Hydrazine group-containing compounds

Abstract

The present disclosure belongs to the field of medicinal chemistry, and provides a hydrazine group-containing compound, specifically a compound represented by formula IA, its pharma- ceutically acceptable salt, its pharmaceutical composition, or its preparation method, and relates to its use in the manufacture of a medicament for treating tumors. [Formula 1] TIFF2025503055000182.tif44170

Description

[Technical field]

[0001] [CROSS REFERENCE TO RELATED APPLICATIONS] This disclosure claims priority to and the benefit of Chinese patent application having application number 202210092492.6 filed with the State Intellectual Property Office of China on January 26, 2022, Chinese patent application having application number 202211104139.1 filed with the State Intellectual Property Office of China on September 9, 2022, and Chinese patent application having application number 202310035797.8 filed with the State Intellectual Property Office of China on January 10, 2023, the disclosures of all of which are incorporated herein by reference in their entireties.

[0002] The present disclosure belongs to the field of medicinal chemistry, and provides a hydrazine group-containing compound, a pharma- ceutically acceptable salt thereof, a pharmaceutical composition thereof, or a method for preparing the same, and relates to its use in the manufacture of a medicament for treating a tumor. [Background technology]

[0003] Ataxia telangiectasia mutated gene (ATM) is closely related to the DNA damage response (DDR) of the body. Patients with ATM gene mutations are usually highly sensitive to X-rays and have a clearly reduced DNA repair ability. The product encoded by the ATM gene is a serine / threonine protein kinase and a member of the phosphatidylinositol 3-kinase (PI3K)-related kinase (PIKK) protein family, which has a catalytic domain homologous to PI3K. ATM kinase is mainly present in the nucleus and microsomes and functions during the S / G2 / M cell cycle transition and at the replication fork, triggering cell cycle checkpoints, chromatin modification, HR repair, and pro-survival signaling cascades. ATM kinase is involved in various important cellular functions such as cell growth, cell proliferation, migration, differentiation, survival, and cell adhesion. In particular, ATM kinase responds to DNA damage by activating cell cycle arrest and DNA repair mechanisms: upon DNA double-strand breaks, ATM kinase is activated within minutes, depolymerizes by autophosphorylation at Ser1981, and binds to the DNA break end point under the control of the MRN complex, thereby helping to repair the broken DNA and maintaining cellular integrity. Summary of the Invention [Problem to be solved by the invention]

[0004] In common anti-cancer treatments, DNA has a large number of single-strand or double-strand breaks, and when ATM kinase is activated, the self-repair function of cancer cells is enhanced, and cancer cells escape apoptosis, necrosis, or autophagy, resulting in poor efficacy of anti-cancer treatment. ATM inhibitors can enhance the activity and sensitivity of anti-cancer therapeutic drugs. Therefore, in view of the role of ATM inhibitors in the treatment of malignant tumors, the discovery of effective new ATM inhibitors has great clinical demand and market value. [Means for solving the problem]

[0005] The present disclosure relates to a compound represented by formula IA, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof.

[0006] [ka]

[0007] (In the formula, R 1 is hydrogen, C 1~10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 3-10 aryl or 3-10 membered heteroaryl, 1~10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 3-10 Aryl or 3-10 membered heteroaryl is halogen, hydroxyl group, amino group, cyano group, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 3-10 optionally substituted with one or more of aryl or 3-10 membered heteroaryl; R 2a and R 2b are each independently hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 3-10 aryl or 3-10 membered heteroaryl; or R 2a and R 2b are bonded to each other to form a 3- to 12-membered heterocycloalkyl, 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 3-10Aryl, 3-10 membered heteroaryl or 3-12 membered heterocycloalkyl may be substituted with deuterium, halogen, hydroxyl group, amino group, cyano group, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 3-10 Aryl, 3-10 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 a halogen, a hydroxyl group, an amino group, a cyano group, a nitro group, or C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 AlkylNH- or (C 1-6 alkyl)2N-, 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 AlkylNH- or (C 1-6 alkyl)2N- may be substituted with one or more of halogen, hydroxyl, 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 5-10 membered heteroaryl; X is 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 3or at least one in Z is selected from CH; R a is hydrogen or C 1-6 alkyl, L is for 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 to 10 membered heterocycloalkyl, -C 3-10 Cycloalkyl-C 1-6 Alkylene- or -3 to 10-membered heterocycloalkyl-C 1-6 alkylene-, R 5 and R 6 are each independently hydrogen, C 1-6 Alkyl, C 3-10 cycloalkyl or 3 to 10 membered heterocycloalkyl, or R 5 and R 6 are bonded to each other to form a 3- to 12-membered heterocycloalkyl, 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl or 3-12 membered heterocycloalkyl may be substituted with deuterium, halogen, hydroxyl group, amino group, cyano group, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl NH-, (C 1-6 alkyl)2N- or C substituted with one or more halogens, hydroxyl groups, amino groups or cyano groups 1-6 may be substituted with one or more groups of alkyl. The present disclosure relates to a compound represented by Formula I, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof.

[0008] [ka]

[0009] (In the formula, R 1is hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 3-10 aryl or 3-10 membered heteroaryl, 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 3-10 The aryl or 3-10 membered heteroaryl is selected from the group consisting of halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 AlkylNH- or (C 1-6 alkyl)N-, R 2a and R 2b are each independently hydrogen or C 1-6 alkyl; or R 2a and R 2b are bonded to each other to form a 3- to 10-membered heterocycloalkyl, 1-6 The alkyl or 3-10 membered heterocycloalkyl may be substituted with deuterium, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 AlkylNH- or (C 1-6 alkyl)N-, R 3 and R 4 are each independently a halogen, a hydroxyl group, an amino group, a cyano group, or 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 X4 is selected from N; X is a single bond, -NR a -, -O- or -S-; R a is hydrogen or C 1-6 alkyl, L is for 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 to 10 membered heterocycloalkyl, -C 3-10 Cycloalkyl-C 1-6 Alkylene- or -3 to 10-membered heterocycloalkyl-C 1-6 alkylene-, R 5 and R 6 are each independently hydrogen, C 1-6 Alkyl, C 3-10 cycloalkyl or 3 to 10 membered heterocycloalkyl; or R 5 and R 6 are bonded to each other to form a 3- to 10-membered heterocycloalkyl, 1-6 Alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl may be substituted with deuterium, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 AlkylNH- or (C 1-6 alkyl)2N-. In some embodiments, R 1 is hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 3-10 aryl or 3-10 membered heteroaryl, 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 3-10The aryl or 3-10 membered heteroaryl is selected from the group consisting of halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 AlkylNH- or (C 1-6 It may be substituted with one or more of alkyl)2N-.

[0010] In some embodiments, R 1 is hydrogen, C 1-4 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 3-8 aryl or 3-8 membered heteroaryl, 1-4 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 3-8 The aryl or 3-8 membered heteroaryl is selected from the group consisting of halogen, hydroxyl, amino, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 AlkylNH- or (C 1-4 It may be substituted with one or more of alkyl)2N-.

[0011] In some embodiments, R 1 is hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 aryl or 3- to 6-membered heteroaryl, 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 The aryl or 3-6 membered heteroaryl is selected from the group consisting of halogen, hydroxyl, amino, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 AlkylNH- or (C 1-4 It may be substituted with one or more of alkyl)2N-.

[0012] In some embodiments, R 1 is C1-3 Alkyl, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, C 5-6 aryl or 5-6 membered heteroaryl, 3-6 Cycloalkyl, 5-6 membered heteroaryl, C 5-6 The aryl or 5- to 6-membered heteroaryl is selected from the group consisting of halogen, hydroxyl, amino, cyano, C 1-3 Alkyl or C 1-3 It may be substituted with one or more alkoxy.

[0013] In some embodiments, R 1 is C 1-3 Alkyl, C 3-5 cycloalkyl, 6-membered heterocycloalkyl, phenyl, or 6-membered heteroaryl, 3-5 Cycloalkyl, 6-membered heterocycloalkyl, phenyl or 6-membered heteroaryl are halogen or C 1-3 It may be substituted with one or more alkoxy.

[0014] In some embodiments, R 1 is selected from propyl, cyclopropyl, cyclobutyl, cyclopentyl, a 6-membered oxygen-containing heterocycloalkyl, or a 6-membered nitrogen-containing heteroaryl, wherein said cyclobutyl, cyclopentyl, 6-membered oxygen-containing heterocycloalkyl, or 6-membered nitrogen-containing heteroaryl are optionally substituted with one or more of fluorine or methoxy.

[0015] In some embodiments, R 1 is selected from propyl, cyclopropyl, cyclobutyl, cyclopentyl, tetrahydropyranyl or pyridyl, said cyclobutyl, cyclopentyl or pyridyl being optionally substituted by one or more of fluorine or methoxy.

[0016] In some embodiments, R 1 isopropyl,

[0017] [ka]

[0018] is selected from.

[0019] In some specific embodiments, R 1 is hydrogen, C 1-6 Alkyl, C 3-10 cycloalkyl or 3 to 10 membered heterocycloalkyl, 1-6 Alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl is selected from the group consisting of halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 AlkylNH- or (C 1-6 It may be substituted with one or more of alkyl)2N-.

[0020] In some specific embodiments, R 1 is C 1-4 Alkyl, C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl, 1-6 Alkyl, C 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl is selected from the group consisting of halogen, hydroxyl, amino, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 AlkylNH- or (C 1-4 It may be substituted with one or more of alkyl)2N-.

[0021] In some specific embodiments, R 1 is C 1-4 Alkyl, C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl; 1-4 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl is selected from the group consisting of halogen, hydroxyl, amino, cyano, C 1-4 Alkyl, C1-4 Alkoxy, C 1-4 AlkylNH- or (C 1-4 It may be substituted with one or more of alkyl)2N-.

[0022] In some specific embodiments, R 1 is C 1-3 Alkyl, C 3-6 cycloalkyl or 5- to 6-membered heterocycloalkyl, 1-3 Alkyl, C 3-6 Cycloalkyl or 5-6 membered heterocycloalkyl is selected from halogen, hydroxyl, amino, cyano, C 1-3 Alkyl or C 1-3 It may be substituted with one or more alkoxy.

[0023] In some specific embodiments, R 1 is C 1-3 Alkyl, C 3-5 cycloalkyl or 6-membered heterocycloalkyl, 1-3 Alkyl, C 3-5 Cycloalkyl or 6-membered heterocycloalkyl may be halogen or C 1-3 It may be substituted with one or more alkoxy.

[0024] In some specific embodiments, R 1 is selected from propyl, cyclopropyl, cyclobutyl, cyclopentyl or a 6-membered oxygen-containing heterocycloalkyl, said cyclopropyl, cyclobutyl, cyclopentyl or 6-membered oxygen-containing heterocycloalkyl being optionally substituted with one or more of fluorine or methoxy.

[0025] In some specific embodiments, R 1 isopropyl,

[0026] [ka]

[0027] is selected from.

[0028] In some embodiments, R 2a and R 2b are each independently hydrogen or C 1-6 Alternatively, R 2a and R 2b are bonded to each other to form a 3- to 10-membered heterocycloalkyl, 1-6 The alkyl or 3-10 membered heterocycloalkyl may be substituted with deuterium, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 AlkylNH- or (C 1-6 It may be substituted with one or more of alkyl)2N-.

[0029] In some embodiments, R 2a and R 2b are each independently hydrogen or C 1-4 Alkyl is selected, or R 2a and R 2b are bonded to each other to form a 3-8 membered heterocycloalkyl, 1-4 The alkyl or 3-8 membered heterocycloalkyl may have 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-.

[0030] In some embodiments, R 2a and R 2b are each independently hydrogen or C 1-4 Alternatively, R 2a and R 2b are bonded to each other to form a 3- to 6-membered heterocycloalkyl, 1-4 Alkyl or 3-6 membered heterocycloalkyl may be substituted with deuterium, halogen, hydroxyl, amino, cyano, C 1-4Alkyl, C 1-4 Alkoxy, C 1-4 AlkylNH- or (C 1-4 It may be substituted with one or more of alkyl)2N-.

[0031] In some embodiments, R 2a and R 2b are each independently hydrogen or C 1-4 Alternatively, R 2a and R 2b are bonded to each other to form a 3-4 membered heterocycloalkyl, 1-4 Alkyl or 3-4 membered heterocycloalkyl may be substituted with deuterium, halogen, hydroxyl, amino, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 AlkylNH- or (C 1-4 It may be substituted with one or more of alkyl)2N-.

[0032] In some embodiments, R 2a and R 2b are each independently hydrogen or C 1-4 alkyl; or R 2a and R 2b are bonded to each other to form a 3-4 membered heterocycloalkyl, 1-4 The alkyl or 3-4 membered heterocycloalkyl may be substituted with deuterium, halogen, hydroxyl, amino, cyano or C 1-3 It may be substituted with one or more alkyl groups.

[0033] In some embodiments, R 2a and R 2b are each independently hydrogen or C 1-4 alkyl, 1-4 The alkyl may be substituted with one or more of deuterium, halogen, hydroxyl, amino or cyano groups.

[0034] In some embodiments, R 2a and R2b are each independently hydrogen or C 1-4 alkyl, 1-4 The alkyl may be optionally substituted with one or more of deuterium, fluorine, chloro or bromo.

[0035] In some embodiments, R 2a and R 2b are each independently hydrogen or C 1-3 alkyl, 1-3 The alkyl may be substituted with one or more deuterium atoms.

[0036] In some embodiments, R 2a and R 2b are each independently selected from hydrogen or CH3-, which may be substituted with one or more deuterium atoms.

[0037] In some embodiments, R 2a and R 2b are each independently selected from hydrogen, CH3-, or CD3-.

[0038] In some embodiments, R 3 and R 4 are each independently a halogen, a hydroxyl group, an amino group, a cyano group, or C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 AlkylNH- or (C 1-6 alkyl)2N-.

[0039] In some embodiments, R 3 and R 4 are each independently a halogen, a hydroxyl group, an amino group, a cyano group, or C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 AlkylNH- or (C 1-3 alkyl)2N-.

[0040] In some embodiments, R 3 and R 4 Each independently represents a halogen or C 1-3 alkoxy.

[0041] In some embodiments, R 3 is fluorine, chloro, bromine or C 1-3 alkoxy.

[0042] In some embodiments, R 3 is selected from fluorine or methoxy. In some embodiments, R 4 is selected from halogen, a hydroxyl group, an amino group, a cyano group, methyl, or methoxy. 4 is selected from a halogen, a hydroxyl group, an amino group, or a cyano group.

[0043] In some embodiments, p and m are independently selected from 0, 1, or 2.

[0044] In some embodiments, p is selected from 0 or 1. In some embodiments, p is selected from 0.

[0045] 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.

[0046] In some embodiments, Ring A is selected from phenyl, 5-6 membered heteroaryl, or 9-10 membered heteroaryl.

[0047] In some embodiments, ring A is selected from 5-6 membered heteroaryl. In some embodiments, ring A is selected from 6 membered heteroaryl. In some embodiments, ring A is selected from 5-6 membered nitrogen containing heteroaryl. In some embodiments, ring A is selected from 6 membered nitrogen containing heteroaryl.

[0048] In some embodiments, ring A is selected from a 5-6 membered heteroaryl or a 9-10 membered heteroaryl.

[0049] In some embodiments, Ring A is selected from pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, triazolyl, pyrazinyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, triazinyl, benzimidazolyl, or imidazopyridyl. In some embodiments, Ring A is selected from pyridyl or pyrimidinyl. In some embodiments, Ring A is selected from pyridyl.

[0050] In some embodiments, 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 is selected from N.

[0051] In some embodiments, 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 two of the following are selected from N:

[0052] In some embodiments, X 4 is selected from N, and X 1, X 2 Or X 3 are each independently selected from N or CH.

[0053] 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.

[0054] In some embodiments, X 4 is selected from N, and X 1 , X 2 Or X 3 is selected from CH.

[0055] In some embodiments, X 3 , X 4 is selected from N, and X 1 , X 2 is selected from CH.

[0056] In some embodiments, X is -NR a In some embodiments, X is selected from -NH- or -O-. In some embodiments, X is selected from -O-.

[0057] In some embodiments, Y 1 , Y 2 , Y 3 or Z is independently selected from N or CH; Y 1 , Y 2 , Y 3 Or one, two, three or four in Z are selected from CH.

[0058] In some embodiments, Y 1 is selected from N, Y 2 , Y 3 is selected from CH.

[0059] In some embodiments, Y 2is selected from N, Y 1 , Y 3 is selected from CH.

[0060] In some embodiments, Y 3 is selected from N, Y 1 , Y 2 is selected from CH. In some embodiments, Y 1 , Y 2 Or Y 3 is selected from CH.

[0061] In some embodiments, Y 1 , Y 2 , Y 3 Or Z is selected from CH.

[0062] In some embodiments, Z is selected from N or CH.

[0063] In some embodiments, Z is selected from N. In some embodiments, Z is selected from CH.

[0064] In some embodiments, R a is hydrogen or C 1-6 is selected from alkyl.

[0065] In some embodiments, R a is hydrogen or C 1-4 is selected from alkyl.

[0066] In some embodiments, R a is hydrogen or C 1-3 is selected from alkyl.

[0067] In some embodiments, R a is selected from hydrogen or methyl. a is selected from hydrogen.

[0068] In some embodiments, L is C1-6 Alkylene, C 3-10 Cycloalkyl, 3-10 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-.

[0069] In some embodiments, L is C 1-4 Alkylene, C 3-8 Cycloalkyl, 3-8 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-.

[0070] In some embodiments, L is C 1-4 Alkylene, C 3-6 Cycloalkyl, 3-6 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-.

[0071] In some embodiments, L is 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-.

[0072] In some embodiments, L is 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-.

[0073] In some embodiments, L is C 2-3 Alkylene, C 4-6 cycloalkyl, -CH2-C4 cycloalkyl- or -C4 cycloalkyl-CH2-.

[0074] In some embodiments, L is -CH2CH2-, -CH2CH2CH2-,

[0075] [ka]

[0076] is selected from.

[0077] In some embodiments, L is C 1-4 alkylene.

[0078] In some embodiments, L is C 2-3 alkylene.

[0079] In some embodiments, L is selected from -CH2CH2- or -CH2CH2CH2-. In some embodiments, L is selected from -CH2CH2CH2-.

[0080] In some embodiments, R 5 and R 6 are each independently hydrogen, C 1-6 Alkyl, C 3-10cycloalkyl or 3 to 10 membered heterocycloalkyl; or R 5 and R 6 are bonded to each other to form a 3- to 10-membered heterocycloalkyl, 1-6 Alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl may be substituted with deuterium, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl NH-, (C 1-6 alkyl)2N-, C substituted with one or more halogens, hydroxyl groups, amino groups or cyano groups 1-6 It may be substituted with one or more groups of alkyl.

[0081] In some embodiments, R 5 and R 6 are each independently hydrogen, C 1-6 Alkyl, C 3-10 cycloalkyl or 3 to 10 membered heterocycloalkyl; or R 5 and R 6 are bonded to each other to form a 3- to 10-membered heterocycloalkyl, 1-6 Alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl may be substituted with deuterium, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl NH-, (C 1-6 alkyl)2N-, C substituted with one or more halogens 1-6 It may be substituted with one or more groups of alkyl.

[0082] In some embodiments, R 5 and R 6 are each independently hydrogen, C 1-4 Alkyl, C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl; or R 5and R 6 are bonded to each other to form a 3-8 membered heterocycloalkyl, 1-4 Alkyl, C 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl may be substituted with deuterium, halogen, hydroxyl, amino, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl NH-, (C 1-4 Alkyl)2N- or halogenated C 1-6 It may be substituted with one or more groups of alkyl.

[0083] In some embodiments, R 5 and R 6 are each independently 1-4 Alkyl or C 3-6 cycloalkyl; or R 5 and R 6 are bonded to each other to form a 3- to 7-membered heterocycloalkyl, 3-6 Cycloalkyl or 3- to 7-membered heterocycloalkyl may be substituted with deuterium, halogen, hydroxyl, amino, cyano, C 1-3 Alkyl, C 1-3 Alkoxy or halogenated C 1-4 It may be substituted with one or more alkyl groups.

[0084] In some embodiments, R 5 and R 6 are each independently 1-4 Alkyl or C 3-6 cycloalkyl; or R 5 and R 6 are bonded to each other to form a 3- to 7-membered heterocycloalkyl, and the 3- to 7-membered heterocycloalkyl is selected from the group consisting of deuterium, halogen, a hydroxyl group, an amino group, a cyano group, C 1-3 Alkyl, C 1-3 Alkoxy or halogenated C 1-4 It may be substituted with one or more alkyl groups.

[0085] In some embodiments, R 5 and R 6 are each independently 1-3 Alkyl or C 3-4 cycloalkyl; or R 5 and R 6 are joined together to form a 4-, 5-, 6- or 7-membered heterocycloalkyl, said heterocycloalkyl being selected from the group consisting of one or more halogen or halogenated C 1-3 It may be substituted with alkyl.

[0086] In some embodiments, R 5 and R 6 are each independently 1-3 Alkyl or C 3-4 In some embodiments, R 5 and R 6 are joined together to form a 4-, 5-, 6- or 7-membered heterocycloalkyl, said heterocycloalkyl being selected from the group consisting of one or more halogen or halogenated C 1-3 It may be substituted with alkyl.

