase is extracted again with 40 mL of DCM. The combined organic phases are dried over anhydrous sodium sulfate, filtered by suction, and the solvent is evaporated to obtain intermediate 23-2 (36 g). GC-MS (EI, M + ) m / z: 253.

[0452] Step B: Synthesis of compound 23-3

[0453] Add 23-2 (8 g), acetonitrile (40 mL), 3-fluoroazetidine hydrochloride (3.6 g), potassium carbonate (13.1 g) and potassium iodide (2.62 g) to a single-necked flask in sequence. Under N2 protection, heat the mixture to 60 °C and react for 2 h. After the reaction is completed, add 100 mL of water, extract with EA, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to dryness to obtain intermediate 23-3 (7.0 g). GC-MS (EI, M + ) m / z: 247.

[0454] Step C: Synthesis of compound 23-4

[0455] Add 23-3 (0.78 g), dioxane (20 mL), and dioxane hydrochloride solution (4 M, 27 mL) to a single-necked flask in sequence. Stir the mixture at room temperature for 2 h. After the reaction is completed, concentrate the reaction solution to remove the solvent, then add 200 mL of EA and 5 g of Na2CO3, stir at room temperature for 30 min, filter by suction, and concentrate the filtrate to remove the solvent to obtain intermediate 23-4 (3.2 g). GC-MS (EI, M + ) m / z: 133.

[0456] Step D: Synthesis of compound 23-5

[0457] Referring to the synthesis of Preparation Example A-3, in the preparation step of A-2, replace A-1 with 23-4 to obtain compound 23-5. MS (ESI+, [M+H] + ) m / z: 288.87.

[0458] Step E: Synthesis of compound 23-6

[0459] Referring to the synthesis of Preparation Example A-3, in the preparation step of A-3, replace A-2 with 23-5 to obtain compound 23-6. MS (ESI+, [M+H] + ) m / z: 337.00.

[0460] Step F: Synthesis of Example 23

[0461] 2-8 (100 mg), 1,4-dioxane (6 mL), 23-6 (mg), potassium carbonate (61 mg) dissolved in 0.5 mL of water, 3-(di-tert-butylphosphino) propane-1-sulfonic acid (4 mg) dissolved in 0.5 mL of water, and disodium tetrachloropalladate(IV) (2 mg) were successively added to a single-necked flask. Under N2 protection, the mixture was heated to 80 °C and stirred for 1 h. After the reaction was completed, 50 mL of water was added, and the mixture was extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and the obtained crude product was purified by silica gel column chromatography to obtain Example 23 (60 mg). MS (ESI+, [M+H] + ) m / z: 469.17. 1 H NMR (500 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.68–8.45 (m, 1H), 8.32 (d, J = 8.0 Hz, 1H), 8.04 (dt, J = 8.5, 2.4 Hz, 1H), 7.91 (d, J = 11.9 Hz, 1H), 6.98 (d, J = 8.6 Hz, 1H), 5.55 (s, 2H), 5.30 (h, J = 6.6 Hz, 1H), 5.15 (dp, J = 57.8, 5.1 Hz, 1H), 4.35 (t, J = 6.6 Hz, 2H), 3.76–3.51 (m, 2H), 3.12–3.00 (m, 2H), 2.58 (t, J = 6.9 Hz, 2H), 1.78 (p, J = 6.7 Hz, 2H), 1.65 (d, J = 6.6 Hz, 6H).

[0462] Example 24

[0463]

[0464] Reaction process:

[0465]

[0466] Step A: Synthesis of Compound 24-1

[0467] Referring to the synthesis of Example 23, in the preparation step of 23-3, 3,3-difluorotrimethyleneimine hydrochloride was used instead of 3-fluoroazetidine hydrochloride to obtain Compound 24-1. GC-MS (EI, M + ) m / z: 265.

[0468] Step B: Synthesis of Compound 24-2

[0469] Referring to the synthesis of Example 23, in the preparation step of 23-4, 23-3 was replaced with 24-1 to obtain compound 24-2. GC-MS (EI, M + ) m / z: 151.

[0470] Step C: Synthesis of compound 24-3

[0471] Referring to the synthesis of Example 23, in the preparation step of 23-5, 23-4 was replaced with 24-2 to obtain compound 24-3. MS (ESI+, [M+H] + ) m / z: 306.87.

[0472] Step D: Synthesis of compound 24-4

[0473] Referring to the synthesis of Example 23, in the preparation step of 23-6, 23-5 was replaced with 24-3 to obtain compound 24-4. MS (ESI+, [M+H] + ) m / z: 355.01.

[0474] Step E: Synthesis of Example 24

[0475] To a single-necked flask were successively added 2-8 (100 mg), 1,4-dioxane (6 mL), 24-4 (157 mg), potassium carbonate (119 mg) dissolved in 0.5 mL of water, 3-(di-tert-butylphosphino) propane-1-sulfonic acid (7.69 mg) dissolved in 0.5 mL of water, and disodium tetrachloropalladate(IV) (4.21 mg). Under N2 protection, the mixture was heated to 80 °C and stirred for 1 h. After the reaction was completed, 50 mL of water was added, and the mixture was extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and the obtained crude product was purified by silica gel column chromatography to obtain Example 24 (60 mg). MS (ESI+, [M+H] + ) m / z: 487.15. 1 1H NMR (500 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.50 (t, J = 1.8 Hz, 1H), 8.32 (d, J = 8.2 Hz, 1H), 8.05 (dt, J = 8.6, 2.3 Hz, 1H), 7.91 (d, J = 12.1 Hz, 1H), 6.99 (d, J = 8.6 Hz, 1H), 5.55 (s, 2H), 5.28 (h, J = 6.7 Hz, 1H), 4.37 (t, J = 6.5 Hz, 2H), 3.58 (t, J = 12.5 Hz, 4H), 2.68 (dd, J = 7.6, 6.0 Hz, 2H), 1.81 (p, J = 6.7 Hz, 2H), 1.65 (d, J = 6.7 Hz, 6H).

[0476] Example 25

[0477]

[0478] Reaction process:

[0479]

[0480] Step A: Synthesis of Compound 25-1

[0481] Referring to the synthesis in Example 23, in the preparation step of 23-3, replace 3-fluorazetidine hydrochloride with 3-(fluoromethyl)pyrrolidine to obtain Compound 25-1. GC-MS (EI, M + ) m / z: 275.

[0482] Step B: Synthesis of Compound 25-2

[0483] Referring to the synthesis in Example 23, in the preparation step of 23-4, replace 23-3 with 25-1 to obtain Compound 25-2. GC-MS (EI, M + ) m / z: 161.

[0484] Step C: Synthesis of Compound 25-3

[0485] Referring to the synthesis in Example 23, in the preparation step of 23-5, replace 23-4 with 25-2 to obtain Compound 25-3. MS (ESI+, [M+H] + ) m / z: 316.91.

[0486] Step D: Synthesis of Compound 25-4

[0487] Referring to the synthesis in Example 23, in the preparation step of 23-6, replace 23-5 with 25-3 to obtain Compound 25-4. MS (ESI+, [M+H] + ) m / z: 365.13.

[0488] Step E: Synthesis of Example 25

[0489] 2-8 (100 mg), 1,4-dioxane (6 mL), 25-4 (157 mg), potassium carbonate (119 mg) dissolved in 0.5 mL of water, 3-(di-tert-butylphosphino)propane-1-sulfonic acid (7.69 mg) dissolved in 0.5 mL of water, and disodium tetrachloropalladate(IV) (4.21 mg) were successively added to a single-necked flask. Under N2 protection, the mixture was heated to 80 °C and stirred for 1 h. After the reaction was completed, 50 mL of water was added, and the mixture was extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and the obtained crude product was purified by silica gel column chromatography to obtain Example 25 (40 mg). MS (ESI+, [M+H] + ) m / z: 497.24. 1 H NMR (500 MHz, Chloroform-d) δ 8.94 (s, 1H), 8.41 (d, J = 2.4 Hz, 1H), 8.18 (d, J = 7.9 Hz, 1H), 7.93–7.84 (m, 2H), 6.89 (d, J = 8.6 Hz, 1H), 5.31–5.13 (m, 1H), 4.50 (s, 2H), 4.44 (t, J = 6.4 Hz, 2H), 4.40–4.37 (m, 1H), 4.31–4.28 (m, 1H), 2.80–2.51 (m, 6H), 2.47 (dd, J = 9.3, 5.4 Hz, 1H), 2.09–2.01 (m, 2H), 1.97 (ddd, J = 13.2, 9.7, 6.6 Hz, 1H), 1.76 (d, J = 6.9 Hz, 6H), 1.57–1.46 (m, 1H).

[0490] Example 26

[0491]

[0492] Reaction process:

[0493]

[0494] Step A: Synthesis of Compound 26-1

[0495] Referring to the synthesis of Example 23, in the preparation step of 23-3, 3-fluorazetidine hydrochloride was replaced with 3,3-difluoropyrrolidine hydrochloride to obtain Compound 26-1. GC-MS (EI, M + ) m / z: 279.

[0496] Step B: Synthesis of Compound 26-2

[0497] Referring to the synthesis of Example 23, in the preparation step of 23-4, 23-3 was replaced with 26-1 to obtain Compound 26-2. GC-MS (EI, M+ ) m / z: 165.

[0498] Step C: Synthesis of Compound 26-3

[0499] Referring to the synthesis of Example 23, in the preparation step of 23-5, replace 23-4 with 26-2 to obtain Compound 26-3. MS(ESI+, [M+H] + ) m / z: 320.86.

[0500] Step D: Synthesis of Compound 26-4

[0501] Referring to the synthesis of Example 23, in the preparation step of 23-6, replace 23-5 with 26-3 to obtain Compound 26-4. MS(ESI+, [M+H] + ) m / z: 369.02.

