A condensed ring compound, its use and pharmaceutical composition containing the same

Abstract

A fused ring compound, its use and a pharmaceutical composition containing the same, the compound has a strong inhibitory effect on BRMATPase and has a good application prospect in BRG1 gene mutation tumors. #imgabs0#

Description

A condensed ring compound, its use and pharmaceutical composition containing the same Technical Field

[0001] The present invention relates to a condensed ring compound, application thereof and a pharmaceutical composition containing the same. Background Art

[0002] Cancer is one of the leading causes of death worldwide and is primarily caused by genetic and epigenetic alterations. These alterations affect gene expression or signaling pathways in normal cells, leading to their transformation into malignant tumors. Cancer genome sequencing of tumor samples has revealed that subunit genes of the human ATP-dependent chromatin remodeling complex SWI / SNF are mutated in >20% of human tumors, with the majority being loss-of-function mutations.

[0003] BRM (Protein brahma homolog) is an ATPase subunit of the SWI / SNF complex and is mutually exclusive with BRG1 (Protein brahma homolog 1), also an ATPase subunit. ATPase hydrolyzes ATP to provide energy for the SWI / SNF complex, enabling it to regulate gene expression and key cellular processes, playing a vital role in maintaining cell viability.

[0004] The BRG1 gene (SMARCA4) is highly mutated in multiple cancer types, including but not limited to melanoma, endometrial cancer, non-small cell lung cancer, esophageal and gastric adenocarcinoma, urothelial bladder cancer, and colorectal cancer. In contrast, the BRM gene (SMARCA2) is rarely mutated. BRM and BRG1 have complementary and redundant functions in regulating cell cycle and hormone pathways, DNA damage repair responses, and other cell viability-related functions. Therefore, in BRG1-deficient tumor cells, BRM can compensate for the loss of BRG1 function, maintaining the function of the SWI / SNF complex and supporting cell viability.

[0005] The synthetic lethality of BRM and BRG1 has been verified in in vitro and in vivo disease models of various types of tumor cells: degrading BRM or silencing BRM gene expression in BRG1 gene-deficient cells will inhibit tumor cell proliferation in vitro and tumor growth in vivo; BRG1 gene-deficient tumor cells are extremely sensitive to shRNA of the BRM gene; inhibiting BRM's ATPase activity can inhibit the in vivo growth of BRG1 gene-deficient tumors... Therefore, BRM is a potential drug treatment target in BRG1 gene mutation tumors.

[0006] Compared to BRG1, drug interference with BRM carries a lower risk of toxicity. The BRM-SWI / SNF complex has far lower ATPase activity and chromatin remodeling capabilities than the BRG1-SWI / SNF complex. In normal cells, the SWI / SNF complex primarily relies on BRG1 for its function. Homozygous knockout of the BRG1 gene does not cause embryonic lethality or affect adult mouse fertility, contrary to the effects of homozygous knockout of the BRM gene.

[0007] Therefore, targeted inhibition of BRM ATPase activity has the potential to become a new treatment option for BRG1 gene mutation tumors.

[0008] Currently, no BRM ATPase inhibitors have entered the clinical stage, but some are in preclinical development. Foghorn's recently disclosed patent WO2022103899 discloses several highly selective BRM ATPase inhibitors. Examples of their structures are shown below:

[0009] Summary of the Invention

[0010] The technical problem to be solved by the present invention is that there are only a few types of BRM ATPase inhibitors available. To this end, the present invention provides a fused-ring compound I or a pharmaceutically acceptable salt thereof. This fused-ring compound has a strong inhibitory effect on BRM ATPase and has promising application prospects in tumors with BRG1 gene mutations.

[0011] The present invention provides a compound as shown in Formula I or a pharmaceutically acceptable salt thereof,

[0012] in,

[0013] Y is C or N;

[0014] R 1 for Hydroxyl, cyano, halogen, amino, deuterium, unsubstituted or replaced by one or more R 1-3 Substituted C1-C6 alkyl, unsubstituted or substituted by one or more R 1-4 Substituted C3-C6 cycloalkyl or unsubstituted or substituted by one or more R 1-5 Substituted 3-6 membered heterocycloalkyl; the heteroatoms in the 3-6 membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0015] R 1-1 is unsubstituted or substituted with one or more R 1-1-1 Substituted C1-C6 alkyl, unsubstituted or C3-C6 cycloalkyl substituted by one or more deuteriums, or -NR1-1-2 R 1-1-3 ;

[0016] R 1-2 O or NR 1-2-1 ; R 1-2-1 is hydrogen or C1-C6 alkyl which is unsubstituted or substituted by one or more deuterium groups;

[0017] Each R 1-1-1 Independently OR 1-1-1-1 , C1-C6 alkyl or deuterium, unsubstituted or substituted with one or more deuterium groups;

[0018] R 1-1-1-1 is hydrogen or C1-C6 alkyl which is unsubstituted or substituted by one or more deuterium groups;

[0019] R 1-1-2 and R 1-1-3 are independently hydrogen or C1-C6 alkyl which is unsubstituted or substituted with one or more deuterium groups;

[0020] Each R 1-3 are independently hydroxy, cyano, halogen, amino, C1-C6 alkyl which is unsubstituted or substituted with one or more deuterium groups, or deuterium;

[0021] Each R 1-4 and R 1-5 are independently hydroxy, deuterium, or C1-C6 alkyl which is unsubstituted or substituted with one or more deuterium groups;

[0022] X is -CR 1-6 R 1-7 -or-NR 1-8 -;

[0023] R 1-6 and R 1-7 are independently hydrogen, deuterium, halogen, or C1-C6 alkyl which is unsubstituted or substituted with one or more deuterium groups;

[0024] R 1-8 is hydrogen or C1-C6 alkyl which is unsubstituted or substituted by one or more deuterium groups;

[0025] R 2 and R 3 The atoms to which it is attached are unsubstituted or replaced by one or more R 2-1 substituted 5-6 membered heteroaryl, unsubstituted or substituted by one or more R 2-2 substituted 4-6 membered heterocycloalkyl, unsubstituted or substituted by one or more R 2-3 Substituted C4-C6 cycloalkyl or unsubstituted or substituted by one or more R 2-4 Substituted C6-C 10The heteroatoms in the 5-6 membered heteroaryl group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 4-6 membered heterocycloalkyl group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0026] Each R 2-1 are independently deuterium, halogen, unsubstituted or substituted with one or more R 2-1-1 Substituted C1-C6 alkyl, oxo (=O), or two R 2-1 Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl group which is unsubstituted or substituted with one or more deuteriums;

[0027] Each R 2-2 are independently deuterium, halogen, unsubstituted or substituted with one or more R 2-2-1 Substituted C1-C6 alkyl, oxo (=O), or two R 2-2 Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl group which is unsubstituted or substituted with one or more deuteriums;

[0028] Each R 2-3 are independently deuterium, halogen, unsubstituted or substituted with one or more R 2-3-1 Substituted C1-C6 alkyl, oxo (=O), or two R 2-3 Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl group which is unsubstituted or substituted with one or more deuteriums;

[0029] Each R 2-4 are independently deuterium, halogen, unsubstituted or substituted with one or more R 2-4-1 Substituted C1-C6 alkyl, oxo (=O), or two R 2-4 Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl group which is unsubstituted or substituted with one or more deuteriums;

[0030] R 2-1-1 、R 2-2-1 、R 2-3-1 and R 2-4-1 are independently deuterium or hydroxyl;

[0031] A is unsubstituted or substituted with one or more deuteriums C6-C 10substituted arylene, a 5-12 membered heteroarylene which is unsubstituted or substituted by one or more deuteriums, or a 5-12 membered heterocycloalkylene which is unsubstituted or substituted by one or more deuteriums; the heteroatoms in the 5-12 membered heteroarylene are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heterocycloalkylene are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0032] L is a linker, a C2-C6 alkenylene group which is unsubstituted or substituted with one or more deuterium groups, or a C1-C6 alkylene group which is unsubstituted or substituted with one or more deuterium groups;

[0033] Q is unsubstituted or substituted with one or more R 3-1 Substituted C6-C 10 arylene, unsubstituted or replaced by one or more R 3-1 Substituted 5-12 membered heteroarylene or unsubstituted or replaced by one or more R 3-1 Substituted 5-12 membered heterocycloalkylene; the heteroatoms in the 5-12 membered heteroarylene are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heterocycloalkylene are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0034] Each R 3-1 are independently halogen or deuterium;

[0035] R 4 is unsubstituted or replaced by one or more R 4-1 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more R 4-2 Substituted C2-C6 alkenyl, unsubstituted or replaced by one or more R 4-3 Substituted C2-C6 alkynyl, unsubstituted or replaced by one or more R 4-4 Substituted C3-C6 cycloalkyl, unsubstituted or replaced by one or more R 4-5 substituted 4-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 4-6 substituted 5-12 membered heteroaryl, unsubstituted or replaced by one or more R 4-7 Substituted C1-C6 alkoxy or -NR 4-9 R 4-8 The heteroatoms in the 4-12 membered heterocycloalkyl group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heteroaryl group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0036] Each R4-1 are independently deuterium, halogen, hydroxy, C1-C6 alkyl which is unsubstituted or substituted by one or more deuterium groups, or C1-C6 alkoxy which is unsubstituted or substituted by one or more deuterium groups;

[0037] Each R 4-2 are independently deuterium, halogen, hydroxyl, or C1-C6 alkyl which is unsubstituted or substituted with one or more deuterium groups;

[0038] Each R 4-3 are independently deuterium, halogen, hydroxyl, or C1-C6 alkyl which is unsubstituted or substituted with one or more deuterium groups;

[0039] Each R 4-4 are independently deuterium, halogen, hydroxyl, or C1-C6 alkyl which is unsubstituted or substituted with one or more deuterium groups;

[0040] Each R 4-5 are independently deuterium, halogen, hydroxyl, unsubstituted or replaced by one or more R 4-5-1 Substituted C1-C6 alkyl, -NR 4-5- 2 R 4-5-3 or C1-C6 alkoxy which is unsubstituted or substituted with one or more deuterium groups;

[0041] Each R 4-5-1 are independently deuterium, hydroxyl or halogen;

[0042] R 4-5-2 and R 4-5-3 are independently hydrogen or C1-C6 alkyl which is unsubstituted or substituted with one or more deuterium groups;

[0043] Each R 4-6 are independently deuterium, halogen, cyano, hydroxy, C1-C6 alkyl which is unsubstituted or substituted by one or more deuterium groups, or C1-C6 alkoxy which is unsubstituted or substituted by one or more deuterium groups;

[0044] Each R 4-7 are independently deuterium, halogen, C1-C6 alkyl which is unsubstituted or substituted by one or more deuterium groups, or C1-C6 alkoxy which is unsubstituted or substituted by one or more deuterium groups;

[0045] R 4-9 and R 4-8 are independently hydrogen, unsubstituted or replaced by one or more R 4-8-1 Substituted C1-C6 alkyl or unsubstituted or substituted by one or more deuterium-substituted 4-6 membered heterocycloalkyl; the heteroatoms in the 4-6 membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0046] Each R4-8-1 are independently deuterium, hydroxy, unsubstituted or replaced by one or more R 4-8-1-1 Substituted C1-C6 alkoxy or OR 4-8-1-2 ;

[0047] Each R 4-8-1-1 is independently deuterium or a C3-C6 cycloalkyl group which is unsubstituted or substituted with one or more deuteriums;

[0048] Each R 4-8-1-2 and independently C3-C6 cycloalkyl, which is unsubstituted or substituted with one or more deuterium groups.

[0049] In a preferred embodiment, such as in the compound of formula I, the definitions of certain groups may be as described below, and the definitions of other groups may be as described in any other embodiment (hereinafter referred to as "in a certain embodiment").

[0050] In one scenario, R 1 In the embodiment, the plurality is 2, 3, 4, 5, 6 or 7.

[0051] In one scenario, R 1 wherein the C1-C6 alkyl group is a methyl group, an ethyl group, a propyl group, an isopropyl group or an isobutyl group.

[0052] In one scenario, R 1 wherein the “unsubstituted or replaced by one or more R 1-4 wherein the C3-C6 cycloalkyl is cyclobutyl, for example,

[0053] In one scenario, R 1 In the embodiment, the heteroatom in the 3-6 membered heterocycloalkyl group is N, O or S, preferably O, and the number of heteroatoms in the 3-6 membered heterocycloalkyl group is preferably 1.

[0054] In one scenario, R 1 wherein the “unsubstituted or replaced by one or more R 1-5 substituted 3-6 membered heterocycloalkyl"; the 3-6 membered heterocycloalkyl is a 4 membered heterocycloalkyl, for example,

[0055] In one scenario, R 1-1 wherein the “unsubstituted or replaced by one or more R 1-1-1 substituted C1-C6 alkyl"; the plurality is 2.

[0056] In one scenario, R 1-1 wherein the C1-C6 alkyl group is a methyl group, an ethyl group or a propyl group.

[0057] In one scenario, R 1-1 wherein the C3-C6 cycloalkyl group is a cyclopropyl group.

[0058] In one scenario, R 1-1-1 wherein the C1-C6 alkyl group is a methyl group.

[0059] In one scenario, R 1-1-1-1 wherein the C1-C6 alkyl group is a methyl group.

[0060] In one scenario, R 1-1-2 and R 1-1-3 wherein the C1-C6 alkyl group is a methyl group.

[0061] In one scenario, R 1-3 wherein the halogen is F, Cl or Br, preferably F.

[0062] In one scenario, R 1-3 In the “C1-C6 alkyl group which is unsubstituted or substituted with one or more deuteriums”, the plurality is 2 or 3.

[0063] In one scenario, R 1-3 wherein the C1-C6 alkyl group is a methyl group or an ethyl group.

[0064] In one scenario, R 1-6 and R 1-7 wherein the C1-C6 alkyl group is a methyl group.

[0065] In one scenario, R 1-8 wherein the C1-C6 alkyl group is a methyl group.

[0066] In one scenario, R 2 and R 3 In the 5-6 membered heteroaryl group, the heteroatoms are independently selected from one or two of N, O and S, and the number of heteroatoms is 1, 2 or 3.

[0067] In one scenario, R 2 and R 3 In the 2 and R 3 The atoms to which it is attached are unsubstituted or replaced by one or more R 2-1 substituted 5-6 membered heteroaryl”; the 5-6 membered heteroaryl is a 5 membered heteroaryl, for example,

[0068] In one scenario, R 2 and R 3In the 4-6 membered heterocycloalkyl group, the heteroatoms are independently selected from one or both of N and O, and the number of heteroatoms is preferably 1 or 2.

[0069] In one scenario, R 2 and R 3 In the 2 and R 3 The atoms to which it is attached are unsubstituted or replaced by one or more R 2-2 substituted 4-6 membered heterocycloalkyl"; the 4-6 membered heterocycloalkyl is a 5-6 membered heterocycloalkyl, for example,

[0070] In one scenario, R 2 and R 3 In the 2 and R 3 The atoms to which it is attached are unsubstituted or replaced by one or more R 2-3 wherein the C4-C6 cycloalkyl group is cyclopentane.

[0071] In one scenario, R 2 and R 3 In the C6-C 10 The aryl group is phenyl.

[0072] In one scenario, R 2-1 wherein the halogen is F, Cl or Br, preferably F.

[0073] In one scenario, R 2-1 wherein the C1-C6 alkyl group is a methyl group or an ethyl group.

[0074] In one scenario, R 2-2 wherein the halogen is F, Cl or Br, preferably F.

[0075] In one scenario, R 2-2 wherein the C3-C6 cycloalkyl group is a cyclopropyl group.

[0076] In one embodiment, in A, the arylene group is a phenylene group.

[0077] In one embodiment, in A, the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or both of N and S, and the number of heteroatoms is 1, 2 or 3.

[0078] In one embodiment, in A, the 5-12 membered heteroarylene group is a 6-membered heteroarylene group, a 6-membered heteroarylene combined with a 5-membered heteroarylene group, or a 6-membered heteroarylene combined with a 6-membered heteroarylene group, for example,

[0079] In one embodiment, in A, the heteroatom in the 5-12 membered heterocycloalkylene group is independently N; the number of heteroatoms is preferably 1.

[0080] In one embodiment, in A, the 5-12 membered heterocycloalkylene group is a 6-membered heteroarylene group and a 6-membered heterocycloalkylene group, for example,

[0081] In one embodiment, in L, the C2-C6 alkenylene group is a vinyl group, for example,

[0082] In one embodiment, in Q, the C6-C 10 The arylene group is a phenylene group.

[0083] In a certain embodiment, in Q, the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or both of N and O, and the number of heteroatoms is 1, 2 or 3.

[0084] In one embodiment, in Q, the "unsubstituted or replaced by one or more R 3-1 wherein the 5-12-membered heteroarylene is a 6-membered heteroarylene, a 5-membered heteroarylene and a 6-membered heteroarylene, or a 6-membered heteroarylene and a 5-membered heteroarylene, for example,

[0085] In one embodiment, in Q, the heteroatoms in the 5-12 membered heterocycloalkylene group are independently selected from one or both of N and O, and the number of heteroatoms is 1, 2 or 3.

[0086] In one embodiment, in Q, the 5-12 membered heterocycloalkylene group is a 6-membered heteroarylene group and a 6-membered heterocycloalkylene group, for example,

[0087] In one scenario, R 3-1 wherein the halogen is F, Cl or Br, preferably F.

[0088] In one scenario, R 4 wherein the “unsubstituted or replaced by one or more R 4-1 wherein the C1-C6 alkyl group is ethyl, for example,

[0089] In one scenario, R 4 wherein the C2-C6 alkynyl group is an ethynyl group.

[0090] In one scenario, R 4 wherein the “unsubstituted or replaced by one or more R4-4 substituted C3-C6 cycloalkyl"; the plurality is two.