[0087] In some embodiments, R 5 and R 6 are joined together to form a 4-, 5- or 6-membered heterocycloalkyl, said heterocycloalkyl being selected from the group consisting of one or more halogen or halogenated C 1-3 In some embodiments, R 5 and R 6 are joined together to form a 4-membered heterocycloalkyl, said heterocycloalkyl being selected from the group consisting of one or more halogen or halogenated C 1-3 In some embodiments, R 5 and R 6 are joined together to form a 5-membered heterocycloalkyl, said heterocycloalkyl being selected from the group consisting of one or more halogen or halogenated C 1-3 In some embodiments, R 5and R 6 are joined together to form a 6-membered heterocycloalkyl, said heterocycloalkyl being selected from the group consisting of one or more halogen or halogenated C 1-3 It may be substituted with alkyl.

[0088] In some embodiments, R 5 and R 6 are each independently selected from methyl or cyclopropyl; 5 and R 6 are linked together to form azetidinyl, pyrrolidinyl, piperidinyl, azaspiroheptyl, or azabicycloheptyl, wherein said azetidinyl or pyrrolidinyl is optionally substituted with one or more F or -CH2F.

[0089] In some embodiments, R 5 and R 6 are each independently selected from methyl or cyclopropyl; 5 and R 6 are linked together to form an azetidinyl, pyrrolidinyl or piperidinyl, wherein the azetidinyl, pyrrolidinyl or piperidinyl is selected from the group consisting of one or more halogen or halogenated C 1-3 It may be substituted with alkyl.

[0090] In some embodiments, R 5 and R 6 are each independently selected from methyl or cyclopropyl; 5 and R 6 are linked together to form an azetidinyl, pyrrolidinyl, or piperidinyl, wherein the azetidinyl or pyrrolidinyl is optionally substituted with one or more F or -CH2F.

[0091] In some specific embodiments, R 5 and R 6 are each independently 1-6 alkyl; or R 5 and R6 are bonded to each other to form a 4- to 6-membered heterocycloalkyl, 1-6 The alkyl or 4- to 6-membered heterocycloalkyl is selected from the group consisting of halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or C substituted with one or more halogens, hydroxyl groups, amino groups or cyano groups 1-6 It may be substituted with one or more groups of alkyl.

[0092] In some specific embodiments, R 5 and R 6 are each independently 1-6 alkyl; or R 5 and R 6 are bonded to each other to form a 4- to 6-membered heterocycloalkyl, 1-6 The alkyl or 4- to 6-membered heterocycloalkyl is a C substituted or unsubstituted alkyl group, optionally substituted with halogen, a hydroxyl group, an amino group, a cyano group, or a halogen. 1-6 It may be substituted with one or more groups of alkyl.

[0093] In some specific embodiments, R 5 and R 6 are each independently 1-3 alkyl; or R 5 and R 6 are bonded to each other to form pyrrolidinyl or piperidinyl, 1-3 Alkyl, pyrrolidinyl or piperidinyl is substituted with halogen, hydroxyl group, amino group, cyano group, C 1-6 Alkyl, C 1-6 Alkoxy or C substituted with one or more halogens, hydroxyl groups, amino groups or cyano groups 1-6 It may be substituted with one or more groups of alkyl.

[0094] In some specific embodiments, R 5 and R 6are each independently 1-3 alkyl; or R 5 and R 6 are bonded to each other to form pyrrolidinyl or piperidinyl, and the pyrrolidinyl or piperidinyl is a halogen, a hydroxyl group, an amino group, a cyano group, or a C optionally substituted with a halogen. 1-6 It may be substituted with one or more groups of alkyl.

[0095] In some specific embodiments, R 5 and R 6 are each independently selected from methyl; or R 5 and R 6 are bonded to each other to form a 5- to 6-membered heterocycloalkyl, which is optionally substituted with one or more -CH2F.

[0096] In some specific embodiments, R 5 and R 6 are each independently selected from methyl; or R 5 and R 6 are linked together to form pyrrolidinyl or piperidinyl, said pyrrolidinyl or piperidinyl being optionally substituted with one or more -CH2F.

[0097] In some further embodiments, R 5 and R 6 are each independently hydrogen, C 1-6 Alkyl, C 3-10 cycloalkyl or 3 to 10 membered heterocycloalkyl; or R 5 and R 6 are bonded to each other to form a 3- to 10-membered heterocycloalkyl, 1-6 Alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl may be substituted with deuterium, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C1-6 AlkylNH- or (C 1-6 It may be substituted with one or more of alkyl)2N-.

[0098] In some further embodiments, R 5 and R 6 are each independently hydrogen, C 1-4 Alkyl, C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl; or R 5 and R 6 are bonded to each other to form a 3-8 membered heterocycloalkyl, 1-4 Alkyl, C 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl may be substituted with deuterium, halogen, hydroxyl, amino, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 AlkylNH- or (C 1-4 It may be substituted with one or more of alkyl)2N-.

[0099] In some further embodiments, R 5 and R 6 are each independently 1-4 Alkyl or C 3-6 cycloalkyl; or R 5 and R 6 are bonded to each other to form a 3- to 6-membered heterocycloalkyl, 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl may be substituted with deuterium, halogen, hydroxyl, amino, cyano, C 1-3 Alkyl or C 1-3 It may be substituted with one or more alkoxy.

[0100] In some further embodiments, R 5 and R 6 are each independently 1-3 Alkyl or C 3-4 cycloalkyl, or joined together to form a 5-6 membered heterocycloalkyl.

[0101] In some further embodiments, R 5 and R 6 are each independently selected from methyl or cyclopropyl, or joined together to form pyrrolidinyl or piperidinyl.

[0102] In some embodiments, when m is selected from 1, R 3 The bonding position of

[0103] [ka]

[0104] As shown in.

[0105] In some embodiments, R 4 X 1 Or X 2 is bound to.

[0106] In some embodiments, the structural fragment

[0107] [ka]

[0108] teeth,

[0109] [ka]

[0110] In some embodiments, the structural fragment is selected from

[0111] [ka]

[0112] teeth,

[0113] [ka]

[0114] is selected from.

[0115] In some specific embodiments, the structural fragment

[0116] [ka]

[0117] teeth,

[0118] [ka]

[0119] In some specific embodiments, the structural fragment

[0120] [ka]

[0121] teeth,

[0122] [ka]

[0123] is selected from.

[0124] In some embodiments, the structural fragment

[0125] [ka]

[0126] teeth,

[0127] [ka]

[0128] is selected from.

[0129] In some specific embodiments, the structural fragment

[0130] [ka]

[0131] teeth,

[0132] [ka]

[0133] is selected from.

[0134] In some other embodiments, the structural fragment

[0135] [ka]

[0136] teeth,

[0137] [ka]

[0138] is selected from.

[0139] In some embodiments, the structural fragment

[0140] [ka]

[0141] teeth,

[0142] [ka]

[0143] In some embodiments, the structural fragment is selected from

[0144] [ka]

[0145] teeth,

[0146] [ka]

[0147] In some embodiments, the structural fragment is selected from

[0148] [ka]

[0149] teeth,

[0150] [ka]

[0151] is selected from.

[0152] In some embodiments, the structural fragment

[0153] [ka]

[0154] teeth,

[0155] [ka]

[0156] In some embodiments, the structural fragment is selected from

[0157] [ka]

[0158] teeth,

[0159] [ka]

[0160] In some embodiments, the structural fragment is selected from

[0161] [ka]

[0162] teeth,

[0163] [ka]

[0164] In some embodiments, the structural fragment is selected from

[0165] [ka]

[0166] teeth,

[0167] [ka]

[0168] In some embodiments, the structural fragment is selected from

[0169] [ka]

[0170] teeth,

[0171] [ka]

[0172] is selected from.

[0173] In some embodiments, the structural fragment

[0174] [ka]

[0175] teeth,

[0176] [ka]

[0177] is selected from.

[0178] In some other embodiments, the structural fragment

[0179] [ka]

[0180] teeth,

[0181] [ka]

[0182] is selected from.

[0183] In some embodiments, the structural fragment

[0184] [ka]

[0185] teeth,

[0186] [ka]

[0187] is selected from.

[0188] In some specific embodiments, the structural fragment

[0189] [ka]

[0190] teeth,

[0191] [ka]

[0192] is selected from.

[0193] In some embodiments, the structural fragment

[0194] [ka]

[0195] teeth,

[0196] [ka]

[0197] is selected from.

[0198] In some other embodiments, the structural fragment

[0199] [ka]

[0200] teeth,

[0201] [ka]

[0202] is selected from.

[0203] In some embodiments, the compound of the present disclosure represented by formula IA or a pharma- ceutically acceptable salt thereof, the compound of formula I or a pharma- ceutically acceptable salt thereof is selected from the compound of formula II or a pharma- ceutically acceptable salt thereof.

[0204] [ka]

[0205] (In the formula, R 1 , R 2a , R 2b , R 3 , R 4 , R 5 , R 6 , X, X 3 , m and p are as defined above.) In some embodiments, the compound of the present disclosure represented by formula IA or a pharma- ceutically acceptable salt thereof, the compound of formula I or a pharma- ceutically acceptable salt thereof, or the compound of formula II or a pharma- ceutically acceptable salt thereof is selected from the compound of formula III or formula IV or a pharma- ceutically acceptable salt thereof.

[0206] [ka]

[0207] (In the formula, R 1 , R3 , R 5 , R 6 The definitions of m and Z are as described above. In some embodiments, the present disclosure encompasses the above-defined variables and embodiments thereof, and any combination thereof.

[0208] The heteroatoms in the heterocycloalkyl or heteroaryl are selected from nitrogen (NH or N), oxygen, sulfur (S), boron, Si, S(O) or S(O)2, and the other ring atoms are selected from carbon. The heteroatoms in the heterocycloalkyl or heteroaryl are selected from nitrogen (NH or N), oxygen or sulfur (S), and the other ring atoms are selected from carbon. In some embodiments, the number of heteroatoms is selected from 1, 2, 3 or 4. In some embodiments, the number of heteroatoms is selected from 1, 2 or 3. In some embodiments, the number of heteroatoms is selected from 1 or 2.

[0209] The present disclosure provides the following compounds, pharma- ceutically acceptable salts thereof, or stereoisomers thereof:

[0210] [ka]

[0211] [ka]

[0212] [ka]

[0213] In another aspect, the present disclosure further provides a pharmaceutical composition comprising a compound according to the present disclosure or a pharma- ceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition of the present disclosure further comprises a pharma- ceutically acceptable additive ingredient.

[0214] In another aspect, the present disclosure further provides methods of treating various ATM-related diseases, comprising administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of a compound according to the present disclosure, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0215] In another aspect, the present disclosure further provides the use of a compound according to the present disclosure, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for treating various ATM-related diseases.

[0216] In another aspect, the present disclosure further provides the use of a compound according to the present disclosure, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the treatment of various ATM-related diseases.

[0217] In another aspect, the present disclosure further provides a compound according to the present disclosure, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof for treating various ATM-related diseases.

[0218] In some embodiments, the ATM-related disease is selected from tumors.

[0219] In some embodiments, the disease or tumor is selected from lung cancer or colon cancer. Effect of the Invention

[0220] The compounds of the present disclosure have inhibitory activity against ATM kinase and have selectivity against ATM kinase compared to ATR and DNA-PK kinase. In addition, the compounds of the present disclosure have good inhibitory activity against CHK2 phosphorylation in NCI-H2228 cells, and have good in vivo and in vitro metabolism data, stable in vitro liver microsomal metabolism (species: human, monkey, dog, rat and mouse), and low plasma protein binding rate in vitro. According to in vivo drug metabolism data including mouse, rat, or dog, the compounds of the present disclosure have high exposure in mouse brain and plasma, and high brain / blood ratio. Furthermore, according to in vivo drug efficacy studies, the compounds of the present disclosure can inhibit tumor growth. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0221] definition Unless otherwise specified, the following terms in the present invention are defined as follows. Certain terms should not be considered uncertain or unclear in the absence of a specific definition, but should be understood according to their usual meaning in the art. Trade names in this specification are intended to refer to the corresponding products or their active ingredients.

[0222] When a covalent bond in any structural unit or group in this disclosure is not attached to a specific atom, it is meant that the covalent bond may be attached to any atom in that structural unit or group, unless contrary to valence bond rules.

[0223] The term "substituted" means that any one or more hydrogen atoms on the specified atom are replaced with a substituent, provided that the valence state of the specified atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced. Substitution with oxo does not occur on aromatic groups.

[0224] The term "may" or "optionally" means that the events or circumstances described below may or may not occur, and the phrase includes both the occurrence and non-occurrence of such events or circumstances. For example, ethyl "may" be substituted with a halogen means that ethyl can be unsubstituted (CH2CH3), monosubstituted (such as CH2CH2F), polysubstituted (such as CHFCH2F, CH2CHF2), or fully substituted (CF2CF3). Those skilled in the art will understand that for any group containing one or more substituents, no substitutions or substitution patterns that are spatially impossible and / or cannot be synthesized are introduced.

[0225] As used herein, "one or more" refers to an integer between 1 and 10. For example, "one or more" refers to one, two, three, four, five, six, seven, eight, nine, or ten. Alternatively, "one or more" refers to one, two, three, four, five, or six. Alternatively, "one or more" refers to one, two, or three.

[0226] In this specification, C m~n means that the moiety has an integer number of carbon atoms within a specified range. For example, "C 1-6 " means that the group may 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 may have 1 carbon atom, 2 carbon atoms, or 3 carbon atoms.

[0227] When any variable (e.g., R) occurs more than one time in any composition or structure of a compound, its definition at each occurrence is independent. Thus, for example, when a group is substituted with two R, each R has independent choice.

[0228] For example, when the number of a linking group is 0, such as -(CH2)0-, it means that the linking group is a covalent bond.

[0229] When a variable is selected from a covalent bond, it means that the two groups connected to it are directly linked, for example, when L' in A-L'-Z represents a covalent bond, it means that the structure is actually AZ.

[0230] If a bond of a substituent crosses two atoms on a ring, then such substituent may be bonded to any atom on the ring. For example, the structural unit

[0231] [ka]

[0232] means that the substituent can be substituted at any one position on the cyclohexyl or cyclohexadiene. Specifically, for example,

[0233] [ka]

[0234] For m=1, R 3 The position of may be a position in the following group:

[0235] [ka]

[0236] The term "halogen" refers to fluorine, chlorine, bromine and iodine.

[0237] The term "alkyl" refers to a group having the general formula C n H 2n+1 The alkyl group may be linear or branched. For example, the term "C 1-6"Alkyl" refers to an alkyl having 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, and the like). Similarly, the alkyl portions (i.e., alkyl) of alkoxy, alkylamino, dialkylamino, alkylhydrazino, alkylsulfonyl, and alkylthio are as defined above. Also, for example, the term "C 1-3 "Alkyl" refers to an alkyl group having 1 to 3 carbon atoms (eg, methyl, ethyl, propyl, and isopropyl).

[0238] The term "alkylene" refers to a divalent group formed by removing one hydrogen at any position of an alkyl. For example, the term "C 1-6 The term "alkyl" refers to an alkylene having 1 to 6 carbon atoms. 1-4 "Alkyl" refers to an alkylene having 1 to 4 carbon atoms, including, but not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2- or -CH2CH2CH2CH2-.

[0239] The term "alkoxy" refers to --O-alkyl.

[0240] The term "cycloalkyl" refers to a carbocyclic group that is fully saturated and can exist as a monocyclic, bridged, or spiro ring, and can be a monovalent or polyvalent (e.g., divalent) group depending on the position in the compound. Unless otherwise specified, the carbocyclic ring is typically a 3-15 membered ring, a 3-12 membered ring, a 3-10 membered ring, or a 3-8 membered ring, or a 4-6 membered ring, or a 5-8 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]pentan-1-yl, and the like. For example, C 3-4 Cycloalkyl includes cyclopropyl and cyclobutyl.

[0241] The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged (including fused) or spirocyclic ring, and can be a monovalent or polyvalent (e.g., divalent) group depending on the position in the compound. Unless otherwise specified, the heterocycle is typically a 3-15-, 3-12-, 3-10-, 3-9-, 3-7-, 4-6-, or 5-6-membered ring containing 1-3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, and / or nitrogen. Examples of 3-membered heterocycloalkyl include, but are not limited to, oxiranyl, thiiranyl, and aziranyl. Non-limiting examples of 4-membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Examples of 5-membered heterocycloalkyl include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidine, imidazolidinyl, and tetrahydropyrazolyl. Examples of 6-membered heterocycloalkyl include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-oxathiyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, and 1,4-dithianyl. Examples of 7-membered heterocycloalkyl include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Monocyclic heterocycloalkyls having 5 or 6 ring atoms are preferred.

[0242] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated pi-electron system. For example, an aryl can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Non-limiting examples of aryl include, but are not limited to, phenyl, naphthyl, anthracenyl, and 1,2,3,4-tetralin.

[0243] The term "heteroaryl" refers to a monocyclic or fused polycyclic group containing at least one ring atom selected from N, O, S, e.g., 1, 2, 3 or 4 ring atoms selected from N, O, S, other ring atoms are C, and at least one aromatic ring. The group can be monovalent or polyvalent (e.g., divalent) depending on the position in the compound. Preferred heteroaryls have one 5-8 or 5-6 membered ring, or multiple fused rings containing 6-14, especially 6-10 ring atoms. Non-limiting examples of heteroaryls include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, benzimidazolyl, imidazopyridyl, indolyl, isoindolyl, and the like. For example, in this disclosure:

[0244] [ka]

[0245] means that the ring system in question is heteroaryl.

[0246] Groups or structural fragments of the present disclosure, such as L and its specific options, are read in a left-to-right order and are correspondingly connected to the groups on the left and right sides of the group or fragment in the general formula, respectively. For example, L is

[0247] [ka]

[0248] If selected from the group consisting of:

[0249] [ka]

[0250] and the right side is attached to the right group, X, and the fragment that is formed is

[0251] [ka]

[0252] It is as follows. L is

[0253] [ka]

[0254] If selected from the group consisting of:

[0255] [ka]

[0256] and the right side of L is attached to X, a group corresponding to the right side of the general formula, forming a fragment

[0257] [ka]

[0258] The other groups are the same as above.

[0259] The term "treating" means administering a compound according to the present disclosure, a pharma- ceutically acceptable salt thereof, a pharmaceutical composition thereof, or a formulation thereof to improve or eliminate a disease or one or more symptoms associated with said disease, and includes the following: (i) To inhibit the disease or condition, i.e., to arrest its progression. (ii) Alleviating the disease or condition, i.e., reducing or eliminating the disease or condition.

[0260] The term "prevent" refers to the administration of a compound according to the present disclosure, a pharma- ceutically acceptable salt thereof, a pharmaceutical composition thereof, or a formulation thereof to prevent a disease or one or more symptoms associated with said disease, and includes preventing the onset of a disease or condition in a mammal, particularly where such a mammal is predisposed to the condition but has not yet been diagnosed as suffering from it.

[0261] The term "therapeutically effective amount" refers to an amount of a compound of the present disclosure that (i) treats or prevents a particular disease, condition, or disorder, (ii) reduces, improves, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of a compound of the present disclosure that constitutes a "therapeutically effective amount" varies depending on the compound, the disease and its severity, the method of administration, and the age of the mammal being treated, but can generally be determined by one of ordinary skill in the art based on his or her own knowledge and the contents of the present disclosure.

[0262] The term "pharmacologically acceptable" means that the compound, material, composition, and / or dosage form is, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0263] Examples of pharma- ceutically acceptable salts include, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like.

[0264] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or salts thereof and pharma- ceutical acceptable additives. Pharmaceutical compositions are intended to facilitate administration of the compounds of the present disclosure to a living organism.

[0265] The term "pharmaceutical acceptable additive" refers to an additive that has no significant irritating effect on the living body and does not impair the biological activity and performance of the active compound. Suitable additives 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.

[0266] The terms "comprise" or "comprise" and their English variants, such as comprises or comprising, are to be understood in an open and non-exclusive sense, i.e., "including but not limited to."

[0267] The compounds and intermediates of the present disclosure may exist in different tautomeric forms, and all such forms are within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can be interconverted via a low energy barrier. For example, proton tautomers (also called prototropic tautomers) include interconversions via the transfer of a proton, such as keto-enol isomerization and imine-enamine isomerization. A specific example of a proton tautomer is the imidazole moiety, where a proton can transfer between two ring nitrogens. Valence tautomers include interconversions via recombination of some of the bonding electrons.

[0268] The present disclosure further includes isotopic labels as described herein, except that one or more atoms are replaced with an atom having an atomic mass or mass number different from that typically found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, e.g., 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 It is Cl.

[0269] Some isotopically labeled versions of the compounds of the present disclosure (e.g., 3 H and 14 C) can be used in compound and / or substrate tissue distribution assays. 3 H) isotopes and carbon-14 (i.e. 14 C) Isotopes are particularly preferred because they are easy to prepare and detect. 15 O. 13 N, 11 C. 18 Positron emitting isotopes such as F are useful for positron emission tomography (PET) studies to measure substrate occupancy. Isotopically labeled compounds of the present disclosure can generally be prepared following procedures similar to those disclosed in the following embodiments and / or examples by substituting isotopically labeled reagents for non-isotopically labeled reagents.

[0270] Additionally, heavier isotopes (e.g. deuterium (i.e. 2 H)) substitution may confer certain therapeutic benefits (e.g., increased in vivo half-life and reduced dosage needs) resulting from greater metabolic stability and therefore may be preferred in some cases. Deuterium substitution may be partial or complete, with partial deuterium substitution meaning that at least one hydrogen is replaced with at least one deuterium. All such forms of the compound are within the scope of the present disclosure.