[0502] Step E: Synthesis of Example 26

[0503] Add 2-8 (100 mg), 1,4-dioxane (6 mL), 26-4 (157 mg), potassium carbonate (119 mg) dissolved in 0.5 mL of water, 3-(di-tert-butylphosphino) propane-1-sulfonic acid (7.69 mg) dissolved in 0.5 mL of water, and disodium tetrachloropalladate(IV) (4.21 mg) into a single-necked flask in sequence. Under N2 protection, heat the mixture to 80 °C and stir for 1 h. After the reaction is completed, add 50 mL of water, extract with dichloromethane, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure to dryness, and purify the obtained crude product by silica gel column chromatography to obtain Example 26 (40 mg). MS(ESI+, [M+H] + ) m / z: 501.15. 1 H NMR(500 MHz, Chloroform-d) δ 8.94 (s, 1H), 8.41 (d, J = 2.4 Hz, 1H), 8.18 (d, J = 7.9 Hz, 1H), 8.03–7.85 (m, 2H), 6.89 (d, J = 8.6 Hz, 1H), 5.29–5.08 (m, 1H), 4.50 (s, 2H), 4.45 (t, J = 6.4 Hz, 2H), 2.94 (t, J = 13.3 Hz, 2H), 2.78 (t, J = 6.9 Hz, 2H), 2.67 (t, J = 7.3 Hz, 2H), 2.29 (tt, J = 14.6, 6.9 Hz, 2H), 2.02 (p, J = 6.6 Hz, 2H), 1.76 (d, J = 7.0 Hz, 6H).

[0504] Example 27

[0505]

[0506] Reaction process:

[0507]

[0508] Step A: Synthesis of compound 27-2

[0509] Add 27-1 (1.0 g), 23-2 (1.0 g), potassium carbonate (1.6 g), potassium iodide (0.33 g), and acetonitrile (15 mL) to a single-necked flask in sequence, and heat to 60 °C for reaction. After the reaction is completed, add 50 mL of water, extract with dichloromethane, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, concentrate the filtrate, and obtain intermediate 27-2 (1.0 g) without purification, which is directly used for the next step. MS (ESI+, [M+H] + ) m / z: 270.23.

[0510] Step B: Synthesis of compound 27-3

[0511] Add 27-2 (1.0 g) and hydrochloric acid ethyl acetate solution (1 M, 20 mL) to a single-necked flask in sequence, and react at room temperature. After the reaction is completed, directly concentrate the reaction system to obtain intermediate 27-3 (0.5 g). MS (ESI+, [M+H] + ) m / z: 156.14.

[0512] Step C: Synthesis of compound 27-4

[0513] Add 27-3 (0.5 g), THF (15 mL), and 5-bromo-2-fluoropyridine (0.68 g) to a single-necked flask in sequence. Add sodium hydride (60 wt%, 0.39 g) under ice bath, and then react at room temperature. After the reaction is completed, add ice-cold saturated ammonium chloride solution to the system, extract with DCM, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate the filtrate to dryness, and purify the obtained crude product by silica gel column chromatography (DCM / MeOH) to obtain intermediate 27-4 (326 mg). MS (ESI+, [M+H] + ) m / z: 310.91.

[0514] Step D: Synthesis of compound 27-5

[0515] Add 27-4 (326 mg), THF (10 mL), and isopropyl alcohol pinacol borate (253 mg) to a single-necked flask in sequence. Under nitrogen protection, cool the temperature to -78 °C, then dropwise add a n-butyllithium n-hexane solution (2.5 M, 1.25 mL). After the addition, keep the reaction mixture at the same temperature for 1 h, and then restore it to room temperature for reaction. After the reaction is completed, add saturated ammonium chloride to quench the reaction under an ice bath, dilute with 50 mL of water, extract with EA, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain intermediate 27-5 (330 mg). MS (ESI+, [M+H] + ) m / z: 359.13.

[0516] Step E: Synthesis of Example 27

[0517] Add 27-5 (330 mg), 1,4-dioxane (10 mL), water (2.5 mL), intermediate 2-8 (150 mg), potassium carbonate (183 mg), 3-(di-tert-butylphosphino) propane-1-sulfonic acid (2.4 mg), and disodium tetrachloropalladate(IV) (1.3 mg) to a single-necked flask in sequence. Under nitrogen protection, react the mixed solution at 80 °C. After the reaction is completed, add 20 mL of water, extract with dichloromethane, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure to dryness, and purify the obtained crude product by silica gel column chromatography (DCM / MeOH) to obtain Example 27 (120 mg). MS (ESI+, [M+H] + ) m / z: 491.26. 1 H NMR (500 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.54–8.49 (m, 1H), 8.32 (d, J = 8.2 Hz, 1H), 8.07 (dt, J = 8.5, 2.3 Hz, 1H), 7.92 (d, J = 12.1 Hz, 1H), 7.00 (d, J = 8.5 Hz, 1H), 5.56 (s, 2H), 5.29 (p, J = 6.8 Hz, 1H), 4.42 (t, J = 6.3 Hz, 2H), 4.10–3.54 (m, 2H), 3.07–2.68 (m, 2H), 2.18–1.99 (m, 2H), 1.92–1.85 (m, 4H), 1.65 (d, J = 6.7 Hz, 6H), 1.56–1.44 (m, 4H).

[0518] Example 28

[0519]

[0520] Reaction process:

[0521]

[0522] Step A: Synthesis of Compound 28-2

[0523] Add 28-1 (5.0 g) and DCM (50 mL) to a single-necked flask in sequence. Slowly add diethylaminosulfur trifluoride (8.61 g) dropwise under an ice bath. After the addition is complete, react at room temperature. After the reaction is completed, slowly add saturated sodium bicarbonate to quench the reaction. Add 200 mL of water, extract with DCM, wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate the filtrate to obtain intermediate 28-2 (5.0 g), which is used directly in the next step without purification. GC-MS (EI, M + ) m / z: 189.

[0524] Step B: Synthesis of Compound 28-3

[0525] Add 28-2 (5.0 g) and 1,4-dioxane hydrochloride solution (4 M, 50 mL) to a single-necked flask in sequence. React at room temperature. After the reaction is completed, directly concentrate the system to obtain intermediate 28-3 (5.0 g). GC-MS (EI, M + ) m / z: 89.

[0526] Step C: Synthesis of Compound 28-4

[0527] Add 28-3 (5.0 g), 23-2 (10.0 g), potassium carbonate (16.37 g), potassium iodide (3.28 g), and acetonitrile (150 mL) to a single-necked flask in sequence. Heat to 60 °C and react. After the reaction is completed, add 500 mL of water, extract with dichloromethane, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, concentrate the filtrate to obtain intermediate 28-4 (5.0 g), which is used directly in the next step without purification. GC-MS (EI, M + ) m / z: 261.

[0528] Step D: Synthesis of Compound 28-5

[0529] Add 28-4 (5.0 g) and 1,4-dioxane hydrochloride solution (4 M, 50 mL) to a single-necked flask in sequence. React at room temperature. After the reaction is completed, directly concentrate the system to obtain intermediate 28-5 (3.0 g). GC-MS (EI, M + ) m / z: 147.

[0530] Step E: Synthesis of Compound 28-6

[0531] Add 28-5 (3.0 g), THF (100 mL), and 5-bromo-2-fluoropyridine (2.43 g) to a single-necked flask in sequence. Add sodium hydride (60 wt%, 1.38 g) under an ice bath, and then react at room temperature. After the reaction is completed, add ice-cold saturated ammonium chloride solution (500 mL) to the reaction system, extract with DCM, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate the filtrate to dryness, and purify the obtained crude product by silica gel column chromatography (DCM / MeOH) to obtain intermediate 28-6 (0.4 g). MS (ESI+, [M+H] + ) m / z: 302.89.

[0532] Step F: Synthesis of Compound 28-7

[0533] Add 28-6 (0.4 g), THF (10 mL), and isopropyl alcohol pinacol borate (319 mg) to a single-necked flask in sequence. Under nitrogen protection, cool to -78 °C, and then dropwise add n-butyllithium in hexane solution (2.5 M, 0.8 mL). After the addition, keep the temperature for 1 h, and then resume the reaction at room temperature. After the reaction is completed, quench the system with saturated ammonium chloride under an ice bath, dilute with 50 mL of water, extract with EA, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain intermediate 28-7 (400 mg). MS (ESI+, [M+H] + ) m / z: 351.10.

[0534] Step G: Synthesis of Example 28

[0535] Add 28-7 (232 mg), 1,4-dioxane (10 mL), water (2.5 mL), intermediate 2-8 (150 mg), potassium carbonate (183 mg), 3-(di-tert-butylphosphino) propane-1-sulfonic acid (2.4 mg), and disodium tetrachloropalladate(IV) (1.3 mg) to a single-necked flask in sequence. Under nitrogen protection, react the mixed solution at 80 °C. After the reaction is completed, add 20 mL of water, extract with dichloromethane, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure to dryness, and purify the obtained crude product by silica gel column chromatography (DCM / MeOH) to obtain Example 28 (90 mg). MS (ESI+, [M+H]+) m / z: 483.17. 11H NMR (500 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.50 (s, 1H), 8.32 (d, J = 8.1 Hz, 1H), 8.04 (dt, J = 8.5, 2.3 Hz, 1H), 7.91 (d, J = 11.9 Hz, 1H), 6.98 (d, J = 8.5 Hz, 1H), 5.55 (s, 2H), 5.34–5.24 (m, 1H), 4.51 (dd, J = 47.6, 6.1 Hz, 2H), 4.34 (t, J = 6.6 Hz, 2H), 3.29 (d, J = 7.3 Hz, 2H), 2.96 (t, J = 6.8 Hz, 2H), 2.78–2.67 (m, 1H), 2.54 (d, J = 7.0 Hz, 2H), 1.80–1.70 (m, 2H), 1.64 (d, J = 6.7 Hz, 6H).