[0091] In one scenario, R 4 wherein the “unsubstituted or replaced by one or more R 4-4 wherein the C3-C6 cycloalkyl is cyclopropyl or cyclobutyl, for example,

[0092] In one scenario, R 4 In the 4-12 membered heterocycloalkyl group, the heteroatoms are independently selected from one or two of N, O and S, and the number of heteroatoms is preferably 1 or 2.

[0093] In one scenario, R 4 wherein said unsubstituted or replaced by one or more R 4-5 In the substituted 4-12 membered heterocycloalkyl group, the plurality is two.

[0094] In one scenario, R 4 wherein the “unsubstituted or replaced by one or more R 4-5 wherein the 4-12 membered heterocycloalkyl is a 4-7 membered heterocycloalkyl or a 7-9 membered double bridged ring, for example,

[0095] In one scenario, R 4 In the 5-12 membered heteroaryl group, the heteroatom is N, and the number of heteroatoms is preferably 1 or 2.

[0096] In one scenario, R 4 wherein the “unsubstituted or replaced by one or more R 4-6 substituted 5-12 membered heteroaryl”; the plurality is two.

[0097] In one scenario, R 4 wherein the “unsubstituted or replaced by one or more R 4-6 substituted 5-12 membered heteroaryl”; the 5-12 membered heteroaryl is a 5-membered or 6-membered heteroaryl, for example,

[0098] In one scenario, R 4 In the embodiment, the C1-C6 alkoxy group is an ethoxy group, for example,

[0099] In one scenario, R 4-1 wherein the C1-C6 alkoxy group is a methoxy group.

[0100] In one scenario, R 4-4 wherein the halogen is F, Cl or Br, preferably F.

[0101] In one scenario, R 4-5 wherein the C1-C6 alkyl group is a methyl group.

[0102] In one scenario, R 4-5 wherein the C1-C6 alkoxy group is a methoxy group.

[0103] In one scenario, R 4-5-2 and R 4-5-3 wherein the C1-C6 alkyl group is a methyl group.

[0104] In one scenario, R 4-6 wherein the halogen is F, Cl or Br, preferably F.

[0105] In one scenario, R 4-6 wherein the C1-C6 alkyl group is a methyl group.

[0106] In one scenario, R 4-9 and R 4-8 The C1-C6 alkyl group is a methyl group or an ethyl group.

[0107] In one scenario, R 4-9 and R 4-8 In the 4-6 membered heterocycloalkyl group, the heteroatom is O, and the number of heteroatoms is preferably 1.

[0108] In one scenario, R 4-9 and R 4-8 wherein the 4-6 membered heterocycloalkyl group is a 5-membered or 6-membered heterocycloalkyl group.

[0109] In one scenario, R 4-8-1-2 wherein the C3-C6 cycloalkyl group is a cyclopropyl group.

[0110] In one embodiment, Y is C or N; preferably C.

[0111] In one scenario, R 1 for By one or more R 1-3 Substituted C1-C6 alkyl, unsubstituted or substituted by one or more R 1-4 Substituted C3-C6 cycloalkyl or unsubstituted or substituted by one or more R 1-5 Substituted 3-6 membered heterocycloalkyl; the heteroatoms in the 3-6 membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably By one or more R1-3 Substituted C1-C6 alkyl or unsubstituted or substituted by one or more R 1-4 Substituted C3-C6 cycloalkyl; further preferably or by one or more R 1-3 Substituted C1-C6 alkyl; further preferably

[0112] In one scenario, R 1-1 is unsubstituted or substituted with one or more R 1-1-1 Substituted C1-C6 alkyl, unsubstituted C3-C6 cycloalkyl or -NR 1-1-2 R 1-1-3 ; preferably unsubstituted or substituted with one or more R 1-1-1 Substituted C1-C6 alkyl or -NR 1-1-2 R 1-1-3 ; Further preferably, it is unsubstituted or substituted with one or more R 1-1-1 Substituted C1-C6 alkyl; more preferably unsubstituted C1-C6 alkyl.

[0113] In one scenario, R 1-2 O or NR 1-2-1 ; Preferably O.

[0114] In one scenario, R 1-2-1 For hydrogen.

[0115] In a certain scheme, each R 1-1-1 Independently OR 1-1-1-1 , unsubstituted C1-C6 alkyl or unsubstituted C1-C6 alkoxy; preferably OR 1-1-1-1 or an unsubstituted C1-C6 alkyl group; further preferably an unsubstituted C1-C6 alkyl group.

[0116] In one scenario, R 1-1-1-1 It is hydrogen or unsubstituted C1-C6 alkyl; preferably it is unsubstituted C1-C6 alkyl.

[0117] In one scenario, R 1-1-2 and R 1-1-3 are independently hydrogen or unsubstituted C1-C6 alkyl.

[0118] In a certain scheme, each R 1-3 It is independently hydroxy, cyano, halogen, amino, unsubstituted C1-C6 alkyl or deuterium; preferably hydroxy, cyano, halogen, unsubstituted C1-C6 alkyl or deuterium; further preferably hydroxy, cyano, halogen or unsubstituted C1-C6 alkyl; further preferably hydroxy or halogen.

[0119] In a certain scheme, each R 1-3 are independently hydroxy, halogen, unsubstituted C1-C6 alkyl or deuterium; preferably hydroxy, halogen or unsubstituted C1-C6 alkyl.

[0120] In one scheme, each R 1-4 and R 1-5 are independently hydroxyl.

[0121] In one embodiment, X is -CR 1-6 R 1-7 -or-NR 1-8 -; preferably -CR 1-6 R 1-7 -.

[0122] In one scenario, R 1-6 and R 1-7 are independently hydrogen or unsubstituted C1-C6 alkyl; preferably hydrogen.

[0123] In one scenario, R 1-8 It is an unsubstituted C1-C6 alkyl group.

[0124] In one scenario, R 2 and R 3 The atoms to which it is attached are unsubstituted or replaced by one or more R 2-1 substituted 5-6 membered heteroaryl, unsubstituted or substituted by one or more R 2-2 substituted 4-6 membered heterocycloalkyl, unsubstituted or substituted by one or more R 2-3 Substituted C4-C6 cycloalkyl or unsubstituted C6-C 10 Preferably, it is unsubstituted or substituted with one or more R 2-1 substituted 5-6 membered heteroaryl, unsubstituted or substituted by one or more R 2-2 Substituted 4-6 membered heterocycloalkyl or unsubstituted or substituted by one or more R 2-3 Substituted C4-C6 cycloalkyl; further preferably unsubstituted or substituted by one or more R 2-1 substituted 5-6 membered heteroaryl, unsubstituted or substituted by one or more R 2-2 Substituted 4-6 membered heterocycloalkyl or unsubstituted C4-C6 cycloalkyl; further preferably unsubstituted or substituted by one or more R 2-1a substituted 5-6 membered heteroaryl, an unsubstituted 4-6 membered heterocycloalkyl or an unsubstituted C4-C6 cycloalkyl; further preferably, an unsubstituted 4-6 membered heterocycloalkyl or an unsubstituted C4-C6 cycloalkyl; the heteroatoms in the 5-6 membered heteroaryl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 4-6 membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3.

[0125] In a certain scheme, each R 2-1 are independently halogen, unsubstituted or substituted with one or more R 2-1-1 Substituted C1-C6 alkyl or oxo (=O); preferably halogen or unsubstituted C1-C6 alkyl; further preferably unsubstituted C1-C6 alkyl.

[0126] In a certain scheme, each R 2-2 are independently halogen, unsubstituted C1-C6 alkyl, oxo (=O), or two R 2- 2 and the carbon atom connected thereto form a C3-C6 cycloalkyl group; preferably an oxo group (=O), or two R 2-2 Together with the carbon atom to which it is connected, it forms a C3-C6 cycloalkyl group; further preferably, it is an oxo group (=O).

[0127] In a certain scheme, each R 2-2 It is independently halogen, unsubstituted C1-C6 alkyl or oxo (=O); preferably halogen.

[0128] In a certain scheme, each R 2-3 are independently oxo (=O).

[0129] In one scenario, R 2-1-1 It is a hydroxyl group.

[0130] In one embodiment, A is an unsubstituted C6-C 10 arylene, unsubstituted 5-12 membered heterocycloalkylene or unsubstituted 5-12 membered heteroarylene; preferably unsubstituted 5-12 membered heteroarylene; the heteroatoms in the 5-12 membered heterocycloalkylene are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heteroarylene are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3.

[0131] In one embodiment, L is a linker or an unsubstituted C2-C6 alkenylene; preferably, L is a linker.

[0132] In one embodiment, Q is an unsubstituted C6-C 10 arylene, unsubstituted or replaced by one or more R 3-1 Substituted 5-12 membered heteroaryl or unsubstituted 5-12 membered heterocycloalkyl; preferably unsubstituted or substituted by one or more R 3-1 a substituted 5-12 membered heteroarylene group or an unsubstituted 5-12 membered heterocycloalkylene group; further preferably an unsubstituted 5-12 membered heteroarylene group or an unsubstituted 5-12 membered heterocycloalkylene group; the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heterocycloalkylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3.

[0133] In one scheme, each R 3-1 are independently halogen.

[0134] In one scenario, R 4 is unsubstituted or replaced by one or more R 4-1 Substituted C1-C6 alkyl, unsubstituted C2-C6 alkynyl, unsubstituted or substituted with one or more R 4-4 Substituted C3-C6 cycloalkyl, unsubstituted or replaced by one or more R 4-5 substituted 4-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 4-6 Substituted 5-12 membered heteroaryl, unsubstituted C1-C6 alkoxy or -NR 4-9 R 4-8 ; preferably by one or more R 4-1 Substituted C1-C6 alkyl, unsubstituted C2-C6 alkynyl, unsubstituted C3-C6 cycloalkyl, unsubstituted or replaced by one or more R 4-5 substituted 4-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 4-6 substituted 5-12 membered heteroaryl or unsubstituted C1-C6 alkoxy; further preferably unsubstituted C2-C6 alkynyl, unsubstituted C3-C6 cycloalkyl, substituted by one or more R 4-5 substituted 4-12 membered heterocycloalkyl, substituted by one or more R 4-6 substituted 5-12 membered heteroaryl or unsubstituted C1-C6 alkoxy; further preferably unsubstituted C2-C6 alkynyl, unsubstituted C3-C6 cycloalkyl or substituted by one or more R 4-6substituted 5-12 membered heteroaryl; the heteroatoms in the 4-12 membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heteroaryl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3.

[0135] In a certain scheme, each R 4-1 and independently unsubstituted C1-C6 alkoxy.

[0136] In a certain scheme, each R 4-4 are independently halogen.

[0137] In a certain scheme, each R 4-5 are independently hydroxy, unsubstituted or substituted with one or more R 4-5-1 Substituted C1-C6 alkyl, -NR 4-5-2 R 4-5-3 or unsubstituted C1-C6 alkoxy; preferably unsubstituted or substituted by one or more R 4-5-1 a substituted C1-C6 alkyl group or an unsubstituted C1-C6 alkoxy group; more preferably an unsubstituted C1-C6 alkoxy group.

[0138] In a certain scheme, each R 4-5-1 are independently hydroxyl.

[0139] In one scenario, R 4-5-2 and R 4-5-3 are independently unsubstituted C1-C6 alkyl.

[0140] In a certain scheme, each R 4-6 are independently cyano, halogen or unsubstituted C1-C6 alkyl; preferably cyano or unsubstituted C1-C6 alkyl.

[0141] In one scenario, R 4-9 and R 4-8 are independently unsubstituted or substituted with one or more R 4-8-1 a substituted C1-C6 alkyl group or an unsubstituted 4-6 membered heterocycloalkyl group; the heteroatoms in the 4-6 membered heterocycloalkyl group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3.

[0142] In a certain scheme, each R 4-8-1 Independently OR 4-8-1-2 .

[0143] In a certain scheme, each R 4-8-1-2 and independently unsubstituted C3-C6 cycloalkyl.

[0144] In one plan,

[0145] Y is C or N;

[0146] R 1 for By one or more R 1-3 Substituted C1-C6 alkyl, unsubstituted or substituted by one or more R 1-4 Substituted C3-C6 cycloalkyl or unsubstituted or substituted by one or more R 1-5 A substituted 3-6 membered heterocycloalkyl group, wherein the heteroatoms in the 3-6 membered heterocycloalkyl group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0147] R 1-1 is unsubstituted or substituted with one or more R 1-1-1 Substituted C1-C6 alkyl, unsubstituted C3-C6 cycloalkyl or -NR 1-1-2 R 1-1- 3 ;

[0148] R 1-2 O or NR 1-2-1 ; R 1-2-1 is hydrogen;

[0149] Each R 1-1-1 Independently OR 1-1-1-1 , unsubstituted C1-C6 alkyl or unsubstituted C1-C6 alkoxy;

[0150] R 1-1-1-1 is hydrogen or unsubstituted C1-C6 alkyl;

[0151] R 1-1-2 and R 1-1-3 are independently hydrogen or unsubstituted C1-C6 alkyl;

[0152] Each R 1-3 are independently hydroxy, cyano, halogen, amino, unsubstituted C1-C6 alkyl or deuterium;

[0153] Each R 1-4 and R 1-5 are independently hydroxyl groups;

[0154] X is -CR 1-6 R 1-7 -or-NR 1-8 -;

[0155] R 1-6 and R 1-7 are independently hydrogen or unsubstituted C1-C6 alkyl;

[0156] R1-8 is an unsubstituted C1-C6 alkyl group;

[0157] R 2 and R 3 The atoms to which it is attached are unsubstituted or replaced by one or more R 2-1 substituted 5-6 membered heteroaryl, unsubstituted or substituted by one or more R 2-2 substituted 4-6 membered heterocycloalkyl, unsubstituted or substituted by one or more R 2-3 Substituted C4-C6 cycloalkyl or unsubstituted C6-C 10 The heteroatoms in the 5-6 membered heteroaryl group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 4-6 membered heterocycloalkyl group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0158] Each R 2-1 are independently halogen, unsubstituted or substituted with one or more R 2-1-1 Substituted C1-C6 alkyl or oxo (=O);

[0159] Each R 2-2 are independently halogen, unsubstituted C1-C6 alkyl, oxo (=O), or two R 2-2 Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl group;

[0160] Each R 2-3 are independently oxo (=O);

[0161] R 2-1-1 is hydroxyl group;

[0162] A is unsubstituted C6-C 10 arylene, unsubstituted 5-12 membered heterocycloalkylene or unsubstituted 5-12 membered heteroarylene; the heteroatoms in the 5-12 membered heterocycloalkylene are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heteroarylene are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0163] L is a linker or unsubstituted C2-C6 alkenylene;

[0164] Q is an unsubstituted C6-C 10 arylene, unsubstituted or replaced by one or more R 3-1a substituted 5-12 membered heteroarylene group or an unsubstituted 5-12 membered heterocycloalkylene group; the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heterocycloalkylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0165] Each R 3-1 are independently halogen;

[0166] R 4 is unsubstituted or replaced by one or more R 4-1 Substituted C1-C6 alkyl, unsubstituted C2-C6 alkynyl, unsubstituted or substituted with one or more R 4-4 Substituted C3-C6 cycloalkyl, unsubstituted or replaced by one or more R 4-5 substituted 4-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 4-6 Substituted 5-12 membered heteroaryl, unsubstituted C1-C6 alkoxy or -NR 4-9 R 4-8 The heteroatoms in the 4-12 membered heterocycloalkyl group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heteroaryl group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0167] Each R 4-1 are independently unsubstituted C1-C6 alkoxy;

[0168] Each R 4-4 are independently halogen;

[0169] Each R 4-5 are independently hydroxy, unsubstituted or substituted with one or more R 4-5-1 Substituted C1-C6 alkyl, -NR 4-5-2 R 4-5-3 or unsubstituted C1-C6 alkoxy;

[0170] Each R 4-5-1 are independently hydroxyl groups;

[0171] R 4-5-2 and R 4-5-3 are independently unsubstituted C1-C6 alkyl;

[0172] Each R 4-6 are independently cyano, halogen or unsubstituted C1-C6 alkyl; preferably cyano or unsubstituted C1-C6 alkyl;

[0173] R4-9 and R 4-8 are independently unsubstituted or substituted with one or more R 4-8-1 Substituted C1-C6 alkyl or unsubstituted 4-6 membered heterocycloalkyl; the heteroatoms in the 4-6 membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0174] Each R 4-8-1 Independently OR 4-8-1-2 ;

[0175] Each R 4-8-1-2 and independently unsubstituted C3-C6 cycloalkyl.