[0271] The compounds of the present disclosure may be asymmetric, such as having one or more stereoisomers.Unless otherwise specified, all stereoisomers include, for example, enantiomers and diastereomers.Compounds of the present disclosure that contain asymmetric carbon atoms can be isolated in optically pure or racemic form.Optical pure forms can be resolved from racemic mixtures or synthesized using chiral raw materials or chiral reagents.

[0272] The pharmaceutical composition of the present disclosure can be prepared by combining the compound of the present disclosure with suitable pharma- ceutical acceptable additives.For example, the pharmaceutical composition of the present disclosure can be prepared into solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.

[0273] Typical routes of administration of the compounds of the present disclosure or pharma- ceutically acceptable salts thereof or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous and intravenous administration.

[0274] The pharmaceutical compositions of the present disclosure can be manufactured by using conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, and lyophilizing methods which are well known in the art.

[0275] In some embodiments, pharmaceutical composition is in oral form.For oral administration, active compound can be mixed with pharmaceutically acceptable additives known in the art to prepare said pharmaceutical composition.These additives can allow the compound of the present disclosure to be formulated into tablets, pills, lozenges, sugar-coated tablets, capsules, liquids, gels, syrups, suspensions, etc. for oral administration to patients.

[0276] The solid oral composition can be prepared by conventional mixing, filling or tabletting methods. For example, the mixture of the active compound and solid additives is optionally milled, other suitable additives are added as necessary, and the mixture is then processed into granules to obtain tablets or sugar-coated cores. Suitable additives include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents.

[0277] The pharmaceutical compositions are suitable for parenteral administration, such as sterile solutions, suspensions, or lyophilized products in appropriate unit dosage forms.

[0278] The therapeutic dose of the compounds of the present disclosure may be determined, for example, based on the specific application of the treatment, the method of administration of the compound, the health of the patient, and the judgment of the prescribing physician. The proportion or concentration of the compounds of the present disclosure in a pharmaceutical composition is not fixed and depends on a variety of factors, including the dose, chemical properties (e.g., hydrophobicity), and the route of administration. For example, the compounds of the present application may be provided for parenteral administration in an aqueous physiological buffer solution containing about 0.1-10% w / v of the compound. Typical dose ranges are about 1 μg / kg to about 1 g / kg of body weight per day. In some embodiments, the dose range is about 0.01 mg / kg to about 100 mg / kg of body weight per day. The dose will depend on such variables as the type and progression of the disease or condition, the general health of the particular patient, the relative biological potency of the selected compound, the formulation of excipients and their route of administration. Effective doses may be obtained by extrapolation of dose-response curves derived from in vitro or animal model test systems.

[0279] The compounds of the present disclosure can be prepared by a variety of synthetic methods known to those of skill in the art, including the specific embodiments exemplified below, embodiments formed in combination with other chemical synthetic methods, and equivalent alternative embodiments known to those of skill in the art, and preferred embodiments include, but are not limited to, the examples of the present disclosure.

[0280] The chemical reactions in the specific embodiments of the present disclosure are completed in a suitable solvent, which must be suitable for the chemical transformations of the present disclosure and the necessary reagents and materials thereof. In order to obtain the compounds of the present disclosure, in some cases, those skilled in the art may need to modify or select synthetic steps or reaction schemes based on existing embodiments.

[0281] One important consideration in designing a synthetic route in the art is the selection of a suitable protecting group for a reactive functional group (e.g., an amino group in the present disclosure). For example, see Greene's Protective Groups in Organic Synthesis (4th Ed.), Hoboken, New Jersey: John Wiley & Sons, Inc.

[0282] In some embodiments, compounds represented by the general formula of the present disclosure can be prepared by one skilled in the art of organic synthesis through the following schemes using conventional or common methods in the art.

[0283] [ka]

[0284] In the above pathway, R 1 , R 2a , R 2b , R 3 , R 4 , R 5 , R 6 , X, X 3 , m and p are as defined above.

[0285] The following abbreviations are used in this disclosure:

[0286] DMF stands for N,N-dimethylformamide, THF stands for tetrahydrofuran, EtOH stands for ethanol, DIPEA stands for N,N-diisopropylethylamine, DCM stands for dichloromethane, EA stands for ethyl acetate, MeOH stands for methanol, DBU stands for 1,8-diazabicyclo[5.4.0]undec-7-ene, TBAB stands for tetrabutylammonium bromide, DMA stands for N,N-dimethylacetamide, and CDI stands for N,N'-carbonyldiimidazole. EXAMPLES

[0287] The present disclosure will be described in detail with reference to the following examples, which are not intended to limit the scope of the present disclosure. All reagents used in the present disclosure are commercially available and can be used without further purification.

[0288] Manufacturing example A-3

[0289] [ka]

[0290] Step A: Synthesis of Compound A-2 A-1 (10.9 g) and THF (150 mL) were added in order to a one-neck flask, and 60% (purity, mass%) sodium hydride (5.8 g) was added under N2 protection, and the mixture was stirred at 50°C for 10 minutes. After that, the mixture was cooled to room temperature, and 5-bromo-2-fluoropyridine (10 g) was further added and stirred at 50°C for 2 hours. After the reaction was completed, the reaction solution was slowly poured into ice-cooled saturated ammonium chloride solution (100 mL) to quench the reaction. The mixture was extracted with dichloromethane (150 mL x 3), and the organic phases were combined, washed with saturated sodium chloride (150 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated under reduced pressure to obtain A-2 (20 g). MS (ESI+, [M+H] + ) m / z:298.97.

[0291] Step B: Synthesis of Compound A-3 A-2 (10.9 g), THF (250 mL), and isopropoxyboronic acid pinacol ester (13.74 g) were added in sequence to a three-neck flask, and the temperature was lowered to -78 ° C under N2 protection, and 2.5 M n-butyllithium tetrahydrofuran solution (31 mL) was slowly added dropwise, and after the addition was completed, stirring was continued for 1 hour, and then the temperature was returned to room temperature and stirred overnight. After the reaction was completed, the reaction solution was slowly poured into ice-cooled saturated ammonium chloride solution (100 mL), extracted with EA (200 mL x 4), the organic phase was washed with saturated sodium chloride (200 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated under reduced pressure to remove the solvent, obtaining A-3 (19 g). MS (ESI +, [M + H] + ) m / z:347.17.

[0292] Manufacturing example A-6

[0293] [ka]

[0294] Step A: Synthesis of Compound A-5 With reference to the synthesis of Preparation A-3, compound A-5 was obtained by using A-4 instead of A-1 in the preparation process of A-2. MS (ESI+, [M+H] + ) m / z:284.94.

[0295] Step B: Synthesis of Compound A-6 With reference to the synthesis of Preparation A-3, compound A-6 was obtained by using A-5 instead of A-2 in the preparation process of A-3. MS (ESI+, [M+H] + ) m / z:333.09.

[0296] Manufacturing example A-9

[0297] [ka]

[0298] Step A: Synthesis of Compound A-8 With reference to the synthesis of Preparation A-3, in the preparation process of A-2, A-7 was used instead of A-1 to obtain compound A-8. MS (ESI+, [M+H] + ) m / z:310.87.

[0299] Step B: Synthesis of Compound A-9 With reference to the synthesis of Preparation A-3, compound A-9 was obtained by using A-8 instead of A-2 in the preparation process of A-3. MS (ESI+, [M+H] + ) m / z:359.12.

[0300] Manufacturing example A-12

[0301] [ka]

[0302] Step A: Synthesis of Compound A-11 With reference to the synthesis of Preparation A-3, in the preparation process of A-2, A-10 was used instead of A-1 to obtain compound A-11. MS (ESI+, [M+H] + ) m / z:258.90.

[0303] Step B: Synthesis of Compound A-12 With reference to the synthesis of Preparation A-3, compound A-12 was obtained by using A-11 instead of A-2 in the preparation process of A-3. MS (ESI+, [M+H] + ) m / z:307.23.

[0304] Example 1

[0305] [ka]

[0306] Reaction Scheme:

[0307] [ka]

[0308] Step A: Synthesis of Compound 1-2 1-1 (10 g), dichloromethane (100 mL), and DMF (0.67 g) were added in this order to a one-neck flask, and oxalyl chloride (8.69 g) was added under ice bath. The resulting mixture was stirred at 0°C for 1 hour, and after the reaction was completed, it was concentrated under reduced pressure to obtain intermediate 1-2 (10 g), which was used directly in the next reaction.

[0309] Step B: Synthesis of Compounds 1-3 1-2 (10 g), toluene (100 mL), and DIPEA (8.16 mL) were added in sequence to a one-neck flask, and ethyl (E)-3-(dimethylamino)acrylate (6.63 g) was added dropwise under N2 protection. The resulting solution was stirred at 70°C for 17 hours, then cooled to room temperature, 4-methoxybenzylamine (5.84 g) was added, and stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was diluted with DCM (300 mL), washed with water (3 x 200 mL) and saturated saline (200 mL) in that order, and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate 1-3 (18 g). MS (ESI+, [M+H] + ) m / z:436.02.

[0310] Step C: Synthesis of Compounds 1-4 1-3 (18 g) and acetone (200 mL) were added in sequence to a one-neck flask, and DBU (6.28 g) was added at 10°C. The mixture was stirred at room temperature for 16 hours under N2 protection. After the reaction was completed, the reaction system was filtered to collect the cake, which was washed with petroleum ether (3 x 5 mL) and dried under reduced pressure to obtain intermediate 1-4 (8.0 g). MS (ESI+, [M+H] + ) m / z: 416.06. 1 H NMR(500MHz,DMSO-d6)δ8.92(s,1H),8.30(d,J=2.4Hz,1H),7.85(dd,J=9.1,2.5Hz,1H),7.67(d,J=9.1Hz,1H) ,7.26-7.17(m,2H),6.95-6.88(m,2H),5.59(s,2H),4.25(q,J=7.1Hz,2H),3.71(s,3H),1.29(t,J=7.1Hz,3H).

[0311] Step D: Synthesis of Compounds 1-5 1-4 (8.3 g), thionyl chloride (47.4 g), and DMF (0.029 g) were added in this order to a one-neck flask, and the mixture was stirred at 70°C under N2 protection for 3 hours. After the reaction was completed, the reaction solution was concentrated to dryness, and the crude product was purified by slurrying with n-hexane (20 mL), and then filtered with suction to obtain intermediate 1-5 (5.3 g). MS (ESI+, [M+H] + ) m / z:313.85.

[0312] Step E: Synthesis of Compounds 1-6 1-5 (2.5 g), DMA (30 mL), isopropylamine (0.705 g), and DIPEA (2.05 g) were added in sequence to a one-neck flask, and the mixture was stirred at 100 °C under N2 protection for 4 h. After the reaction was completed, the reaction solution was poured into ice water (150 mL), the cake was collected, the cake was washed with water (10 mL × 3), and dried under vacuum to obtain intermediate 1-6 (2.7 g). MS (ESI +, [M + H] + ) m / z:336.97.

[0313] Step F: Synthesis of Compounds 1-7 1-6 (2.7 g), THF (30 mL), water (10 mL), and NaOH (1.6 g) were added in sequence to a one-neck flask, and the mixture was stirred at 60 °C for 5 h. After the reaction was completed, the reaction solution was concentrated, diluted with water (50 mL), and adjusted to pH 2-3 with 2 M hydrochloric acid. The cake was collected, washed with water (5 mL × 3), and dried under vacuum to obtain intermediate 1-7 (2.1 g). MS (ESI +, [M + H] + ) m / z:308.88.

[0314] Step g: Synthesis of Compounds 1-8 1-7 (1.6 g), DMF (15 mL), and triethylamine (1.571 g) were added in sequence to a single-neck flask and stirred at room temperature for 30 min under N2 protection. Diphenylphosphoryl azide (1.709 g) was further added, and the reaction solution was stirred at room temperature for another 30 min, and then stirred at 60 °C for 3 h. After the reaction was completed, the reaction solution was poured into ice water (100 mL), filtered to collect the cake, washed the cake with water (5 mL × 3), and dried under vacuum to obtain intermediate 1-8 (1.5 g). MS (ESI +, [M + H] + ) m / z:305.88.

[0315] Step H: Synthesis of Compounds 1-9 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) were added in sequence to a one-neck flask and stirred at room temperature for 24 hours under nitrogen gas protection. After the reaction was completed, the mixture was concentrated under reduced pressure to remove a part of the solvent, and the cake was collected by filtration. The cake was slurried with 5 mL of acetonitrile and dried under vacuum to obtain intermediate 1-9 (95 mg). MS (ESI+, [M+H] + ) m / z:320.86.

[0316] Step I: Synthesis of Example 1 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), and disodium tetrachloropalladate (IV) (0.870 mg) were added to a one-neck flask in this order, and the mixture was stirred at 80 ° C for 1 hour under N2 protection. After the reaction was completed, the reaction solution was concentrated, the residue was dissolved in DCM (50 mL), washed with saturated saline (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was then purified by high-pressure fractionation (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. 1H NMR(500MHz,DMSO-d6)δ8.80(s,1H),8.65(d,J=2.6Hz,1H),8.39(d,J=2.0Hz,1H),8.18( dd,J=8.6,2.6Hz,1H),8.13(d,J=8.8Hz,1H),7.92(dd,J=8.8,1.9Hz,1H),6.97(d,J=8.6 Hz,1H),5.55(s,2H),5.36(p,J=6.8Hz,1H),4.35(t,J=6.6Hz,2H),2.43-2.23(m,6H),1. 91(q,J=6.8Hz,2H),1.68(d,J=6.7Hz,6H),1.49(p,J=5.5Hz,4H),1.38(q,J=5.9Hz,2H).

[0317] Example 2

[0318] [ka]

[0319] Reaction Scheme:

[0320] [ka]

[0321] Step A: Synthesis of Compound 2-2 2-1 (50 g), EtOH (500 mL), and diethyl 1,3-2-(ethoxymethylene)malonate (62.6 g) were added in this order to a three-neck flask, and the mixture was heated to 80° C. under N2 protection and reacted for 4 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure. After standing, it was suction filtered and the 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.

[0322] Step B: Synthesis of Compound 2-3 2-2 (90 g) and diphenyl ether (600 g) were added in order to a three-neck flask, and the mixture was heated to 240° C. under N2 protection and reacted for 8 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the cake was washed with petroleum ether (20 mL x 5) and dried under reduced pressure to obtain intermediate 2-3 (40 g). MS (ESI+, [M+H] + ) m / z:313.82.

[0323] Step C: Synthesis of Compound 2-4 2-3 (40 g), EtOH (400 mL), water (80 mL), and NaOH (25.5 g) were added in order to a one-neck flask, and the reaction solution was stirred at 75 °C for 2 hours under N2 protection. After the reaction was completed, the reaction solution was cooled in an ice bath, adjusted to pH 4-5 with 2N hydrochloric acid, filtered, and the cake was washed with water (20 mL x 3) and dried under vacuum to obtain intermediate 2-4 (35 g). MS (ESI+, [M+H] + ) m / z:285.82.

[0324] Step D: Synthesis of Compound 2-5 2-4 (31.6 g), thionyl chloride (120 mL), and DMF (0.16 g) were added to a single-neck flask in that order, and the reaction solution was heated to reflux under N2 protection and reacted for 2 hours. After the reaction was completed, the reaction solution was cooled and concentrated under reduced pressure, and then the concentrate was added to a solution of ammonium hydroxide (63.8 mL) at 0°C, vigorously stirred at room temperature for 15 minutes, filtered, and the cake was washed with water (15 mL x 3), and then dried under vacuum to obtain intermediate 2-5 (30 g). MS (ESI+, [M+H] + ) m / z:302.86.

[0325] Step E: Synthesis of Compound 2-6 2-5 (3.0 g), potassium carbonate (2.73 g), acetonitrile (40 mL), and isopropylamine (0.88 g) were added in sequence to a one-neck flask, and the mixture was stirred at 95° C. for 4 hours under N2 protection. After the reaction was completed, the reaction solution was cooled, 150 mL of water was added, filtered, and the cake was washed with water (5 mL×4) and dried under vacuum to obtain intermediate 2-6 (2.8 g). MS (ESI+, [M+H] + ) m / z:325.89.

[0326] Step F: Synthesis of Compound 2-7 2-6 (2.8 g), DBU (2.61 g), and methanol (30 mL) were added in order to a one-neck flask, and 1,3,5-trichloro-1,3,5-triazine-2,4,6-trione (1.00 g) was added at 5°C, and the mixture was stirred at room temperature for 1 hour under N2 protection. After the reaction was completed, the reaction solution was filtered as it was, and the cake was washed with water (10 mL x 2) and dried under vacuum to obtain intermediate 2-7 (2.4 g). MS (ESI+, [M+H] + ) m / z:323.86.

[0327] Step G: Synthesis of Compound 2-8 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 added in sequence to a one-neck flask, and the mixture was stirred at room temperature for 24 hours under N2 protection. After completion of the reaction, it was concentrated to remove most of the solvent, filtered, and the cake was slurried in 10 mL of acetonitrile and dried under vacuum to obtain intermediate 2-8 (1.8 g). MS (ESI+, [M+H] + ) m / z:338.88.

[0328] Step H: Synthesis of Example 2 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 added in sequence to a one-neck flask, and the mixture was stirred at 80 ° C for 1 hour under N2 protection. After the reaction was completed, the reaction solution was concentrated, and the residue was dissolved in DCM (50 mL), washed with saturated saline (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was slurried by adding acetonitrile (5 mL) to obtain Example 2 (70.0 mg). MS (ESI +, [M + H] + ) m / z: 479.30. 1H NMR(500MHz,DMSO-d6)δ8.82(s,1H),8.53-8.47(m,1H),8.32(d,J=8.2Hz,1H),8.0 4(dt,J=8.7,2.3Hz,1H),7.91(d,J=12.0Hz,1H),6.98(d,J=8.6Hz,1H),5.55(s,2H) ,5.35-5.23(m,1H),4.36(t,J=6.6Hz,2H),2.39(t,J=7.2Hz,2H),2.33(s,4H),1.9 6-1.85(m,2H),1.64(d,J=6.7Hz,6H),1.49(p,J=5.6Hz,4H),1.38(d,J=6.1Hz,2H).

[0329] Example 3

[0330] [ka]

[0331] Reaction Scheme:

[0332] [ka]

[0333] 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 added in sequence to a one-neck flask, and the mixture was stirred at 80° C. for 1 hour 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 a crude product, which was slurried with acetonitrile (5 mL) to obtain Example 3 (25 mg). MS (ESI+, [M+H] + ) m / z: 465.25. 1H NMR(500MHz,DMSO-d6)δ8.82(s,1H),8.52-8.48(m,1H),8.32(d,J=8.2Hz,1H), 8.04(dt,J=8.6,2.3Hz,1H),7.91(d,J=12.0Hz,1H),6.99(d,J=8.6Hz,1H),5.5 5(s,2H),5.29(p,J=6.8Hz,1H),4.38(t,J=6.6Hz,2H),2.55(t,J=7.1Hz,2H),2 .48-2.43(m,4H),1.97-1.89(m,2H),1.71-1.67(m,4H),1.65(d,J=6.8Hz,6H).

[0334] Example 4

[0335] [ka]

[0336] Reaction Scheme:

[0337] [ka]

[0338] 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) were added in sequence to a one-neck flask and stirred at 80 ° C. for 1 hour under N2 protection. The reaction solution was concentrated, and the residue was dissolved in DCM (50 mL), washed with saturated saline (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by high-pressure preparative purification (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. 1H NMR(500MHz,DMSO-d6)δ8.82(s,1H),8.50(s,1H),8.32(d,J=8.1Hz,1H),8.04(dt,J=8. 8,2.3Hz,1H),7.91(d,J=12.0Hz,1H),6.99(d,J=8.6Hz,1H),5.55(s,2H),5.35-5.21(m, 1H),4.34(t,J=6.5Hz,2H),2.82(t,J=7.4Hz,2H),2.03(p,J=6.8Hz,2H),1.90(tt,J=6. 8,3.8Hz,2H),1.64(d,J=6.7Hz,6H),0.42(dt,J=6.3,3.1Hz,4H),0.32(p,J=4.2Hz,4H).

[0339] Example 5

[0340] [ka]

[0341] Reaction Scheme:

[0342] [ka]

[0343] Step A: Synthesis of Compound 5-1 2-5 (1.0 g), DMF (10 mL), DIPEA (1.28 g) and 4-aminotetrahydropyran (0.40 g) were added in order to a one-neck flask, and the mixture was heated to 90° C. under N2 protection and reacted for 1 hour. After the reaction was completed, the reaction solution was poured into 100 mL of water, filtered, and the cake was washed with water (10 mL x 2) and dried under vacuum to obtain intermediate 5-1 (1.1 g). MS (ESI+, [M+H] + ) m / z:368.95. 1H NMR(500MHz,DMSO-d6)δ8.71(d,J=7.5Hz,1H),8.58(s,1H),8.13(s,1H),8.02(d,J=8.5Hz,1H),7.71(d,J=10.0Hz,1H),7.62(s,1H), 4.08-3.96(m,1H),3.88(d,J=11.5Hz,2H),3.36(d,J=1.3Hz,1H),3.32(s,1H),1.91(d,J=12.3Hz,2H),1.60(td,J=14.2,4.0Hz,2H).