[0536] Example 29

[0537]

[0538] Reaction process:

[0539]

[0540] Step A: Synthesis of compound 29-2

[0541] Add 29-1 (0.20 g), 23-2 (0.38 g), potassium carbonate (0.62 g), potassium iodide (0.13 g), and acetonitrile (15 mL) to a single-necked flask in sequence, and heat to 60 °C for reaction. After the reaction is completed, add 50 mL of water, extract with dichloromethane, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain intermediate 29-2 (0.15 g) without purification and directly use it for the next step. GC-MS (EI, M + ) m / z: 269.

[0542] Step B: Synthesis of compound 29-3

[0543] Add 29-2 (0.15 g) and hydrochloric acid ethyl acetate solution (1 M, 10 mL) to a single-necked flask in sequence, and react at room temperature. After the reaction is completed, directly concentrate the system to obtain intermediate 29-3 (0.12 g). GC-MS (EI, M + ) m / z: 155.

[0544] Step C: Synthesis of compound 29-4

[0545] To a single-necked flask, add 29-3 (0.12 g), THF (10 mL), and 5-bromo-2-fluoropyridine (0.14 g) successively. Add sodium hydride (60 wt%, 0.08 g) under an ice bath, and then react at room temperature. After the reaction is completed, add ice-cold saturated ammonium chloride solution to the system, extract with DCM, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate the filtrate to dryness, and purify the obtained crude product by silica gel column chromatography (DCM / MeOH) to obtain intermediate 29-4 (120 mg). MS (ESI+, [M+H] + ) m / z: 310.92.

[0546] Step D: Synthesis of Compound 29-5

[0547] To a single-necked flask, add 29-4 (120 mg), THF (10 mL), and isopropyl alcohol pinacol borate (93 mg) successively. Under nitrogen protection, cool the temperature to -78 °C, and then dropwise add n-butyllithium in hexane solution (2.5 M, 0.23 mL). After the addition is complete, keep the reaction at the same temperature for 1 h, and then resume the reaction at room temperature. After the reaction is completed, add saturated ammonium chloride to quench the reaction under an ice bath, dilute with 50 mL of water, extract with EA, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain intermediate 29-5 (130 mg). MS (ESI+, [M+H] + ) m / z: 359.12.

[0548] Step E: Synthesis of Example 29 To a single-necked flask, add 29-5 (130 mg), 1,4-dioxane (10 mL), water (2.5 mL), 2-8 (150 mg), potassium carbonate (122 mg), 3-(di-tert-butylphosphino) propane-1-sulfonic acid (1.58 mg), and disodium tetrachloropalladate(IV) (0.87 mg) successively. Under nitrogen protection, react the mixed solution at 80 °C. After the reaction is completed, add 20 mL of water, extract with dichloromethane, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure to dryness, and purify the obtained crude product by silica gel column chromatography (DCM / MeOH) to obtain Example 29 (55 mg). MS (ESI+, [M+H] + ) m / z: 491.26. 11H NMR (500 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.52–8.44 (m, 1H), 8.32 (d, J = 8.2 Hz, 1H), 8.04 (dt, J = 8.5, 2.3 Hz, 1H), 7.91 (d, J = 12.1 Hz, 1H), 6.97 (d, J = 8.5 Hz, 1H), 5.55 (s, 2H), 5.34–5.21 (m, 1H), 4.32 (t, J = 6.6 Hz, 2H), 3.07 (s, 4H), 2.44 (t, J = 7.0 Hz, 2H), 2.02 (t, J = 7.6 Hz, 4H), 1.79–1.68 (m, 4H), 1.64 (d, J = 6.9 Hz, 6H).

[0549] Example 30

[0550]

[0551] Reaction process:

[0552]

[0553] Step A: Synthesis of compound 30-1

[0554] Add 3-fluoro-5-methoxypyridin-4-amine (1.34 g) and DMF (20 mL) to a single-necked flask in sequence. Under nitrogen protection at 0 °C, slowly add 60 wt% sodium hydride (1.26 g). After stirring for 10 min, add 10-1 (2.0 g). React at room temperature for 20 min. After the reaction is completed, add ice water (100 mL), stir for 10 min, filter, collect the filter cake, and wash the filter cake with water (5 mL × 3) and petroleum ether (5 mL × 2) in sequence to obtain intermediate 30-1 (2.5 g). MS (ESI+, [M+H] + ) m / z: 422.95.

[0555] Step B: Synthesis of compound 30-2

[0556] Add 30-1 (2.5 g), DCM (50 mL), acetic acid (20 mL), and iron powder (1.65 g) to a single-necked flask in sequence. React at room temperature for 1 h under nitrogen protection. After the reaction is completed, filter the reaction solution, concentrate the filtrate to dryness, adjust the pH of the residue to 8 - 9 with saturated sodium bicarbonate solution (25 mL), extract with DCM (40 mL × 5), combine the organic phases, wash with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain intermediate 30-2 (1.8 g). MS (ESI+, [M+H] + ) m / z: 392.93.

[0557] Step C: Synthesis of compound 30-3

[0558] Add 30-2 (1.8 g), THF (40 mL), DIPEA (2.86 g), and CDI (2.28 g) to a single-necked flask in sequence, and react at room temperature for 4 h under nitrogen protection. After the reaction is completed, add ice water (200 mL) to the reaction solution, filter, collect the filter cake, wash the filter cake with water (10 mL × 3) and petroleum ether (10 mL × 2) in sequence, and drain to obtain intermediate 30-3 (1.2 g). MS (ESI+, [M+H] + ) m / z: 419.06.

[0559] Step D: Synthesis of compound 30-4

[0560] Add 30-3 (1.0 g), DCM (30 mL), water (15 mL), TBAB (77 mg), 2,4-dinitrophenylhydroxylamine (712 mg), and NaOH (191 mg) to a single-necked flask in sequence. Stir at room temperature for 24 h under N2 protection. After the reaction is completed, concentrate to remove the organic solvent, filter, and slurry the filter cake with a mixed solvent of acetonitrile:water = 1:1 (10 mL), and dry under vacuum to obtain intermediate 30-4 (0.8 g). MS (ESI+, [M+H] + ) m / z: 433.95. Step E: Synthesis of Example 30

[0561] Add 30-4 (100 mg), 1,4-dioxane (5 mL), water (2 mL), A-3 (130 mg), potassium carbonate (95 mg), 3-(di-tert-butylphosphino)propane-1-sulfonic acid (1.24 mg), and disodium tetrachloropalladate(IV) (0.68 mg) to a single-necked flask in sequence. Stir the mixed solution at 80 °C for 1 h under nitrogen protection. After the reaction is completed, concentrate the reaction solution, dissolve the residue in DCM (50 mL), wash with saturated brine (2 × 10 mL), dry with anhydrous sodium sulfate, filter and concentrate to obtain the crude product, and purify the crude product by silica gel column chromatography to obtain Example 30 (40.0 mg). HRMS (ESI+, [M+H] + ) m / z: 574.2573. 11H NMR (500 MHz, DMSO-d6) δ 8.86 (s, 1H), 8.69 (s, 1H), 8.65 (s, 1H), 7.99 (d, J = 2.6 Hz, 1H), 7.66 (dd, J = 8.5, 2.6 Hz, 1H), 7.58 (s, 1H), 6.93 (s, 1H), 6.81 (d, J = 8.7 Hz, 1H), 5.80 (s, 2H), 4.28 (t, J = 6.6 Hz, 2H), 3.91 (s, 3H), 3.87 (s, 3H), 2.45–2.28 (m, 6H), 1.92–1.84 (m, 2H), 1.55–1.47 (m, 4H), 1.43–1.36 (m, 2H).

[0562] Example 31

[0563]

[0564] Reaction process:

[0565]

[0566] 30-4 (100 mg), 1,4-dioxane (5 mL), water (2 mL), A-6 (133 mg), potassium carbonate (95 mg), 3-(di-tert-butylphosphino) propane-1-sulfonic acid (1.24 mg) and disodium tetrachloropalladate(IV) (0.68 mg) were successively added to a single-necked flask. Under nitrogen protection, the mixed solution was stirred at 80 °C for 1 h. After the reaction was completed, the reaction solution was concentrated, and the residue was dissolved in DCM (50 mL), washed with saturated brine (2 × 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain Example 31 (37.0 mg). HRMS (ESI+, [M+H] + ) m / z: 560.2412.

[0567] 1 1H NMR (500 MHz, DMSO-d6) δ 8.86 (s, 1H), 8.69 (s, 1H), 8.65 (s, 1H), 7.99 (d, J = 2.4 Hz, 1H), 7.66 (dd, J = 8.6, 2.5 Hz, 1H), 7.58 (s, 1H), 6.93 (s, 1H), 6.82 (d, J = 8.5 Hz, 1H), 5.80 (s, 2H), 4.30 (t, J = 6.6 Hz, 2H), 3.91 (s, 3H), 3.87 (s, 3H), 2.55–2.51 (m, 2H), 2.48–2.45 (m, 2H), 1.92–1.86 (m, 2H), 1.72–1.66 (m, 4H).