[0176] In one plan,

[0177] Y is C or N;

[0178] R 1 for By one or more R 1-3 Substituted C1-C6 alkyl or unsubstituted or substituted by one or more R 1-4 Substituted C3-C6 cycloalkyl;

[0179] R 1-1 is unsubstituted or substituted with one or more R 1-1-1 Substituted C1-C6 alkyl or -NR 1-1-2 R 1-1-3 ;

[0180] R 1-2 O or NR 1-2-1 ; R 1-2-1 is hydrogen;

[0181] Each R 1-1-1 Independently OR 1-1-1-1 or unsubstituted C1-C6 alkyl;

[0182] R 1-1-1-1 is hydrogen or unsubstituted C1-C6 alkyl;

[0183] R 1-1-2 and R 1-1-3 are independently hydrogen or unsubstituted C1-C6 alkyl;

[0184] Each R 1-3 are independently hydroxy, cyano, halogen, unsubstituted C1-C6 alkyl or deuterium;

[0185] Each R 1-4 is hydroxyl group;

[0186] X is -CR 1-6 R 1-7-or-NR 1-8 -;

[0187] R 1-6 and R 1-7 are independently hydrogen or unsubstituted C1-C6 alkyl;

[0188] R 1-8 is an unsubstituted C1-C6 alkyl group;

[0189] R 2 and R 3 The atoms to which it is attached are unsubstituted or replaced by one or more R 2-1 substituted 5-6 membered heteroaryl, unsubstituted or substituted by one or more R 2-2 Substituted 4-6 membered heterocycloalkyl or unsubstituted or substituted by one or more R 2-3 substituted C4-C6 cycloalkyl; the heteroatoms in the 5-6 membered heteroaryl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 4-6 membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatoms in the 4-6 membered heterocycloalkyl are N or O, and the number of heteroatoms is 1 or 2;

[0190] Each R 2-1 are independently halogen or unsubstituted C1-C6 alkyl;

[0191] Each R 2-2 are independently halogen, unsubstituted C1-C6 alkyl, oxo (=O), or two R 2-2 Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl group;

[0192] Each R 2-3 are independently oxo (=O);

[0193] A is an unsubstituted 5-12 membered heteroarylene group, wherein the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or both of N and S, and the number of heteroatoms is 1, 2 or 3;

[0194] L is a linker or unsubstituted C2-C6 alkenylene;

[0195] Q is unsubstituted or replaced by one or more R 3-1a substituted 5-12 membered heteroarylene group or an unsubstituted 5-12 membered heterocycloalkylene group; the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heterocycloalkylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatom in the 5-12 membered heteroarylene group is N, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heterocycloalkylene group are independently selected from one or both of N and O, and the number of heteroatoms is 1, 2 or 3;

[0196] Each R 3-1 are independently halogen;

[0197] R 4 For one or more R 4-1 Substituted C1-C6 alkyl, unsubstituted C2-C6 alkynyl, unsubstituted C3-C6 cycloalkyl, unsubstituted or replaced by one or more R 4-5 substituted 4-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 4-6 substituted 5-12 membered heteroaryl or unsubstituted C1-C6 alkoxy; the heteroatoms in the 4-12 membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heteroaryl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, R 4 For one or more R 4-1 Substituted C1-C6 alkyl, unsubstituted C2-C6 alkynyl, unsubstituted C3-C6 cycloalkyl, unsubstituted or replaced by one or more R 4-5 substituted 4-6 membered heterocycloalkyl, unsubstituted or replaced by one or more R 4-6 a substituted 5-6 membered heteroaryl or an unsubstituted C1-C6 alkoxy group; the heteroatoms in the 4-6 membered heterocycloalkyl group are independently selected from one or both of N and O, and the number of heteroatoms is 1 or 2; the heteroatom in the 5-6 membered heteroaryl group is N, and the number of heteroatoms is 1 or 2;

[0198] R 4-1 are independently unsubstituted C1-C6 alkoxy;

[0199] Each R 4-5 are independently unsubstituted or substituted with one or more R 4-5-1 Substituted C1-C6 alkyl or unsubstituted C1-C6 alkoxy;

[0200] Each R 4-5-1 are independently hydroxyl groups;

[0201] Each R 4-6 are independently cyano, halogen or unsubstituted C1-C6 alkyl.

[0202] In one plan,

[0203] Y is C or N;

[0204] R 1 for By one or more R 1-3 Substituted C1-C6 alkyl or unsubstituted or substituted by one or more R 1-4 Substituted C3-C6 cycloalkyl;

[0205] R 1-1 is unsubstituted or substituted with one or more R 1-1-1 Substituted C1-C6 alkyl or -NR 1-1-2 R 1-1-3 ;

[0206] R 1-2 O or NR 1-2-1 ; R 1-2-1 is hydrogen;

[0207] Each R 1-1-1 Independently OR 1-1-1-1 or unsubstituted C1-C6 alkyl;

[0208] R 1-1-1-1 is an unsubstituted C1-C6 alkyl group;

[0209] R 1-1-2 and R 1-1-3 are independently hydrogen or unsubstituted C1-C6 alkyl;

[0210] Each R 1-3 are independently hydroxy, cyano, halogen or unsubstituted C1-C6 alkyl;

[0211] Each R 1-4 is hydroxyl group;

[0212] X is -CR 1-6 R 1-7 -or-NR 1-8 -;

[0213] R 1-6 and R 1-7 are independently hydrogen or unsubstituted C1-C6 alkyl;

[0214] R 1-8 is an unsubstituted C1-C6 alkyl group;

[0215] R 2 and R 3The atoms to which it is attached are unsubstituted or replaced by one or more R 2-1 substituted 5-6 membered heteroaryl, unsubstituted or substituted by one or more R 2-2 Substituted 4-6 membered heterocycloalkyl or unsubstituted or substituted by one or more R 2-3 substituted C4-C6 cycloalkyl; the heteroatoms in the 5-6 membered heteroaryl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 4-6 membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatoms in the 4-6 membered heterocycloalkyl are N or O, and the number of heteroatoms is 1 or 2;

[0216] Each R 2-1 are independently unsubstituted C1-C6 alkyl;

[0217] Each R 2-2 are independently halogen, unsubstituted C1-C6 alkyl, oxo (=O), or two R 2-2 Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl group;

[0218] Each R 2-3 are independently oxo (=O);

[0219] A is an unsubstituted 5-12 membered heteroarylene group, wherein the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or both of N and S, and the number of heteroatoms is 1, 2 or 3;

[0220] L is a linker or unsubstituted C2-C6 alkenylene;

[0221] Q is unsubstituted or replaced by one or more R 3-1 a substituted 5-12 membered heteroarylene group or an unsubstituted 5-12 membered heterocycloalkylene group; the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heterocycloalkylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatom in the 5-12 membered heteroarylene group is N, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heterocycloalkylene group are independently selected from one or both of N and O, and the number of heteroatoms is 1, 2 or 3;

[0222] Each R 3-1 are independently halogen;

[0223] R 4 For one or more R 4-1 Substituted C1-C6 alkyl, unsubstituted C2-C6 alkynyl, unsubstituted C3-C6 cycloalkyl, unsubstituted or replaced by one or more R 4-5 substituted 4-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 4-6 substituted 5-12 membered heteroaryl or unsubstituted C1-C6 alkoxy; the heteroatoms in the 4-12 membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heteroaryl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, R 4 For one or more R 4-1 Substituted C1-C6 alkyl, unsubstituted C2-C6 alkynyl, unsubstituted C3-C6 cycloalkyl, unsubstituted or replaced by one or more R 4-5 substituted 4-6 membered heterocycloalkyl, unsubstituted or replaced by one or more R 4-6 a substituted 5-6 membered heteroaryl or an unsubstituted C1-C6 alkoxy group; the heteroatoms in the 4-6 membered heterocycloalkyl group are independently selected from one or both of N and O, and the number of heteroatoms is 1 or 2; the heteroatom in the 5-6 membered heteroaryl group is N, and the number of heteroatoms is 1 or 2;

[0224] R 4-1 are independently unsubstituted C1-C6 alkoxy;

[0225] Each R 4-5 are independently unsubstituted or substituted with one or more R 4-5-1 Substituted C1-C6 alkyl or unsubstituted C1-C6 alkoxy;

[0226] Each R 4-5-1 are independently hydroxyl groups;

[0227] Each R 4-6 are independently cyano, halogen or unsubstituted C1-C6 alkyl.

[0228] In one plan,

[0229] Y is C or N;

[0230] R 1 for By one or more R 1-3 Substituted C1-C6 alkyl or unsubstituted or substituted by one or more R 1-4 Substituted C3-C6 cycloalkyl;

[0231] R1-1 is unsubstituted or substituted with one or more R 1-1-1 Substituted C1-C6 alkyl or -NR 1-1-2 R 1-1-3 ;

[0232] R 1-2 O or NR 1-2-1 ; R 1-2-1 is hydrogen;

[0233] Each R 1-1-1 Independently OR 1-1-1-1 or unsubstituted C1-C6 alkyl;

[0234] R 1-1-1-1 is an unsubstituted C1-C6 alkyl group;

[0235] R 1-1-2 and R 1-1-3 are independently hydrogen or unsubstituted C1-C6 alkyl;

[0236] Each R 1-3 are independently hydroxy, cyano, halogen or unsubstituted C1-C6 alkyl;

[0237] Each R 1-4 is hydroxyl group;

[0238] X is -CR 1-6 R 1-7 -or-NR 1-8 -;

[0239] R 1-6 and R 1-7 are independently hydrogen or unsubstituted C1-C6 alkyl;

[0240] R 1-8 is an unsubstituted C1-C6 alkyl group;

[0241] R 2 and R 3 The atoms to which it is attached are unsubstituted or replaced by one or more R 2-1 substituted 5-6 membered heteroaryl, unsubstituted or substituted by one or more R 2-2 Substituted 4-6 membered heterocycloalkyl or unsubstituted or substituted by one or more R 2-3 substituted C4-C6 cycloalkyl; the heteroatoms in the 5-6 membered heteroaryl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 4-6 membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatoms in the 4-6 membered heterocycloalkyl are N or O, and the number of heteroatoms is 1 or 2;

[0242] Each R 2-1 are independently unsubstituted C1-C6 alkyl;

[0243] Each R 2-2 are independently halogen, unsubstituted C1-C6 alkyl, oxo (=O), or two R 2-2 Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl group;

[0244] Each R 2-3 are independently oxo (=O);

[0245] A is an unsubstituted 5-12 membered heteroarylene group, wherein the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or both of N and S, and the number of heteroatoms is 1, 2 or 3;

[0246] L is a linker or unsubstituted C2-C6 alkenylene;

[0247] Q is unsubstituted or replaced by one or more R 3-1 a substituted 5-12 membered heteroarylene group or an unsubstituted 5-12 membered heterocycloalkylene group; the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heterocycloalkylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatom in the 5-12 membered heteroarylene group is N, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heterocycloalkylene group are independently selected from one or both of N and O, and the number of heteroatoms is 1, 2 or 3;

[0248] Each R 3-1 are independently halogen;

[0249] R 4 For one or more R 4-1 Substituted C1-C6 alkyl, unsubstituted C2-C6 alkynyl, unsubstituted C3-C6 cycloalkyl, unsubstituted or replaced by one or more R 4-5 substituted 4-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 4-6substituted 5-12 membered heteroaryl or unsubstituted C1-C6 alkoxy; the heteroatoms in the 4-12 membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heteroaryl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, R 4 For one or more R 4-1 Substituted C1-C6 alkyl, unsubstituted C2-C6 alkynyl, unsubstituted C3-C6 cycloalkyl, unsubstituted or replaced by one or more R 4-5 substituted 4-6 membered heterocycloalkyl, unsubstituted or replaced by one or more R 4-6 a substituted 5-6 membered heteroaryl or an unsubstituted C1-C6 alkoxy group; the heteroatoms in the 4-6 membered heterocycloalkyl group are independently selected from one or both of N and O, and the number of heteroatoms is 1 or 2; the heteroatom in the 5-6 membered heteroaryl group is N, and the number of heteroatoms is 1 or 2;

[0250] R 4-1 are independently unsubstituted C1-C6 alkoxy;

[0251] Each R 4-5 are independently unsubstituted or substituted with one or more R 4-5-1 Substituted C1-C6 alkyl or unsubstituted C1-C6 alkoxy;

[0252] Each R 4-5-1 are independently hydroxyl groups;

[0253] Each R 4-6 are independently cyano or unsubstituted C1-C6 alkyl.

[0254] In one plan,

[0255] Y is C;

[0256] R 1 for By one or more R 1-3 Substituted C1-C6 alkyl or unsubstituted or substituted by one or more R 1-4 Substituted C3-C6 cycloalkyl;

[0257] R 1-1 is unsubstituted or substituted with one or more R 1-1-1 Substituted C1-C6 alkyl or -NR 1-1-2 R 1-1-3 ;

[0258] R 1-2 O or NR 1-2-1 ; R 1-2-1 is hydrogen;

[0259] Each R 1-1-1 are independently unsubstituted C1-C6 alkyl;

[0260] R 1-1-2 and R 1-1-3 are independently hydrogen or unsubstituted C1-C6 alkyl;

[0261] Each R 1-3 are independently hydroxy or halogen;

[0262] Each R 1-4 is hydroxyl group;

[0263] X is -CR 1-6 R 1-7 -or-NR 1-8 -;

[0264] R 1-6 and R 1-7 are independently hydrogen or unsubstituted C1-C6 alkyl;

[0265] R 1-8 is an unsubstituted C1-C6 alkyl group;

[0266] R 2 and R 3 The atoms to which it is attached are unsubstituted or replaced by one or more R 2-1 substituted 5-6 membered heteroaryl, unsubstituted or substituted by one or more R 2-2 a substituted 4-6 membered heterocycloalkyl or an unsubstituted C4-C6 cycloalkyl; the heteroatoms in the 5-6 membered heteroaryl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 4-6 membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatoms in the 5-6 membered heteroaryl are independently selected from one or both of N and S, and the number of heteroatoms is 1 or 2; the heteroatoms in the 4-6 membered heterocycloalkyl are N or O, and the number of heteroatoms is 1 or 2;

[0267] Each R 2-1 are independently unsubstituted C1-C6 alkyl;

[0268] Each R 2-2 are independently oxo (=O), or two R 2-2 and the carbon atom to which it is attached to form a C3-C6 cycloalkyl group;

[0269] A is an unsubstituted 5-12 membered heteroarylene group; the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or both of N and S, and the number of heteroatoms is 1, 2 or 3;

[0270] L is a linker or unsubstituted C2-C6 alkenylene;

[0271] Q is an unsubstituted 5-12 membered heteroarylene group or an unsubstituted 5-12 membered heterocycloalkylene group; the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heterocycloalkylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0272] R 4 is an unsubstituted C2-C6 alkynyl, an unsubstituted C3-C6 cycloalkyl, or one or more R 4-5 substituted 4-12 membered heterocycloalkyl, substituted by one or more R 4-6 substituted 5-12 membered heteroaryl or unsubstituted C1-C6 alkoxy; the heteroatoms in the 4-12 membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heteroaryl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, R 4 is an unsubstituted C2-C6 alkynyl, an unsubstituted C3-C6 cycloalkyl, or one or more R 4-5 substituted 4-6 membered heterocycloalkyl, one or more R 4-6 a substituted 5-6 membered heteroaryl or an unsubstituted C1-C6 alkoxy group; the heteroatoms in the 4-6 membered heterocycloalkyl group are independently selected from one or both of N and O, and the number of heteroatoms is 1 or 2; the heteroatom in the 5-6 membered heteroaryl group is N, and the number of heteroatoms is 1;

[0273] Each R 4-5 are independently unsubstituted C1-C6 alkyl;

[0274] Each R 4-6 are independently cyano or unsubstituted C1-C6 alkyl.

[0275] In one plan,

[0276] Y is C;

[0277] R 1 for By one or more R 1-3 Substituted C1-C6 alkyl or unsubstituted or substituted by one or more R 1-4 Substituted C3-C6 cycloalkyl;

[0278] R 1-1 is unsubstituted or substituted with one or more R 1-1-1 Substituted C1-C6 alkyl;

[0279] R 1-2 is O;

[0280] Each R 1-1-1 are independently unsubstituted C1-C6 alkyl;

[0281] Each R 1-3 are independently halogen;

[0282] Each R 1-4 is hydroxyl group;

[0283] X is -CR 1-6 R 1-7 -or-NR 1-8 -;

[0284] R 1-6 and R 1-7 are independently hydrogen;

[0285] R 1-8 is an unsubstituted C1-C6 alkyl group;

[0286] R 2 and R 3 The atoms to which it is attached are unsubstituted or replaced by one or more R 2-1 substituted 5-6 membered heteroaryl, unsubstituted or substituted by one or more R 2-2 a substituted 4-6 membered heterocycloalkyl or an unsubstituted C4-C6 cycloalkyl; the heteroatoms in the 5-6 membered heteroaryl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 4-6 membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatom in the 5-6 membered heteroaryl is N, and the number of heteroatoms is 1 or 2; the heteroatom in the 4-6 membered heterocycloalkyl is N or O, and the number of heteroatoms is 1 or 2;

[0287] Each R 2-1 are independently unsubstituted C1-C6 alkyl;

[0288] Each R 2-2 are independently oxo (=O);

[0289] A is an unsubstituted 5-12 membered heteroarylene group; the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or both of N and S, and the number of heteroatoms is 1, 2 or 3;

[0290] L is a linker or unsubstituted C2-C6 alkenylene;

[0291] Q is an unsubstituted 5-12 membered heteroarylene group or an unsubstituted 5-12 membered heterocycloalkylene group; the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heterocycloalkylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, Q is an unsubstituted 5-6 membered heteroarylene group or an unsubstituted 5-12 membered heterocycloalkylene group; the heteroatom in the 5-6 membered heteroarylene group is N, and the number of heteroatoms is 1; the heteroatoms in the 5-12 membered heterocycloalkylene group are independently selected from one or both of N and O, and the number of heteroatoms is 1, 2 or 3;

[0292] R 4 is an unsubstituted C2-C6 alkynyl, an unsubstituted C3-C6 cycloalkyl, or one or more R 4-5 substituted 4-12 membered heterocycloalkyl, substituted by one or more R 4-6 substituted 5-12 membered heteroaryl or unsubstituted C1-C6 alkoxy; the heteroatoms in the 4-12 membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heteroaryl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, R 4 is an unsubstituted C2-C6 alkynyl, an unsubstituted C3-C6 cycloalkyl, or one or more R 4-5 substituted 4-6 membered heterocycloalkyl, one or more R 4-6 a substituted 5-6 membered heteroaryl or an unsubstituted C1-C6 alkoxy group; the heteroatoms in the 4-6 membered heterocycloalkyl group are independently selected from one or both of N and O, and the number of heteroatoms is 1 or 2; the heteroatom in the 5-6 membered heteroaryl group is N, and the number of heteroatoms is 1;

[0293] Each R 4-5 are independently unsubstituted C1-C6 alkyl;

[0294] Each R 4-6 are independently cyano or unsubstituted C1-C6 alkyl.