[0344] Step B: Synthesis of Compound 5-2 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) were added in sequence to a one-neck flask, and the suspension was stirred at room temperature under N2 protection for 1 h. After the reaction was completed, it was directly filtered, and the cake was washed with water (10 mL x 2) and dried under vacuum to obtain intermediate 5-2 (0.85 g). MS (ESI+, [M+H] + ) m / z:365.92. 1 H NMR(500MHz,DMSO-d6)δ8.67(s,1H),8.54(d,J=7.3Hz,1H),7.89(d,J=10.2Hz,1H),4.98-4.83(m ,1H),4.03(dd,J=11.3,4.2Hz,2H),3.58(t,J=11.3Hz,3H),2.76-2.62(m,2H),1.86-1.77(m,2H).

[0345] Step C: Synthesis of Compound 5-3 5-2 (0.65 g), THF (10 mL), sodium hydride (60% purity, mass %, 0.11 g) and 2,4-dinitrophenylhydroxylamine (0.42 g) were added in order to a one-neck flask, and the mixture was stirred at room temperature for 24 hours under N2 protection. After the reaction was completed, 50 mL of water was added, and the mixture was extracted with EA (50 mL x 3). The organic phases were combined, washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The obtained crude product was subjected to 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.

[0346] Step D: Synthesis of Example 5 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 added in sequence to a one-neck flask, and the mixture was reacted for 1 hour by heating to 80 ° C under N2 protection. After the reaction was completed, 50 mL of water was added, extracted with dichloromethane (50 mL × 3), the organic phase was combined, washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (cleaning agent: DCM / MeOH = 10 / 1) to obtain Example 5 (44 mg). MS (ESI +, [M + H] + ) m / z:507.28. 1H NMR(500MHz,DMSO-d6)δ8.84(d,J=1.7Hz,1H),8.54(t,J=2.5Hz,1H),8.34(d,J=8.1Hz,1H),8.1 0-8.07(m,1H),7.93(dd,J=12.1,1.6Hz,1H),7.00(d,J=8.2Hz,1H),5.58(s,2H),5.09(ddt,J=11 .8,8.2,4.2Hz,1H),4.40-4.37(m,2H),4.03(dd,J=11.4,4.6Hz,2H),3.54(t,J=11.9Hz,2H),2. 74-2.66(m,2H),2.54(t,J=7.2Hz,2H),2.46-2.43(m,4H),1.96-1.89(m,4H),1.70-1.67(m,4H).

[0347] Example 6

[0348] [ka]

[0349] Reaction Scheme:

[0350] [ka]

[0351] 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 chloropalladate (1.5 mg) were added in sequence to a one-neck flask, and the mixture was reacted for 1 hour by heating to 80 ° C under N2 protection. After the reaction was completed, 50 mL of water was added, extracted with dichloromethane (50 mL × 3), the organic phase was combined, washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (washing agent: DCM / MeOH = 10 / 1) to obtain Example 6 (94 mg). MS (ESI +, [M + H] + ) m / z:533.34.1 H NMR(500MHz,DMSO-d6)δ8.83(s,1H),8.54(s,1H),8.34(d,J=7.9Hz,1H),8.08(d,J=7.0Hz,1H),7.93(d ,J=12.1Hz,1H),7.00(d,J=8.6Hz,1H),5.58(s,2H),5.09(t,J=11.6Hz,1H),4.38(t,J=6.5Hz,2H),4.1 0-4.00(m,2H),3.54(t,J=11.8Hz,2H),2.70(dt,J=20.1,10.0Hz,2H),2.01(qd,J=11.9,4.4Hz,2H),2. 08-2.01(m,4H),1.89(tt,J=6.8,3.8Hz,2H),0.42(dd,J=6.6,2.2Hz,4H),0.32(dd,J=3.7,2.3Hz,4H).

[0352] Example 7

[0353] [ka]

[0354] Reaction Scheme:

[0355] [ka]

[0356] Step A: Synthesis of Compound 7-1 2-8 (100 mg), DMF (5 mL), NaOH (35.4 mg) and CH3I (62.8 mg) were added in order to a one-neck flask and reacted at room temperature for 14 hours under N2 protection. After the reaction was completed, 50 mL of water was added to the system, filtered, the cake was washed with water (5 mL x 2) and dried under reduced pressure to obtain intermediate 7-1 (100 mg). MS (ESI+, [M+H] + ) m / z:352.92.

[0357] Step B: Synthesis of Example 7 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) were added in sequence to a one-neck flask, and the mixture was stirred at 80 ° C. for 1 hour under N2 protection. The reaction solution was concentrated, and the residue was dissolved in DCM (50 mL), washed with saturated saline (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by high-pressure fractionation (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 H NMR(500MHz,DMSO-d6)δ8.81(s,1H),8.50(t,J=1.8Hz,1H),8.32(d,J=8.1Hz,1H),8.04(dt, J=8.6,2.3Hz,1H),7.92(d,J=11.9Hz,1H),6.98(d,J=8.6Hz,1H),6.27(d,J=5.6Hz,1H),5.28 (p,J=6.8Hz,1H),4.36(t,J=6.6Hz,2H),2.77(d,J=5.4Hz,3H),2.39(t,J=7.2Hz,2H),2.38- 2.28(m,4H),1.95-1.86(m,2H),1.65(d,J=6.7Hz,6H),1.54-1.45(m,4H),1.42-1.35(m,2H).

[0358] Example 8

[0359] [ka]

[0360] Reaction Scheme:

[0361] [ka]

[0362] Step A: Synthesis of Compound 8-1 2-8 (50 mg), DMF (5 mL), NaOH (17.7 mg) and CD3I (31.2 mg) were added in order to a one-neck flask and reacted at room temperature for 14 hours under N2 protection. After the reaction was completed, 50 mL of water was added, filtered, the cake was washed with water (5 mL x 2) and dried under reduced pressure to obtain intermediate 8-1 (45 mg). MS (ESI+, [M+H] + ) m / z:356.01.

[0363] Step B: Synthesis of Example 8 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) were added in sequence to a one-neck flask, and the mixture was stirred at 80 ° C for 1 hour under N2 protection. The reaction solution was concentrated, and the residue was dissolved in DCM (50 mL), washed with saturated saline (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by high-pressure fractionation (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(500MHz,DMSO-d6)δ8.82(s,1H),8.58-8.50(m,1H),8.32(d,J=8.1Hz,1H),8.09(dt, J=8.6,2.2Hz,1H),7.93(d,J=11.9Hz,1H),7.01(d,J=8.6Hz,1H),6.25(s,1H),5.28(h,J =6.7Hz,1H),4.43(t,J=6.1Hz,2H),3.47(d,J=11.9Hz,2H),3.24-3.11(m,2H),2.96-2.7 9(m,2H),2.31-2.17(m,2H),1.86-1.74(m,4H),1.74-1.68(m,2H),1.65(d,J=6.7Hz,6H).

[0364] Example 9

[0365] [ka]

[0366] Reaction Scheme:

[0367] [ka]

[0368] Step A: Synthesis of Compound 9-1 2-8 (100 mg), DMF (5 mL), and sodium hydride (35.4 mg, 60% purity, mass%) were added to a one-neck flask in that order, and the mixture was stirred at room temperature for 10 minutes under N2 protection, and CD3I (107 mg) was added and reacted at room temperature for 14 hours. After the reaction was completed, the mixture was quenched by adding 50 mL of ice water, filtered, and the cake was washed with water (5 mL x 2) and dried under reduced pressure to obtain intermediate 9-1 (70 mg). MS (ESI+, [M+H] + ) m / z:372.99.

[0369] Step B: Synthesis of Example 9 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) were added in sequence to a one-neck flask, and the mixture was stirred at 80° C. for 1 hour under N2 protection. The reaction solution was concentrated, and the residue was dissolved in DCM (50 mL), washed with saturated saline (2×10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by high-pressure fractionation (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. 1H NMR(500MHz,DMSO-d6)δ8.80(s,1H),8.52(t,J=1.9Hz,1H),8.30(d,J=8.2Hz,1 H),8.08(dt,J=8.7,2.2Hz,1H),7.94(d,J=11.9Hz,1H),7.01(d,J=8.6Hz,1H),5 .28-5.18(m,1H),4.42(t,J=6.2Hz,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=6.8Hz,6H).

[0370] Example 10

[0371] [ka]

[0372] Reaction Scheme:

[0373] [ka]

[0374] Step A: Synthesis of compound 10-2 Cyclopropylamine (0.27 g) and THF (10 mL) were added in sequence to a one-neck flask, and under N2 protection, 60% (purity, mass%) sodium hydride (0.38 g) was added at 0°C, stirred for 10 minutes, 10-1 (1.0 g) was further added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was poured into 50 mL of ice water, stirred for 30 minutes, filtered to collect the cake, washed with water (5 mL x 3) and then with petroleum ether (5 mL x 4), to obtain intermediate 10-2 (1.06 g). MS (ESI+, [M+H] + ) m / z:337.84. 1 H NMR(500MHz,DMSO-d6)δ9.08(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).

[0375] Step B: Synthesis of Compound 10-3 10-2 (0.27 g), MeOH (60 mL), 15 mL aqueous solution of ammonium chloride (1.5 g), and iron powder (0.8 g) were added in sequence to a one-neck flask, and the mixture was heated to 65 °C under N2 protection and reacted for 1 hour. After the reaction was completed, it was filtered, the cake was washed with dichloromethane (10 mL x 3), the filtrate was concentrated to dryness under reduced pressure, and the obtained crude product was slurried with water (50 mL) and filtered to obtain intermediate 10-3 (883 mg). MS (ESI+, [M+H] + ) m / z:307.83.

[0376] Step C: Synthesis of Compound 10-4 10-3 (0.78 g), THF (20 mL), N,N-diisopropylethylamine (1.6 g) and N,N'-carbonyldiimidazole (2 g) were added in sequence to a one-neck flask, and the mixture was stirred at room temperature for 4 hours under N2 protection. After the reaction was completed, the reaction solution was poured into 100 mL of ice water, stirred for 30 minutes, and filtered to collect the cake. The cake was washed with water (5 mL x 3) and then with petroleum ether (5 mL x 4) to obtain intermediate 10-4 (784 mg). MS (ESI+, [M+H] + ) m / z:333.82.

[0377] Step D: Synthesis of compound 10-5 10-4 (0.68 g), DCM (20 mL), 2,4-dinitrophenylhydroxylamine (0.6 g), tetrabutylammonium bromide (65 mg) and 10 mL of aqueous sodium hydroxide (160 mg) were added in sequence to a one-neck flask, and the mixture was stirred at room temperature overnight. After the reaction was completed, the reaction solution was concentrated as it was to remove the organic phase, acetonitrile (10 mL) was added and stirred for 5 minutes, and the cake was collected by filtration. The cake was washed with water (5 mL x 3) and acetonitrile (5 mL x 3) in sequence to obtain intermediate 10-5 (515 mg). MS (ESI+, [M+H] + ) m / z:349.02.

[0378] Step E: Synthesis of Example 10 10-5 (100 mg), 1,4-dioxane (6 mL), A-3 (143 mg), potassium carbonate (119 mg) water (0.5 mL) solution, 3-(di-tert-butylphosphino)propane-1-sulfonic acid (7.69 mg) water (0.5 mL) solution, and disodium tetrachloropalladate (IV) (4.21 mg) were added in sequence to a one-neck flask, and the mixture was heated to 80 ° C. under N2 protection and stirred for 1 hour. After the reaction was completed, 50 mL of water was added, extracted with dichloromethane (50 mL × 3), the organic phases were combined, washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to obtain Example 10 (101 mg). MS (ESI +, [M + H] + ) m / z:489.31. 1 H NMR(500MHz,DMSO-d6)δ8.69(s,1H),8.62(s,1H),8.41(d,J=2.4Hz,1H),7.97(dd,J=8.6 ,2.5Hz,1H),7.55(s,1H),6.91(d,J=8.6Hz,1H),5.47(s,2H),4.33(t,J=6.6Hz,2H),3.9 3(s,3H),3.49(tt,J=7.0,3.7Hz,1H),2.39(t,J=7.2Hz,2H),2.33(s,4H),1.89(p,J=6.8 Hz,2H), 1.49(p,J=5.6Hz,4H),1.40-1.38(m,2H),1.23-1.19(m,2H),1.12-1.09(m,2H).

[0379] Example 11

[0380] [ka]

[0381] Reaction Scheme:

[0382] [ka]

[0383] Step A: Synthesis of Example 11 10-5 (100 mg), 1,4-dioxane (6 mL), A-6 (143 mg), potassium carbonate (119 mg) water (0.5 mL) solution, 3-(di-tert-butylphosphino)propane-1-sulfonic acid (7.69 mg) water (0.5 mL) solution, and disodium tetrachloropalladate (IV) (4.21 mg) were added in sequence to a one-neck flask, and the mixture was heated to 80 ° C. under N2 protection and stirred for 1 hour. After the reaction was completed, 50 mL of water was added, extracted with dichloromethane (50 mL × 3), the organic phases were combined, washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to obtain Example 11 (74 mg). MS (ESI +, [M + H] + ) m / z:475.32. 1 H NMR(500MHz,DMSO-d6)δ8.69(s,1H),8.61(s,1H),8.40(d,J=2.5Hz,1H),7.97(dd,J =8.6,2.5Hz,1H),7.55(s,1H),6.91(d,J=8.6Hz,1H),5.47(s,2H),4.35(t,J=6.6Hz, 2H),3.93(s,3H),3.48(tt,J=6.9,3.7Hz,1H),2.53(t,J=7.2Hz,2H),2.46-2.42(m, 4H), 1.92 (p, J=6.8Hz, 2H), 1.71-1.66 (m, 4H), 1.23-1.19 (m, 2H), 1.12-1.09 (m, 2H).

[0384] Example 12

[0385] [ka]

[0386] Reaction Scheme:

[0387] [ka]

[0388] Step A: Synthesis of compound 12-2 12-1 (0.27 g) and DMF (30 mL) were added in order to a two-neck flask, and 60% sodium hydride (0.3 g) was added under N2 protection at 0°C and stirred for 30 minutes, and iodine methane (1.0 g) was further added and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was slowly poured into 50 mL of ice water, stirred for 10 minutes, extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain intermediate 12-2 (1 g).

[0389] Step B: Synthesis of Compound 12-3 12-2 (1 g) and 4 M hydrogen chloride-dioxane solution (10 mL) were added in this order to a one-neck flask, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was concentrated to dryness under reduced pressure to obtain intermediate 12-3 (690 mg).

[0390] Step C: Synthesis of Compound 12-4 2-5 (1 g), N,N-diisopropylethylamine (2.4 g) and 12-3 (0.5 g) were added in sequence to a one-neck flask, and the mixture was heated to 95°C under N2 protection and stirred for 2 hours. After the reaction was completed, the reaction solution was poured into 100 mL of water, stirred for 5 minutes, and filtered to collect the cake. The cake was washed with water (5 mL x 3) and then with petroleum ether (5 mL x 4) to obtain intermediate 12-4 (889 mg). MS (ESI+, [M+H] + ) m / z:381.94.

[0391] Step D: Synthesis of Compound 12-5 12-4 (600 mg), DBU (478 mg), and methanol (12 mL) were added in order to a one-neck flask, and 1,3,5-trichloro-1,3,5-triazine-2,4,6-trione (182 mg) was added at 5°C. The mixture was stirred at room temperature for 1 hour under N2 protection. After the reaction was completed, the reaction solution was filtered as it was, and the cake was washed with water (10 mL x 2) and dried under vacuum to obtain intermediate 12-5 (589 mg). MS (ESI+, [M+H] + ) m / z:379.93.

[0392] Step E: Synthesis of Compound 12-6 12-5 (515 mg), DCM (20 mL), 2,4-dinitrophenylhydroxylamine (405 mg), tetrabutylammonium bromide (43 mg) and 10 mL aqueous solution of sodium hydroxide (108 mg) were added in sequence to a one-neck flask, and the mixture was stirred at room temperature overnight. After the reaction was completed, the reaction solution was concentrated to remove the organic phase, acetonitrile (10 mL) was added and stirred at room temperature for 10 minutes, filtered to collect the cake, washed the cake with water (5 mL x 3) and then with acetonitrile (5 mL x 3), to obtain intermediate 12-6 (268 mg). MS (ESI+, [M+H] + ) m / z:394.97.

[0393] Step F: Synthesis of Example 12 12-6 (88 mg), 1,4-dioxane (6 mL), A-3 (115 mg), potassium carbonate (92 mg) water (0.5 mL) solution, 3-(di-tert-butylphosphino)propane-1-sulfonic acid (5.97 mg) water (0.5 mL) solution, and disodium tetrachloropalladate (IV) (3.28 mg) were added in sequence to a one-neck flask, and the mixture was heated to 80 ° C. under N2 protection and stirred for 1 hour. After the reaction was completed, 50 mL of water was added, extracted with dichloromethane (50 mL × 3), the organic phases were combined, washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (cleaning agent: DCM / MeOH = 10 / 1) to obtain Example 12 (86 mg). MS (ESI +, [M + H] + ) m / z:535.33. 1H (500MHz,DMSO-d6)δ8.85(s,1H),8.47-8.46(m,1H),8.41(d,J=8.2Hz,1H),8.03-8. 00(m,1H),7.91(d,J=11.9Hz,1H),6.97(d,J=8.6Hz,1H),5.59(s,2H),5.33(p,J=9.3 Hz,1H),4.36(t,J=6.6Hz,2H),3.91(p,J=6.0Hz,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=5.6Hz,4H),1.38(q,J=5.9Hz,2H).

[0394] Example 13

[0395] [ka]

[0396] Reaction Scheme:

[0397] [ka]

[0398] Step A: Synthesis of Example 13 12-6 (88 mg), 1,4-dioxane (6 mL), A-6 (111 mg), potassium carbonate (92 mg) water (0.5 mL) solution, 3-(di-tert-butylphosphino)propane-1-sulfonic acid (5.97 mg) water (0.5 mL) solution, and disodium tetrachloropalladate (IV) (3.28 mg) were added in sequence to a one-neck flask, and the mixture was heated to 80 ° C. under N2 protection and stirred for 1 hour. After the reaction was completed, 50 mL of water was added, extracted with dichloromethane (50 mL × 3), the organic phases were combined, washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (cleaning agent: DCM / MeOH = 10 / 1) to obtain Example 13 (84 mg). MS (ESI +, [M + H] + ) m / z:521.25.1 H NMR(500MHz,DMSO-d6)δ8.85(s,1H),8.46(t,J=1.7Hz,1H),8.41(d,J=8.1Hz,1H),8.01(dt, J=8.7,2.3Hz,1H),7.91(d,J=12.0Hz,1H),6.97(d,J=8.5Hz,1H),5.59(s,2H),5.33(p,J=9.3 Hz,1H),4.38(t,J=6.6Hz,2H),3.91(p,J=6.0Hz,1H),3.05(s,3H),2.54(t,J=7.2Hz,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).

[0399] Example 14

[0400] [ka]

[0401] Reaction Scheme:

[0402] [ka]

[0403] Step A: Synthesis of Example 14 12-6 (88 mg), 1,4-dioxane (6 mL), A-12 (111 mg), potassium carbonate (92 mg) water (0.5 mL) solution, 3-(di-tert-butylphosphino)propane-1-sulfonic acid (5.97 mg) water (0.5 mL) solution, and disodium tetrachloropalladate (IV) (3.28 mg) were added in sequence to a one-neck flask, and the mixture was heated to 80 ° C. under N2 protection and stirred for 1 hour. After the reaction was completed, 50 mL of water was added, extracted with dichloromethane (50 mL × 3), the organic phases were combined, washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to obtain Example 14 (91 mg). MS (ESI +, [M + H]+ ) m / z:495.33. 1 H NMR(500MHz,DMSO-d6)δ8.85(s,1H),8.46(d,J=2.3Hz,1H),8.42(dd,J=8.4,2.7Hz,1H),8.01(dt,J= 8.6,2.3Hz,1H),7.91(dd,J=11.9,2.7Hz,1H),6.97(dd,J=8.6,2.5Hz,1H),5.59(s,2H),5.33(p,J=9. 4Hz,1H),4.37(td,J=6.6,2.4Hz,2H),3.91(p,J=5.9Hz,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).

[0404] Example 15

[0405]

change

[0406] Reflection:

[0407]

change

[0408] Project A: Synthesis of Example 15 5-3 (130 mg), 1,4-dioxane (10 mL), A-3 (177 mg), potassium carbonate (141 mg) water (0.5 mL) solution, 3-(di-tert-butylphosphino)propane-1-sulfonic acid (9.15 mg) water (0.5 mL) solution, and disodium tetrachloropalladate (IV) (5.02 mg) were added in sequence to a one-neck flask, and the mixture was heated to 80 ° C. under N2 protection and stirred for 1 hour. After the reaction was completed, 50 mL of water was added, extracted with dichloromethane (50 mL × 3), the organic phases were combined, washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to obtain Example 15 (158 mg). MS (ESI +, [M + H] + ) m / z:521.29. 1 H NMR(500MHz,DMSO-d6)δ8.83(s,1H),8.54(t,J=2.0Hz,1H),8.33(d,J=8.2Hz,1H),8.08(dt,J=8. 6,2.2Hz,1H),7.93(d,J=12.1Hz,1H),7.00(d,J=8.6Hz,1H),5.58(s,2H),5.09(tt,J=11.8,4.3Hz ,1H),4.36(t,J=6.6Hz,2H),4.03(dd,J=11.3,4.6Hz,2H),3.54(td,J=12.0,1.9Hz,2H),2.70(qd ,J=12.5,4.7Hz,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).