[0568] Example 32

[0569]

[0570] Reaction process:

[0571]

[0572] Step A: Synthesis of Compound 32-1

[0573] Add 2-1 (3.0 g), water (50 mL), concentrated hydrochloric acid (26.3 mL), and acetic acid (18.08 mL) into a three-necked flask in sequence. At 0 °C, drip an aqueous solution (30 mL) of sodium nitrite (1.20 g). After dripping, maintain the reaction at 0 °C for 2 h. Then, add sodium acetate (10.36 g) in batches while maintaining this temperature. After adding, keep stirring at the same temperature for 30 min. Denote the system as solution a. Separately, add 2-cyanoacetamide (1.6 g), ethanol (50 mL), and water (200 mL) into a single-necked flask. Add sodium acetate (51.8 g) while maintaining 0 °C. After dissolving clearly, keep the reaction at the same temperature for 30 min, and denote it as solution b. Then, drip solution a into solution b at 0 °C. After dripping, keep the reaction at the same temperature for 2 h. After the reaction is completed, let the system stand still and then filter. Wash the filter cake with water (10 mL × 5), and dry it under reduced pressure to obtain intermediate 32-1 (4.3 g).

[0574] Step B: Synthesis of Compound 32-2

[0575] Add 32-1 (4.0 g), o-dichlorobenzene (50 mL), and aluminum trichloride (5.61 g) into a three-necked flask in sequence. Under N2 protection, heat the mixture to 120 °C and react for 24 h. After the reaction is completed, cool the reaction solution, add 300 mL of water to quench the reaction under an ice bath, stir for 30 min, filter, collect the filter cake, wash it with 100 mL of water, then wash it with 20 mL of acetonitrile, and then wash it with 10 mL of petroleum ether, and dry it to obtain intermediate 32-2 (4.0 g). MS (ESI+, [M+H] + ) m / z: 284.78.

[0576] Step C: Synthesis of Compound 32-3

[0577] Add 32-2 (4.0 g), DMSO (20 mL), and 4M sulfuric acid (20 mL) into a single-necked flask in sequence. Under N2 protection, react the reaction solution at 130 °C for 30 h. After the reaction is completed, cool the reaction solution under an ice bath, add water (150 mL), filter, wash the filter cake with water (10 mL × 3), and dry it under vacuum to obtain intermediate 32-3 (3.0 g). MS (ESI-, [M+H] - ) m / z: 284.94.

[0578] Step D: Synthesis of Compound 32-4

[0579] Add 32-3 (3.0 g), thionyl chloride (30 mL), and DMF (0.06 g) successively into a single-necked flask. Under N2 protection, heat the reaction solution to reflux for 2 h. After the reaction is completed, cool the reaction solution, concentrate it under reduced pressure, add 100 mL of toluene and ultrasonicate, then concentrate again. Repeat this twice to obtain intermediate 32-4 (3.5 g), which is directly used in the next step of the reaction.

[0580] Step E: Synthesis of Compound 32-5

[0581] Add 32-4 (3.5 g) and acetonitrile (50 mL) into a single-necked flask and disperse them by ultrasonication. Then, drop 25% ammonium hydroxide solution (10 mL) into it at 0 °C. After dropping, stir vigorously for 30 minutes, filter, wash the filter cake with water (5 mL × 3), and dry it under vacuum to obtain intermediate 32-5 (2.1 g).

[0582] Step F: Synthesis of Compound 32-6

[0583] Add 32-5 (2.1 g), DIPEA (1.783 g), acetonitrile (30 mL), and isopropylamine (0.408 g) successively into a single-necked flask. Under N2 protection, stir the mixture at 80 °C for 5 h. After the reaction is completed, cool the reaction solution, add 100 mL of water, filter, wash the filter cake with water (5 mL × 4), and dry it under vacuum to obtain intermediate 32-6 (2.26 g). MS (ESI+, [M+H] + ) m / z: 326.87.

[0584] Step G: Synthesis of Compound 32-7

[0585] Add 32-6 (2.26 g), DBU (2.103 g), and methanol (20 mL) successively into a single-necked flask. At 5 °C, add 1,3,5-trichloro-1,3,5-triazine-2,4,6-trione (0.803 g). Under N2 protection, stir at room temperature for 1 h. After the reaction is completed, add 50 mL of water and stir for 10 min, filter, wash the filter cake with water (5 mL × 3), and dry it under vacuum to obtain intermediate 32-7 (2.0 g). MS (ESI+, [M+H] + ) m / z: 324.83.

[0586] Step H: Synthesis of Compound 32-8

[0587] To a single-necked flask, 32-7 (1.3 g), DCM (40 mL), water (20 mL), TBAB (198 mg), 2,4-dinitrophenylhydroxylamine (0.919 g), and NaOH (345 mg) were added successively. Under N2 protection, the reaction was carried out at room temperature for 24 h. After the reaction was completed, 100 mL of water was added, and the mixture was extracted with DCM (20 mL × 5). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain intermediate 32-8 (580 mg). MS (ESI+, [M+H] + ) m / z: 339.89.

[0588] Step I: Synthesis of Example 32

[0589] To a single-necked flask, 32-8 (80 mg), 1,4-dioxane (5 mL), water (2 mL), A-3 (163 mg), potassium carbonate (98 mg), 3-(di-tert-butylphosphino)propane-1-sulfonic acid (1.26 mg), and disodium tetrachloropalladate(IV) (0.69 mg) were added successively. Under N2 protection, the mixed solution was stirred at 80 °C for 1 h. After the reaction was completed, the reaction solution was concentrated, and the obtained residue was dissolved in DCM (50 mL), washed with saturated brine (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The obtained crude product was purified by high-pressure preparation (chromatographic column: Polar RP (10 μm, 21.2 × 250 mm); mobile phase: 10 mM ammonium acetate-0.1% acetic acid aqueous solution: acetonitrile = 60:40) to obtain Example 32 (40.0 mg). HRMS (ESI+, [M+H] + ) m / z: 480.2517. 1 1H NMR (500 MHz, DMSO-d6) δ 8.53 (t, J = 2.0 Hz, 1H), 8.35 (d, J = 7.8 Hz, 1H), 8.21 (d, J = 11.4 Hz, 1H), 8.07 (dt, J = 8.5, 2.3 Hz, 1H), 7.00 (d, J = 8.7 Hz, 1H), 5.59 (s, 2H), 5.26 (p, J = 6.8 Hz, 1H), 4.37 (t, J = 6.6 Hz, 2H), 2.39 (t, J = 7.2 Hz, 2H), 2.34–2.31 (m, 4H), 1.91 (p, J = 6.7 Hz, 2H), 1.64 (d, J = 6.7 Hz, 6H), 1.52–1.46 (m, 4H), 1.40–1.35 (m, 2H).

[0590] Example 33

[0591]

[0592] Reaction process:

[0593]

[0594] Step A: Synthesis of Compound 33-1

[0595] Add 32-8 (0.36 mg), THF (5 mL), NaOH (200 mg), and CH3I (0.9 g) into a single-necked flask in sequence, and react at room temperature for 1 h under N2 protection. After the reaction is completed, add 50 mL of water to the system, extract with EA (15 mL×3), wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate. The crude product is purified by silica gel column chromatography to obtain Intermediate 33-1 (120 mg). MS (ESI+, [M+H] + ) m / z: 353.96.

[0596] Step B: Synthesis of Example 33

[0597] Add 33-1 (65 mg), 1,4-dioxane (5 mL), water (2 mL), A-3 (127 mg), potassium carbonate (76 mg), 3-(di-tert-butylphosphino) propane-1-sulfonic acid (1.00 mg), and disodium tetrachloropalladate(IV) (0.5 mg) into a single-necked flask in sequence. Stir the mixed solution at 80 °C for 1 h under N2 protection. Concentrate the reaction solution, dissolve the residue in DCM (50 mL), wash with saturated brine (2×10 mL), dry over anhydrous sodium sulfate, filter, and concentrate to obtain the crude product, which is purified by high-pressure preparation (chromatographic column: Polar RP (10 μm, 21.2×250 mm); mobile phase: 10 mM ammonium acetate - 0.1% acetic acid aqueous solution: acetonitrile = 60:40) to obtain Example 33 (29 mg). HRMS (ESI+, [M+H] + ) m / z: 494.2683. 11H NMR (500 MHz, DMSO-d6) δ 8.53 (t, J = 2.1 Hz, 1H), 8.35 (d, J = 7.8 Hz, 1H), 8.21 (d, J = 11.4 Hz, 1H), 8.07 (dt, J = 8.5, 2.4 Hz, 1H), 7.00 (d, J = 8.5 Hz, 1H), 6.31 (q, J = 5.6 Hz, 1H), 5.30–5.20 (m, 1H), 4.37 (t, J = 6.6 Hz, 2H), 2.83 (d, J = 5.5 Hz, 3H), 2.39 (t, J = 7.2 Hz, 2H), 2.36–2.30 (m, 4H), 1.94–1.87 (m, 2H), 1.64 (d, J = 6.9 Hz, 6H), 1.52–1.47 (m, 4H), 1.42–1.34 (m, 2H).

[0598] Example 34

[0599]

[0600] Reaction process:

[0601]

[0602] Step A: Synthesis of Example 34

[0603] To a single-necked flask, 32-8 (65 mg), 1,4-dioxane (5 mL), water (2 mL), A-6 (127 mg), potassium carbonate (76 mg), 3-(di-tert-butylphosphino)propane-1-sulfonic acid (1.00 mg) and disodium tetrachloropalladate(IV) (0.5 mg) were added successively. The mixed solution was stirred at 80 °C for 1 h under N2 protection. The reaction solution was concentrated, and the residue was dissolved in DCM (50 mL), washed with saturated brine (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was purified by high-pressure preparation (chromatographic column: Polar RP (10 μm, 21.2 × 250 mm); mobile phase: 10 mM ammonium acetate - 0.1% acetic acid aqueous solution: acetonitrile = 60:40) to obtain Example 34 (49 mg). HRMS (ESI+, [M+H] + ) m / z: 466.2368. 11H NMR (500 MHz, DMSO-d6) δ 8.56–8.50 (m, 1H), 8.35 (d, J = 7.8 Hz, 1H), 8.20 (d, J = 11.4 Hz, 1H), 8.07 (dt, J = 8.5, 2.4 Hz, 1H), 7.00 (d, J = 8.7 Hz, 1H), 5.58 (s, 2H), 5.26 (p, J = 6.8 Hz, 1H), 4.39 (t, J = 6.6 Hz, 2H), 2.54 (t, J = 7.2 Hz, 2H), 2.44 (dq, J = 7.6, 3.8 Hz, 4H), 1.94 (q, J = 6.9 Hz, 2H), 1.71–1.67 (m, 4H), 1.64 (d, J = 6.7 Hz, 6H).