[0295] In one plan,

[0296] Y is C;

[0297] R 1 for or unsubstituted or substituted by one or more R 1-3 Substituted C1-C6 alkyl;

[0298] R 1-1 is unsubstituted or substituted with one or more R 1-1-1 Substituted C1-C6 alkyl;

[0299] R 1-2 is O;

[0300] Each R 1-1-1 Independently OR 1-1-1-1 ;

[0301] R 1-1-1-1 is hydrogen or unsubstituted C1-C6 alkyl;

[0302] Each R 1-3 are independently hydroxy, halogen, unsubstituted C1-C6 alkyl or deuterium;

[0303] X is -CR 1-6 R 1-7 -;

[0304] R 1-6 and R 1-7 are independently hydrogen;

[0305] R 2 and R 3 The atoms to which it is attached are unsubstituted or replaced by one or more R 2-1 substituted 5-6 membered heteroaryl, unsubstituted or substituted by one or more R 2-2 a substituted 4-6 membered heterocycloalkyl or an unsubstituted C4-C6 cycloalkyl; the heteroatoms in the 5-6 membered heteroaryl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 4-6 membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatom in the 4-6 membered heterocycloalkyl is O; the number of heteroatoms is 1 or 2;

[0306] Each R 2-1 are independently halogen or unsubstituted C1-C6 alkyl;

[0307] Each R 2-2 are independently halogen, unsubstituted C1-C6 alkyl or oxo (=O);

[0308] A is an unsubstituted 5-12 membered heteroarylene group; the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatom in the 5-12 membered heteroarylene group is N, and the number of heteroatoms is 1 or 2;

[0309] L is a linker or unsubstituted C2-C6 alkenylene;

[0310] Q is an unsubstituted 5-12 membered heteroarylene group or an unsubstituted 5-12 membered heterocycloalkylene group; the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heterocycloalkylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, Q is an unsubstituted 5-6 membered heteroarylene group or an unsubstituted 5-12 membered heterocycloalkylene group; the heteroatom in the 5-6 membered heteroarylene group is N, and the number of heteroatoms is 1; the heteroatoms in the 5-12 membered heterocycloalkylene group are independently selected from one or both of N and O, and the number of heteroatoms is 1, 2 or 3;

[0311] Each R 3-1 are independently halogen;

[0312] R 4 is an unsubstituted C2-C6 alkynyl, an unsubstituted C3-C6 cycloalkyl, or one or more R 4-5 substituted 4-12 membered heterocycloalkyl, substituted by one or more R 4-6 substituted 5-12 membered heteroaryl or unsubstituted C1-C6 alkoxy; the heteroatoms in the 4-12 membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heteroaryl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, R 4 is an unsubstituted C2-C6 alkynyl, an unsubstituted C3-C6 cycloalkyl, or one or more R 4-5 substituted 4-6 membered heterocycloalkyl, one or more R 4-6 a substituted 5-6 membered heteroaryl or an unsubstituted C1-C6 alkoxy group; the heteroatoms in the 4-6 membered heterocycloalkyl group are independently selected from one or both of N and O, and the number of heteroatoms is 1 or 2; the heteroatom in the 5-6 membered heteroaryl group is N, and the number of heteroatoms is 1;

[0313] Each R 4-5 are independently unsubstituted C1-C6 alkyl;

[0314] Each R 4-6 are independently cyano, halogen or unsubstituted C1-C6 alkyl.

[0315] In one plan,

[0316] Y is C;

[0317] R 1 for or by one or more R 1-3 Substituted C1-C6 alkyl;

[0318] R 1-1 is unsubstituted or substituted with one or more R 1-1-1 Substituted C1-C6 alkyl;

[0319] R 1-2 is O;

[0320] Each R 1-1-1 Independently OR 1-1-1-1 ;

[0321] R 1-1-1-1 is hydrogen or unsubstituted C1-C6 alkyl;

[0322] Each R 1-3 are independently hydroxy, halogen, unsubstituted C1-C6 alkyl or deuterium;

[0323] X is -CR 1-6 R 1-7 -;

[0324] R 1-6 and R 1-7 are independently hydrogen;

[0325] R 2 and R 3 The atoms to which it is attached are unsubstituted or replaced by one or more R 2-1 substituted 5-6 membered heteroaryl, unsubstituted or substituted by one or more R 2-2 a substituted 4-6 membered heterocycloalkyl or an unsubstituted C4-C6 cycloalkyl; the heteroatoms in the 5-6 membered heteroaryl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 4-6 membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatom in the 4-6 membered heterocycloalkyl is O; the number of heteroatoms is 1 or 2;

[0326] Each R 2-1 are independently halogen or unsubstituted C1-C6 alkyl;

[0327] Each R2-2 are independently halogen, unsubstituted C1-C6 alkyl or oxo (=O);

[0328] A is an unsubstituted 5-12 membered heteroarylene group, wherein the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatom in the 5-12 membered heteroarylene group is N, and the number of heteroatoms is 1 or 2;

[0329] L is a linker or unsubstituted C2-C6 alkenylene;

[0330] Q is an unsubstituted 5-12 membered heteroarylene group or an unsubstituted 5-12 membered heterocycloalkylene group; the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heterocycloalkylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, Q is an unsubstituted 5-6 membered heteroarylene group or an unsubstituted 5-12 membered heterocycloalkylene group; the heteroatom in the 5-6 membered heteroarylene group is N, and the number of heteroatoms is 1; the heteroatoms in the 5-12 membered heterocycloalkylene group are independently selected from one or both of N and O, and the number of heteroatoms is 1, 2 or 3;

[0331] Each R 3-1 are independently halogen;

[0332] R 4 is an unsubstituted C2-C6 alkynyl, an unsubstituted C3-C6 cycloalkyl, or one or more R 4-5 substituted 4-12 membered heterocycloalkyl, substituted by one or more R 4-6 substituted 5-12 membered heteroaryl or unsubstituted C1-C6 alkoxy; the heteroatoms in the 4-12 membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heteroaryl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, R 4 is an unsubstituted C2-C6 alkynyl, an unsubstituted C3-C6 cycloalkyl, or one or more R 4-5 substituted 4-6 membered heterocycloalkyl, one or more R 4-6 a substituted 5-6 membered heteroaryl or an unsubstituted C1-C6 alkoxy group; the heteroatoms in the 4-6 membered heterocycloalkyl group are independently selected from one or both of N and O, and the number of heteroatoms is 1 or 2; the heteroatom in the 5-6 membered heteroaryl group is N, and the number of heteroatoms is 1;

[0333] Each R4-5 are independently unsubstituted C1-C6 alkyl;

[0334] Each R 4-6 are independently cyano, halogen or unsubstituted C1-C6 alkyl.

[0335] In one plan,

[0336] Y is C;

[0337] R 1 for or by one or more R 1-3 Substituted C1-C6 alkyl;

[0338] R 1-1 is unsubstituted or substituted with one or more R 1-1-1 Substituted C1-C6 alkyl;

[0339] R 1-2 is O;

[0340] Each R 1-1-1 Independently OR 1-1-1-1 ;

[0341] R 1-1-1-1 is an unsubstituted C1-C6 alkyl group;

[0342] Each R 1-3 are independently hydroxy, halogen or unsubstituted C1-C6 alkyl;

[0343] X is -CR 1-6 R 1-7 -;

[0344] R 1-6 and R 1-7 are independently hydrogen;

[0345] R 2 and R 3 The atoms to which it is attached are unsubstituted or replaced by one or more R 2-1 substituted 5-6 membered heteroaryl, unsubstituted or substituted by one or more R 2-2 a substituted 4-6 membered heterocycloalkyl or an unsubstituted C4-C6 cycloalkyl; the heteroatoms in the 5-6 membered heteroaryl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 4-6 membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatom in the 4-6 membered heterocycloalkyl is O; the number of heteroatoms is 1 or 2;

[0346] Each R 2-1are independently unsubstituted C1-C6 alkyl;

[0347] Each R 2-2 are independently halogen;

[0348] A is an unsubstituted 5-12 membered heteroarylene group; the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatom in the 5-12 membered heteroarylene group is N, and the number of heteroatoms is 1 or 2;

[0349] L is a linker or unsubstituted C2-C6 alkenylene;

[0350] Q is an unsubstituted 5-12 membered heteroarylene group or an unsubstituted 5-12 membered heterocycloalkylene group; the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heterocycloalkylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, Q is an unsubstituted 5-6 membered heteroarylene group or an unsubstituted 5-12 membered heterocycloalkylene group; the heteroatom in the 5-6 membered heteroarylene group is N, and the number of heteroatoms is 1; the heteroatoms in the 5-12 membered heterocycloalkylene group are independently selected from one or both of N and O, and the number of heteroatoms is 1, 2 or 3;

[0351] Each R 3-1 are independently halogen;

[0352] R 4 is an unsubstituted C2-C6 alkynyl, an unsubstituted C3-C6 cycloalkyl, or one or more R 4-5 substituted 4-12 membered heterocycloalkyl, substituted by one or more R 4-6 substituted 5-12 membered heteroaryl or unsubstituted C1-C6 alkoxy; the heteroatoms in the 4-12 membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heteroaryl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, R 4 is an unsubstituted C2-C6 alkynyl, an unsubstituted C3-C6 cycloalkyl, or one or more R 4-5 substituted 4-6 membered heterocycloalkyl, one or more R 4-6 a substituted 5-6 membered heteroaryl or an unsubstituted C1-C6 alkoxy group; the heteroatoms in the 4-6 membered heterocycloalkyl group are independently selected from one or both of N and O, and the number of heteroatoms is 1 or 2; the heteroatom in the 5-6 membered heteroaryl group is N, and the number of heteroatoms is 1;

[0353] Each R 4-5 are independently unsubstituted C1-C6 alkyl;

[0354] Each R 4-6 are independently cyano, halogen or unsubstituted C1-C6 alkyl.

[0355] In one plan,

[0356] Y is C;

[0357] R 1 for or by one or more R 1-3 Substituted C1-C6 alkyl;

[0358] R 1-1 is unsubstituted or substituted with one or more R 1-1-1 Substituted C1-C6 alkyl;

[0359] R 1-2 is O;

[0360] Each R 1-1-1 Independently OR 1-1-1-1 ;

[0361] R 1-1-1-1 is an unsubstituted C1-C6 alkyl group;

[0362] Each R 1-3 are independently hydroxy, halogen or unsubstituted C1-C6 alkyl;

[0363] X is -CR 1-6 R 1-7 -;

[0364] R 1-6 and R 1-7 are independently hydrogen;

[0365] R 2 and R 3 The atoms to which it is attached are unsubstituted or replaced by one or more R 2-1 a substituted 5-6 membered heteroaryl, an unsubstituted 4-6 membered heterocycloalkyl or an unsubstituted C4-C6 cycloalkyl; the heteroatoms in the 5-6 membered heteroaryl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 4-6 membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatom in the 5-6 membered heteroaryl is N or O, and the number of heteroatoms is 1 or 2; the heteroatom in the 4-6 membered heterocycloalkyl is O, and the number of heteroatoms is 1 or 2;

[0366] Each R 2-1 are independently unsubstituted C1-C6 alkyl;

[0367] A is an unsubstituted 5-12 membered heteroarylene group; the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatom in the 5-12 membered heteroarylene group is N, and the number of heteroatoms is 1 or 2;

[0368] L is a linker or unsubstituted C2-C6 alkenylene;

[0369] Q is an unsubstituted 5-12 membered heteroarylene group or an unsubstituted 5-12 membered heterocycloalkylene group; the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heterocycloalkylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, Q is an unsubstituted 5-6 membered heteroarylene group or an unsubstituted 5-12 membered heterocycloalkylene group; the heteroatom in the 5-6 membered heteroarylene group is N, and the number of heteroatoms is 1; the heteroatoms in the 5-12 membered heterocycloalkylene group are independently selected from one or both of N and O, and the number of heteroatoms is 1, 2 or 3;

[0370] R 4 is an unsubstituted C2-C6 alkynyl, an unsubstituted C3-C6 cycloalkyl, or one or more R 4-5 substituted 4-12 membered heterocycloalkyl, substituted by one or more R 4-6 substituted 5-12 membered heteroaryl or unsubstituted C1-C6 alkoxy; the heteroatoms in the 4-12 membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heteroaryl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, R 4 is an unsubstituted C2-C6 alkynyl, an unsubstituted C3-C6 cycloalkyl, or one or more R 4-5 substituted 4-6 membered heterocycloalkyl, one or more R 4-6 a substituted 5-6 membered heteroaryl or an unsubstituted C1-C6 alkoxy group; the heteroatoms in the 4-6 membered heterocycloalkyl group are independently selected from one or both of N and O, and the number of heteroatoms is 1 or 2; the heteroatom in the 5-6 membered heteroaryl group is N, and the number of heteroatoms is 1;

[0371] Each R 4-5 are independently unsubstituted C1-C6 alkyl;

[0372] Each R 4-6 are independently cyano or unsubstituted C1-C6 alkyl.

[0373] In one plan,

[0374] Y is C;

[0375] R 1 for

[0376] R 1-1 is an unsubstituted C1-C6 alkyl group;

[0377] R 1-2 is O;

[0378] X is -CR 1-6 R 1-7 -;

[0379] R 1-6 and R 1-7 are independently hydrogen;

[0380] R 2 and R 3 The atoms connected thereto form an unsubstituted 4-6 membered heterocycloalkyl group or an unsubstituted C4-C6 cycloalkyl group; the heteroatoms in the 4-6 membered heterocycloalkyl group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatom in the 4-6 membered heterocycloalkyl group is O; the number of heteroatoms is 1;

[0381] A is an unsubstituted 5-12 membered heteroarylene group; the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatom in the 5-12 membered heteroarylene group is N, and the number of heteroatoms is 1 or 2;

[0382] L is the connection key;

[0383] Q is an unsubstituted 5-12 membered heteroarylene group or an unsubstituted 5-12 membered heterocycloalkylene group; the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heterocycloalkylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, Q is an unsubstituted 5-6 membered heteroarylene group or an unsubstituted 5-12 membered heterocycloalkylene group; the heteroatom in the 5-6 membered heteroarylene group is N, and the number of heteroatoms is 1; the heteroatoms in the 5-12 membered heterocycloalkylene group are independently selected from one or both of N and O, and the number of heteroatoms is 1, 2 or 3;

[0384] R 4 is an unsubstituted C2-C6 alkynyl, an unsubstituted C3-C6 cycloalkyl, or is replaced by one or more R 4-6 substituted 5-12 membered heteroaryl; the heteroatoms in the 5-12 membered heteroaryl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, R 4 is an unsubstituted C2-C6 alkynyl, an unsubstituted C3-C6 cycloalkyl, or is replaced by one or more R 4-6 A substituted 5-6 membered heteroaryl group; wherein the heteroatom in the 5-6 membered heteroaryl group is N, and the number of heteroatoms is 1;

[0385] Each R 4-6 are independently cyano or unsubstituted C1-C6 alkyl.

[0386] In one scenario, R 1 for

[0387] In one embodiment, X is methylene,

[0388] In one plan, for

[0389] In a certain scheme, A is

[0390] In one scheme, L is

[0391] In one scenario, Q is

[0392] In one scenario, R 4 for

[0393] The present invention provides the following compound or a pharmaceutically acceptable salt thereof:

[0394] The present invention also provides use of the above-mentioned compound or a pharmaceutically acceptable salt thereof in the preparation of a BRM ATPase inhibitor.

[0395] The present invention also provides a pharmaceutical composition comprising the compound shown above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0396] The present invention also provides use of the above-mentioned compound or a pharmaceutically acceptable salt thereof in preparing a medicament for treating BRM ATPase-related diseases.

[0397] The present invention also provides the use of the compound shown above or a pharmaceutically acceptable salt thereof in preparing a medicament for treating melanoma, endometrial cancer, non-small cell lung cancer, esophageal and gastric adenocarcinoma, urothelial bladder cancer or colorectal cancer.

[0398] As used herein, the term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable organic or inorganic salt of a compound of the present invention.

[0399] The term "alkyl" refers to a linear or branched, saturated, monovalent hydrocarbon group having a specified number of carbon atoms (eg, C1-C6); for example, C1-C6 alkyl.

[0400] The term "alkynyl" refers to a straight or branched monovalent hydrocarbon radical of two to twenty-two carbon atoms having at least one site of unsaturation, ie, a carbon-carbon sp triple bond; for example, C2-C6 alkynyl.

[0401] The term "cycloalkyl" refers to a group having the specified number of ring carbon atoms (e.g., C 3- C6 or C4-C6), a saturated monocyclic group consisting of ring atoms consisting only of carbon atoms. For example, C 3- C6 cycloalkyl or C4-C6 cycloalkyl.

[0402] The term "heterocycloalkyl" refers to a saturated monocyclic ring (e.g., 3-6, 4-6, or 4-12 members) with a specified number of ring atoms (e.g., 1, 2, or 3 heteroatoms), a specified type of heteroatom or heteroatom group (1, 2, or 3 of N, O, and S). ), spiro ring (e.g., ) or bridged rings (e.g., ), unsaturated and cyclic

[0403] The term "heterocycloalkylene" refers to a divalent group that is connected to the rest of the molecule by two single bonds, and the rest of the definition is the same as the term "heterocycloalkyl". The term "heteroaryl" refers to a cyclic group with a specified number of ring atoms (e.g., 5-12 members or 5-6 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (e.g., one, two, or more of N, O, and S), which is monocyclic or bicyclic. Monocyclic heteroaryl includes, but is not limited to, furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, triazole, furoxazolyl, thiazolyl, pyridyl, pyrimidinyl, indolyl, for example, Bicyclic heteroaryl groups include, but are not limited to, 5-membered heteroarylene and 6-membered heteroarylene or 6-membered heteroarylene and 5-membered heteroarylene; for example,

[0404] The term "aryl" refers to a group having the specified number of ring carbon atoms (e.g., C6-C 10 ). Examples of aryl groups include, but are not limited to, phenyl.