[0409] Example 16

[0410] [ka]

[0411] Reaction Scheme:

[0412] [ka]

[0413] Step A: Synthesis of compound 16-1 Isopropylamine (167.4 mg) and THF (15 mL) were added in sequence to a one-neck flask, and sodium hydride (228 mg) was added under nitrogen gas protection at 0°C. After stirring for 5 minutes, 10-1 (600 mg) was added. The mixture was stirred at room temperature for 15 minutes. After the reaction was completed, water (50 mL) was added, and the cake was collected by filtration. The cake was washed with water (5 mL x 3) and petroleum ether (5 mL x 2) in that order to obtain intermediate 16-1 (500 mg). MS (ESI+, [M+H] + ) m / z:339.92.

[0414] Step B: Synthesis of compound 16-2 16-1 (500 mg), DCM (20 mL), acetic acid (10 mL), and iron powder (410 mg) were added in this order to a one-neck flask. The mixture was reacted at room temperature for 1 hour under nitrogen gas protection. After the reaction was completed, the mixture was filtered and the filtrate was concentrated to dryness, and the residue was adjusted to pH 8-9 with saturated sodium bicarbonate solution and extracted with DCM (20 mL x 5). The organic phases were combined, washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain intermediate 16-2 (400 mg). MS (ESI+, [M+H] + ) m / z:309.90.

[0415] Step C: Synthesis of compound 16-3 16-2 (0.3 g), THF (10 mL), DIPEA (0.625 g), and CDI (0.784 g) were added in this order to a one-neck flask. The reaction was carried out at room temperature for 12 hours under nitrogen gas protection. After the reaction was completed, ice water (100 ml) was added, and the cake was collected by filtration. The cake was washed with water (5 mL x 3) and petroleum ether (5 mL x 2) in this order to obtain intermediate 16-3 (0.23 g). MS (ESI+, [M+H] + ) m / z:335.83.

[0416] Step D: Synthesis of compound 16-4 16-3 (180 mg), DCM (5 mL), water (2 mL), TBAB (17.26 mg), 2,4-dinitrophenylhydroxylamine (160 mg) and NaOH (0.59 mg) were added in sequence to a one-neck flask and stirred at room temperature under N2 protection for 24 hours. After completion of the reaction, it was concentrated to remove most of the solvent, filtered, and the cake was slurried with acetonitrile (10 mL) and dried under vacuum to give intermediate 16-4 (118 mg). MS (ESI+, [M+H] + ) m / z:350.88.

[0417] Step E: Synthesis of Example 16 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 in sequence to a one-neck flask, and the mixture was stirred at 80 ° C for 1 hour under nitrogen gas protection. After the reaction was completed, the reaction solution was concentrated, the residue was dissolved in DCM (50 mL), washed with saturated saline (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by column chromatography to obtain Example 16 (38.6 mg). MS (ESI +, [M + H] + ) m / z:491.28. 1 H NMR(500MHz,DMSO-d6)δ8.72(s,1H),8.39(d,J=2.4Hz,1H),8.11(s,1H),7.96(dd,J =8.5,2.6Hz,1H),7.57(s,1H),6.91(d,J=8.5Hz,1H),5.50(s,2H),5.22(p,J=6.7Hz ,1H),4.34(t,J=6.6Hz,2H),3.92(s,3H),2.39(t,J=7.2Hz,2H),2.36-2.32(m,4H), 1.90(p,J=6.7Hz,2H),1.62(d,J=6.7Hz,6H),1.53-1.46(m,4H),1.41-1.33(m,2H).

[0418] Example 17

[0419] [ka]

[0420] Reaction Scheme:

[0421] [ka]

[0422] 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 in sequence to a one-neck flask, and the mixture was stirred at 80 ° C for 1 hour under nitrogen gas protection. After the reaction was completed, the reaction solution was concentrated, and the residue was dissolved in DCM (50 mL), washed with saturated saline (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by column chromatography to obtain Example 17 (10.3 mg). MS (ESI +, [M + H] + ) m / z:477.26. 1 H NMR(500MHz,DMSO-d6)δ8.72(s,1H),8.39(d,J=2.6Hz,1H),8.11(s,1H),7. 96(dd,J=8.5,2.6Hz,1H),7.57(s,1H),6.91(d,J=8.5Hz,1H),5.50(s,2H),5 .27-5.15(m,1H),4.36(t,J=6.6Hz,2H),3.92(s,3H),2.65-2.55(m,4H),2.0 4-1.86(m,2H),1.77-1.66(m,4H),1.62(d,J=6.9Hz,6H),1.28-1.22(m,2H).

[0423] Example 18

[0424] [ka]

[0425] Reaction Scheme:

[0426] [ka]

[0427] Step A: Synthesis of compound 18-1 2-5 (1.0 g), potassium carbonate (1.37 g), acetonitrile (40 mL), and cyclopropylamine (0.28 g) were added in sequence to a one-neck flask, and the mixture was stirred at 95° C. for 4 hours under N2 protection. After the reaction was completed, the reaction solution was cooled, 150 mL of water was added, filtered, the cake was washed with water (5 mL×4), and dried under vacuum to obtain intermediate 18-1 (985 mg). MS (ESI+, [M+H] + ) m / z:323.85.

[0428] Step B: Synthesis of compound 18-2 18-1 (750 mg), iodobenzene diacetate (745 mg), acetonitrile (10 mL), ethyl acetate (10 mL), water (10 mL) and KOH (260 mg) were added in that order to a one-neck flask, and the mixture was stirred at room temperature overnight to react. After the reaction was completed, the reaction solution was filtered as it was, and the cake was washed with water (10 mL x 2) and dried under vacuum to obtain intermediate 18-2 (700 mg). MS (ESI+, [M+H] + ) m / z:321.92.

[0429] Step C: Synthesis of compound 18-3 18-2 (700 mg), DCM (20 mL), water (10 mL), TBAB (70 mg), 2,4-dinitrophenylhydroxylamine (650 mg), and NaOH (175 mg) were added in sequence to a one-neck flask and reacted at room temperature overnight with stirring. After completion of the reaction, the mixture was concentrated to remove most of the solvent, filtered, and the cake was slurried in 5 mL of acetonitrile and dried under vacuum to obtain intermediate 18-3 (350 mg). MS (ESI+, [M+H] + ) m / z:336.98.

[0430] Step D: Synthesis of Example 18 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) were added in sequence to a one-neck flask, and the mixture was stirred at 80 ° C for 1 hour under N2 protection. After completion of the reaction, the reaction solution was concentrated, and the residue was dissolved in DCM (50 mL), washed with saturated saline (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was slurried by adding acetonitrile (5 mL) to obtain Example 18 (80 mg). MS (ESI +, [M + H] + ) m / z:477.27. 1 H NMR(500MHz,DMSO-d6)δ8.91-8.77(m,2H),8.61(s,1H),8.13-7.99(m,1H),7.89(d,J=12.3Hz,1H),6.99(d,J=8.6Hz,1H),5.53(s,2H),4.36(t,J= 6.6Hz,2H),3.69-3.43(m,1H),2.50-2.28(m,6H),1.99-1.78(m,2H),1.5 8-1.45(m,4H),1.45-1.33(m,2H),1.33-1.21(m,2H),1.17-1.10(m,2H).

[0431] Example 19

[0432] [ka]

[0433] Reaction Scheme:

[0434] [ka]

[0435] 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) were added in sequence to a one-neck flask, and the mixture was stirred at 80 ° C for 1 hour under N2 protection. After completion of the reaction, the reaction solution was concentrated, and the residue was dissolved in DCM (50 mL), washed with saturated saline (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was slurried by adding acetonitrile (5 mL) to obtain Example 19 (60 mg). MS (ESI +, [M + H] + ) m / z:463.37. 1 H NMR(500MHz,DMSO-d6)δ9.00-8.75(m,2H),8.50(s,1H),8.05(dt,J=8.6,2. 2Hz,1H),7.89(d,J=12.3Hz,1H),6.99(d,J=8.5Hz,1H),5.53(s,2H),4.37(t ,J=6.6Hz,2H),3.59-3.51(m,1H),2.55(t,J=7.2Hz,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).

[0436] Example 20

[0437] [ka]

[0438] Reaction Scheme:

[0439] [ka]

[0440] Step A: Synthesis of compound 20-1 2-5 (1.0 g), potassium carbonate (1.37 g), acetonitrile (40 mL), and 3-methoxycyclobutylamine hydrochloride (0.46 g) were added in sequence to a one-neck flask, and the mixture was stirred at 95° C. for 4 hours under N2 protection. After the reaction was completed, the reaction solution was cooled, 150 mL of water was added, filtered, and the cake was washed with water (5 mL×4) and dried under vacuum to obtain intermediate 20-1 (1.06 g). MS (ESI+, [M+H] + ) m / z:367.95.

[0441] Step B: Synthesis of compound 20-2 20-1 (500 mg), DBU (413 mg), and methanol (30 mL) were added in order to a one-neck flask, and 1,3,5-trichloro-1,3,5-triazine-2,4,6-trione (158 mg) was added at 5°C, and the mixture was stirred at room temperature for 1 hour under N2 protection. After the reaction was completed, the reaction solution was filtered as it was, and the cake was washed with water (10 mL x 2) and dried under vacuum to obtain intermediate 20-2 (350 mg). MS (ESI+, [M+H] + ) m / z:366.94.

[0442] Step C: Synthesis of compound 20-3 20-2 (350 mg), DCM (20 mL), water (10 mL), TBAB (31 mg), 2,4-dinitrophenylhydroxylamine (285 mg) and NaOH (76 mg) were added in sequence to a one-neck flask and reacted at room temperature overnight with stirring. After completion of the reaction, the mixture was concentrated to remove most of the solvent, filtered, and the cake was slurried in 5 mL of acetonitrile and dried under vacuum to obtain intermediate 20-3 (240 mg). MS (ESI+, [M+H] + ) m / z:380.97.

[0443] Step D: Synthesis of Example 20 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) were added in sequence to a one-neck flask, and the mixture was stirred at 80 ° C for 1 hour under N2 protection. After completion of the reaction, the reaction solution was concentrated, and the residue was dissolved in DCM (50 mL), washed with saturated saline (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was slurried by adding acetonitrile (5 mL) to obtain Example 20 (80 mg). MS (ESI +, [M + H] + ) m / z:521.31. 1 H NMR(500MHz,DMSO-d6)δ8.82(s,1H),8.56-8.47(m,1H),8.37(d,J=8.1Hz,1H),8.09-7 .99(m,1H),7.90(d,J=12.0Hz,1H),6.98(d,J=8.5Hz,1H),5.55(s,2H),5.21-5.02(m,1 H),4.36(t,J=6.6Hz,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).

[0444] Example 21

[0445] [ka]

[0446] Reaction Scheme:

[0447] [ka]

[0448] 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 added in sequence to a one-neck flask, and the mixture was stirred at 80 ° C for 1 hour under N2 protection. After completion of the reaction, the reaction solution was concentrated, and the residue was dissolved in DCM (50 mL), washed with saturated saline (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was slurried by adding acetonitrile (5 mL) to obtain Example 21 (95 mg). MS (ESI +, [M + H] + ) m / z:481.31. 1 H NMR(500MHz,DMSO-d6)δ8.91-8.77(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,1 H),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).

[0449] Example 22

[0450] [ka]

[0451] Reaction Scheme:

[0452] [ka]

[0453] Step A: Synthesis of compound 22-1 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) were added in sequence to a one-neck flask, and the mixture was heated to 80 ° C. under N2 protection and stirred for 1 hour. After the reaction was completed, 10 mL of water was added, extracted with dichloromethane, the organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (eluent: DCM / MeOH) to obtain intermediate 22-1 (105 mg). MS (ESI +, [M + H] + ) m / z:356.05. 1 H NMR(500MHz,DMSO-d6)δ8.84(s,1H),8.60(t,J=1.7Hz,1H),8.39(d,J=8.1Hz,1H),8.35(tt,J=8.1,2.1Hz,1H), 7.96(d,J=12.0Hz,1H),7.40(dd,J=8.5,2.8Hz,1H),5.56(s,2H),5.31(p,J=6.7Hz,1H),1.64(d,J=6.7Hz,6H).

[0454] Step B: Synthesis of compound 22-3 22-2 (1 g), ethanol (100 mL), tetrahydropyrrole (555 mg) and 10% (purity, mass%) Pd / C (0.831 g) were added in this order to a one-neck flask, and the mixture was stirred overnight at room temperature under a H2 atmosphere. After the reaction was completed, the mixture was suction filtered through diatomaceous earth, and the filtrate was concentrated to dryness under reduced pressure to obtain intermediate 22-3 (1.4 g).

[0455] Step C: Synthesis of compound 22-4 22-3 (200 mg) and tetrahydrofuran (5 mL) were added in this order to a one-neck flask, and 2.5 M lithium tetrahydroaluminum-tetrahydrofuran solution (1.31 mL) was added at 0° C., and the mixture was stirred at room temperature for 1 hour under N2 protection. After completion of the reaction, the reaction solution was poured into 2 mL of water, stirred for 5 minutes, and suction filtered through diatomaceous earth. The filtrate was concentrated to dryness under reduced pressure to obtain intermediate 22-4 (150 mg).

[0456] Step D: Synthesis of Example 22 22-4 (131 mg) and tetrahydrofuran (5 mL) were added in order to a one-neck flask, and 60 wt% sodium hydrogen (56 mg) was added under N2 protection at 0 ° C., the mixture was heated to 50 ° C. and stirred for 20 minutes, and 22-1 (100 mg) was added and stirred for 2 hours. After the reaction was completed, the reaction solution was slowly poured into 10 mL of ice water, stirred for 10 minutes, extracted with dichloromethane, the organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (washing agent: DCM / MeOH) to obtain Example 22 (66 mg). MS (ESI +, [M + H] + ) m / z:491.25. 1 H NMR(500MHz,DMSO-d6)δ8.82(s,1H),8.49(s,1H),8.32(d,J=8.1Hz,1H),8.04(dt,J=8. 6,2.3Hz,1H),7.91(d,J=12.0Hz,1H),6.98(d,J=8.6Hz,1H),5.55(s,2H),5.33-5.25(m, 1H),4.30(d,J=6.5Hz,2H),2.80(p,J=7.8Hz,1H),2.44(q,J=8.0Hz,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=6.7Hz,6H).

[0457] Example 23

[0458] [ka]

[0459] Reaction Scheme:

[0460] [ka]

[0461] Step A: Synthesis of compound 23-2 3-Bromopropanol (20 g), DCM (150 mL) and imidazole (17.14 g) were added in this order to a one-neck flask, and t-butyldimethylchlorosilane (21.69 g) was added at 0°C under N2 protection, stirred for 15 minutes, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, 50 mL of DCM and 50 mL of saturated saline were added to the reaction solution, and after separation, the aqueous phase was further extracted with 40 mL of DCM. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered by suction, and the solvent was evaporated to obtain intermediate 23-2 (36 g). GC-MS (EI, M + ) m / z:253.

[0462] Step B: Synthesis of compound 23-3 23-2 (8 g), acetonitrile (40 mL), 3-fluoroazetidine hydrochloride (3.6 g), potassium carbonate (13.1 g) and potassium iodide (2.62 g) were added in this order to a one-neck flask, and the mixture was heated to 60° C. under N2 protection and reacted for 2 hours. After the reaction was completed, 100 mL of water was added, extracted with EA, the organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain intermediate 23-3 (7.0 g). GC-MS (EI, M + ) m / z:247.

[0463] Step C: Synthesis of compound 23-4 23-3 (0.78 g), dioxane (20 mL), and a solution of hydrochloric acid in dioxane (4 M, 27 mL) were added in this order to a one-neck flask, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated to remove the solvent, and then 200 mL of EA and 5 g of Na2CO3 were added. The mixture was stirred at room temperature for 30 minutes, and then filtered by suction. The filtrate was concentrated to remove the solvent, and intermediate 23-4 (3.2 g) was obtained. GC-MS (EI, M+ ) m / z:133.

[0464] Step D: Synthesis of compound 23-5 With reference to the synthesis of Preparation A-3, in the preparation process of A-2, 23-4 was used instead of A-1 to obtain compound 23-5. MS (ESI+, [M+H] + ) m / z:288.87.

[0465] Step E: Synthesis of compound 23-6 With reference to the synthesis of Preparation A-3, 23-5 was used instead of A-2 in the preparation process of A-3 to obtain compound 23-6. MS (ESI+, [M+H] + ) m / z:337.00.

[0466] Step F: Synthesis of Example 23 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 added in sequence to a one-neck flask, and the mixture was heated to 80 ° C. under N2 protection and stirred for 1 hour. After the reaction was completed, 50 mL of water was added, extracted with dichloromethane, the organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure, 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. 1H NMR(500MHz,DMSO-d6)δ8.82(s,1H),8.68-8.45(m,1H),8.32(d,J=8.0Hz,1H),8.04(dt ,J=8.5,2.4Hz,1H),7.91(d,J=11.9Hz,1H),6.98(d,J=8.6Hz,1H),5.55(s,2H),5.30(h ,J=6.6Hz,1H),5.15(dp,J=57.8,5.1Hz,1H),4.35(t,J=6.6Hz,2H),3.76-3.51(m,2H), 3.12-3.00(m,2H),2.58(t,J=6.9Hz,2H),1.78(p,J=6.7Hz,2H),1.65(d,J=6.6Hz,6H).

[0467] Example 24

[0468] [ka]

[0469] Reaction Scheme:

[0470] [ka]

[0471] Step A: Synthesis of compound 24-1 With reference to the synthesis of Example 23, in the preparation process of 23-3, 3,3-difluoroazetidine hydrochloride was used instead of 3-fluoroazetidine hydrochloride to obtain compound 24-1. GC-MS (EI, M + ) m / z:265.

[0472] Step B: Synthesis of compound 24-2 Referring to the synthesis of Example 23, 24-1 was used instead of 23-3 in the preparation process of 23-4 to obtain compound 24-2. GC-MS (EI, M + ) m / z:151.

[0473] Step C: Synthesis of compound 24-3 Referring to the synthesis of Example 23, 24-2 was used instead of 23-4 in the preparation process of 23-5 to obtain compound 24-3. MS (ESI+, [M+H] + ) m / z:306.87.

[0474] Step D: Synthesis of compound 24-4 Referring to the synthesis of Example 23, 24-3 was used instead of 23-5 in the preparation process of 23-6 to obtain compound 24-4. MS (ESI+, [M+H] + ) m / z:355.01.

[0475] Step E: Synthesis of Example 24 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) were added in sequence to a one-neck flask, and the mixture was heated to 80 ° C. under N2 protection and stirred for 1 hour. After the reaction was completed, 50 mL of water was added, extracted with dichloromethane, the organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure, 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 H NMR(500MHz,DMSO-d6)δ8.82(s,1H),8.50(t,J=1.8Hz,1H),8.32(d,J=8.2Hz, 1H),8.05(dt,J=8.6,2.3Hz,1H),7.91(d,J=12.1Hz,1H),6.99(d,J=8.6Hz,1H) ,5.55(s,2H),5.28(h,J=6.7Hz,1H),4.37(t,J=6.5Hz,2H),3.58(t,J=12.5Hz, 4H), 2.68(dd,J=7.6,6.0Hz,2H),1.81(p,J=6.7Hz,2H),1.65(d,J=6.7Hz,6H).

[0476] Example 25

[0477] [ka]

[0478] Reaction Scheme:

[0479] [ka]

[0480] Step A: Synthesis of compound 25-1 With reference to the synthesis of Example 23, in the preparation process of 23-3, 3-(fluoromethyl)pyrrolidine was used instead of 3-fluoroazetidine hydrochloride to obtain compound 25-1. GC-MS (EI, M + ) m / z:275.

[0481] Step B: Synthesis of compound 25-2 Referring to the synthesis of Example 23, 25-1 was used instead of 23-3 in the preparation process of 23-4 to obtain compound 25-2. GC-MS (EI, M + ) m / z:161.

[0482] Step C: Synthesis of compound 25-3 Referring to the synthesis of Example 23, 25-2 was used instead of 23-4 in the preparation of 23-5 to give compound 25-3. MS (ESI+, [M+H] + ) m / z:316.91.

[0483] Step D: Synthesis of compound 25-4 Referring to the synthesis of Example 23, 25-3 was used instead of 23-5 in the preparation process of 23-6 to give compound 25-4. MS (ESI+, [M+H] + ) m / z:365.13.

[0484] Step E: Synthesis of Example 25 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 added in sequence to a one-neck flask, and the mixture was heated to 80 ° C. under N2 protection and stirred for 1 hour. After the reaction was completed, 50 mL of water was added, extracted with dichloromethane, the organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure, 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(500MHz,Chloroform-d)δ8.94(s,1H),8.41(d,J=2.4Hz,1H),8.18(d,J=7.9Hz,1H),7.9 3-7.84(m,2H),6.89(d,J=8.6Hz,1H),5.31-5.13(m,1H),4.50(s,2H),4.44(t,J=6.4Hz,2H) ,4.40-4.37(m,1H),4.31-4.28(m,1H),2.80-2.51(m,6H),2.47(dd,J=9.3,5.4Hz,1H),2.09 -2.01(m,2H),1.97(ddd,J=13.2,9.7,6.6Hz,1H),1.76(d,J=6.9Hz,6H),1.57-1.46(m,1H).