[0604] Example 35

[0605]

[0606] Reaction process:

[0607]

[0608] Step A: Synthesis of Example 35

[0609] To a single-necked flask, 33-1 (55 mg), 1,4-dioxane (5 mL), water (2 mL), A-6 (103 mg), potassium carbonate (65 mg), 3-(di-tert-butylphosphino)propane-1-sulfonic acid (0.83 mg) and disodium tetrachloropalladate(IV) (0.45 mg) were added successively. Under N2 protection, the mixed solution was reacted at 80 °C for 1 h. After the reaction was completed, the reaction solution was concentrated. The obtained residue was dissolved in DCM (50 mL), washed with saturated brine (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was purified by high-pressure preparation (chromatographic column: Polar RP (10 μm, 21.2 × 250 mm); mobile phase: 10 mM ammonium acetate-0.1% acetic acid aqueous solution: acetonitrile = 60:40) to obtain Example 35 (6 mg). HRMS (ESI+, [M+H] + ) m / z: 480.2521. 11H NMR (500 MHz, DMSO-d6) δ 8.53 (t, J = 2.0 Hz, 1H), 8.35 (d, J = 7.8 Hz, 1H), 8.21 (d, J = 11.4 Hz, 1H), 8.07 (dt, J = 8.7, 2.4 Hz, 1H), 7.00 (d, J = 8.8 Hz, 1H), 6.31 (q, J = 5.6 Hz, 1H), 5.31–5.17 (m, 1H), 4.39 (t, J = 6.6 Hz, 2H), 2.83 (d, J = 5.5 Hz, 3H), 2.54 (t, J = 7.2 Hz, 2H), 2.48–2.40 (m, 4H), 1.93 (p, J = 6.8 Hz, 2H), 1.71–1.67 (m, 4H), 1.64 (d, J = 6.7 Hz, 6H).

[0610] Example 36

[0611]

[0612] Reaction process:

[0613]

[0614] Step A: Synthesis of compound 36-1

[0615] Add 32-5 (5.0 g), DIPEA (6.37 g), acetonitrile (100 mL), and cyclopropylamine (1.88 g) to a single-necked flask in sequence. React at 95 °C for 4 h under N2 protection. After the reaction is completed, cool the reaction solution, add 150 mL of water, filter, wash the filter cake with water (30 mL × 4), and dry it under vacuum to obtain intermediate 36-1 (4.1 g). MS (ESI+, [M+H] + ) m / z: 324.87.

[0616] Step B: Synthesis of compound 36-2

[0617] Add 36-1 (4.1 g), iodobenzene diacetate (4.06 g), acetonitrile (30 mL), ethyl acetate (30 mL), water (30 mL), and KOH (1.4 g) to a single-necked flask in sequence. Stir the reaction at room temperature overnight. After the reaction is completed, filter the reaction solution directly, wash the filter cake with water (10 mL × 2), and dry it under vacuum to obtain intermediate 36-2 (2.8 g). MS (ESI+, [M+H] + ) m / z: 322.85.

[0618] Step C: Synthesis of compound 36-3

[0619] To a single-necked flask, add 36-2 (2.0 g), DCM (50 mL), water (20 mL), TBAB (200 mg), 2,4-dinitrophenylhydroxylamine (1.8 g), and NaOH (500 mg) in sequence, and stir the reaction overnight at room temperature. After the reaction is completed, concentrate to remove the organic solvent, filter, wash the filter cake with 10 mL of acetonitrile, and dry under vacuum to obtain intermediate 36-3 (800 mg). MS (ESI+, [M+H] + ) m / z: 337.88.

[0620] Step D: Synthesis of Example 36

[0621] To a single-necked flask, add 36-3 (100 mg), 1,4-dioxane (5 mL), water (2 mL), A-3 (205 mg), potassium carbonate (123 mg), 3-(di-tert-butylphosphino) propane-1-sulfonic acid (7.9 mg), and disodium tetrachloropalladate(IV) (4.4 mg) in sequence. Under N2 protection, react the mixed solution at 80 °C for 2 h. After the reaction is completed, concentrate the reaction solution, dissolve the residue in DCM (50 mL), wash with saturated brine (10 mL × 2), dry with anhydrous sodium sulfate, filter and concentrate to obtain the crude product. The obtained crude product is purified by silica gel column chromatography to obtain Example 36 (30 mg). MS (ESI+, [M+H] + ) m / z: 478.29. 1 1H NMR (500 MHz, Chloroform-d) δ 8.59 (d, J = 7.7 Hz, 1H), 8.44 (s, 1H), 8.15 (d, J = 11.2 Hz, 1H), 7.90 (d, J = 8.6 Hz, 1H), 6.89 (d, J = 8.6 Hz, 1H), 4.74 (s, 2H), 4.42 (t, J = 6.4 Hz, 2H), 3.40–3.26 (m, 1H), 2.54–2.40 (m, 6H), 2.07–2.02 (m, 2H), 1.63–1.58 (m, 4H), 1.51–1.41 (m, 4H), 1.32–1.29 (m, 2H).

[0622] Example 37

[0623]

[0624] Reaction process:

[0625]

[0626] 36-3 (100 mg), 1,4-dioxane (5 mL), water (2 mL), A-6 (197 mg), potassium carbonate (123 mg), 3-(di-tert-butylphosphino) propane-1-sulfonic acid (7.9 mg) and disodium tetrachloropalladate(IV) (4.4 mg) were successively added to a single-necked flask. Under N2 protection, the mixed solution was stirred at 80 °C for 2 h. After the reaction was completed, the reaction solution was concentrated, the residue was dissolved in DCM (50 mL), washed with saturated brine (2 × 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product. The obtained crude product was purified by silica gel column chromatography to obtain Example 37 (35 mg). MS (ESI+, [M+H] + ) m / z: 464.27. 1 H NMR (500 MHz, Chloroform-d) δ 8.59 (d, J = 7.7 Hz, 1H), 8.44 (s, 1H), 8.15 (d, J = 11.2 Hz, 1H), 7.91 (d, J = 8.7 Hz, 1H), 6.90 (d, J = 8.6 Hz, 1H), 4.73 (s, 2H), 4.44 (t, J = 6.5 Hz, 2H), 3.39–3.31 (m, 1H), 2.68–2.63 (m, 2H), 2.59–2.52 (m, 4H), 2.10–2.02 (m, 2H), 1.82–1.79 (m, 4H), 1.48–1.38 (m, 2H), 1.32–1.29 (m, 2H).

[0627] Test Example 1: In vitro kinase inhibitory activity

[0628] 1.1 Determination of ATM kinase inhibitory activity

[0629] The ATM kinase solution (concentration 25 ng / μL) was added to the detection wells at 6 μL per well. Different compounds dissolved in DMSO were added to the detection wells using a nanoliter pipettor to make the final concentration of the compounds 10,000 nM - 2.44 nM. This experiment was set up with 2 replicates, and a control was also set. After incubating the above system at room temperature for 30 minutes, ATP (100 μM) and p53 substrate (50 nM) were mixed at a ratio of 1:1 and added to the detection wells at 4 μL per well; after reacting at room temperature for 2 hours, 5 μL of EDTA was added to terminate the reaction, and then 5 μL of the detection antibodies Mab Anti-phospho p53 and Mab Anti GST-d2 (manufacturer: perkinelmer) were added and incubated at room temperature for 1 hour; The PerkinElmer Envision multifunctional microplate reader was used for plate reading detection (excitation 320 nm, emission 620 nm / 665 nm), and four-parameter fitting was used to calculate the IC 50 .

[0630] 1.2 ATR (Ataxia telangiectasia and Rad3-related) Kinase Inhibitory Activity Assay

[0631] Add 6 μL of ATR / ATPIP (ATR-interacting protein) kinase solution (concentration 50 ng / μL) to each well of the detection wells. Use a nanoliter pipettor to add different compounds dissolved in DMSO to the detection wells to make the final concentration of the compounds 10,000 nM - 2.44 nM. This experiment sets 2 replicates, and a control is also set. After incubating the above system at room temperature for 30 minutes, mix ATP (5 μM) and p53 substrate (50 nM) at a ratio of 1:1, and add 4 μL to each well of the detection wells; after reacting at room temperature for 2 hours, add 5 μL of EDTA to terminate the reaction, and then add 5 μL of detection antibodies Mab Anti-phospho p53 and Mab Anti GST-d2 (manufacturer: perkinelmer), and incubate at room temperature for 1 hour; Use a PerkinElmer Envision multimode microplate reader for plate reading detection (excitation 320 nm, emission 620 nm / 665 nm), and use four-parameter fitting to calculate IC 50 。

[0632] 1.3 DNA-PK (DNA-dependent protein kinase) Kinase Inhibitory Activity Assay

[0633] Add 6 μL of DNA-PK kinase solution (concentration 0.15 ng / μL) to each well of the detection wells. Use a nanoliter pipettor to add different compounds dissolved in DMSO to the detection wells to make the final concentration of the compounds 10,000 nM - 2.44 nM. This experiment sets 2 replicates, and a control is also set. After incubating the above system at room temperature for 30 minutes, mix ATP (100 μM) and p53 substrate (50 nM) at a ratio of 1:1, and add 4 μL to each well of the detection wells; after reacting at room temperature for 2 hours, add 5 μL of EDTA to terminate the reaction, and then add 5 μL of detection antibodies Mab Anti-phospho p53 and Mab Anti GST-d2 (manufacturer: perkinelmer), and incubate at room temperature for 1 hour; Use a PerkinElmer Envision multimode microplate reader for plate reading detection (excitation 320 nm, emission 620 nm / 665 nm), and use four-parameter fitting to calculate IC 50 。

[0634] The test results are shown in Table 1.