[0405] The term "arylene" refers to a divalent group connected to the rest of the molecule by two single bonds, and the rest is the same as the definition of the term "aryl".

[0406] The term "halogen" refers to F, Cl or Br.

[0407] The term "heteroarylene" refers to a divalent group that is attached to the rest of the molecule by two single bonds, and the rest is the same as the definition of the term "heteroaryl".

[0408] The term "alkenyl" refers to a linear or branched monovalent hydrocarbon group of two to twenty-two carbon atoms (eg, C1-C6 alkenyl) having at least one site of unsaturation, ie, a carbon-carbon sp2 double bond.

[0409] The term "alkenylene" refers to a divalent group that is attached to the rest of the molecule by two single bonds, and the rest is the same as the definition of the term "alkenyl".

[0410] The term "alkoxy" refers to a group R X -O-, where R X is an alkyl group as defined above.

[0411] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0412] The reagents and raw materials used in the present invention are commercially available.

[0413] The positive progress of the present invention is that the compound of the present invention has a strong inhibitory effect on BRM ATPase and has a good application prospect in BRG1 gene mutation tumors. DETAILED DESCRIPTION

[0414] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0415] Example 1 EVO33109

[0416] Step 1:

[0417] 5-Bromo-7-fluoro-1-indanone (1 g, 4.37 mmol) was dissolved in DMF (15 mL) at room temperature, and an aqueous solution of NaSCH₃ (2.29 g, 6.55 mmol, 20% purity) was added. The reaction system was stirred at room temperature overnight. The reaction system was diluted with water and extracted once with EA. The organic phases were combined, washed once with water and once with saturated sodium chloride solution, dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain the crude product. The product was purified by medium-pressure normal-phase column chromatography (PE / DCM = 5-50%) to afford EVO33109-A1 (700 mg, 62% yield) as a white solid.

[0418] Step 2:

[0419] At room temperature, EVO33109-A1 (257 mg, 1.0 mmol), Pd(dppf)Cl2-DCM (81 mg, 0.1 mmol), TEA (303 mg, 3.0 mmol), DMF (6 mL), and MeOH (3 mL) were added sequentially to a single-necked flask. The reaction system was purged with CO3 three times and heated at 80°C with stirring overnight. After the reaction, the system was cooled to room temperature, water (30 mL) and EA (30 mL) were added, and the aqueous phase was extracted once with EA. The organic phases were combined, washed once with water and once with saturated sodium chloride solution, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The product was purified by medium-pressure normal phase column chromatography (PE / DCM = 10-50%) to obtain EVO33109-C1 (160 mg, yield: 67%) as a white solid. LCMS (ESI) m / z = 237.1 [M+H] + .

[0420] Step 3:

[0421] At room temperature, EVO33109-C1 (160 mg, 0.68 mmol) was suspended in MeOH (10 mL), H2O (10 mL), and CH3CN (10 mL). Solid Oxone (1.24 g, 2.03 mmol) was added, and the reaction system was stirred at room temperature overnight. After the reaction, the reaction system was concentrated, and water (30 mL) and EA (30 mL) were added. The aqueous phase was extracted once with EA. The organic phases were combined, washed once with water and once with saturated sodium chloride solution, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The product was purified by medium-pressure normal phase column chromatography (DCM / EA = 0-10%) to obtain EVO33109-C2 (150 mg, yield: 82%) as a white solid. 1 H NMR (400MHz, CDCl3) δ8.72(s,1H),8.42(s,1H),4.00(s,3H),3.45(s,3H),3.31-3.28(m,2H),2.90-2.87(m,2H).

[0422] Step 4:

[0423] At room temperature, EVO33109-C2 (20 mg, 0.075 mmol) was suspended in MeOH (1 mL), H₂O (0.5 mL), and THF (1 mL). Solid LiOH·H₂O (9 mg, 0.22 mmol) was added. The reaction system gradually changed from a white turbid liquid to a light yellow turbid liquid and then to a dark green clear liquid. The reaction system was stirred at room temperature for 1 hour. After the reaction, the reaction system was adjusted to pH 3–5 with dilute HCl (1 M). The reaction system was concentrated to obtain EVO33109-C3 (25 mg, crude) as a black solid. LCMS (ESI) m / z = 253.1 [MH] - .

[0424] Step 5:

[0425] At room temperature, intermediate 1 (30 mg, 0.067 mmol) was dissolved in 1,4-dioxane (0.5 mL), and a solution of hydrogen chloride in 1,4-dioxane (3 mL) was added. The reaction system was stirred at room temperature for 1 hour. The reaction system was concentrated to give the crude yellow solid intermediate 1-A1 (22 mg, yield: 95%). LCMS (ESI) m / z = 350.4 [M+H] + .

[0426] Step 6:

[0427] EVO33109-C3 (20 mg, 0.078 mmol) and intermediate 1-A1 (22 mg, 0.063 mmol) were dissolved in DMF (3 mL) at room temperature. TEA (40 mg, 0.39 mmol) and HATU (45 mg, 0.12 mmol) were added sequentially, and the reaction system was stirred at room temperature for 1 hour. The reaction was quenched with water and extracted twice with EA. The combined organic phases were washed once with water and once with saturated sodium chloride solution, dried over anhydrous Na2SO4, filtered, concentrated, and purified by medium-pressure normal phase column chromatography (DCM / EA = 10-50%; then DCM / 10% MeOH = 10-30%) to obtain the crude product. The crude product was then prepared by Prep-HPLC and lyophilized to afford EVO33109 (7 mg, yield: 15%) as a pale yellow solid. LCMS (ESI) m / z = 586.1 [M+H] + , purity: 99.3%, 1 H NMR(400MHz,DMSO-d6)δ9.75(t,J=5.8Hz,1H),9.41(s,1H),8.70-8.60(m,2H), 8.50-8.47(m,2H),7.90(d,J=7.4Hz,2H),7.84(s,1H),7.78–7.72(m,1H),7.03 (d,J=8.8Hz,1H),4.84(d,J=5.8Hz,2H),4.31(d,J=12.4Hz,2H),3.72-3.62(m, 2H), 3.47 (s, 3H), 3.30-3.25 (m, 4H), 2.87-2.82 (m, 2H), 1.21 (d, J = 6.2Hz, 6H).

[0428] Example 2 EVO33127

[0429] Step 1:

[0430] EVO33109-A1 (180 mg, 0.70 mmol) was dissolved in TFA (5 mL) at room temperature, and Et3SiH (406 mg, 3.50 mmol) was added. The reaction system was stirred at room temperature overnight. After completion of the reaction, the mixture was concentrated and diluted with EA (30 mL) and water (30 mL). The organic phase was washed once with saturated NaHCO3 solution, once with water, and once with saturated sodium chloride solution, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by medium-pressure normal-phase column chromatography to obtain EVO33127-A1 (150 mg, yield: 88%) as a colorless oil, which turned into a white solid upon standing. 1H NMR (400MHz, CDCl3) δ7.14 (s, 1H), 7.04 (s, 1H), 2.91 (t, J = 7.2Hz, 2H), 2.77 (t, J = 7.2Hz, 2H), 2.46 (s, 3H), 2.12-2.05 (m, 2H).

[0431] Step 2:

[0432] At room temperature, EVO33127-A1 (150 mg, 0.62 mmol) was dissolved in CH3CN (6 mL) and H2O (6 mL), and Oxone (1.13 g, 1.85 mmol) was added, and solid precipitated. The reaction system was stirred at room temperature overnight. After the reaction was completed, it was concentrated, diluted with EA (30 mL) and water (30 mL), and the aqueous phase was extracted once with EA. After the organic phases were combined, they were washed once with water and saturated sodium chloride solution, dried over anhydrous Na2SO4, filtered, and concentrated to give a crude white solid EVO33127-A2 (140 mg, yield: 82%). 1 H NMR (400MHz, CDCl3) δ7.89 (s, 1H), 7.61 (s, 1H), 3.22 (t, J = 7.6Hz, 2H), 3.04 (s, 3H), 2.97 (t, J = 7.6Hz, 2H), 2.21-2.13 (m, 2H).

[0433] Step 3:

[0434] To a single-necked flask at room temperature were added EVO33127-A2 (90 mg, 0.33 mmol), Pd(OAc)2 (7 mg, 0.033 mmol), DCCP-2HBF4 (20 mg, 0.033 mmol), K2CO3 (135 mg, 0.99 mmol), H2O (0.1 mL), and DMSO (3 mL). The reaction system was purged with CO3 three times and then heated to 100°C with stirring overnight. After the reaction was complete, the reaction system was cooled to room temperature and filtered. The filter cake was washed twice with water. The filtrate was extracted once with EA, the organic phase was discarded, the aqueous phase was adjusted to pH 3 with dilute HCl (1 M), and extracted three times with DCM / MeOH = 10 / 1. The organic phases were combined and concentrated to obtain a crude product, which was purified by medium-pressure reverse-phase column chromatography (H2O / CH3CN = 0-50%) and lyophilized to obtain a pale pink solid EVO33127-A3 (60 mg, yield: 80%), LCMS (ESI) m / z = 239.2 [MH] - .

[0435] Step 4:

[0436] EVO33127-A3 (15 mg, 0.062 mmol) and intermediate 1-A1 (22 mg, 0.062 mmol) were dissolved in DMF (3 mL) at room temperature. TEA (32 mg, 0.31 mmol) and HATU (35 mg, 0.093 mmol) were added sequentially, and the reaction system was stirred at room temperature for 1 hour. The reaction system was quenched with water and extracted twice with EA. The organic phases were combined, washed once with water and once with saturated sodium chloride solution, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. After Prep-HPLC preparation, the product was lyophilized to obtain EVO33127 (15 mg, yield: 42%) as a pale yellow solid. LCMS (ESI) m / z = 572.37 [M+H] + . Purity: 99.17%. 1 H NMR(400MHz,DMSO-d6)δ9.46(t,J=5.9Hz,1H),9.39(s,1H),8.70-8.60(m,2H),8.28(s ,1H),8.18(s,1H),7.90(d,J=7.4Hz,1H),7.80(s,1H),7.77-7.71(m,1H),7.03(d,J=8 .5Hz,1H),4.80(d,J=5.8Hz,2H),4.31(d,J=11.9Hz,2H),3.72-3.63(m,2H),3.30-3.2 5(m,4H),3.23(s,3H),3.02(t,J=7.6Hz,2H),2.20-2.10(m,2H),1.21(d,J=6.2Hz,6H).

[0437] Example 3 EVO33314

[0438] The reference compound EVO33127 was separated by HPLC preparative column and freeze-dried to give a yellow solid EVO33314 (15 mg, yield: 38%), LCMS (ESI) m / z = 586.4 [M+H] + , purity: 99.13%, 1H NMR (400MHz, DMSO-d6) δ9.47(t,J=5.9Hz,1H),9.39(s,1H),8.69-8.59(m,2H),8.23(s,1H),8.19(s,1H),7.90(d,J= 7.2Hz,1H),7.80(s,1H),7.74(t,J=8.0Hz,1H),7.02(d,J=8.6Hz,1H),4.80(d,J=5.8Hz,2H),4.31(d,J=12.6Hz,2H), 3.73-3.61(m,2H),3.30-3.21(m,4H),3.03(t,J=7.4Hz,2H),2.56-2.50 (m,2H),2.18-2.08(m,2H),1.21(d,J=6.2Hz,6H),1.13(t,J=7.4Hz,3H).

[0439] Example 4 EVO33319

[0440] The reference compound EVO33127 was separated by HPLC preparative column and freeze-dried to obtain yellow solid EVO33319 (25 mg, yield: 46%), LCMS (ESI) m / z = 600.5 [M+H] + , purity: 97.9%, 1 H NMR (400MHz, DMSO-d6) δ9.49 (t, J = 5.6 Hz, 1H), 9.39 (s, 1H), 8.67-8.61 (m, 2H), 8.20 (d, J = 3. 6Hz,2H),7.90(d,J=7.6Hz,1H),7.80(s,1H),7.74(t,J=7.2Hz,1H),7.03(d,J=8.4Hz,1H),4. 80(d,J=5.6Hz,2H),4.31(d,J=10.8Hz,2H),3.70-3.64(m,2H),3.48-3.41(m,1H),3.24(t,J= 8.8Hz,2H),3.02(d,J=7.2Hz,2H),2.53-2.51(m,2H),2.15-2.08(m,2H),1.22-1.18(m,12H).

[0441] Example 5 EVO33168

[0442] Step 1:

[0443] Under Ar protection, a solution of 5-bromo-7-fluoroindazole (1.03 g, 4.80 mmol) and sodium thiomethoxide (0.93 g, 12 mmol) in DMF (5 mL) was reacted at 80°C for 12 hours. The reaction mixture was quenched with ice water and extracted with EA. The combined organic phases were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to afford EVO33168-A1 (1.28 g, 98% yield) as a white solid. LCMS (ESI) m / z = 245.04 [M+H] + .

[0444] Step 2:

[0445] Under Ar protection, NaH (200 mg, 4.94 mmol) was added to a solution of compound EVO33168-A1 (300 mg, 1.23 mmol) in DMF (5 mL) in an ice-water bath. The mixture was stirred for 10 minutes, followed by the dropwise addition of CH3I (350 mg, 2.46 mmol) and continued stirring for 15 minutes. The reaction mixture was quenched with ice water and extracted with EA. The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford EVO33168-A2 (380 mg, 98% yield) as a white solid. LCMS (ESI) m / z = 259.07 [M+H] + .

[0446] Step 3:

[0447] At room temperature, EVO33168-A2 (380 mg, 1.23 mmol) was dissolved in acetonitrile (5 mL) and water (5 mL). Solid Oxone (1.60 g, 2.46 mmol) was added and the reaction was stirred overnight. The reaction solution was concentrated, EA and water were added, and the mixture was separated and extracted. The organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by medium-pressure normal phase column chromatography (PE / EA = 3 / 1) to obtain EVO33168-A3 (210 mg, yield: 60%) as a white solid. LCMS (ESI) m / z = 291.10 [M+H] + .

[0448] Step 4:

[0449] Compound EVO33168-A3 (195 mg, 0.68 mmol), Pd(OAc)2 (15 mg, 0.068 mmol), 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) (41 mg, 0.068 mmol), K2CO3 (281 mg, 2.04 mmol), DMSO (2 mL), and water (0.2 mL) were added to a reaction flask at room temperature. After CO2 substitution three times, the reaction solution was stirred at 100°C for 4 hours. Water was added to the reaction solution, filtered, and the filter cake was washed with a small amount of water. The filtrate was acidified to pH 1-2 and extracted with EA. The organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford EVO33168-A4 (140 mg, 80% yield) as a pale yellow solid. LCMS (ESI) m / z = 255.17 [M+H] + .

[0450] Step 5:

[0451] To a solution of intermediate 1-A1 (40 mg, 0.11 mmol) in DCM (5 mL) were added compound EVO33168-A4 (42 mg, 0.15 mmol), HOBt (22 mg, 0.16 mmol), EDCI (31 mg, 0.16 mmol), and DIPEA (28.7 mg, 0.22 mmol) at room temperature. The reaction was stirred for 1 hour. The mixture was washed with water and saturated sodium chloride solution once each, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by Prep-HPLC and freeze-dried to afford EVO33168 (25.6 mg, 42% yield) as a yellow solid with a purity of 97%. LCMS (ESI) m / z = 586.44 [M+H] + , 1 H NMR(400MHz,DMSO-d6)δ9.59(t,J=6.0Hz,1H),9.43(s,1H),8.89(d,J=1.6Hz,1H) ,8.72-8.62(m,3H),8.56(s,1H),7.93(d,J=7.6Hz,1H),7.87(s,1H),7.78(t,J=7 .9Hz,1H),7.06(d,J=7.0Hz,1H),4.88(d,J=5.7Hz,2H),4.49(s,3H),4.37-4.29( m,2H),3.75-3.65(m,2H),3.57(s,3H),2.57-2.46(m,2H),1.24(d,J=6.2Hz,6H).

[0452] Example 6 EVO33135

[0453] The reference compound EVO33168 was separated by HPLC preparative column and freeze-dried to obtain a yellow solid EVO33135 (15.5 mg, yield: 16.3%), LCMS (ESI) m / z = 571.05 [M+H] + , 1 H NMR(400MHz,DMSO-d6)δ11.62(s,1H),9.47-9.40(m,1H),9.40(s,1H),8.70-8.59(m,3 H),8.29(d,J=1.6Hz,1H),7.89(d,J=7.4Hz,1H),7.82(s,1H),7.72(t,J=8.0Hz,1H),7. 61-7.56(m,1H),7.02(d,J=8.5Hz,1H),6.85-6.79(m,1H),4.83(d,J=5.8Hz,2H),4.35- 4.26(m,2H),3.72-3.61(m,2H),3.35(s,3H),3.33-3.31(m,2H),1.21(d,J=6.2Hz,6H).

[0454] Example 7 EVO33136

[0455] The reference compound EVO33168 was separated by HPLC preparative column and freeze-dried to give a yellow solid EVO33136 (13.58 mg, yield: 31%), LCMS (ESI) m / z = 585.46 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ9.47-9.42(m,1H),9.39(s,1H),8.70-8.59(m,3H),8.43(d,J= 1.6Hz,1H),7.89(d,J=7.2Hz,1H),7.82(s,1H),7.74-7.70(m,1H),7.63(d,J=3.2Hz,1H ),7.03-7.00(m,1H),6.86(d,J=3.2Hz,1H),4.83(d,J=5.6Hz,2H),4.34-4.27(m,2H), 4.23(s,3H),3.71-3.63(m,2H),3.51(s,3H),2.53-2.50(m,2H),1.21(d,J=6.4Hz,6H).