[0485] Example 26

[0486] [ka]

[0487] Reaction Scheme:

[0488] [ka]

[0489] Step A: Synthesis of compound 26-1 With reference to the synthesis of Example 23, in the preparation process of 23-3, 3,3-difluoropyrrolidine hydrochloride was used instead of 3-fluoroazetidine hydrochloride to obtain compound 26-1. GC-MS (EI, M + ) m / z:279.

[0490] Step B: Synthesis of compound 26-2 Referring to the synthesis of Example 23, 26-1 was used instead of 23-3 in the preparation process of 23-4 to obtain compound 26-2. GC-MS (EI, M + ) m / z:165.

[0491] Step C: Synthesis of compound 26-3 Referring to the synthesis of Example 23, 26-2 was used instead of 23-4 in the preparation of 23-5 to give compound 26-3. MS (ESI+, [M+H] + ) m / z:320.86.

[0492] Step D: Synthesis of compound 26-4 Referring to the synthesis of Example 23, 26-3 was used instead of 23-5 in the preparation process of 23-6 to give compound 26-4. MS (ESI+, [M+H] + ) m / z:369.02.

[0493] Step E: Synthesis of Example 26 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) were added in sequence to a one-neck flask, and the mixture was heated to 80 ° C. under N2 protection and stirred for 1 hour. After the reaction was completed, 50 mL of water was added, extracted with dichloromethane, the organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to obtain Example 26 (40 mg). MS (ESI +, [M + H] +) m / z:501.15. 1 H NMR(500MHz,Chloroform-d)δ8.94(s,1H),8.41(d,J=2.4Hz,1H),8.18(d,J=7.9Hz ,1H),8.03-7.85(m,2H),6.89(d,J=8.6Hz,1H),5.29-5.08(m,1H),4.50(s,2H),4. 45(t,J=6.4Hz,2H),2.94(t,J=13.3Hz,2H),2.78(t,J=6.9Hz,2H),2.67(t,J=7.3H z,2H),2.29(tt,J=14.6,6.9Hz,2H),2.02(p,J=6.6Hz,2H),1.76(d,J=7.0Hz,6H).

[0494] Example 27

[0495] [ka]

[0496] Reaction Scheme:

[0497] [ka]

[0498] Step A: Synthesis of compound 27-2 27-1 (1.0 g), 23-2 (1.0 g), potassium carbonate (1.6 g), potassium iodide (0.33 g), and acetonitrile (15 mL) were added in this order to a one-neck flask, and the mixture was heated to 60°C to react. After the reaction was completed, 50 mL of water was added, the mixture was extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain intermediate 27-2 (1.0 g), which was used in the next step without purification. MS (ESI+, [M+H] + ) m / z:270.23.

[0499] Step B: Synthesis of compound 27-3 27-2 (1.0 g) and a solution of hydrogen chloride in ethyl acetate (1 M, 20 mL) were added in that order to a one-neck flask and reacted at room temperature. After the reaction was completed, the reaction system was concentrated as it was to obtain intermediate 27-3 (0.5 g). MS (ESI+, [M+H] + ) m / z:156.14.

[0500] Step C: Synthesis of compound 27-4 27-3 (0.5 g), THF (15 mL), and 5-bromo-2-fluoropyridine (0.68 g) were added in order to a one-neck flask, and sodium hydride (60 wt%, 0.39 g) was added under ice bath, and the mixture was allowed to react at room temperature. After the reaction was completed, an ice-cooled saturated ammonium chloride solution was added to the system, extracted with DCM, the organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The obtained crude product was purified by silica gel column chromatography (DCM / MeOH) to obtain intermediate 27-4 (326 mg). MS (ESI+, [M+H] + ) m / z:310.91.

[0501] Step D: Synthesis of compound 27-5 27-4 (326 mg), THF (10 mL), and isopropoxyboronic acid pinacol ester (253 mg) were added in sequence to a one-neck flask, and the temperature was lowered to -78°C under nitrogen gas protection, and then n-butyllithium n-hexane solution (2.5 M, 1.25 mL) was added dropwise, and the reaction was allowed to proceed for 1 hour after the dropwise addition, and then the reaction was allowed to proceed at room temperature. After the reaction was completed, the system was quenched by adding saturated ammonium chloride in an ice bath, diluted with 50 mL of water, extracted with EA, and the organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain intermediate 27-5 (330 mg). MS (ESI+, [M+H] + ) m / z:359.13.

[0502] Step E: Synthesis of Example 27 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) were added in sequence to a one-neck flask, and the mixture was reacted at 80 ° C under nitrogen gas protection. After the reaction was completed, 20 mL of water was added, extracted with dichloromethane, the organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (DCM / MeOH) to obtain Example 27 (120 mg). MS (ESI +, [M + H] + ) m / z:491.26. 1 H NMR(500MHz,DMSO-d6)δ8.82(s,1H),8.54-8.49(m,1H),8.32(d,J=8.2Hz,1H),8.0 7(dt,J=8.5,2.3Hz,1H),7.92(d,J=12.1Hz,1H),7.00(d,J=8.5Hz,1H),5.56(s,2H) ),5.29(p,J=6.8Hz,1H),4.42(t,J=6.3Hz,2H),4.10-3.54(m,2H),3.07-2.68(m,2 H),2.18-1.99(m,2H),1.92-1.85(m,4H),1.65(d,J=6.7Hz,6H),1.56-1.44(m,4H).

[0503] Example 28

[0504] [ka]

[0505] Reaction Scheme:

[0506] [ka]

[0507] Step A: Synthesis of compound 28-2 28-1 (5.0 g) and DCM (50 mL) were added in order to a one-neck flask, and diethylamine sulfur trifluoride (8.61 g) was slowly added dropwise under ice bath. After the addition was completed, the reaction was allowed to proceed at room temperature. After the reaction was completed, saturated sodium bicarbonate was slowly added dropwise to quench the reaction, 200 mL of water was added, the mixture was extracted with DCM, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain intermediate 28-2 (5.0 g), which was used in the next step without purification. GC-MS (EI, M + ) m / z:189.

[0508] Step B: Synthesis of compound 28-3 28-2 (5.0 g) and a solution of hydrochloric acid in 1,4-dioxane (4 M, 50 mL) were added in that order to a one-neck flask and reacted at room temperature. After the reaction was completed, the system was concentrated as it was to obtain intermediate 28-3 (5.0 g). GC-MS (EI, M + ) m / z:89.

[0509] Step C: Synthesis of compound 28-4 28-3 (5.0 g), 23-2 (10.0 g), potassium carbonate (16.37 g), potassium iodide (3.28 g), and acetonitrile (150 mL) were added in this order to a one-neck flask, and the mixture was heated to 60°C to react. After the reaction was completed, 500 mL of water was added, the mixture was extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain intermediate 28-4 (5.0 g), which was used in the next step without purification. GC-MS (EI, M + ) m / z:261.

[0510] Step D: Synthesis of compound 28-5 28-4 (5.0 g) and a solution of hydrochloric acid in 1,4-dioxane (4 M, 50 mL) were added in that order to a one-neck flask and reacted at room temperature. After the reaction was completed, the system was concentrated as it was to obtain intermediate 28-5 (3.0 g). GC-MS (EI, M + ) m / z:147.

[0511] Step E: Synthesis of compound 28-6 28-5 (3.0 g), THF (100 mL), and 5-bromo-2-fluoropyridine (2.43 g) were added in order to a one-neck flask, and sodium hydride (60 wt%, 1.38 g) was added under ice bath, and then the reaction was carried out at room temperature. After the reaction was completed, ice-cooled saturated ammonium chloride solution (500 mL) was added to the reaction system, extracted with DCM, the organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The obtained crude product was purified by silica gel column chromatography (DCM / MeOH) to obtain intermediate 28-6 (0.4 g). MS (ESI+, [M+H] + ) m / z:302.89.

[0512] Step F: Synthesis of compound 28-7 28-6 (0.4 g), THF (10 mL), and isopropoxyboronic acid pinacol ester (319 mg) were added in sequence to a one-neck flask, and the temperature was lowered to -78 ° C under nitrogen gas protection, and then n-butyllithium n-hexane solution (2.5 M, 0.8 mL) was added dropwise, and the reaction was allowed to proceed for 1 hour after the dropwise addition, and then the reaction was allowed to proceed at room temperature. After the reaction was completed, the system was quenched by adding saturated ammonium chloride in an ice bath, diluted with 50 mL of water, extracted with EA, and the organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain intermediate 28-7 (400 mg). MS (ESI +, [M + H] + ) m / z:351.10.

[0513] Step G: Synthesis of Example 28 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) were added in sequence to a one-neck flask, and the mixture was reacted at 80° C. under nitrogen gas protection. After the reaction was completed, 20 mL of water was added, extracted with dichloromethane, the organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (DCM / MeOH) to obtain Example 28 (90 mg). MS (ESI+, [M+H]+) m / z: 483.17. 1 H NMR(500MHz,DMSO-d6)δ8.82(s,1H),8.50(s,1H),8.32(d,J=8.1Hz,1H),8.04(dt,J=8.5, 2.3Hz,1H),7.91(d,J=11.9Hz,1H),6.98(d,J=8.5Hz,1H),5.55(s,2H),5.34-5.24(m,1H), 4.51(dd,J=47.6,6.1Hz,2H),4.34(t,J=6.6Hz,2H),3.29(d,J=7.3Hz,2H),2.96(t,J=6.8H z,2H),2.78-2.67(m,1H),2.54(d,J=7.0Hz,2H),1.80-1.70(m,2H),1.64(d,J=6.7Hz,6H).

[0514] Example 29

[0515] [ka]

[0516] Reaction Scheme:

[0517] [ka]

[0518] Step A: Synthesis of compound 29-2 29-1 (0.20 g), 23-2 (0.38 g), potassium carbonate (0.62 g), potassium iodide (0.13 g), and acetonitrile (15 mL) were added in this order to a one-neck flask, and the mixture was heated to 60°C to react. After the reaction was completed, 50 mL of water was added, the mixture was extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain intermediate 29-2 (0.15 g), which was used in the next step without purification. GC-MS (EI, M + ) m / z:269.

[0519] Step B: Synthesis of compound 29-3 29-2 (0.15 g) and a solution of hydrogen chloride in ethyl acetate (1M, 10 mL) were added in that order to a one-neck flask and reacted at room temperature. After the reaction was completed, the system was concentrated as it was to obtain intermediate 29-3 (0.12 g). GC-MS (EI, M + ) m / z:155.

[0520] Step C: Synthesis of compound 29-4 29-3 (0.12 g), THF (10 mL), and 5-bromo-2-fluoropyridine (0.14 g) were added in order to a one-neck flask, and sodium hydride (60 wt%, 0.08 g) was added under ice bath, and then the reaction was carried out at room temperature. After the reaction was completed, an ice-cooled saturated ammonium chloride solution was added to the system, extracted with DCM, the organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The obtained crude product was purified by silica gel column chromatography (DCM / MeOH) to obtain intermediate 29-4 (120 mg). MS (ESI+, [M+H] + ) m / z:310.92.

[0521] Step D: Synthesis of compound 29-5 29-4 (120 mg), THF (10 mL), and isopropoxyboronic acid pinacol ester (93 mg) were added in order to a one-neck flask, and the temperature was lowered to -78 ° C under nitrogen gas protection, and then n-butyllithium n-hexane solution (2.5 M, 0.23 mL) was added dropwise, and the reaction was allowed to proceed for 1 hour after the dropwise addition, and then the reaction was allowed to proceed at room temperature. After the reaction was completed, the system was quenched by adding saturated ammonium chloride in an ice bath, diluted with 50 mL of water, extracted with EA, and the organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain intermediate 29-5 (130 mg). MS (ESI +, [M + H] + ) m / z:359.12.

[0522] Step E: Synthesis of Example 29 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) were added in sequence to a one-neck flask, and the mixture was reacted at 80 ° C under nitrogen gas protection. After the reaction was completed, 20 mL of water was added, extracted with dichloromethane, the organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (DCM / MeOH) to obtain Example 29 (55 mg). MS (ESI +, [M + H] + ) m / z:491.26. 1 H NMR(500MHz,DMSO-d6)δ8.82(s,1H),8.52-8.44(m,1H),8.32(d,J=8.2Hz,1H ),8.04(dt,J=8.5,2.3Hz,1H),7.91(d,J=12.1Hz,1H),6.97(d,J=8.5Hz,1H), 5.55(s,2H),5.34-5.21(m,1H),4.32(t,J=6.6Hz,2H),3.07(s,4H),2.44(t,J =7.0Hz,2H),2.02(t,J=7.6Hz,4H),1.79-1.68(m,4H),1.64(d,J=6.9Hz,6H).

[0523] Example 30

[0524] [ka]

[0525] Reaction Scheme:

[0526] [ka]

[0527] Step A: Synthesis of compound 30-1 3-Fluoro-5-methoxypyridin-4-amine (1.34 g) and DMF (20 mL) were added to a one-neck flask in that order, and 60 wt% sodium hydride (1.26 g) was slowly added under nitrogen gas protection at 0°C and stirred for 10 minutes, after which 10-1 (2.0 g) was added. The reaction was allowed to proceed at room temperature for 20 minutes, and after completion of the reaction, ice water (100 mL) was added and stirred for 10 minutes, and the cake was collected by filtration. The cake was washed with water (5 mL x 3) and petroleum ether (5 mL x 2) in that order to obtain intermediate 30-1 (2.5 g). MS (ESI+, [M+H] + ) m / z:422.95.

[0528] Step B: Synthesis of compound 30-2 30-1 (2.5 g), DCM (50 mL), acetic acid (20 mL), and iron powder (1.65 g) were added in this order to a one-neck flask. The reaction was allowed to proceed at room temperature for 1 hour under nitrogen gas protection. After the reaction was completed, the reaction solution was filtered and the filtrate was concentrated to dryness. The residue was adjusted to pH 8-9 with saturated sodium bicarbonate solution (25 mL), extracted with DCM (40 mL x 5), and the organic phases were combined, washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain intermediate 30-2 (1.8 g). MS (ESI+, [M+H] + ) m / z:392.93.

[0529] Step C: Synthesis of compound 30-3 30-2 (1.8 g), THF (40 mL), DIPEA (2.86 g), and CDI (2.28 g) were added to a one-neck flask in that order, and the mixture was reacted at room temperature for 4 hours under nitrogen gas protection. After the reaction was completed, ice water (200 mL) was added to the reaction solution, and the mixture was filtered to collect the cake. The cake was washed with water (10 mL x 3) and petroleum ether (10 mL x 2) in that order, and the cake was suctioned to remove any moisture to obtain intermediate 30-3 (1.2 g). MS (ESI+, [M+H] + ) m / z:419.06.

[0530] Step D: Synthesis of compound 30-4 30-3 (1.0 g), DCM (30 mL), water (15 mL), TBAB (77 mg), 2,4-dinitrophenylhydroxylamine (712 mg) and NaOH (191 mg) were added in this order to a one-neck flask and stirred at room temperature under N2 protection for 24 hours. After the reaction was completed, the mixture was concentrated to remove the organic solvent, filtered, and the cake was slurried in a mixed solvent of acetonitrile:water = 1:1 (10 mL) and dried under vacuum to obtain intermediate 30-4 (0.8 g). MS (ESI+, [M+H] + ) m / z: 433.95.

[0531] Step E: Synthesis of Example 30 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) were added in sequence to a one-neck flask, and the mixture was stirred at 80 ° C for 1 hour under nitrogen gas protection. After the reaction was completed, the reaction solution was concentrated, the residue was dissolved in DCM (50 mL), washed with saturated saline (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain Example 30 (40.0 mg). HRMS (ESI +, [M + H] + ) m / z:574.2573. 1H NMR(500MHz,DMSO-d6)δ8.86(s,1H),8.69(s,1H),8.65(s,1H),7.99(d,J=2 .6Hz,1H),7.66(dd,J=8.5,2.6Hz,1H),7.58(s,1H),6.93(s,1H),6.81(d,J =8.7Hz,1H),5.80(s,2H),4.28(t,J=6.6Hz,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).

[0532] Example 31

[0533] [ka]

[0534] Reaction Scheme:

[0535] [ka]

[0536] 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 added in sequence to a one-neck flask, and the mixture was stirred at 80 ° C for 1 hour under nitrogen gas protection. After the reaction was completed, the reaction solution was concentrated, the residue was dissolved in DCM (50 mL), washed with saturated saline (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain Example 31 (37.0 mg). HRMS (ESI +, [M + H] + ) m / z:560.2412. 1H NMR(500MHz,DMSO-d6)δ8.86(s,1H),8.69(s,1H),8.65(s,1H),7.99(d,J=2 .4Hz,1H),7.66(dd,J=8.6,2.5Hz,1H),7.58(s,1H),6.93(s,1H),6.82(d,J =8.5Hz,1H),5.80(s,2H),4.30(t,J=6.6Hz,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).

[0537] Example 32

[0538] [ka]

[0539] Reaction Scheme:

[0540] [ka]

[0541] Step A: Synthesis of compound 32-1 2-1 (3.0 g), water (50 mL), concentrated hydrochloric acid (26.3 mL), and acetic acid (18.08 mL) were added in order to a three-neck flask. An aqueous solution (30 mL) of sodium nitrite (1.20 g) was added dropwise at 0°C, and after the addition was completed, the temperature was maintained at 0°C and the reaction was allowed to proceed for 2 hours. Thereafter, sodium acetate (10.36 g) was added in several portions while maintaining the temperature, and after the addition was completed, the mixture was stirred for 30 minutes while keeping the temperature constant. This system was designated as liquid a. 2-cyanoacetamide (1.6 g), ethanol (50 mL), and water (200 mL) were added to another one-neck flask, and the temperature was maintained at 0°C. Sodium acetate (51.8 g) was added, and after complete dissolution, the mixture was kept warm and reacted for 30 minutes, to obtain liquid b. Then, liquid a was added dropwise to liquid b at 0°C, and after the addition was completed, the mixture was kept warm and reacted for 2 hours. After the reaction was completed, the system was left to stand and filtered by suction. The cake was washed with water (10 mL x 5) and dried under reduced pressure to obtain intermediate 32-1 (4.3 g).

[0542] Step B: Synthesis of compound 32-2 32-1 (4.0 g), o-dichlorobenzene (50 mL), and aluminum trichloride (5.61 g) were added in order to a three-neck flask, and the mixture was heated to 120 °C under N2 protection and reacted for 24 hours. After the reaction was completed, the reaction solution was cooled, and 300 mL of water was added under an ice bath to quench the reaction, stirred for 30 minutes, and filtered to collect the cake, which was washed with 100 mL of water, further washed with 20 mL of acetonitrile, then washed with 10 mL of petroleum ether, and dried to obtain intermediate 32-2 (4.0 g). MS (ESI+, [M+H] + ) m / z:284.78.

[0543] Step C: Synthesis of compound 32-3 32-2 (4.0 g), DMSO (20 mL), and 4M sulfuric acid (20 mL) were added to a one-neck flask in that order, and the reaction solution was stirred and reacted at 130° C. for 30 hours under N2 protection. After the reaction was completed, the reaction solution was cooled in an ice bath, water (150 mL) was added, filtered, the cake was washed with water (10 mL×3), and dried under vacuum to obtain intermediate 32-3 (3.0 g). MS (ESI-, [M+H] - ) m / z:284.94.

[0544] Step D: Synthesis of compound 32-4 32-3 (3.0 g), thionyl chloride (30 mL), and DMF (0.06 g) were added to a single-neck flask in that order, and the reaction solution was heated to reflux under N2 protection and reacted for 2 hours. After the reaction was completed, the reaction solution was cooled and concentrated under reduced pressure, 100 mL of toluene was added, and the mixture was sonicated and concentrated again, which was repeated twice to obtain intermediate 32-4 (3.5 g), which was then directly used in the next reaction step.

[0545] Step E: Synthesis of compound 32-5 32-4 (3.5 g) and acetonitrile (50 mL) were added in this order to a single-neck flask and dispersed by ultrasonication. Then, 25% ammonium hydroxide solution (10 mL) was added dropwise at 0°C. After the addition was completed, the mixture was stirred vigorously for 30 minutes, filtered, and the cake was washed with water (5 mL x 3) and then dried under vacuum to obtain intermediate 32-5 (2.1 g).

[0546] Step F: Synthesis of compound 32-6 32-5 (2.1 g), DIPEA (1.783 g), acetonitrile (30 mL), and isopropylamine (0.408 g) were added in sequence to a one-neck flask, and the mixture was stirred at 80° C. for 5 hours under N2 protection. After the reaction was completed, the reaction solution was cooled, 100 mL of water was added, filtered, and the cake was washed with water (5 mL×4) and dried under vacuum to obtain intermediate 32-6 (2.26 g). MS (ESI+, [M+H] + ) m / z:326.87.

[0547] Step G: Synthesis of compound 32-7 32-6 (2.26 g), DBU (2.103 g), and methanol (20 mL) were added in order to a one-neck flask, and 1,3,5-trichloro-1,3,5-triazine-2,4,6-trione (0.803 g) was added at 5°C, and the mixture was stirred at room temperature for 1 hour under N2 protection. After the reaction was completed, 50 mL of water was added and the mixture was stirred for 10 minutes, filtered, and the cake was washed with water (5 mL x 3) and dried under vacuum to obtain intermediate 32-7 (2.0 g). MS (ESI+, [M+H] + ) m / z:324.83.