[0635] Table 1

[0636]

[0637]

[0638] Among them, A represents an IC 50 < 50 nM.

[0639] The test results show that the compounds of the present application have good inhibitory activity against ATM kinase and have selective kinase inhibitory activity compared with ATR and / or DNA-PK.

[0640] Test Example 2: Determination of in vitro cell inhibitory activity

[0641] 2.1 Inhibitory activity of NCI-H2228 cells on CHK2 phosphorylation

[0642] Take NCI-H2228 cells in good growth state, collect them into a centrifuge tube, adjust the cell density to 1.25×10 6 cells / mL, inoculate them on a 384-well plate (8 μL / well). After equilibrating in a cell incubator for 1.5 hours, use a nanoliter sampler to add the compound so that the final concentration of the compound is 200 nM - 0.049 nM. This experiment sets 2 replicates and a control at the same time. After continuing to culture in the cell incubator for 1 hour, use a p-CHK2(Thr68) detection kit (manufacturer: perkinelmer), and detect with the AlphaLISA program of an Envision microplate reader. Perform four-parameter analysis, fit the dose-effect curve, and calculate the IC 50 . The test results are shown in Table 2.

[0643] Table 2

[0644] Embodiment <![CDATA[NCI-H2228(IC 50 nM)]]> 2 A 3 A 5 A 7 A 11 A 13 A 14 A 17 A 18 A 19 A 20 A 21 A 22 A 23 A 24 A 25 A 26 A 27 A 28 A 29 A 31 A 32 A

[0645] Among them, A represents an IC 50 < 50 nM.

[0646] The test results show that the compounds of the present application have good inhibitory activity against CHK2 phosphorylation in NCI-H2228 cells.

[0647] Test Example 3: In vitro pharmacokinetics

[0648] 3.1 In vitro hepatic microsomal metabolic stability

[0649] Liver microsome incubation samples were prepared by mixing PBS buffer (pH 7.4), liver microsome solution (0.5 mg / ml, species: human, monkey, dog, rat and mouse), test compound and NADPH + MgCl2 solution and incubating at 37 °C and 300 rpm for 1 hour. 0-hour samples were prepared by mixing PBS buffer (pH 7.4), liver microsome solution (0.5 mg / mL), and test compound. Samples were added to acetonitrile solution containing internal standard for protein precipitation to prepare supernatant, which was diluted and used for LC / MS / MS determination. The results are shown in Table 3 below.

[0650] Table 3

[0651]

[0652] The results showed that the test compound of this application was stable in vitro metabolism (such as more remaining amount at 60 min).

[0653] 3.2 In vitro plasma protein binding rate

[0654] Plasma samples were prepared as blank plasma (mouse, rat, dog and human), test compound solution (3 μM). Samples for high-throughput equilibrium dialysis device (RED) were prepared by incubating plasma samples in the red chamber and PBS buffer samples in the white chamber at 37 °C and 100 rpm for 4 h. Plasma and buffer samples were added to acetonitrile solution containing internal standard for protein precipitation to prepare supernatant, which was diluted and used for LC / MS / MS determination.

[0655] The results showed that the test compound of this application had a low in vitro plasma protein binding rate.

[0656] Test Example 4: In vivo pharmacokinetics

[0657] 4.1 Pharmacokinetics in mice

[0658] ICR mice, weighing 21 - 23 g, were randomly divided into groups of 9 each after 3 - 5 days of adaptation, and the solution of Example 1 was administered by gavage at a dose of 10 mg / kg.

[0659] Blood sampling time points were 0 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 24 h. Blood was collected from the orbital cavity to prepare plasma samples for testing.

[0660] 20 μL of plasma samples for testing and standard curve samples were taken, added to acetonitrile solution containing internal standard to obtain supernatant by protein precipitation, which was diluted and used for LC / MS / MS determination. Non-compartmental model fitting was used.

[0661] 4.2 Pharmacokinetics in rats

[0662] SD rats, weighing 200 - 220 g, were randomly divided into groups of 3 after 3 - 5 days of adaptation. The solution of Example 1 was administered by gavage at a dose of 10 mg / kg.

[0663] Blood sampling time points were 0 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, and 24 h. Blood was collected from the orbital cavity to prepare plasma samples for testing.

[0664] 50 μL of the plasma sample for testing and the standard curve sample were taken, and acetonitrile solution containing internal standard was added. The supernatant was obtained after protein precipitation and diluted for LC / MS / MS determination. Non - compartmental model fitting was used.

[0665] 4.3 Pharmacokinetics in dogs

[0666] Beagle dogs, weighing 10 - 12 kg, were randomly divided into groups of 3 after 3 - 5 days of adaptation. The solution of Example 1 was administered by gavage at a dose of 2 mg / kg.

[0667] Blood sampling time points were 0 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, and 24 h. Blood was collected from the anterior limb vein to prepare plasma samples for testing.

[0668] 50 μL of the plasma sample for testing and the standard curve sample were taken, and acetonitrile solution containing internal standard was added. The supernatant was obtained after protein precipitation and diluted for LC / MS / MS determination. Non - compartmental model fitting was used. The results are shown in Table 4.

[0669] Table 4

[0670]

[0671] The test results show that the compound of this application has good in - vivo pharmacokinetic properties (in mice, rats and dogs), and shows advantages in aspects such as C max 、AUC、t 1 / 2 and so on.

[0672] 4.4 Mouse brain distribution experiment

[0673] ICR mice, weighing 22 - 24 g, were randomly divided into groups of 9 after 3 - 5 days of adaptation. The solution of Example 1 was administered by gavage at a dose of 20 mg / kg.

[0674] Blood sampling time points were 15 min, 30 min, and 8 h. Blood was collected from the orbital cavity to prepare plasma samples for testing.

[0675] Tissue sampling time points were 15 min, 30 min, and 8 h. After bleeding and sacrificing the animals at the corresponding time, the brain tissues were taken out and homogenized with ice - cold normal saline at a ratio of 1:3 (W / V) to prepare brain homogenate samples for testing.

[0676] Absorb 20 μL of plasma and brain homogenate samples to be tested and corresponding standard curve samples, add acetonitrile solution containing internal standard, obtain supernatant after protein precipitation, and dilute it for LC / MS / MS determination. Non-compartmental model fitting is adopted.

[0677] The experimental results show that the compound of the present application has a high exposure (AUC) in plasma and brain, and has a high brain-blood ratio (brain / plasma).

[0678] Test Example 5: In vivo pharmacodynamic study

[0679] Inoculate HCT116 cells subcutaneously in the right axilla of SPF-grade female nude mice, 1×10 7 cells / mouse. When the average tumor volume reaches about 200 mm 3 , group the animals (the grouping day is day d0).

[0680] Administer different doses of the compound of the present application (15 mpk, 30 mpk, or 60 mpk, by gavage), with a 7-day dosing cycle. Measure the tumor volume 2-3 times a week, weigh the mice at the same time, record the data; observe and record the general performance of the mice daily. After the experiment, dissect the tumors, weigh them, and take pictures.

[0681] The detection indexes and calculation formulas are as follows:

[0682] Tumor volume, TV (mm 3 ) = 1 / 2×(a×b 2 ); where a is the long diameter of the tumor and b is the short diameter of the tumor.

[0683] Relative tumor volume, RTV = TV t / TV0; where TV0 is the tumor volume on day 0, and TV t is the tumor volume at each measurement.

[0684] Relative tumor proliferation rate, T / C (%) = T RTV / C RTV ×100%; where T RTV is the RTV of the treatment group; C RTV is the RTV of the vehicle control group. Tumor growth inhibition rate, TGI (%) = (1 - TW / TW0)×100%; where TW is the tumor weight of the treatment group and TW0 is the tumor weight of the vehicle control group. Body weight change rate, WCR (%) = (Wt t -Wt0) / Wt0×100%; where Wt0 is the body weight of the mice on day 0, and Wt t is the body weight of the mice at each measurement.

[0685] The experimental results show that the compound of the present application can inhibit tumor growth in vivo.