[0456] Example 8 EVO33165

[0457] Reference compound EVO33168 was separated by HPLC preparative column and freeze-dried to obtain yellow solid EVO33165 (5.6 mg, yield: 12%, purity: 97.3%), LCMS (ESI) = 572.43 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ13.86(s,1H),9.61(t,J=5.6,1H),9.44(s,1H),8.90(d,J= 1.2,1H),8.73-8.62(m,2H),8.57(s,1H),8.53(d,J=1.6Hz,1H),7.93(d,J=7.2,1H) ,7.87(s,1H),7.79-7.71(m,1H),7.05(d,J=8.5Hz,1H),4.88(d,J=5.6,2H),4.38-4 .29(m,2H),3.75-3.65(m,2H),3.45(s,3H),2.58-2.46(m,2H),1.24(d,J=6.2,6H).

[0458] Example 9 EVO33070

[0459] Step 1:

[0460] At room temperature, ethyl difluorobromoacetate (7.96 g, 39.20 mmol) and DMSO (50 mL) were added to the reaction flask. After dissolution, Cu (2.49 g, 39.20 mmol) was added. The reaction solution was stirred at room temperature for 1 hour, and then 2,6-difluoro-4-bromoiodobenzene (5 g, 16 mmol) was added. The mixture was stirred in an oil bath at 75°C overnight. The reaction system was cooled to room temperature, and EA (300 mL) and water (300 mL) were added. A large amount of solid precipitated, which was filtered and the filter cake was washed with EA. The organic phases were separated and combined, washed once with water and once with saturated sodium chloride solution, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by medium-pressure normal phase column chromatography (PE / DCM = 0-15%) to obtain EVO33070-A1 (4 g, yield: 81%) as a colorless oil. 1 H NMR (400MHz, DMSO-d6) δ7.78–7.75 (m, 2H), 4.37 (q, J = 6.8Hz, 2H), 1.24 (t, J = 7.2Hz, 3H).

[0461] Step 2:

[0462] At room temperature, EVO33070-A1 (1 g, 3.17 mmol), CH3CN (50 mL), and NaSCH3 (222 mg, 3.17 mmol) were added to the reaction flask and stirred overnight. After the reaction system was concentrated, EA (50 mL) and water (50 mL) were added for dilution. The liquids were separated, and the aqueous phase was extracted twice with EA. The organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by medium-pressure normal phase column chromatography (PE / DCM = 0-10%) to obtain EVO33070-A2 (600 mg, yield: 55%) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ7.13 (s, 1H), 7.09–7.06 (m, 1H), 4.11 (t, J = 13.2Hz, 2H), 2.47 (t, J = 4.4Hz, 3H).

[0463] Step 3:

[0464] At room temperature, EVO33070-A2 (600 mg, 1.75 mmol), CH3OH (6 mL), and THF (6 mL) were added to the reaction flask. After stirring at 0°C for 5-10 minutes, NaBH4 (133 mg, 3.50 mmol) was added and stirred for 1 hour. The mixture was then warmed to room temperature and stirred overnight. The reaction system was quenched with water, concentrated, and extracted twice with EA. The organic phases were combined, dried over anhydrous Na2SO4, filtered, concentrated, and purified by medium-pressure normal phase column chromatography (PE / DCM = 50%-70%) to obtain EVO33070-A3 (440 mg, yield: 83%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ7.58 (d, J = 5.6 Hz, 1H), 7.49 (s, 1H), 4.34 (q, J = 7.2 Hz, 2H), 2.55 (s, 3H), 1.23 (t, J = 6.8 Hz, 3H).

[0465] Step 4:

[0466] At room temperature, Cs2CO3 (953 mg, 2.92 mmol), TBAB (47 mg, 0.15 mmol), and CH3CN (50 mL) were added to the reaction flask and heated to 85°C. A solution of EVO33070-A3 (440 mg, 1.46 mmol) in CH3CN (5 mL) was then added dropwise to the reaction system. After completion of the addition, the mixture was stirred overnight in an oil bath at 90°C. The reaction system was cooled to room temperature, filtered, and the filtrate was concentrated to obtain the crude product, which was purified by medium-pressure normal phase column chromatography (PE / DCM = 0-2%) to obtain EVO33070-A4 (160 mg, yield: 39%) as a white solid. 1H NMR (400MHz, DMSO-d6) δ7.14 (q, J=1.6Hz, 1H), 7.06 (d, J=1.2Hz, 1H), 4.81 (t, J=16.8Hz, 2H), 2.57 (s, 3H).

[0467] Step 5:

[0468] At room temperature, EVO33070-A4 (160 mg, 0.57 mmol), CH3OH (5 mL), and H2O (5 mL) were added to the reaction flask, followed by Oxone (1.05 g, 1.71 mmol). The reaction solution was stirred at room temperature for 2-4 hours. The reaction system was diluted with water and extracted twice with EA. The organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by medium-pressure normal phase column chromatography (PE / DCM = 0-50%) to obtain EVO33070-A5 (140 mg, yield: 78%) as a white solid. 1 H NMR (400MHz, CDCl3) δ7.82 (d, J=1.2Hz, 1H), 7.43 (q, J=1.6Hz, 1H), 4.74 (t, J=16.0Hz, 2H), 3.19 (s, 3H).

[0469] Step 6:

[0470] At room temperature, EVO33070-A5 (140 mg, 0.45 mmol), Pd(OAc)2 (10 mg, 0.045 mmol), DCCP-2HBF4 (27 mg, 0.045 mmol), K2CO3 (185 mg, 1.34 mmol), DMSO (5 mL) and H2O (0.2 mL) were added sequentially to a single-necked flask. The reaction system was replaced with CO 3 times, heated to 100°C and stirred overnight. The reaction system was cooled to room temperature and filtered. The filter cake was washed with water, and the aqueous phase was extracted once with EA. The organic phase was discarded, and the aqueous phase was adjusted to pH 3-5 with dilute HCl (1 M) and extracted three times with DCM / MeOH (10 / 1). The organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product, which was purified by reverse phase column chromatography (H2O / CH3CN=5-50%) and freeze-dried to obtain EVO33070-A6 (65 mg, yield: 52%) as a white solid. LCMS (ESI) m / z=277.0 [MH] - .

[0471] Step 7:

[0472] EVO33070-A6 (20 mg, 0.072 mmol) and intermediate 1-A1 (25 mg, 0.072 mmol) were dissolved in DMF (2 mL) at room temperature, and TEA (36 mg, 0.36 mmol) and HATU (55 mg, 0.14 mmol) were added sequentially. The reaction system was stirred at room temperature for 2 hours. The reaction system was quenched by adding water and extracted twice with EA. The organic phases were combined, washed once with water and once with saturated sodium chloride solution, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. After purification by Prep-HPLC, the product was freeze-dried to obtain EVO33070 (5 mg, yield: 11%). LCMS (ESI) m / z = 610.34 [M+H] + , purity: 98%, 1 H NMR(400MHz,DMSO-d6)δ9.67(t,J=5.6Hz,1H),9.40(s,1H),8.68-8.61(m,2H),8.16(d, J=1.2Hz,1H),8.03(d,J=1.2Hz,1H),7.91-7.90(m,1H),7.84(s,1H),7.77-7.73(m,1H) ,7.03(d,J=8.4Hz,1H),5.00(t,J=17.0Hz,2H),4.82(d,J=6.0Hz,2H),4.31(d,J=12.4H z,2H),3.70-3.65(m,2H),3.31-3.29(m,3H),2.53–2.46(m,2H),1.21(d,J=6.0Hz,6H).

[0473] Example 10 EVO33074

[0474] The reference compound EVO33070 was separated by HPLC preparative column and freeze-dried to obtain a light yellow solid EVO33074 (10 mg, yield: 35%), LCMS (ESI) m / z = 589.9 [M+H] + , purity: 88.7%, 1H NMR(400MHz, DMSO-d6)δ9.68(t,J=6.0Hz,1H),9.40(s,1H),8.77(d,J=4.0Hz,1 H),8.68-8.61(m,3H),8.49(d,J=1.2Hz,1H),7.89(d,J=7.2Hz,1H),7.85(s,1H) ,7.75-7.71(m,1H),7.02(d,J=8.4Hz,1H),4.85(d,J=6.0Hz,2H),4.33-4.29(m ,2H),3.69-3.64(m,2H),3.38(s,3H),2.53–2.46(m,2H),1.21(d,J=6.0Hz,6H).

[0475] Example 11 EVO33137

[0476] Step 1:

[0477] At room temperature, 1-bromo-3-hydroxynaphthalene (3.8 g, 17.04 mmol) was dissolved in CH3CN (80 mL), and K2CO3 (7.05 g, 51.11 mmol) and CH3I (7.36 g, 51.11 mmol) were added in sequence. The reaction system was stirred at room temperature overnight. The reaction system was filtered, the filtrate was concentrated, diluted with water, and extracted with EA. The organic phase was washed once with water and once with saturated sodium chloride solution, dried over anhydrous Na2SO4, filtered, and concentrated to obtain a crude brown oil EVO33137-A1 (4 g). 1 H NMR (400MHz, DMSO-d6) δ8.02 (d, J = 8.8 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.58-7.48 (m, 3H), 7.43 (d, J = 2.4 Hz, 1H), 3.89 (s, 3H).

[0478] Step 2:

[0479] At room temperature, EVO33137-A1 (3.5 g, 14.76 mmol), Pd2(dba)3 (1.35 g, 1.48 mmol), Xantphos (1.71 g, 2.95 mmol), Cs2CO3 (14.44 g, 44.29 mmol), t-BuOH (6 mL), and toluene (60 mL) were added to a single-necked flask in sequence. After purging the atmosphere with argon three times, methyl thioacetate (6.65 g, 73.81 mmol) was added and purged with argon once more. The reaction system was heated to 100°C and stirred overnight. The reaction system was filtered, the filter cake was washed with EA, and the filtrate was concentrated to obtain the crude product, which was purified by medium-pressure normal phase column chromatography (PE / DCM = 0-5%) to obtain EVO33137-A2 (2 g, yield: 66%) as a colorless oil. 1 H NMR(400MHz,DMSO-d6)δ7.98(d,J=8.4Hz,1H),7.82(d,J=8.4Hz,1H),7.51-7.47(m,1H),7 .41-7.37(m,1H),7.13(d,J=2.4Hz,1H),6.98(d,J=2.4Hz,1H),3.87(s,3H),2.57(s,3H).

[0480] Step 3:

[0481] At room temperature, EVO33137-A2 (1 g, 4.90 mmol) was suspended in CH3CN (30 mL) and H2O (30 mL), and Oxone (8.99 g, 14.69 mmol) was added. The reaction system was stirred at room temperature overnight. After concentration, the reaction system was diluted with water and extracted once with EA. The organic phase was washed once with water and once with saturated sodium chloride solution, dried over anhydrous Na2SO4, filtered, and concentrated to obtain a crude light yellow solid EVO33137-A3 (1 g, yield: 86%). 1 H NMR (400MHz, DMSO-d6) δ8.51(d,J=8.4Hz,1H),7.82(d,J=8.8Hz,1H),7.80-7.77(m,2H),7.67-7.58(m,2H),3.95(s,3H),3.36(s,3H).

[0482] Step 4:

[0483] EVO33137-A3 (200 mg, 0.85 mmol) and DCM (5 mL) were added to an argon-filled three-necked flask. The reaction system was cooled to -70°C and BBr3 (2.54 mL, 2.54 mmol, 1 M in DCM) was slowly added dropwise. After completion of the dropwise addition, the reaction system was slowly warmed to room temperature and stirred for 2 hours. The reaction system was cooled to 0°C, quenched with water, and extracted twice with DCM. The organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by medium-pressure normal phase column chromatography (DCM / 10% MeOH = 0-30%) to obtain EVO33137-A4 (130 mg, yield: 69%) as a pale yellow solid. LCMS (ESI) m / z = 221.1 [MH] - .

[0484] Step 5:

[0485] At 0°C, EVO33137-A4 (130 mg, 0.58 mmol) was dissolved in pyridine (3 mL), and Tf2O (495 mg, 1.75 mmol) was slowly added dropwise. After completion of the addition, the reaction system was warmed to room temperature and stirred overnight. After the reaction system was concentrated, EA was added for dilution, and the mixture was washed once with saturated NaHCO3 solution, once with water, and once with saturated sodium chloride solution. After drying over anhydrous Na2SO4, the mixture was filtered and concentrated to obtain the crude product. The crude product was purified by medium-pressure normal phase column chromatography (PE / DCM = 0-50%) to obtain EVO33137-A5 (120 mg, yield: 58%) as a colorless oil. 1 HNMR (400MHz, DMSO-d6) δ8.68-8.66(m,2H),8.32(d,J=8.0Hz,1H),7.19(d,J=2.4Hz,1H),7.95-7.91(m,1H),7.88-7.84(m,1H),3.47(s,3H).

[0486] Step 6:

[0487] At room temperature, EVO33137-A5 (120 mg, 0.34 mmol), Pd(OAc)2 (7.6 mg, 0.034 mmol), DCCP-2HBF4 (21 mg, 0.034 mmol), K2CO3 (140 mg, 1.02 mmol), H2O (0.1 mL) and DMSO (3 mL) were added sequentially to a single-necked flask. The reaction system was replaced with CO 3 times and then heated to 100°C and stirred overnight. The reaction system was filtered, the filter cake was washed with water, and the filtrate was extracted once with EA. The organic phase was discarded, and the aqueous phase was adjusted to pH 3-5 with dilute HCl (2M). After extraction three times with DCM / MeOH (10 / 1), the organic phases were combined and concentrated to obtain the crude product, which was purified by medium-pressure reverse-phase column chromatography (H2O / CH3CN = 5-50%) and lyophilized to obtain EVO33137-A6 (60 mg, yield: 70%) as a white solid. LCMS (ESI) m / z = 249.1 [MH] - .

[0488] Step 7:

[0489] EVO33137-A6 (25 mg, 0.1 mmol) and intermediate 1-A1 (35 mg, 0.1 mmol) were dissolved in DMF (3 mL) at room temperature. TEA (51 mg, 0.5 mmol) and HATU (76 mg, 0.2 mmol) were added sequentially, and the reaction system was stirred at room temperature for 1 hour. The reaction system was quenched with water and extracted once with EA. The organic phase was washed once with water and once with saturated sodium chloride solution, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was prepared by Prep-HPLC and lyophilized to obtain EVO33137 (25 mg, yield: 43%) as a yellow solid. LCMS (ESI) m / z = 582.4 [M+H] + , purity: 98.6%, 1 H NMR(400MHz,DMSO-d6)δ9.73(t,J=5.6Hz,1H),9.42(s,1H),9.00(s,1H),8 .75-8.61(m,4H),9.30(d,J=8.0Hz,1H),7.94-7.87(m,3H),7.84-7.71(m, 2H),7.02(d,J=8.8Hz,1H),4.88(d,J=5.6Hz,2H),4.31(d,J=12.4Hz,2H), 3.69-3.64(m,2H),3.41(s,3H),2.49-2.46(m,2H),1.20(d,J=6.0Hz,6H).

[0490] Example 12 EVO33167

[0491] Reference compounds EVO33168 and EVO33137 were separated by HPLC preparative column and freeze-dried to obtain a yellow solid EVO33167 (20.11 mg, yield: 31.3%), LCMS (ESI) m / z = 572.4 [M+H] + , purity: 99.0%, 1 H NMR(400MHz,DMSO-d6)δ14.10(br,1H),9.70(t,J=6.0Hz,1H),9.41(s,1H),8.71-8.56 (m,3H),8.46(s,1H),8.29(d,J=1.2Hz,1H),7.90(d,J=7.6Hz,1H),7.85(s,1H),7.73( t,J=8.0Hz,1H),7.02(d,J=8.4Hz,1H),4.86(d,J=5.6Hz,2H),4.31(dd,J1=2.4Hz,J2= 12.8Hz,2H),3.71-3.63(m,2H),3.36(s,3H),2.56-2.45(m,2H),1.21(d,J=6.0Hz,6H).

[0492] Example 13 EVO33111

[0493] first step:

[0494] In an ice-water bath, 5-bromo-2,3-dihydrobenzofuran (1.00 g, 5.02 mmol) and chlorosulfonic acid (2 mL) were added to the reaction flask. After 2 hours, the reaction solution was poured into ice water and extracted with DCM (20 mL*3). The organic phase was concentrated and purified by medium-pressure preparation to obtain EVO33111-A1 (1.00 g, yield: 67.1%).

[0495] Step 2:

[0496] At room temperature, a reaction flask was charged with EVO33111-A1 (1.00 g, 3.36 mmol), sodium sulfite (667.74 mg, 5.38 mmol), sodium bicarbonate (451.74 mg, 5.38 mmol), water (10 mL), and 1,4-dioxane (10 mL). The mixture was heated to 80°C in an oil bath. After completion of the reaction, EVO33111-A2 (1.20 g, yield: >99%) was prepared by medium-pressure reverse phase chromatography.

[0497] Step 3:

[0498] EVO33111-A2 (1.10 g, 1.93 mmol) and DMF (5 mL) were added to a reaction flask at room temperature, followed by the dropwise addition of CH3I (821.50 mg, 5.79 mmol). After the reaction, EVO33111-A3 (290 mg, yield: 27.1%) was obtained under medium pressure.

[0499] Step 4:

[0500] At room temperature, a reaction flask was charged with EVO33111-A3 (290.00 mg, 1.05 mmol), palladium acetate (23.49 mg, 0.10 mmol), 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) (63.86 mg, 0.10 mmol), potassium carbonate (433.88 mg, 3.14 mmol), DMSO (3 mL), and water (0.3 mL). The reaction mixture was replaced with CO 3 times, and the temperature was raised to 80°C. After completion of the reaction, EVO33111-A4 (20 mg, yield: 7.9%) was prepared under medium pressure.