[0548] Step H: Synthesis of Compound 32-8 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 in order to a one-neck flask, and reacted at room temperature for 24 hours under N2 protection. 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 saline, 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.

[0549] Step I: Synthesis of Example 32 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 in sequence to a one-neck flask, and the mixture was stirred at 80 ° C. for 1 hour under N2 protection. After the reaction was completed, the reaction solution was concentrated, and the resulting residue was dissolved in DCM (50 mL), washed with saturated saline (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was then subjected to high-pressure fractionation purification (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 H NMR(500MHz,DMSO-d6)δ8.53(t,J=2.0Hz,1H),8.35(d,J=7.8Hz,1H),8.21(d,J=1 1.4Hz,1H),8.07(dt,J=8.5,2.3Hz,1H),7.00(d,J=8.7Hz,1H),5.59(s,2H),5.26( p,J=6.8Hz,1H),4.37(t,J=6.6Hz,2H),2.39(t,J=7.2Hz,2H),2.34-2.31(m,4H),1 .91(p,J=6.7Hz,2H),1.64(d,J=6.7Hz,6H),1.52-1.46(m,4H),1.40-1.35(m,2H).

[0550] Example 33

[0551] [ka]

[0552] Reaction Scheme:

[0553] [ka]

[0554] Step A: Synthesis of compound 33-1 32-8 (0.36 mg), THF (5 mL), NaOH (200 mg) and CHI (0.9 g) were added in this order to a one-neck flask, and the mixture was reacted at room temperature for 1 hour under N2 protection. After the reaction was completed, 50 mL of water was added to the system, and the mixture was extracted with EA (15 mL x 3). The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered and concentrated, and the obtained crude product was purified by silica gel column chromatography to obtain intermediate 33-1 (120 mg). MS (ESI+, [M+H] + ) m / z:353.96.

[0555] Step B: Synthesis of Example 33 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) were added in sequence to a one-neck flask, and the mixture was stirred at 80° C. for 1 hour under N2 protection. The reaction solution was concentrated, and the residue was dissolved in DCM (50 mL), washed with saturated saline (2×10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by high-pressure preparative purification (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. 1H NMR(500MHz,DMSO-d6)δ8.53(t,J=2.1Hz,1H),8.35(d,J=7.8Hz,1H),8.21(d,J=11.4Hz, 1H),8.07(dt,J=8.5,2.4Hz,1H),7.00(d,J=8.5Hz,1H),6.31(q,J=5.6Hz,1H),5.30-5.2 0(m,1H),4.37(t,J=6.6Hz,2H),2.83(d,J=5.5Hz,3H),2.39(t,J=7.2Hz,2H),2.36-2.30 (m,4H),1.94-1.87(m,2H),1.64(d,J=6.9Hz,6H),1.52-1.47(m,4H),1.42-1.34(m,2H).

[0556] Example 34

[0557] [ka]

[0558] Reaction Scheme:

[0559] [ka]

[0560] Step A: Synthesis of Example 34 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 in sequence to a one-neck flask, and the mixture was stirred at 80° C. for 1 hour under N2 protection. The reaction solution was concentrated, and the residue was dissolved in DCM (50 mL), washed with saturated saline (2×10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by high-pressure fractionation (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. 1 H NMR(500MHz,DMSO-d6)δ8.56-8.50(m,1H),8.35(d,J=7.8Hz,1H),8.20(d,J=11 .4Hz,1H),8.07(dt,J=8.5,2.4Hz,1H),7.00(d,J=8.7Hz,1H),5.58(s,2H),5.2 6(p,J=6.8Hz,1H),4.39(t,J=6.6Hz,2H),2.54(t,J=7.2Hz,2H),2.44(dq,J=7. 6,3.8Hz,4H),1.94(q,J=6.9Hz,2H),1.71-1.67(m,4H),1.64(d,J=6.7Hz,6H).

[0561] Example 35

[0562] [ka]

[0563] Reaction Scheme:

[0564] [ka]

[0565] Step A: Synthesis of Example 35 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 in sequence to a one-neck flask, and the mixture was reacted at 80 ° C for 1 hour under N2 protection. After the reaction was completed, the reaction solution was concentrated, and the resulting residue was dissolved in DCM (50 mL), washed with saturated saline (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was then purified by high-pressure fractionation (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. 1 H NMR(500MHz,DMSO-d6)δ8.53(t,J=2.0Hz,1H),8.35(d,J=7.8Hz,1H),8.21(d,J=11. 4Hz,1H),8.07(dt,J=8.7,2.4Hz,1H),7.00(d,J=8.8Hz,1H),6.31(q,J=5.6Hz,1H),5 .31-5.17(m,1H),4.39(t,J=6.6Hz,2H),2.83(d,J=5.5Hz,3H),2.54(t,J=7.2Hz,2H) ,2.48-2.40(m,4H),1.93(p,J=6.8Hz,2H),1.71-1.67(m,4H),1.64(d,J=6.7Hz,6H).

[0566] Example 36

[0567] [ka]

[0568] Reaction Scheme:

[0569] [ka]

[0570] Step A: Synthesis of compound 36-1 32-5 (5.0 g), DIPEA (6.37 g), acetonitrile (100 mL), and cyclopropylamine (1.88 g) were added in sequence to a one-neck flask and reacted at 95° C. for 4 hours under N2 protection. After the reaction was completed, the reaction solution was cooled, 150 mL of water was added, filtered, the cake was washed with water (30 mL×4), and dried under vacuum to obtain intermediate 36-1 (4.1 g). MS (ESI+, [M+H] + ) m / z:324.87.

[0571] Step B: Synthesis of compound 36-2 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) were added in this order to a one-neck flask, and the mixture was stirred at room temperature overnight to react. After the reaction was completed, the reaction solution was filtered as it was, and the cake was washed with water (10 mL x 2) and dried under vacuum to obtain intermediate 36-2 (2.8 g). MS (ESI+, [M+H] + ) m / z:322.85.

[0572] Step C: Synthesis of compound 36-3 36-2 (2.0 g), DCM (50 mL), water (20 mL), TBAB (200 mg), 2,4-dinitrophenylhydroxylamine (1.8 g) and NaOH (500 mg) were added in sequence to a one-neck flask and reacted at room temperature overnight with stirring. After completion of the reaction, the mixture was concentrated to remove the organic solvent, filtered, and the cake was slurried in 10 mL of acetonitrile and dried under vacuum to obtain intermediate 36-3 (800 mg). MS (ESI+, [M+H] + ) m / z:337.88.

[0573] Step D: Synthesis of Example 36 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) were added in sequence to a one-neck flask, and the mixture was reacted at 80 ° C for 2 hours under N2 protection. After the reaction was completed, the reaction solution was concentrated, and the residue was dissolved in DCM (50 mL), washed with saturated saline (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain Example 36 (30 mg). MS (ESI +, [M + H] + ) m / z: 478.29. 1H NMR(500MHz,Chloroform-d)δ8.59(d,J=7.7Hz,1H),8.44(s,1H),8.15(d,J=11.2Hz,1H),7.90(d,J=8.6Hz,1H),6.89(d,J=8.6Hz,1H),4.74(s ,2H),4.42(t,J=6.4Hz,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).

[0574] Example 37

[0575] [ka]

[0576] Reaction Scheme:

[0577] [ka]

[0578] 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 added in sequence to a one-neck flask, and the mixture was stirred at 80 ° C for 2 hours under N2 protection. After the reaction was completed, the reaction solution was concentrated, and the residue was dissolved in DCM (50 mL), washed with saturated saline (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain Example 37 (35 mg). MS (ESI +, [M + H] + ) m / z:464.27. 1H NMR(500MHz,Chloroform-d)δ8.59(d,J=7.7Hz,1H),8.44(s,1H),8.15(d,J=11.2Hz,1H),7.91(d,J=8.7Hz,1H),6.90(d,J=8.6Hz,1H),4.73(s,2H),4.4 4(t,J=6.5Hz,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).

[0579] Test Example 1: In vitro kinase inhibitory activity 1.1 Measurement of ATM kinase inhibitory activity ATM kinase solution (concentration 25ng / μL) was added to the detection wells to make 6μL per well, and each compound dissolved in DMSO was added to the detection wells using a nanoliter pipetter to make the final compound concentration 10000nM to 2.44nM. In this experiment, two wells were set up and a control was set up at the same time. After incubating the above system at room temperature for 30 minutes, ATP (100μM) and p53 substrate (50nM) were mixed 1:1 and added to the detection wells to make 4μL per well. After reacting at room temperature for 2 hours, 5μL of EDTA was added to stop the reaction, and 5μL of detection antibodies Mab Anti-phospho p53 and Mab AntiGST-d2 (PerkinElmer) were added and incubated at room temperature for 1 hour. Reading and detection were performed with a PerkinElmer Envision multimode plate reader (excitation 320nm, emission 620nm / 665nm), and IC was calculated by fitting with 4 parameters. 50 was calculated.

[0580] 1.2 Measurement of ATR (Ataxia telangiectasia and Rad3-related) kinase inhibitory activity ATR / ATPIP (ATR-interacting protein) kinase solution (concentration 50ng / μL) was added to the detection wells to make the amount 6μL per well, and each compound dissolved in DMSO was added to the detection wells using a nanoliter pipetter so that the final concentration of the compound was 10000nM to 2.44nM. In this experiment, two wells were set up and a control was set up at the same time. After incubating the above system at room temperature for 30 minutes, ATP (5μM) and p53 substrate (50nM) were mixed 1:1 and added to the detection wells to make the amount 4μL per well. After reacting at room temperature for 2 hours, 5μL of EDTA was added to stop the reaction, and 5μL of detection antibodies Mab Anti-phospho p53 and Mab AntiGST-d2 (manufactured by PerkinElmer) were added and incubated at room temperature for 1 hour. Reading and detection were performed using a PerkinElmer Envision multimode plate reader (excitation 320nm, emission 620nm / 665nm), and IC was calculated by fitting with 4 parameters. 50 was calculated.

[0581] 1.3 Measurement of DNA-PK (DNA-dependent protein kinase) kinase inhibitory activity DNA-PK kinase solution (concentration 0.15ng / μL) was added to the detection wells to make 6μL per well, and various compounds dissolved in DMSO were added to the detection wells using a nanoliter pipettor to make the final compound concentrations 10000nM to 2.44nM. In this experiment, two wells were set up and a control was set up at the same time. After incubating the above system at room temperature for 30 minutes, ATP (100μM) and p53 substrate (50nM) were mixed 1:1 and added to the detection wells to make 4μL per well. After reacting at room temperature for 2 hours, 5μL of EDTA was added to stop the reaction, and 5μL of detection antibodies Mab Anti-phospho p53 and Mab AntiGST-d2 (PerkinElmer) were added and incubated at room temperature for 1 hour. Reading and detection were performed with a PerkinElmer Envision multimode plate reader (excitation 320nm, emission 620nm / 665nm), and IC was calculated by fitting with 4 parameters. 50 was calculated.

[0582] The test results are shown in Table 1.

[0583] [Table 1]

[0584] A is IC 50 <50nM. The test results show that the compounds according to the present disclosure have good inhibitory activity against ATM kinase, and selective kinase inhibitory activity against ATR and / or DNA-PK.

[0585] Test Example 2: Measurement of in vitro cell inhibition activity 2.1 CHK2 phosphorylation inhibitory activity in NCI-H2228 cells NCI-H2228 cells in good growth condition were collected in a centrifuge tube and the cell density was adjusted to 1.25 × 10 6The solution was adjusted to 1 / mL and seeded in a 384-well plate (8 μL / well). After equilibration in a cell culture incubator for 1.5 hours, compounds were added using a nanoliter pipetter so that the final compound concentration was 200 nM-0.049 nM. In this experiment, 2 wells were set up and a control was set at the same time. After continuing to culture in a cell culture incubator for 1 hour, detection was performed using a p-CHK2 (Thr68) detection kit (PerkinElmer) and the Envision plate reader AlphaLISA program, and a 4-parameter analysis was performed to fit the dose-response curve and determine the IC 50 The test results are shown in Table 2.

[0586] [Table 2]

[0587] A is IC 50 <50nM. The test results show that the compounds according to the present disclosure have good inhibitory activity against CHK2 phosphorylation in NCI-H2228 cells.

[0588] Test Example 3: In vitro pharmacokinetics 3.1 In vitro liver microsomal metabolic stability The liver microsome incubation samples were prepared by mixing PBS buffer (pH=7.4), liver microsome solution (0.5mg / mL, species: human, monkey, dog, rat and mouse), test compound and NADPH+MgCl2 solution, and incubating at 37℃ and 300rpm for 1 hour. The 0-hour sample was prepared by mixing PBS buffer (pH=7.4), liver microsome solution (0.5mg / mL) and test compound. Acetonitrile solution containing an internal standard was added to the sample, proteins were precipitated to prepare the supernatant, and the supernatant was diluted and used for LC / MS / MS measurement. The test results are shown in Table 3.

[0589] [Table 3]

[0590] The results show that test compounds of the present disclosure have stable metabolism in vitro (eg, high excess after 60 minutes).

[0591] 3.2 In vitro plasma protein binding rate Plasma samples were prepared from blank plasma (mouse, rat, dog, and human) and test compound solution (3 μM). High-throughput equilibrium dialysis (RED) samples were prepared by incubating the plasma sample in the red chamber and the PBS buffer sample in the white chamber at 37°C and 100 rpm for 4 hours. Acetonitrile solution containing internal standards was added to the plasma sample and the buffer sample, respectively, to precipitate proteins and prepare supernatants, which were then diluted and used for LC / MS / MS measurements.

[0592] The results show that the compounds tested herein have low plasma protein binding in vitro.

[0593] Test Example 4: In vivo pharmacokinetics 4.1 Pharmacokinetics in mice ICR mice weighing 21 to 23 g were acclimated for 3 to 5 days, then randomly divided into groups (9 mice per group), and the solution of Example 1 was administered intragastrically at a dose of 10 mg / kg.

[0594] Blood was collected from the orbit at the following collection times: 0 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, and 24 h, and plasma samples for testing were prepared.

[0595] 20 μL of the test plasma sample and the calibration curve sample were taken, and an acetonitrile solution containing an internal standard was added to precipitate the proteins to obtain the supernatant. After dilution, the supernatant was used for LC / MS / MS measurement. Fitting was performed using a non-compartment model.

[0596] 4.2 Pharmacokinetics in rats SD rats weighing 200 to 220 g were acclimated for 3 to 5 days, then randomly divided into groups of 3 rats per group, and the solution of Example 1 was administered intragastrically at a dose of 10 mg / kg.

[0597] Blood was collected from the orbit at the following collection times: 0 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, and 24 h, and plasma samples for testing were prepared.

[0598] 50 μL of the test plasma sample and the calibration curve sample were taken, and an acetonitrile solution containing an internal standard was added to precipitate the proteins to obtain the supernatant. After dilution, the supernatant was used for LC / MS / MS measurement. Fitting was performed using a non-compartment model.

[0599] 4.3 Pharmacokinetics in dogs Beagle dogs weighing 10 to 12 kg were acclimated for 3 to 5 days, then randomly divided into groups (3 dogs per group), and the solution of Example 1 was administered intragastrically at a dose of 2 mg / kg.

[0600] Blood was collected from the forelimb vein at the following collection times: 0 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, and 24 h, and plasma samples for testing were prepared.

[0601] 50 μL of the test plasma sample and the calibration curve sample were taken, and an acetonitrile solution containing an internal standard was added to precipitate the proteins to obtain the supernatant. After dilution, the supernatant was used for LC / MS / MS measurement. Fitting was performed using a non-compartment model.

[0602] The results are shown in Table 4.

[0603] [Table 4]

[0604] Test results show that the compounds of the present disclosure have good in vivo pharmacokinetic properties (in mice, rats and dogs) and C max, AUC,t 1 / 2 These results show that the FT-IR 1000 series has superiority in the following areas:

[0605] 4.4 Mouse brain distribution experiment ICR mice weighing 22 to 24 g were acclimated for 3 to 5 days, then randomly divided into groups (9 mice per group), and the solution of Example 1 was administered intragastrically at a dose of 20 mg / kg.

[0606] At 15 minutes, 30 minutes, and 8 hours, blood was drawn from the orbit and plasma samples were prepared for testing.

[0607] Tissue collection time points were 15 min, 30 min, and 8 h, and at the corresponding time points, the animals were killed by exsanguination, brain tissue was removed, and homogenized with ice-cold saline at a ratio of 1:3 (W / V) to prepare brain homogenate samples for testing.

[0608] 20 μL of the plasma and brain homogenate samples to be tested and the corresponding calibration curve samples were taken, and acetonitrile solution was added to precipitate proteins to obtain the supernatant. After dilution, the supernatant was used for LC / MS / MS measurement. Fitting was performed using a non-compartmental model.

[0609] The results show that compounds of the present disclosure have high exposure (AUC) in the plasma and brain, and high brain-blood ratios (brain / plasma).

[0610] Test Example 5: In vivo efficacy study HCT116 cells were inoculated into the right axilla of SPF level female nude mice at 1 × 10 7 Cells / mouse were inoculated subcutaneously. The average tumor volume was approximately 200 mm 3 When the animals reached this age, they were divided into groups (the day of grouping was designated as day 0).

[0611] The compounds of the present disclosure were administered at different doses (15mpk, 30mpk, or 60mpk, intragastrically), with a cycle of administration lasting 7 days. The tumor volume was measured 2-3 times a week, and the mice were weighed and recorded, and the general performance of the mice was observed and recorded daily. After the experiment, the tumors were excised, weighed, and photographed.

[0612] The detection index and calculation formula are as follows:

[0613] Tumor volume, TV (mm 3 )=1 / 2×(a×b 2 ) (where a is the longest diameter of the tumor and b is the shortest diameter of the tumor.) Relative tumor volume, RTV=TV t / TV0 (where TV0 is the tumor volume on day 0, TV t is the tumor volume at each measurement.) Relative tumor growth rate, T / C(%)=T RTV / C RTV ×100% (where T RTV is the RTV of the treatment group, and C RTV is the RTV of the vehicle control group.) Tumor growth inhibition rate, TGI (%) = (1-TW / TW0) x 100% (where TW is the tumor weight in the treatment group and TW0 is the tumor weight in the solvent control group). Weight change rate, WCR(%)=(Wt t -Wt0) / Wt0 × 100% (where Wt0 is the mouse weight on day 0 and Wt t is the body weight of the mouse at each measurement.)

[0614] Test results show that compounds of the present disclosure can inhibit tumor growth in vivo.

Claims

1. A compound represented by formula IA, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof. 【Chemistry 1】 (In the formula, R １ is hydrogen, C １－１０ Alkyl, C ３－１０ Cycloalkyl, 3-10 membered heterocycloalkyl, C ３－１０ aryl or 3- to 10-membered heteroaryl, １－１０ Alkyl, C ３－１０ Cycloalkyl, 3-10 membered heterocycloalkyl, C ３－１０ The aryl or 3- to 10-membered heteroaryl is selected from the group consisting of halogen, hydroxyl, amino, cyano, C １－６ Alkyl, C １－６ Alkoxy, C １－６ AlkylNH-, (C １－６ Alkyl) ２ N-, C ３－１０ Cycloalkyl, 3-10 membered heterocycloalkyl, C ３－１０ optionally substituted with one or more of aryl or 3-10 membered heteroaryl; R ２ａ and R ２ｂ are each independently hydrogen, C １－６ Alkyl, C ３－１０ Cycloalkyl, 3-10 membered heterocycloalkyl, C ３－１０ aryl or 3-10 membered heteroaryl, or R ２ａ and R ２ｂ are bonded to each other to form a 3-12 membered heterocycloalkyl, １－６ Alkyl, C ３－１０ Cycloalkyl, 3-10 membered heterocycloalkyl, C ３－１０ The aryl, 3- to 10-membered heteroaryl, or 3- to 12-membered heterocycloalkyl may be substituted with deuterium, halogen, a hydroxyl group, an amino group, a cyano group, C １－６ Alkyl, C １－６ Alkoxy, C １－６ AlkylNH-, (C １－６ Alkyl) ２ N-, C ３－１０ Cycloalkyl, 3-10 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 , -SO ２ N.H.C. １－６ Alkyl or -SO ２ N (C １－６ Alkyl) ２ and optionally substituted with one or more of R ３ and R ４ each independently represents a halogen, a hydroxyl group, an amino group, a cyano group, a nitro group, １－６ Alkyl, C １－６ Alkoxy, C １－６ AlkylNH- or (C １－６ Alkyl) ２ N-, wherein C １－６ Alkyl, C １－６ Alkoxy, C １－６ AlkylNH- or (C １－６ Alkyl) ２ N- may be substituted with one or more of a halogen, a hydroxyl group, an amino group, a cyano group, a nitro group, or -COOH; p and m are independently selected from 0, 1, 2, 3, or 4; Ring A is selected from phenyl or 5-10 membered heteroaryl; X is a single bond, -NR ａ -, -O- or -S-; Y １ , Y ２ , Y ３ or Z is independently selected from N or CH; and Y １ , Y ２ , Y ３ or at least one in Z is selected from CH; R ａ is hydrogen or C １－６ alkyl, L is 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-, R ５ and R ６ are each independently hydrogen, C １－６ Alkyl, C ３－１０ cycloalkyl or 3-10 membered heterocycloalkyl; or R ５ and R ６ are bonded to each other to form a 3-12 membered heterocycloalkyl, １－６ Alkyl, C ３－１０ Cycloalkyl, 3- to 10-membered heterocycloalkyl or 3- to 12-membered heterocycloalkyl may be substituted with deuterium, halogen, a hydroxyl group, an amino group, a cyano group, C １－６ Alkyl, C １－６ Alkoxy, C １－６ AlkylNH-, (C １－６ Alkyl) ２ N- or C substituted with one or more halogens, hydroxyl groups, amino groups or cyano groups １－６ may be substituted with one or more groups of alkyl.