Claims

1. A compound of formula I-A, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein, R 1 selected from hydrogen, C 1-10 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 3-10 aryl or 3- to 10-membered heteroaryl, wherein the C 1-10 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 3-10 aryl or 3- to 10-membered heteroaryl is optionally substituted by one or more halogen, hydroxy, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylNH-, (C 1-6 alkyl)2N-, C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 3-10 aryl or 3- to 10-membered heteroaryl; R 2a and R 2b are each independently selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heteroalkyl, C 3-10 aryl or 3- to 10-membered heteroaryl, or R 2a and R 2b are joined to form a 3- to 12-membered heteroalkyl, wherein the C 1-6 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heteroalkyl, C 3-10 aryl, 3- to 10-membered heteroaryl or 3- to 12-membered heteroalkyl is optionally substituted by one or more deuterium, halogen, hydroxy, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylNH-, (C 1-6 alkyl)2N-, C 3-10 cycloalkyl, 3- to 10-membered heteroalkyl, C 3-10 aryl, 3- to 10-membered heteroaryl, -COC 1-6 alkyl, -COOC 1-6 alkyl, -OCOC 1-6 alkyl, -CONHC 1-6 alkyl, -CON(C 1-6 alkyl)2, -SO2NHC 1-6 alkyl or -SO2N(C 1-6 alkyl)2; R 3 and R 4 are each independently selected from halogen, hydroxy, amino, cyano, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylNH- or (C 1-6 alkyl)2N-, and the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylNH- or (C 1-6 alkyl)2N- is optionally substituted by one or more halogen, hydroxy, amino, cyano, nitro or -COOH; p and m are independently selected from 0, 1, 2, 3 or 4; ring A is selected from phenyl or a 5- to 10-membered heteroaryl; X is selected from a single bond, -NR a -, -O-, or -S-; Y 1 、Y 2 、Y 3 or Z are each independently selected from N or CH, and Y 1 、Y 2 、Y 3 or at least one of Z is selected from CH; R a selected from hydrogen or C 1-6 alkyl; L is selected from C 1-6 alkylene, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, -C 1-6 alkylene-C 3-10 cycloalkyl-, -C 1-6 alkylene-3-10 membered heterocycloalkyl, -C 3-10 cycloalkyl-C 1-6 alkylene- or 3-10 membered heterocycloalkyl-C 1-6 alkylene-; R 5 and R 6 are each independently selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, or 3- to 10-membered heterocycloalkyl, or R 5 and R 6 are joined to form a 3- to 12-membered heterocycloalkyl, and the C 1-6 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, or 3- to 12-membered heterocycloalkyl is optionally substituted with one or more of the following groups: deuterium, halogen, hydroxy, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylNH-, (C 1-6 alkyl)2N-, or C 1-6 alkyl substituted with one or more halogen, hydroxy, amino, or cyano.

2. The compound, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof according to claim 1, which is selected from a compound of formula I, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein, R 1 selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heteroalkyl, C 3-10 aryl or 3- to 10-membered heteroaryl, wherein the C 1-6 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heteroalkyl, C 3-10 aryl or 3- to 10-membered heteroaryl is optionally substituted by one or more halogen, hydroxy, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylNH- or (C 1-6 alkyl)2N-; R 2a and R 2b are each independently selected from hydrogen or C 1-6 alkyl, or R 2a and R 2b are joined to each other to form a 3- to 10-membered heteroalkyl group, and the C 1-6 alkyl or 3- to 10-membered heteroalkyl group is optionally substituted by one or more deuterium, halogen, hydroxy, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylNH- or (C 1-6 alkyl)2N-; R 3 and R 4 are each independently selected from halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylNH- or (C 1-6 alkyl)2N-; p and m are independently selected from 0, 1 or 2; X 1 、 X 2 、 X 3 or X 4 are each independently selected from N or CH, and X 1 、 X 2 、 X 3 or X 4 one or more of which are selected from N; X is selected from a single bond, -NR a -, -O-, or -S-; R a selected from hydrogen or C 1-6 alkyl; L is selected from C 1-6 alkylene, C 3-10 cycloalkylene, 3- to 10-membered heterocycloalkylene, -C 1-6 alkylene-C 3-10 cycloalkylene-, -C 1-6 alkylene-3- to 10-membered heterocycloalkylene, -C 3-10 cycloalkylene-C 1-6 alkylene- or 3- to 10-membered heterocycloalkylene-C 1-6 alkylene-; R 5 and R 6 are each independently selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl or 3- to 10-membered heterocycloalkyl, or R 5 and R 6 are joined to form a 3- to 10-membered heterocycloalkyl, and the C 1-6 alkyl, C 3-10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted with one or more deuterium, halogen, hydroxy, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylNH- or (C 1-6 alkyl)2N-.

3. The compound, pharmaceutically acceptable salt or stereoisomer thereof according to claim 1 or 2, R 1 is selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heteroalkyl, C 3-10 aryl or 3- to 10-membered heteroaryl, wherein the C 1-6 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heteroalkyl, C 3-10 aryl or 3- to 10-membered heteroaryl is optionally substituted by one or more halogen, hydroxy, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylNH- or (C 1-6 alkyl)2N-; Optionally, R 1 is selected from hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 aryl or 3-6 membered heteroaryl, wherein the C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 aryl or 3-6 membered heteroaryl is optionally substituted by one or more halogen, hydroxy, amino, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylNH- or (C 1-4 alkyl)2N-; Optionally, R 1 is selected from C 1-3 alkyl, C 3-6 cycloalkyl, 5- or 6-membered heteroalkyl, C 5-6 aryl or 5- or 6-membered heteroaryl, wherein the C 4-6 cycloalkyl, 5- or 6-membered heteroaryl, C 5-6 aryl or 5- or 6-membered heteroaryl is optionally substituted with one or more halogen, hydroxy, amino, cyano, C 1-3 alkyl or C 1-3 alkoxy; Optionally, R 1 is selected from C 1-3 alkyl, C 3-5 cycloalkyl, 6-membered heteroalkyl, phenyl or 6-membered heteroaryl, wherein the C 4-5 cycloalkyl, 6-membered heteroalkyl, phenyl or 6-membered heteroaryl is optionally substituted by one or more halogens or C 1-3 alkoxy; Optionally, R 1 is selected from propyl, cyclopropyl, cyclobutyl, cyclopentyl, 6-membered oxygen-containing heterocycloalkyl or 6-membered nitrogen-containing heteroaryl, and the cyclobutyl, cyclopentyl, 6-membered oxygen-containing heterocycloalkyl or 6-membered nitrogen-containing heteroaryl is optionally substituted with one or more fluorine or methoxy groups; Optionally, R 1 is selected from propyl, cyclopropyl, cyclobutyl, cyclopentyl, tetrahydropyranyl or pyridyl, wherein the cyclobutyl, cyclopentyl or pyridyl is optionally substituted with one or more fluorine or methoxy groups; Optionally, R 1 is selected from isopropyl, Optionally, R 2a and R 2b are each independently selected from hydrogen or C 1-6 alkyl, or R 2a and R 2b are joined together to form a 3- to 10-membered heteroalkyl group, and the C 1-6 alkyl or 3- to 10-membered heteroalkyl group is optionally substituted by one or more deuterium, halogen, hydroxy, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylNH- or (C 1-6 alkyl)2N-; Optionally, R 2a and R 2b are each independently selected from hydrogen or C 1-4 alkyl, or R 2a and R 2b are joined together to form a 3- to 8-membered heterocycloalkyl, the C 1-4 alkyl or 3- to 8-membered heterocycloalkyl optionally substituted by one or more deuterium, halogen, hydroxy, amino, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylNH- or (C 1-4 alkyl)2N-; Optionally, R 2a and R 2b are each independently selected from hydrogen or C 1-4 alkyl, or R 2a and R 2b are joined to form a 3- to 4-membered heteroalkyl ring, and the C 1-4 alkyl or 3- to 4-membered heteroalkyl ring is optionally substituted with one or more deuterium, halogen, hydroxy, amino, cyano or C 1-3 alkyl; Optionally, R 2a and R 2b are each independently selected from hydrogen or C 1-4 alkyl, where the C 1-4 alkyl is optionally substituted with one or more deuterium, halogen, hydroxy, amino or cyano groups; Optionally, R 2a and R 2b are each independently selected from hydrogen or C 1-4 alkyl, where the C 1-4 alkyl is optionally substituted with one or more deuterium, fluorine, chlorine or bromine; Optionally, R 2a and R 2b are each independently selected from hydrogen or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with one or more deuteriums; Optionally, R 2a and R 2b are each independently selected from hydrogen or CH3—, where the CH3— is optionally substituted with one or more deuteriums; Optionally, R 2a and R 2b are each independently selected from hydrogen, CH3— or CD3—.

4. The compound of formula, its pharmaceutically acceptable salt or its stereoisomer according to any one of claims 1-3, R 3 and R 4 are each independently selected from halogen, hydroxy, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylNH- or (C 1-6 alkyl)2N-; Optionally, R 3 and R 4 are each independently selected from halogen, hydroxy, amino, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylNH- or (C 1-3 alkyl)2N-; Optionally, R 3 and R 4 are each independently selected from halogen or C 1-3 alkoxy; Optionally, R 3 is selected from fluorine, chlorine, bromine or C 1-3 alkoxy; Optionally, R 3 is selected from fluorine or methoxy; Optionally, R 4 is selected from halogen, hydroxyl, amino, cyano, methyl or methoxy; Optionally, p and m are independently selected from 0, 1 or 2; Optionally, p is selected from 0 or 1; Optionally, p is selected from 0; Optionally, m is selected from 0 or 1.

5. The compound, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof according to any one of claims 1, 3 or 4, wherein ring A is selected from phenyl, a 5- to 6-membered heteroaryl or a 9- to 10-membered heteroaryl; Optionally, ring A is selected from a 5- to 6-membered heteroaryl or a 9- to 10-membered heteroaryl; Optionally, ring A is selected from pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, triazolyl, pyrazinyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, triazinyl, benzimidazolyl or imidazopyridyl; Optionally, ring A is selected from pyridyl or pyrimidinyl; Optionally, Y 1 、Y 2 、Y 3 or Z are each independently selected from N or CH, and one, two, three, or four of Y 1 、Y 2 、Y 3 or Z are selected from CH; Optionally, Y 1 is selected from N, and Y 2 , Y 3 is selected from CH; Alternatively, Y 2 is selected from N, and Y 1 , Y 3 is selected from CH; Or, Y 3 is selected from N, and Y 1 , Y 2 is selected from CH; Alternatively, Y 1 , Y 2 or Y 3 is selected from CH; Alternatively, Y 1 , Y 2 , Y 3 or Z is selected from CH; Optionally, Z is selected from N or CH; Alternatively, Z is selected from N; or alternatively, Z is selected from CH.