[0501] Step 5:

[0502] At room temperature, EVO33111-A4 (20.00 mg, 0.08 mmol), intermediate 1-A1 (28.85 mg, 0.08 mmol), HATU (47.09 mg, 0.12 mmol), and DMF (5 mL) were added to the reaction flask. DIPEA (42.68 mg, 0.33 mmol) was then added at room temperature. After completion of the reaction, the product was purified by Prep-HPLC and freeze-dried to obtain EVO33111 (13 mg, yield: 27.5%). LCMS (ESI) m / z = 574.36 [M+H] + , purity: 99.80%, 1 H NMR(400MHz,DMSO-d6)δ9.41(d,J=6.5Hz,2H),8.72-8.61(m,2H),8.27–8.1 9(m,2H),7.93(d,J=7.4Hz,1H),7.83-7.73(m,2H),7.06(d,J=8.5Hz,1H),4. 90(t,J=8.8Hz,2H),4.81(d,J=5.8Hz,2H),4.38-4.30(m,2H),3.71(m,2H),3 .39(t,J=8.8Hz,2H),3.29(s,3H),2.57-2.47(m,2H),1.24(d,J=6.2Hz,6H).

[0503] Example 14 EVO33138

[0504] Step 1:

[0505] At room temperature, 5-bromo-3-fluorobenzene-1,2-diol (1 g, 4.83 mmol) was dissolved in DMF (30 mL), followed by the addition of K2CO3 (3.34 g, 24.15 mmol) and dibromomethane (4.20 g, 24.15 mmol). The reaction system was heated to 80°C and stirred overnight. After the reaction was completed, the mixture was cooled to room temperature, diluted with EA and water, and the organic phase was washed once with water and once with saturated sodium chloride solution, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by medium-pressure normal phase column chromatography (PE / DCM = 2-5%) to obtain EVO33138-A1 (300 mg, yield: 28%) as a colorless oil. 1 H NMR (400MHz, DMSO-d6) δ7.16 (dd, J1, J2 = 1.6Hz, 9.6Hz, 1H), 7.12-7.11 (m, 1H), 6.16 (s, 2H).

[0506] Step 2:

[0507] EVO33138-A1 (100 mg, 0.46 mmol) was dissolved in DMF (3 mL) at room temperature, and NaSCH3 (479.44 mg, 1.37 mmol, 20% purity in H2O) was added. The reaction was stirred at room temperature overnight. The reaction was quenched with water and extracted with EA. The combined organic phases were washed once with water and once with saturated sodium chloride solution, dried over anhydrous Na2SO4, filtered, and concentrated to afford the crude product, EVO33138-A2 (100 mg), as a colorless oil.

[0508] Step 3:

[0509] EVO33138-A2 (100 mg, 0.40 mol) was suspended in CH3CN (3 mL) and H2O (3 mL) at room temperature, and Oxone (745 mg, 1.21 mmol) was added. The reaction system was stirred at room temperature overnight. The reaction system was concentrated, diluted with EA and water, and the organic phases were combined, washed once with water and once with saturated sodium chloride solution, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The product was purified by medium-pressure normal phase column chromatography (PE / DCM = 20-50%, DCM / 10% MeOH = 10%) to obtain EVO33138-A3 (50 mg, yield: 44%) as a white solid.

[0510] Step 4:

[0511] At room temperature, EVO33138-A3 (50 mg, 0.18 mmol), Pd(OAc)2 (4 mg, 0.018 mol), DCCP-2HBF4 (11 mg, 0.018 mmol), K2CO3 (74 mg, 0.54 mmol), H2O (0.1 mL) and DMSO (3 mL) were added sequentially to a single-necked flask. The reaction system was replaced with CO 3 times and heated to 100°C with stirring overnight. The reaction system was cooled to room temperature and filtered. The filter cake was washed with water and the filtrate was washed once with EA. The organic phase was discarded and the aqueous phase was adjusted to pH 3-5 with dilute HCl (1 M). The mixture was then extracted three times with DCM / MeOH (10 / 1). The organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by reverse phase column chromatography (H2O / CH3CN = 5-50%) and lyophilized to obtain EVO33138-A4 (26 mg, yield: 59%) as a white solid. LCMS (ESI) m / z = 243.1 [MH] - .

[0512] Step 5:

[0513] EVO33138-A4 (16 mg, 0.065 mmol) and intermediate 1-A1 (23 mg, 0.065 mmol) were dissolved in DMF (3 mL) at room temperature, followed by the addition of TEA (33 mg, 0.33 mol) and HATU (50 mg, 0.13 mmol). The reaction was stirred at room temperature for 1 hour. The reaction system was quenched with water and extracted twice with EA. The combined organic phases were washed once with water and once with saturated sodium chloride solution, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The product was purified by medium-pressure normal phase column chromatography (DCM / EA = 10-50%, DCM / 10% MeOH = 10-50%) and lyophilized to obtain EVO33138 (20 mg, yield: 53%) as a yellow solid. LCMS (ESI) m / z = 576.0 [M+H] + , purity: 98.6%, 1 H NMR (400MHz, DMSO-d6) δ9.41-9.39(m,2H),8.67-8.60(m,2H),7.93-7.89(m,2H),7.80-7.72(m,3H),7.03(d,J=8.4Hz,1H),6.37(s,2H) ,4.77(d,J=6.0Hz,2H),4.31(dd,J1,J2=2.4Hz,12.8Hz,2H),3.70-3.65(m,2H),3.31(s,3H),2.55–2.44(m,2H),1.21(d,J=6.4Hz,6H).

[0514] Example 15 EVO33157

[0515] The reference compound EVO33138 was separated by HPLC preparative column and freeze-dried to give a yellow solid EVO33157 (10 mg, yield: 36%), LCMS (ESI) m / z = 590.1 [M+H] + , purity: 99.94%, 1 H NMR (400MHz, DMSO-d6) δ9.42-9.38(m,2H),8.64(q,J=8.8Hz,2H),8.03(d,J=2.4Hz ,1H),7.91-7.89(m,1H),7.85(d,J=2.0Hz,1H),7.76-7.72(m,2H),7.02(d,J=8.8H z,1H),4.77(d,J=6.0Hz,2H),4.53-4.51(m,2H),4.42-4.40(m,2H),4.31(d,J=12. 0Hz, 2H), 3.70-3.65 (m, 2H), 3.30 (s, 3H), 2.57-2.42 (m, 2H), 1.21 (d, J = 6.4Hz, 6H).

[0516] Example 16 EVO33173

[0517] Step 1:

[0518] To a single-necked flask at room temperature were added 2,6-dibromopyridine (1 g, 4.22 mmol), cyclopropylboronic acid (725 mg, 8.44 mmol), Pd(dppf)Cl2·DCM (345 mg, 0.42 mmol), K2CO3 (1.75 g, 12.66 mmol), and 1,4-dioxane (20 mL). The reaction system was replaced with argon three times and then heated to 100°C with stirring overnight. The reaction system was filtered, and the filter cake was washed with EA. The filtrate was concentrated and purified by medium-pressure normal-phase column chromatography (PE / DCM = 1-5%) to afford EVO33173-A1 (500 mg, 59% yield) as a colorless oil. LCMS (ESI) m / z = 197.9 / 199.9 [M+H]+.

[0519] Step 2:

[0520] To a single-necked flask at room temperature were added EVO33173-A1 (180 mg, 0.91 mmol), hexamethyltin (596 mg, 1.82 mmol), Pd(PPh3)4 (105 mg, 0.091 mmol), and 1,4-dioxane (5 mL). The reaction system was replaced with argon three times and then heated to 100°C with stirring for 3 hours. After the reaction was completed, the reaction system was cooled to room temperature, KF (aq.) was added, stirred for 30 minutes, and filtered. The filter cake was washed with EA, the layers were separated, and the organic phases were combined, washed once with water and once with saturated sodium chloride solution, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product EVO33173-A2 (300 mg) as a brown oil.

[0521] Step 3:

[0522] At room temperature, intermediate 2 (120 mg, 0.41 mmol), EVO33173-A2 (230 mg, 0.82 mmol), Pd(PPh3)2Cl2 (58 mg, 0.082 mol), and 1,4-dioxane (5 mL) were added sequentially to a single-necked flask. The reaction system was purged with argon three times and then heated to 110°C with stirring overnight. The reaction system was cooled to room temperature and concentrated to obtain the crude product, which was purified by medium-pressure normal-phase column chromatography (PE / EA = 0-50%) to afford EVO33173-A3 (100 mg, yield: 65%) as a pale yellow oil. LCMS (ESI) m / z = 377.2 [M+H] + .

[0523] Step 4:

[0524] At room temperature, EVO33173-A3 (30 mg, 0.08 mmol) was dissolved in DCM (3 mL), TFA (1.5 mL) was added, and the reaction system was stirred at room temperature for 1 hour. The reaction system was concentrated to obtain the crude product EVO33173-A4 (25 mg) as a pale yellow oil. LCMS (ESI) m / z = 277.2 [M+H] + .

[0525] Step 5:

[0526] EVO33127-A3 (20 mg, 0.083 mmol) and EVO33173-A4 (23 mg, 0.083 mol) were dissolved in DMF (3 mL) at room temperature. TEA (42 mg, 0.42 mmol) and HATU (63 mg, 0.17 mmol) were added sequentially, and the reaction system was stirred at room temperature for 1 hour. The reaction was quenched with water and extracted once with EA. The organic phases were combined, washed once with water and once with saturated sodium chloride solution, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The product was prepared by Prep-HPLC and lyophilized to obtain EVO33173 (20 mg, yield: 48%) as a white solid. LCMS (ESI) m / z = 499.0 [M+H] + , purity: 99.68%, 1 H NMR(400MHz,DMSO-d6)δ9.47(t,J=6.0Hz,1H),9.40(s,1H),8.69-8.60(m,2 H),8.33(d,J=8.0Hz,1H),8.27(s,1H),8.18(s,1H),7.86-7.81(m,2H),7.4 7-7.45(m,1H),4.80(d,J=6.0Hz,2H),3.29-3.28(m,2H),3.23(s,3H),3.02 (t,J=7.6Hz,2H),2.26-2.20(m,1H),2.18-2.10(m,2H),1.12-1.02(m,4H).

[0527] Example 17 EVO33175

[0528] The reference compound EVO33173 was separated by HPLC preparative column and freeze-dried to give a white solid EVO33175 (17 mg, yield: 43%), LCMS (ESI) m / z = 503.0 [M+H] + , purity: 99.74%, 1H NMR(400MHz,DMSO-d6)δ9.48(t,J=6.0Hz,1H),9.41(s,1H),8.72-8.61(m,2H) ,8.27(s,1H),8.20-8.18(m,2H),7.89(t,J=7.6Hz,1H),7.81(s,1H),6.97(d, J=8.2Hz,1H),4.80(d,J=5.6Hz,2H),4.51(q,J=6.8Hz,2H),3.29-3.26(m,2H) ,3.23(s,3H),3.02(t,J=7.6Hz,2H),2.18-2.11(m,2H),1.41(t,J=7.2Hz,3H).

[0529] Example 18 EVO33174

[0530] Step 1:

[0531] In a 25 mL reaction bottle, intermediate 2 (100 mg, 340.62 μmol), EVO33174-A1 (54 mg, 283.85 μmol), freshly dried Cs2CO3 solid (277 mg, 851.55 μmol), Ruphos (26 mg, 56.77 μmol, Ruphos-pd-G3 (24 mg, 28.39 μmol), anhydrous dioxane (5 mL) were added, and the Ar gas was replaced three times. The reaction was carried out in an oil bath at 110 ° C for 2.5 hours. Cooled to room temperature, filtered, the filter cake was rinsed with EA, and the filtrate was concentrated under reduced pressure and passed through a medium pressure column (PE:EA = 0-30%) to obtain a light yellow viscous product EVO33174-A2 (44 mg, yield: 34.6%). 1 H NMR (400MHz, DMSO-d6) δ9.06(s,1H),8.44(d,J=9.2Hz,1H),8.30(d,J=9.2Hz,1H),7.54(t,J=6.0Hz,1H),7.46(s,1H),7.24(d,J=8.0 Hz,1H),6.89(d,J=8.0Hz,1H),4.38-4.36(m,6H),3.54(m,1H),2.25-2.19(m,4H),1.97-1.91(m,1H),1.86-1.79(m,1H),1.43(s,9H).

[0532] Step 2:

[0533] To a 25 mL reaction flask, EVO33174-A2 (39 mg, 87.15 μmol) and DCM (1.0 mL) were added. The mixture was placed in an ice-water bath, protected with Ar, and TFA (0.5 mL) was added. The mixture was stirred in an ice-water bath for 20 minutes, then stirred at room temperature for 1.5 hours. The mixture was concentrated under reduced pressure, EA (10 mL) was added, and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution. Extraction was performed with EA (10 mL x 2). The organic phases were combined, washed once with water and once with saturated sodium chloride solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford EVO33174-A3 (36 mg crude product, yield: >99%). LCMS (ESI) m / z = 348.2 [M+H] + .

[0534] Step 3:

[0535] To a 50 mL reaction vial were added EVO33127-A3 (21 mg, 87.40 μmol), EVO33174-A3 (30 mg, 87.40 μmol), TEA (44 mg, 437.00 μmol, 60.91 μL), and anhydrous DMF (2 mL). Ar was then added, and finally, HATU (66 mg, 174.80 μmol) was added. The mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction system, and the mixture was extracted with EA (15 mL x 3). The combined organic phases were washed once with water and once with saturated sodium chloride solution, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to afford a yellow viscous product. This product was purified by Prep-HPLC and freeze-dried to afford EVO33174 (22 mg, 44.2%) as an off-white solid. LCMS (ESI) m / z = 570.0 [M+H] + , purity: 93.9%, 1 H NMR (400MHz, DMSO-d6) δ9.42(t,J=2.0Hz,1H),9.10(s,1H),8.46(d,J=9.2Hz,1H),8.32(d,J=9.2Hz, 1H),8.27(d,J=1.6Hz,1H),8.17(d,J=1.6Hz,1H),7.49(s,1H),7.24(d,J=8.0Hz,1H),6.89(d,J=8.0H z,1H),4.73(d,J=6.0Hz,2H),4.40-4.26(m,4H),3.59-3.48(m,1H),3.28(t,J=7.2Hz,2H),3.23(s,3H ), 3.02(t,J=7.6Hz,2H),2.27-2.17(m,4H),2.17-2.09(m,2H),2.00-1.87(m,1H),1.87-1.76(m,1H).

[0536] Example 19 EVO33071

[0537] The reference compound EVO33174 was separated by HPLC preparative column and freeze-dried to give a pale yellow solid EVO33071 (8 mg, yield: 17%), LCMS (ESI) m / z = 629.9 [M+H] + , purity: 97.9%, 1 H NMR (400MHz, DMSO-d6) δ9.61(t,J=6.0Hz,1H),9.11(s,1H),8.31(d,J=9.2Hz,1H),8.19(d,J= 9.6Hz,1H),8.15(d,J=1.2Hz,1H),8.01(s,1H),7.53(s,1H),7.33(d,J=8.0Hz,1H),7.12(d,J =8.0Hz,1H),5.00(t,J=17.2Hz,2H),4.75(d,J=6.0Hz,2H),4.53-4.47(m,1H),4.41-4.29(m, 2H),4.16-4.10(m,1H),3.28(s,3H),3.14-3.06(m,1H),2.09-1.98(m,1H),1.98-1.86(m,1H).

[0538] Example 20 EVO33176

[0539] The reference compound EVO33174 was separated by HPLC preparative column and freeze-dried to give a white solid EVO33176 (10 mg, yield: 21%), LCMS (ESI) m / z = 554.0 [M+H] + , purity: 93.4%, 1 H NMR(400MHz,DMSO-d6)δ9.40(t,J=6.0Hz,1H),9.05(s,1H),8.26(s,1H),8.18-8.1 6(m,2H),7.81(d,J=9.2Hz,1H),7.45-7.42(m,2H),6.96(d,J=7.6Hz,1H),4.71(d,J =6.0Hz,2H),4.13-4.02(m,2H),3.29-3.25(m,2H),3.22(s,3H),3.02(t,J=7.6Hz,2 H), 2.76 (d, J = 6.5Hz, 2H), 2.19-2.08 (m, 2H), 2.03-1.89 (m, 3H), 0.89-0.72 (m, 4H).

[0540] Example 21 EVO33177

[0541] Reference compound EVO33174 was separated by HPLC preparative column and freeze-dried to give a pale yellow solid EVO33177 (6 mg, yield: 14%), LCMS (ESI) m / z = 556.4 [M+H] + , purity: 97.7%, 1 H NMR(400MHz,DMSO-d6)δ9.42(t,J=6.0Hz,1H),9.09(s,1H),8.31-8.26(m,2H) ,8.21-8.16(m,2H),7.47(s,1H),7.21(d,J=8.0Hz,1H),6.98(d,J=8.0Hz,1H) ,4.71(d,J=5.6Hz,2H),4.30-4.26(m,4H),3.29-3.25(m,2H),3.22(s,3H),3. 02(t,J=7.6Hz,2H),2.19-2.08(m,2H),2.06-1.95(m,1H),0.90-0.75(m,4H).

[0542] Example 22 EVO33321

[0543] The reference compound EVO33174 was separated by HPLC preparative column and freeze-dried to obtain a white solid EVO33321 (21.52 mg, yield 44.9%), LCMS (ESI) m / z = 568.42 [M+H] + , HPLC purity: 99.65%, 1 H NMR(400MHz, CDCl3)δ9.01(s,1H),8.48(d,J=9.2Hz,1H),8.19(s,1H),8.13–8.05(m ,2H),7.75-7.65(m,2H),7.18(d,J=8.2Hz,1H),7.09(d,J=8.2Hz,1H),4.92(d,J=5.2 Hz,2H),4.54–4.48(m,2H),4.43–4.36(m,2H),3.32(t,J=7.5Hz,2H),3.15(q,J=7.4H z, 2H), 3.04 (t, J = 7.6Hz, 2H), 2.25-2.13 (m, 2H), 2.06 (s, 3H), 1.29 (t, J = 7.4Hz, 3H).