2. The compound according to claim 1, selected from the compounds of formula I, their pharma- ceutically acceptable salts, or their stereoisomers. 【Chemistry 2】 (In the formula, R １ is hydrogen, C １－６ Alkyl, C ３－１０ Cycloalkyl, 3-10 membered heterocycloalkyl, C ３－１０ aryl or 3- to 10-membered heteroaryl, １－６ Alkyl, C ３－１０ Cycloalkyl, 3-10 membered heterocycloalkyl, C ３－１０ The aryl or 3- to 10-membered heteroaryl is selected from the group consisting of halogen, hydroxyl, amino, cyano, C １－６ Alkyl, C １－６ Alkoxy, C １－６ AlkylNH- or (C １－６ Alkyl) ２ optionally substituted with one or more N-; R ２ａ and R ２ｂ are each independently hydrogen or C １－６ alkyl; or R ２ａ and R ２ｂ are bonded to each other to form a 3- to 10-membered heterocycloalkyl, １－６ The alkyl or 3- to 10-membered heterocycloalkyl may be selected from the group consisting of deuterium, halogen, hydroxyl, amino, cyano, C １－６ Alkyl, C １－６ Alkoxy, C １－６ AlkylNH- or (C １－６ Alkyl) ２ optionally substituted with one or more N-; R ３ and R ４ each independently represents a halogen, a hydroxyl group, an amino group, a cyano group, C １－６ Alkyl, C １－６ Alkoxy, C １－６ AlkylNH- or (C １－６ Alkyl) ２ N-, 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 is selected from N; X is a single bond, -NR ａ -, -O- or -S-; R ａ is hydrogen or C １－６ alkyl, L is 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-, R ５ and R ６ are each independently hydrogen, C １－６ Alkyl, C ３－１０ cycloalkyl or 3-10 membered heterocycloalkyl; or R ５ and R ６ are bonded to each other to form a 3- to 10-membered heterocycloalkyl, １－６ Alkyl, C ３－１０ Cycloalkyl or 3- to 10-membered heterocycloalkyl may be substituted with deuterium, halogen, a hydroxyl group, an amino group, a cyano group, C １－６ Alkyl, C １－６ Alkoxy, C １－６ AlkylNH- or (C １－６ Alkyl) ２ may be substituted with one or more N-.

3. R １ is hydrogen, C １－６ Alkyl, C ３－１０ Cycloalkyl, 3-10 membered heterocycloalkyl, C ３－１０ aryl or 3- to 10-membered heteroaryl, １－６ Alkyl, C ３－１０ Cycloalkyl, 3-10 membered heterocycloalkyl, C ３－１０ The aryl or 3- to 10-membered heteroaryl is selected from the group consisting of halogen, hydroxyl, amino, cyano, C １－６ Alkyl, C １－６ Alkoxy, C １－６ AlkylNH- or (C １－６ Alkyl) ２ optionally substituted with one or more N-; Optionally, R １ is hydrogen, C １－４ Alkyl, C ３－８ Cycloalkyl, 3-8 membered heterocycloalkyl, C ３－８ aryl or 3-8 membered heteroaryl, １－４ Alkyl, C ３－８ Cycloalkyl, 3-8 membered heterocycloalkyl, C ３－８ The aryl or 3-8 membered heteroaryl is selected from the group consisting of halogen, hydroxyl, amino, cyano, C １－４ Alkyl, C １－４ Alkoxy, C １－４ AlkylNH- or (C １－４ Alkyl) ２ optionally substituted with one or more N-; Optionally, R １ is hydrogen, C １－４ Alkyl, C ３－６ Cycloalkyl, 3-6 membered heterocycloalkyl, C ３－６ aryl or 3- to 6-membered heteroaryl, １－４ Alkyl, C ３－６ Cycloalkyl, 3-6 membered heterocycloalkyl, C ３－６ The aryl or 3- to 6-membered heteroaryl is selected from the group consisting of halogen, hydroxyl, amino, cyano, C １－４ Alkyl, C １－４ Alkoxy, C １－４ AlkylNH- or (C １－４ Alkyl) ２ optionally substituted with one or more N-; Optionally, R １ is C １－３ Alkyl, C ３－６ Cycloalkyl, 5-6 membered heterocycloalkyl, C ５－６ aryl or 5- to 6-membered heteroaryl, ４－６ Cycloalkyl, 5-6 membered heteroaryl, C ５－６ The aryl or 5- to 6-membered heteroaryl is selected from the group consisting of halogen, hydroxyl, amino, cyano, C １－３ Alkyl or C １－３ may be substituted with one or more alkoxy Optionally, R １ is C １－３ Alkyl, C ３－５ cycloalkyl, 6-membered heterocycloalkyl, phenyl, or 6-membered heteroaryl; ４－５ Cycloalkyl, 6-membered heterocycloalkyl, phenyl or 6-membered heteroaryl are halogen or C １－３ may be substituted with one or more alkoxy Optionally, R １ is selected from propyl, cyclopropyl, cyclobutyl, cyclopentyl, a 6-membered oxygen-containing heterocycloalkyl or a 6-membered nitrogen-containing heteroaryl, said cyclobutyl, cyclopentyl, 6-membered oxygen-containing heterocycloalkyl or 6-membered nitrogen-containing heteroaryl being optionally substituted with one or more of fluorine or methoxy; Optionally, R １ is selected from propyl, cyclopropyl, cyclobutyl, cyclopentyl, tetrahydropyranyl or pyridyl, said cyclobutyl, cyclopentyl or pyridyl being optionally substituted by one or more of fluorine or methoxy; Optionally, R １ isopropyl, 【Chemistry 3】 The compound according to claim 1 or 2, or a pharma- ceutically acceptable salt or stereoisomer thereof, selected from:

4. R ２ａ and R ２ｂ are each independently hydrogen or C １－６ alkyl; or R ２ａ and R ２ｂ are bonded to each other to form a 3- to 10-membered heterocycloalkyl, １－６ The alkyl or 3- to 10-membered heterocycloalkyl may be selected from the group consisting of deuterium, halogen, hydroxyl, amino, cyano, C １－６ Alkyl, C １－６ Alkoxy, C １－６ AlkylNH- or (C １－６ Alkyl) ２ optionally substituted with one or more N-; Optionally, R ２ａ and R ２ｂ are each independently hydrogen or C １－４ alkyl; or R ２ａ and R ２ｂ are bonded to each other to form a 3- to 8-membered heterocycloalkyl, １－４ The alkyl or 3-8 membered heterocycloalkyl may be selected from the group consisting of deuterium, halogen, hydroxyl, amino, cyano, C １－４ Alkyl, C １－４ Alkoxy, C １－４ AlkylNH- or (C １－４ Alkyl) ２ optionally substituted with one or more N-; Optionally, R ２ａ and R ２ｂ are each independently hydrogen or C １－４ alkyl; or R ２ａ and R ２ｂ are bonded to each other to form a 3-4 membered heterocycloalkyl, １－４ Alkyl or 3-4 membered heterocycloalkyl is selected from the group consisting of deuterium, halogen, hydroxyl, amino, cyano or C １－３ may be substituted with one or more alkyl groups; Optionally, R ２ａ and R ２ｂ are each independently hydrogen or C １－４ alkyl, １－４ The alkyl may be optionally substituted with one or more of deuterium, halogen, hydroxyl, amino or cyano groups; Optionally, R ２ａ and R ２ｂ are each independently hydrogen or C １－４ alkyl, １－４ The alkyl may be substituted with one or more of deuterium, fluorine, chloro, or bromo; Optionally, R ２ａ and R ２ｂ are each independently hydrogen or C １－３ alkyl, １－３ The alkyl may be substituted with one or more deuterium atoms; Optionally, R ２ａ and R ２ｂ are each independently hydrogen or CH ３ -, wherein said CH ３ - may be substituted with one or more deuterium atoms; Optionally, R ２ａ and R ２ｂ are each independently hydrogen, CH ３ - or CD ３ The compound according to any one of claims 1 to 3, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, selected from:

5. R ３ and R ４ each independently represents a halogen, a hydroxyl group, an amino group, a cyano group, C １－６ Alkyl, C １－６ Alkoxy, C １－６ AlkylNH- or (C １－６ Alkyl) ２ N-, Optionally, R ３ and R ４ each independently represents a halogen, a hydroxyl group, an amino group, a cyano group, C １－３ Alkyl, C １－３ Alkoxy, C １－３ AlkylNH- or (C １－３ Alkyl) ２ N-, Optionally, R ３ and R ４ Each independently represents a halogen or C １－３ alkoxy; Optionally, R ３ is fluorine, chloro, bromo or C １－３ alkoxy; Optionally, R ３ is selected from fluorine or methoxy; Optionally, R ４ The compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt or stereoisomer thereof, wherein is selected from halogen, a hydroxyl group, an amino group, a cyano group, methyl or methoxy.

6. 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; 6. The compound according to any one of claims 1 to 5, wherein optionally m is selected from 0 or 1, or a pharma- ceutically acceptable salt or stereoisomer thereof.

7. Ring A is selected from phenyl, 5- to 6-membered heteroaryl, or 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; 7. The compound according to claim 1 or any one of claims 3 to 6, or a pharma- ceutically acceptable salt or stereoisomer thereof, wherein optionally Ring A is selected from pyridyl or pyrimidinyl.

8. Y １ , Y ２ , Y ３ or Z is independently selected from N or CH; and Y １ , Y ２ , Y ３ or one, two, three or four in Z are selected from CH; Optionally, Y １ is selected from N, Y ２ , Y ３ is selected from CH; Or Y ２ is selected from N, Y １ , Y ３ is selected from CH; Or Y ３ is selected from N, Y １ , Y ２ is selected from CH; Or Y １ , Y ２ Or Y ３ is selected from CH; Or 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; alternatively, Z is selected from CH. The compound of any one of claims 1 or 3 to 7, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof.

9. 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 is selected from N; Optionally, 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 two of are selected from N; Optionally, X ４ is selected from N, and X １ , X ２ Or X ３ are each independently selected from N or CH; 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 The compound according to any one of claims 2 to 6, or a pharma- ceutically acceptable salt or stereoisomer thereof, wherein:

10. X is -NR ａ - or -O-; Optionally, X is selected from -NH- or -O-; 10. The compound according to any one of claims 1 to 9, or a pharma- ceutically acceptable salt or stereoisomer thereof, optionally wherein X is selected from -O-.

11. R ａ is hydrogen or C １－６ alkyl, Optionally, R ａ is hydrogen or C １－４ alkyl, Optionally, R ａ is hydrogen or C １－３ alkyl, Optionally, R ａ is selected from hydrogen or methyl; Optionally, R ａ The compound according to any one of claims 1 to 10, or a pharma- ceutically acceptable salt or stereoisomer thereof, wherein is selected from hydrogen.

12. L is 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-, Optionally, L is 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-, Optionally, L is 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 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-, Optionally, L is 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-, Optionally, L is C. ２－３ Alkylene, C ４－６ Cycloalkyl, -CH ２ -C ４ Cycloalkyl- or -C ４ Cycloalkyl-CH ２ - selected from Optionally, L is -CH ２ CH ２ --, --CH ２ CH ２ CH ２ --, 【Chemistry 4】 The compound according to any one of claims 1 to 11, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, selected from the group consisting of:

13. R ５ and R ６ are each independently hydrogen, C １－６ Alkyl, C ３－１０ cycloalkyl or 3-10 membered heterocycloalkyl; or R ５ and R ６ are bonded to each other to form a 3- to 10-membered heterocycloalkyl, １－６ Alkyl, C ３－１０ Cycloalkyl or 3- to 10-membered heterocycloalkyl may be substituted with deuterium, halogen, a hydroxyl group, an amino group, a cyano group, C １－６ Alkyl, C １－６ Alkoxy, C １－６ AlkylNH-, (C １－６ Alkyl) ２ N-, C substituted with one or more halogens, hydroxyl groups, amino groups or cyano groups １－６ may be substituted with one or more groups of alkyl; Optionally, R ５ and R ６ are each independently hydrogen, C １－６ Alkyl, C ３－１０ cycloalkyl or 3-10 membered heterocycloalkyl; or R ５ and R ６ are bonded to each other to form a 3- to 10-membered heterocycloalkyl, １－６ Alkyl, C ３－１０ Cycloalkyl or 3- to 10-membered heterocycloalkyl may be substituted with deuterium, halogen, a hydroxyl group, an amino group, a cyano group, C １－６ Alkyl, C １－６ Alkoxy, C １－６ AlkylNH-, (C １－６ Alkyl) ２ N-, C substituted with one or more halogens １－６ may be substituted with one or more groups of alkyl; Or, R ５ and R ６ are each independently hydrogen, C １－４ Alkyl, C ３－８ cycloalkyl or 3-8 membered heterocycloalkyl; or R ５ and R ６ are bonded to each other to form a 3- to 8-membered heterocycloalkyl, １－４ Alkyl, C ３－８ Cycloalkyl or 3-8 membered heterocycloalkyl may be substituted with deuterium, halogen, hydroxyl, amino, cyano, C １－４ Alkyl, C １－４ Alkoxy, C １－４ AlkylNH-, (C １－４ Alkyl) ２ N- or halogenated C １－６ may be substituted with one or more groups of alkyl; Or, R ５ and R ６ are each independently １－４ Alkyl or C ３－６ cycloalkyl; or R ５ and R ６ are bonded to each other to form a 3- to 7-membered heterocycloalkyl, ３－６ Cycloalkyl or 3- to 7-membered heterocycloalkyl may be substituted with deuterium, halogen, hydroxyl, amino, cyano, C １－３ Alkyl, C １－３ Alkoxy or halogenated C １－４ may be substituted with one or more groups of alkyl; Or, R ５ and R ６ are each independently １－４ Alkyl or C ３－６ cycloalkyl; or R ５ and R ６ are bonded to each other to form a 3- to 7-membered heterocycloalkyl, and the 3- to 7-membered heterocycloalkyl is selected from the group consisting of deuterium, halogen, hydroxyl, amino, cyano, C １－３ Alkyl, C １－３ Alkoxy or halogenated C １－４ may be substituted with one or more groups of alkyl; Or, R ５ and R ６ are each independently １－３ Alkyl or C ３－４ cycloalkyl; or R ５ and R ６ are joined together to form a 4-, 5-, 6- or 7-membered heterocycloalkyl, said heterocycloalkyl being halogen or halogenated C １－３ may be substituted with one or more alkyl groups; Or, R ５ and R ６ are each independently １－３ Alkyl or C ３－４ cycloalkyl; Or, R ５ and R ６ are joined together to form a 4-, 5-, 6- or 7-membered heterocycloalkyl, said heterocycloalkyl being halogen or halogenated C １－３ may be substituted with one or more alkyl groups; Or, R ５ and R ６ are joined together to form a 4-, 5- or 6-membered heterocycloalkyl, said heterocycloalkyl being halogen or halogenated C １－３ may be substituted with one or more alkyl groups; Or, R ５ and R ６ are bonded together to form a 4-membered heterocycloalkyl, said heterocycloalkyl being halogen or halogenated C １－３ may be substituted with one or more alkyl groups; Or, R ５ and R ６ are bonded together to form a 5-membered heterocycloalkyl, said heterocycloalkyl being halogen or halogenated C １－３ may be substituted with one or more alkyl groups; Or, R ５ and R ６ are bonded together to form a 6-membered heterocycloalkyl, said heterocycloalkyl being halogen or halogenated C １－３ may be substituted with one or more alkyl groups; Or, R ５ and R ６ are each independently selected from methyl or cyclopropyl; ５ and R ６ are linked together to form azetidinyl, pyrrolidinyl, piperidinyl, azaspiroheptyl, or azabicycloheptyl, wherein the azetidinyl or pyrrolidinyl is F or —CH ２ optionally substituted with one or more of F; Or, R ５ and R ６ are each independently selected from methyl or cyclopropyl; ５ and R ６ are bonded together to form an azetidinyl, pyrrolidinyl or piperidinyl, wherein the azetidinyl, pyrrolidinyl or piperidinyl is a halogen or halogenated C １－３ may be substituted with one or more alkyl groups; Or, R ５ and R ６ are each independently selected from methyl or cyclopropyl; ５ and R ６ are linked together to form an azetidinyl, pyrrolidinyl, or piperidinyl, wherein the azetidinyl or pyrrolidinyl is F or —CH ２ optionally substituted with one or more of F; Optionally, R ５ and R ６ are each independently hydrogen, C １－６ Alkyl, C ３－１０ cycloalkyl or 3-10 membered heterocycloalkyl; or R ５ and R ６ are bonded to each other to form a 3- to 10-membered heterocycloalkyl, １－６ Alkyl, C ３－１０ Cycloalkyl or 3- to 10-membered heterocycloalkyl may be substituted with deuterium, halogen, a hydroxyl group, an amino group, a cyano group, C １－６ Alkyl, C １－６ Alkoxy, C １－６ AlkylNH- or (C １－６ Alkyl) ２ optionally substituted with one or more N-; Or, R ５ and R ６ are each independently hydrogen, C １－４ Alkyl, C ３－８ cycloalkyl or 3-8 membered heterocycloalkyl; or R ５ and R ６ are bonded to each other to form a 3- to 8-membered heterocycloalkyl, １－４ Alkyl, C ３－８ Cycloalkyl or 3-8 membered heterocycloalkyl may be substituted with deuterium, halogen, hydroxyl, amino, cyano, C １－４ Alkyl, C １－４ Alkoxy, C １－４ AlkylNH- or (C １－４ Alkyl) ２ optionally substituted with one or more N-; Or, R ５ and R ６ are each independently １－４ Alkyl or C ３－６ cycloalkyl; or R ５ and R ６ are bonded to each other to form a 3- to 6-membered heterocycloalkyl, ３－６ Cycloalkyl or 3- to 6-membered heterocycloalkyl may be substituted with deuterium, halogen, hydroxyl, amino, cyano, C １－３ Alkyl or C １－３ may be substituted with one or more alkoxy Or, R ５ and R ６ are each independently １－３ Alkyl or C ３－４ cycloalkyl, or joined together to form a 5-6 membered heterocycloalkyl; Or, R ５ and R ６ are each independently selected from methyl or cyclopropyl, or are joined together to form pyrrolidinyl or piperidinyl, or a pharma- ceutically acceptable salt or stereoisomer thereof according to any one of claims 1 to 12.

14. Structural Fragment 【Chemistry 5】 teeth, 【Chemistry 6】 The compound according to any one of claims 2 to 6 or claims 9 to 13, or a pharma- ceutically acceptable salt or stereoisomer thereof, selected from the group consisting of:

15. Structural Fragment 【Chemistry 7】 teeth, 【Chemistry 8】 Alternatively, a structural fragment 【Chemistry 9】 teeth, 【Chemistry 10】 is selected from Optionally, a structural fragment 【Chemistry 11】 teeth, 【Chemistry 12】 Alternatively, a structural fragment 【Chemistry 13】 teeth, 【Chemistry 14】 Alternatively, a structural fragment 【Chemistry 15】 teeth, 【Chemistry 16】 Alternatively, a structural fragment 【Chemistry 17】 teeth, 【Chemistry 18】 Alternatively, a structural fragment 【Chemistry 19】 teeth, 【Chemistry 20】 is selected from Optionally, a structural fragment 【Chemistry 21】 teeth, 【Chemical 22】 Alternatively, a structural fragment 【Chemistry 23】 teeth, 【Chemistry 24】 is selected from Optionally, a structural fragment 【Chemistry 25】 teeth, 【Chemistry 26】 Alternatively, a structural fragment 【Chemical 27】 teeth, 【Chemistry 28】 The compound according to any one of claims 1 to 14, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, selected from the group consisting of:

16. The compound according to any one of claims 1 to 15, wherein the compound represented by formula IA or formula I is selected from the compound represented by formula II, or a pharma- ceutically acceptable salt or stereoisomer thereof. 【Chemical formula 29】

17. The compound according to any one of claims 1 to 16, wherein the compound represented by formula IA, formula I or formula II is selected from the compound represented by formula III or the compound represented by formula IV, or a pharma- ceutically acceptable salt or stereoisomer thereof. 【Chemistry 30】

18. The following compound, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof: 【Chemistry 31】 【Chemistry 32】 【Chemical 33】 【Chemical Formula 34】

19. A pharmaceutical composition comprising the compound according to any one of claims 1 to 18, or a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof.

20. A method for treating a tumor, comprising administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1 to 18, or a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutical composition according to claim 19.

21. Use of a compound according to any one of claims 1 to 18, or a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutical composition according to claim 19, in the manufacture of a medicament for treating a tumor.

22. Use of a compound according to any one of claims 1 to 18, or a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutical composition according to claim 19, in the treatment of tumors.

23. A compound according to any one of claims 1 to 18, or a pharma- ceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition according to claim 19, for treating a tumor.

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