6. The compound, pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 2-4, X 1 , X 2 , X 3 or X 4 is independently selected from N or CH, respectively, and X 1 , X 2 , X 3 or X 4 one or more of which are selected from N; Optionally, X 1 , X 2 , X 3 or X 4 is independently selected from N or CH, and X 1 , X 2 , X 3 or X 4 one or two of which are selected from N; Optionally, X 4 is selected from N, and X 1 , X 2 or X 3 is independently selected from N or CH, respectively; Optionally, X 4 is selected from N, and X 3 is selected from N or CH, X 1 、X 2 is selected from CH; Optionally, X 4 is selected from N, and X 1 , X 2 or X 3 is selected from CH; Optionally, X 3 , X 4 is selected from N, and X 1 , X 2 is selected from CH.

7. The compound, pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1-6, wherein X is selected from -NR a -, or -O-; Optionally, X is selected from -NH- or -O-; Optionally, X is selected from -O-; Optionally, L is selected from C 1-6 alkylene, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, -C 1-6 alkylene-C 3-10 cycloalkyl-, -C 1-6 alkylene-3-10 membered heterocycloalkyl, -C 3-10 cycloalkyl-C 1-6 alkylene- or 3-10 membered heterocycloalkyl-C 1-6 alkylene-; Optionally, L is selected from C 1-4 alkylene, C 3-8 cycloalkylene, 3-8 membered heteroalkylene, -C 1-4 alkylene-C 3-8 cycloalkylene-, -C 1-4 alkylene-3-8 membered heteroalkylene-, -C 3-8 cycloalkylene-C 1-4 alkylene- or 3-8 membered heteroalkylene-C 1-4 alkylene-; Optionally, L is selected from C 1-4 alkylene, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, -C 1-4 alkylene-C 3-6 cycloalkyl-, -C 1-4 alkylene-3- to 6-membered heterocycloalkyl-, -C 3-6 cycloalkyl-C 1-4 alkylene- or 3- to 6-membered heterocycloalkyl-C 1-4 alkylene-; Optionally, L is selected from C 1-4 alkylene, C 3-6 cycloalkylene, -C 1-4 alkylene-C 3-6 cycloalkylene- or -C 3-6 cycloalkylene-C 1-4 alkylene-; Optionally, L is selected from C 2-4 alkylene, C 4-6 cycloalkylene, -C 1-2 alkylene-C 4-6 cycloalkylene- or -C 4-6 cycloalkylene-C 1-2 alkylene-; Optionally, L is selected from C 2-3 alkylene, C 4-6 cycloalkylene, -CH2-C4 cycloalkylene- or -C4 cycloalkylene-CH2-; Optionally, L is selected from -CH2CH2-, -CH2CH2CH2-, Optionally, R a is selected from hydrogen or C 1-6 alkyl; Optionally, R a is selected from hydrogen or C 1-4 alkyl; Optionally, R a is selected from hydrogen or C 1-3 alkyl; Optionally, R a is selected from hydrogen or methyl; Optionally, R a is selected from hydrogen.

8. A compound, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any one of claims 1-7, R 5 and R 6 are each independently selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl or 3-10 membered heterocycloalkyl, or R 5 and R 6 are joined to form a 3-10 membered heterocycloalkyl, and the C 1-6 alkyl, C 3-10 cycloalkyl or 3-10 membered heterocycloalkyl is optionally substituted by one or more of the following groups: deuterium, halogen, hydroxy, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylNH-, (C 1-6 alkyl)2N-, C 1-6 alkyl substituted by one or more halogen, hydroxy, amino or cyano; Optionally, R 5 and R 6 are each independently selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl or 3- to 10-membered heteroalkyl, or R 5 and R 6 are joined to form a 3- to 10-membered heteroalkyl, and the C 1-6 alkyl, C 3-10 cycloalkyl or 3- to 10-membered heteroalkyl is optionally substituted with one or more of the following groups: deuterium, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylNH-, (C 1-6 alkyl)2N-, C 1-6 alkyl substituted with one or more halogens; Alternatively, R 5 and R 6 are each independently selected from hydrogen, C 1-4 alkyl, C 3-8 cycloalkyl or 3- to 8-membered heterocycloalkyl, or R 5 and R 6 are joined to form a 3- to 8-membered heterocycloalkyl, and the C 1-4 alkyl, C 3-8 cycloalkyl or 3- to 8-membered heterocycloalkyl is optionally substituted with one or more of the following groups: deuterium, halogen, hydroxy, amino, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylNH-, (C 1-4 alkyl)2N- or haloC 1-6 alkyl; Alternatively, R 5 and R 6 are each independently selected from C 1-4 alkyl or C 3-6 cycloalkyl, or R 5 and R 6 are connected to each other to form a 3- to 7-membered heterocycloalkyl group, and the C 3-6 cycloalkyl or 3- to 7-membered heterocycloalkyl group is optionally substituted with one or more of the following groups: deuterium, halogen, hydroxy, amino, cyano, C 1-3 alkyl, C 1-3 alkoxy or halo C 1-4 alkyl; Alternatively, R 5 and R 6 are each independently selected from C 1-4 alkyl or C 3-6 cycloalkyl, or R 5 and R 6 are joined together to form a 3- to 7-membered heteroalkyl group, which is optionally substituted by one or more of the following groups: deuterium, halogen, hydroxyl, amino, cyano, C 1-3 alkyl, C 1-3 alkoxy or halo C 1-4 alkyl; Alternatively, R 5 and R 6 are each independently selected from C 1-3 alkyl or C 3-4 cycloalkyl, or R 5 and R 6 are joined to form a 4-, 5-, 6- or 7-membered heteroalkyl group, which heteroalkyl group is optionally substituted by one or more halogen or halo-C 1-3 alkyl; Alternatively, R 5 and R 6 are each independently selected from C 1-3 alkyl or C 3-4 cycloalkyl; Alternatively, R 5 and R 6 are connected to each other to form a 4-, 5-, 6- or 7-membered heteroalkyl group, which heteroalkyl group is optionally substituted by one or more halogen atoms or halo C 1-3 alkyl groups; Alternatively, R 5 and R 6 are connected to each other to form a 4-, 5- or 6-membered heterocycloalkyl group, which heterocycloalkyl group is optionally substituted by one or more halogen atoms or halo-C 1-3 alkyl groups; Alternatively, R 5 and R 6 are connected to each other to form a 4-membered heterocycloalkyl group, which is optionally substituted by one or more halogen atoms or halo C 1-3 alkyl groups; Alternatively, R 5 and R 6 are connected to each other to form a 5-membered heteroalkyl group, and the heteroalkyl group is optionally substituted with one or more halogen atoms or halo C 1-3 alkyl groups; Alternatively, R 5 and R 6 are connected to each other to form a 6-membered heterocycloalkyl group, which heterocycloalkyl group is optionally substituted by one or more halogen atoms or halo C 1-3 alkyl groups; Alternatively, R 5 and R 6 are each independently selected from methyl or cyclopropyl, or R 5 and R 6 are connected to each other to form azetidinyl, pyrrolidinyl, piperidinyl, azaspiroheptyl or azabicycloheptyl, and the azetidinyl or pyrrolidinyl is optionally substituted with one or more F or -CH2F; Alternatively, R 5 and R 6 are each independently selected from methyl or cyclopropyl, or R 5 and R 6 are joined to each other to form azetidinyl, pyrrolidinyl or piperidinyl, and the azetidinyl, pyrrolidinyl or piperidinyl is optionally substituted with one or more halogens or halo C 1-3 alkyl; Alternatively, R 5 and R 6 are each independently selected from methyl or cyclopropyl, or R 5 and R 6 are connected to each other to form azetidinyl, pyrrolidinyl or piperidinyl, and the azetidinyl or pyrrolidinyl is optionally substituted by one or more F or -CH2F; Optionally, R 5 and R 6 are each independently selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl or 3- to 10-membered heterocycloalkyl, or R 5 and R 6 are joined to form a 3- to 10-membered heterocycloalkyl, and the C 1-6 alkyl, C 3-10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by one or more deuterium, halogen, hydroxy, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylNH- or (C 1-6 alkyl)2N-; Alternatively, R 5 and R 6 are each independently selected from hydrogen, C 1-4 alkyl, C 3-8 cycloalkyl or 3- to 8-membered heterocycloalkyl, or R 5 and R 6 are connected to each other to form a 3- to 8-membered heterocycloalkyl, and the C 1-4 alkyl, C 3-8 cycloalkyl or 3- to 8-membered heterocycloalkyl is optionally substituted by one or more deuterium, halogen, hydroxyl, amino, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylNH- or (C 1-4 alkyl)2N-; Alternatively, R 5 and R 6 are each independently selected from C 1-4 alkyl or C 3-6 cycloalkyl, or R 5 and R 6 are connected to each other to form a 3- to 6-membered heterocycloalkyl group, and the C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl group is optionally substituted with one or more deuterium, halogen, hydroxy, amino, cyano, C 1-3 alkyl or C 1-3 alkoxy; Alternatively, R 5 and R 6 are each independently selected from C 1-3 alkyl or C 3-4 cycloalkyl, or are joined together to form a 5- to 6-membered heteroalkyl group; Alternatively, R 5 and R 6 are each independently selected from methyl or cyclopropyl, or are linked to each other to form a pyrrolidinyl or piperidinyl group.

9. The compound, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof according to any one of claims 1-8, wherein the compound of formula I-A or formula I is selected from a compound of formula II, III or IV, 10. The following compound, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:

11. A pharmaceutical composition comprising the compound according to any one of claims 1-10, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

12. Use of the compound according to any one of claims 1-10, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or the pharmaceutical composition according to claim 11 in the preparation of a medicament for treating tumors.

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