[0544] Example 23 EVO33162

[0545] With reference to compound EVO33138, yellow solid EVO33162 (25 mg, yield: 49%) was obtained. LCMS (ESI) m / z = 590.4 [M+H] + . Purity: 99.42%. 1 H NMR (400MHz, DMSO-d6) δ9.42-9.39(m,2H),8.64(q,J=8.8Hz,2H),7.91-7.89(m,2H),7.80-7.73(m,3H),7.03(d,J=8.4Hz,1H),6.35( s, 2H), 4.77 (d, J = 5.6Hz, 2H), 4.32 (d, J = 12.4Hz, 2H), 3.70-3.65 (m, 2H), 3.38 (q, J = 7.2Hz, 2H), 2.53-2.46 (m, 2H), 1.22-1.16 (m, 9H).

[0546] Example 24 EVO33163

[0547] The reference compound EVO33138 was prepared by prep-HPLC and lyophilized to obtain yellow solid EVO33163 (30 mg, yield: 75%). LCMS (ESI) m / z = 604.4 [M+H] + . Purity: 99.20%. 1 H NMR (400MHz, DMSO-d6) δ9.42-9.39(m,2H),8.64(q,J=8.8Hz,2H),7.92-7.86(m,2H),7.81-7.73(m,3H),7.03(d,J=8.4Hz,1H),6.33 (s,2H),4.77(d,J=5.6Hz,2H),4.32(d,J=12.4Hz,2H),3.70-3.65(m,2H),3.52-3.42(m,1H),2.53-2.47(m,2H),1.25-1.20(m,12H).

[0548] Example 25 EVO33110

[0549] Step 1:

[0550] At room temperature, 4-bromo-2,6-difluorophenylacetic acid (3 g, 11.95 mmol, 1.69 mL) was dissolved in THF (30 mL). CDI (2.91 g, 17.93 mmol) was added. After monitoring for the disappearance of the starting material, sodium borohydride (904.27 mg, 23.90 mmol) was added and stirred overnight. After completion of the reaction, methanol was added to quench the reaction. The solvent was evaporated to dryness, and water (50 mL) was added. The mixture was extracted with EA (3 x 30 mL). The organic phase was concentrated and re-pressed to obtain EVO33110-A1 (1.6 g, yield: 56.84%). 1 H NMR (400MHz, Chloroform-d) δ7.10-7.02 (m, 2H), 3.82 (t, J = 6.7Hz, 2H), 2.90 (d, J = 1.3Hz, 2H).

[0551] Step 2:

[0552] At room temperature, EVO33110-A1 (1.2 g, 5.06 mmol) was dissolved in THF (20 mL), and potassium tert-butoxide (1.70 g, 15.19 mmol) was added. After the reaction was completed, the mixture was washed with saturated sodium chloride solution (20 mL), and the organic phase was concentrated to obtain EVO33110-A2 (400 mg, yield: 36.41%) under medium pressure. 1 H NMR (400MHz, Chloroform-d) δ6.77-6.71 (m, 2H), 4.63 (t, J = 8.7 Hz, 2H), 3.19 (td, J = 8.8, 1.1 Hz, 2H).

[0553] Step 3:

[0554] EVO33110-A2 (240 mg, 1.11 mmol) was dissolved in DMF (5 mL) at room temperature, and sodium thiomethoxide (116.26 mg, 1.66 mmol) was added. The temperature was raised to 120°C overnight. After the reaction, water (50 mL) was added, and the mixture was extracted with EA (3 x 30 mL). The organic phase was concentrated and pressure-pressed to obtain EVO33110-A3 (184 mg, yield: 67.88%).

[0555] Step 4:

[0556] EVO33110-A3 (184 mg, 750.60 μmol) was dissolved in acetonitrile (10 mL) and water (10 mL) at room temperature, and Oxone (460.87 mg, 750.60 μmol) was added. The reaction was incubated at 30°C overnight. After completion of the reaction, the mixture was filtered, the acetonitrile was evaporated, and water (50 mL) was added. The mixture was extracted with EA (3 x 30 mL). The organic phase was concentrated to afford EVO33110-A4 (110 mg, yield: 52.88%), which was used directly in the next step.

[0557] Step 5:

[0558] EVO33110-A4 (110 mg, 396.92 μmol) was dissolved in DMSO (5 mL) and water (0.5 mL) at room temperature. Palladium acetate (17.82 mg, 79.38 μmol), 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) (48.44 mg, 79.38 μmol), and potassium carbonate (164.57 mg, 1.19 mmol) were added. The mixture was incubated at 110°C overnight under a CO atmosphere. After completion of the reaction, EVO33110-A5 (41 mg, 42.64% yield) was obtained by reverse phase reaction.

[0559] Step 6:

[0560] At room temperature, EVO33110-A5 (20 mg, 82.56 μmol) was dissolved in DMF (2 mL), followed by the addition of intermediate 1-A1 (28.85 mg, 82.56 μmol), triethylamine (41.69 mg, 412.80 μmol), and HATU (69.06 mg, 181.63 μmol). The mixture was stirred overnight. After completion of the reaction, water (50 mL) was added to the reaction solution, and the mixture was extracted with EA (3 x 30 mL). The organic phase was concentrated and purified by high pressure to obtain EVO33110 (14 mg, yield: 29.56%). LCMS (ESI) m / z = 574.01 [M+H] + . Purity: 99.25%. 1 H NMR(400MHz,DMSO-d6)δ9.46(t,J=6.0Hz,1H),9.39(s,1H),8.64(q,J=8.8Hz,2H),7.9 6(s,1H),7.91(d,J=7.2Hz,1H),7.79(s,1H),7.77-7.72(m,1H),7.67(s,1H),7.03(d,J =8.4Hz,1H),4.79(d,J=5.6Hz,2H),4.72(t,J=8.8Hz,2H),4.36-4.27(m,2H),3.72-3.6 3(m,2H),3.58(t,J=8.8Hz,2H),3.26(s,3H),2.53-2.47(m,2H),1.21(d,J=6.2Hz,6H).

[0561] Example 26 EVO33357

[0562] The reference compound EVO33110 was separated by HPLC preparative column and freeze-dried to give a yellow solid EVO33357 (1.8 mg, yield: 5.45%), LCMS (ESI) m / z = 588.41 [M+H] + , purity: 92.5%. 1 H NMR (400MHz, DMSO-d6) δ9.46(t,J=5.6Hz,1H),9.39(s,1H),8.64(q,J=8.8Hz,2H),7.91(t, J=4.4Hz,2H),7.80(s,1H),7.75(t,J=8.0Hz,1H),7.68(s,1H),7.03(d,J=8.4Hz,1H),4.79( d,J=5.6Hz,2H),4.71(t,J=8.8Hz,2H),4.38-4.27(m,2H),3.71-3.62(m,2H),3.56(t,J=8.8 Hz, 2H), 3.38-3.37 (m, 2H), 2.53-2.47 (m, 2H), 1.21 (d, J = 6.0Hz, 6H), 1.16 (t, J = 7.2Hz, 3H).

[0563] Example 27 EVO33115

[0564] Step 1:

[0565] 4-Bromo-2-fluoro-6-methylbenzoic acid (4 g, 17.16 mmol) was dissolved in water (40 mL) at room temperature, followed by the addition of KMnO₄ (8.14 g, 51.49 mmol) and NaOH (2.75 g, 68.66 mmol). The reaction was incubated at 80°C overnight. After completion, the reaction was filtered, and the filtrate was acidified with 1N hydrochloric acid to pH 3. The mixture was extracted with EA (3 x 50 mL). The organic phases were combined, dried over anhydrous Na₂SO₄, filtered, and the filtrate was evaporated to dryness to afford EVO33115-A1 (4 g, yield: 88.60%). 1 H NMR (400MHz, DMSO-d6) δ7.95 (dd, J=8.9, 1.8Hz, 1H), 7.85 (d, J=1.8Hz, 1H).

[0566] Step 2:

[0567] EVO33115-A1 (8 g, 30.42 mmol) was dissolved in methanol (150 mL) and concentrated sulfuric acid (14.92 g, 152.08 mmol) and refluxed overnight. After the reaction, the solvent was evaporated, water (100 mL) was added, and extraction was performed with EA (3 x 50 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated to obtain EVO33115-A2 (8.5 g, yield: 96.01%).

[0568] Step 3:

[0569] At 0°C, EVO33115-A2 (8.5 g, 29.20 mmol) was dissolved in anhydrous THF (50 mL), and lithium aluminum tetrahydride (2.44 g, 64.25 mmol) was added. After the reaction was completed, water (5 mL) was added to quench the reaction, and the mixture was filtered. Water (100 mL) was added to the filtrate, and the mixture was extracted with EA (3*50 mL). The organic phase was concentrated and EVO33115-A3 (4.5 g, yield: 65.56%) was prepared under medium pressure.

[0570] Step 4:

[0571] At room temperature, EVO33115-A3 (4.6 g, 19.57 mmol) was dissolved in dichloromethane (50 mL), and manganese dioxide (8.17 g, 93.94 mmol) was added. After the starting material disappeared, the mixture was filtered, and the filtrate was taken. Triethylsilane (6.83 g, 58.71 mmol) and trifluoroacetic acid (10.71 g, 93.94 mmol) were added. After 2 hours, the reaction was completed. After evaporation of the solvent, water (100 mL) was added, and the mixture was extracted with EA (3*50 mL). The organic phase was concentrated and EVO33115-A4 (3.6 g, yield: 84.76%) was prepared under medium pressure.

[0572] Step 5:

[0573] At room temperature, EVO33115-A4 (220 mg, 1.01 mmol) was dissolved in DMF (5 mL), and sodium thiomethoxide (355.24 mg, 5.07 mmol) was added. The reaction temperature was raised to 100°C. After 2 hours, the reaction was completed. Water (30 mL) was added and extracted with EA (3*50 mL). The organic phase was evaporated to dryness to obtain EVO33115-A5 (90 mg, yield: 36.22%), which was used directly in the next step.

[0574] Step 6:

[0575] EVO33115-A5 (260 mg, 1.06 mmol) was dissolved in acetonitrile (10 mL) and water (10 mL) at room temperature, and Oxone (3.26 g, 5.30 mmol) was added. The temperature was then raised to 60°C. The reaction was complete after 1 hour, and the acetonitrile was evaporated. Water (30 mL) was added, and the mixture was extracted with EA (3 x 50 mL). The organic phase was evaporated to dryness to obtain EVO33115-A6 (290 mg, yield: 98.66%), which was used directly in the next step.

[0576] Step 7:

[0577] To EVO33115-A6 (90 mg, 324.75 μmol) was added DMSO (5 mL), water (0.5 mL), palladium acetate (14.58 mg, 64.95 μmol), 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) (39.64 mg, 64.95 μmol), and potassium carbonate (134.65 mg, 974.26 μmol) at room temperature. The reaction was incubated at 100°C under a CO atmosphere overnight. EVO33115-A7 (10 mg, 12.71% yield) was obtained by reverse phase reaction.

[0578] Step 8:

[0579] At room temperature, EVO33115-A7 (10 mg, 41.28 μmol) was dissolved in DMF (2 mL), followed by the addition of intermediate 1-A1 (21.64 mg, 61.92 μmol), DIPEA (21.34 mg, 165.12 μmol), and HATU (23.54 mg, 61.92 μmol). The mixture was stirred overnight. After completion of the reaction, water (50 mL) was added, and the mixture was extracted with EA (3 x 30 mL). The organic phase was concentrated and purified by high pressure to afford EVO33115 (14 mg, yield: 59.12%). LCMS (ESI) m / z = 574.4 [M+H] + . Purity: 98.4%. 1H NMR(400MHz,DMSO-d6)δ9.58(t,J=6.0Hz,1H),9.40(s,1H),8.65(q,J=8.4Hz,2H),8 .37(s,1H),8.25(s,1H),7.90(d,J=7.2Hz,1H),7.83(s,1H),7.79-7.71(m,1H),7.03 (d,J=8.4Hz,1H),5.35(t,J=2.0Hz,2H),5.14(s,2H),4.82(d,J=5.6Hz,2H),4.35-4. 27(m,2H),3.71-3.62(m,2H),3.29(s,3H),2.54-2.47(m,2H),1.21(d,J=6.0Hz,6H).

[0580] Example 28 EVO33369

[0581] The reference compound EVO33115 was separated by HPLC preparative column and freeze-dried to give a yellow solid EVO33369 (10 mg, yield: 36.34%), LCMS (ESI) m / z = 588.4 [M+H] + , purity: 95.8%. 1 H NMR (400MHz, DMSO-d6) δ9.59(t,J=6.0Hz,1H),9.40(s,1H),8.65(q,J=8.4Hz,2H),8.32(s ,1H),8.27(s,1H),7.90(d,J=7.2Hz,1H),7.83(s,1H),7.77-7.73(m,1H),7.03(d,J=8.4Hz ,1H),5.32(s,2H),5.14(s,2H),4.82(d,J=5.6Hz,2H),4.34-4.28(m,2H),3.75-3.62(m,2 H), 3.38 (q, J = 7.2Hz, 2H), 2.53-2.47 (m, 2H), 1.21 (d, J = 6.0Hz, 6H), 1.15 (t, J = 7.2Hz, 3H).

[0582] Example 29 EVO33124

[0583] Step 1:

[0584] 8-Fluoro-2,3-dihydrochromen-4-one (900 mg, 5.42 mmol) and triethylsilane (2.52 g, 21.67 mmol) were added to trifluoroacetic acid (5 mL) and reacted at 25°C for 72 hours. The reaction was monitored by TLC. The reaction solution was concentrated under reduced pressure and purified by medium-pressure normal-phase flash column chromatography to afford EVO33124-A1 (670 mg, 81% yield) as a colorless oil.

[0585] Step 2:

[0586] Compound EVO33124-A1 (530 mg, 3.49 mmol) was added to acetic acid (5 mL), followed by bromine (613 mg, 3.84 mmol). The mixture was allowed to react at 25°C for 15 minutes. After completion of the reaction, the reaction solution was concentrated under reduced pressure and purified by medium-pressure normal-phase flash column chromatography to afford EVO33124-A2 (450 mg, 55% yield) as a colorless oil.

[0587] Step 3:

[0588] Compound EVO33124-A2 (176 mg, 0.76 mmol) and sodium thiomethoxide (80 mg, 1.14 mmol) were added to DMF (2 mL) and reacted at 50°C for 2 hours. After completion of the reaction, EA and water were added to the reaction mixture, and the mixture was separated and extracted. The organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by medium-pressure normal-phase column chromatography (PE / EA = 50 / 1) to obtain the product EVO33124-A3 (165 mg, yield: 83%). 1 H NMR (400MHz, Chloroform-d) δ7.00 (s, 1H), 6.97 (s, 1H), 4.26 (t, J = 5.2Hz 2H), 2.75 (t, J = 6.4Hz, 2H), 2.41 (s, 3H), 2.05-1.94 (m, 2H).

[0589] Step 4:

[0590] EVO33124-A3 (165 mg, 0.64 mmol) was dissolved in acetonitrile (2 mL) and water (2 mL) at room temperature, and solid Oxone (1.17 g, 1.91 mmol) was added. The reaction was stirred overnight. After completion of the reaction, the reaction solution was concentrated, EA and water were added, and the mixture was separated and extracted. The organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The product was purified by medium-pressure normal phase column chromatography (PE / EA = 10 / 1) to obtain the product EVO33124-A4 (176 mg, yield: 94%).

[0591] Step 5:

[0592] At room temperature, EVO33124-A4 (176 mg, 0.604 mmol), Pd(OAc)2 (14 mg, 0.06 mmol), DCCP-2HBF4 (74 mg, 0.121 mmol), K2CO3 (167 mg, 1.21 mmol), H2O (0.1 mL), and DMSO (3 mL) were added sequentially to a single-necked flask. The reaction system was purged with CO3 three times and then heated to 100°C and stirred overnight. After completion of the reaction, the pH was adjusted to 3 with dilute HCl (1 M), and the product was purified by medium-pressure reverse-phase column chromatography (H2O / CH3CN = 0-50%) and lyophilized to obtain EVO33124-A5 (65 mg, yield: 41%) as a white solid. LCMS (ESI) m / z = 255.2 [MH] - .

[0593] Step 6:

[0594] EVO33124-A5 (23 mg, 0.089 mmol) and intermediate 1-A1 (31 mg, 0.089 mmol) were dissolved in DMF (3 mL) at room temperature. DIPEA (35 mg, 0.267 mmol) and HATU (51 mg, 0.134 mmol) were added sequentially, and the reaction system was stirred at room temperature for 1 hour. After completion of the reaction, the reaction system was quenched with water and extracted twice with EA. The organic phases were combined, washed once with water and once with saturated sodium chloride solution, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. After Prep-HPLC preparation, the product was lyophilized to obtain EVO33124 (11 mg, yield: 20%) as a pale yellow solid. LCMS (ESI) m / z = 588.1 [M+H] + . Purity: 99.67%. 1 H NMR(400MHz,DMSO-d6)δ9.39(s,2H),8.68-8.61(m,2H),8.27(s,1H),8.08(s,1H),7.90 (d,J=7.2Hz,1H),7.76(s,1H),7.73(d,J=7.2Hz,1H),7.03(d,J=8.4Hz,1H),4.77(d,J= 5.2Hz,2H),4.42(t,J=5.2Hz,2H),4.35-4.26(m,2H),3.72-3.63(m,2H),3.27(s,3H),2 .94-2.87(d,J=6.4Hz,2H),2.56-2.52(m,2H),2.06-2.00(m,2H),1.21(d,J=6.0Hz,6H).

[0595] Example 30 EVO33025

[0596] The reference compound EVO33168 was separated by HPLC preparative column and freeze-dried to obtain a yellow solid EVO33025 (10 mg, yield: 43.4%), LCMS (ESI) m / z = 586.1 [M+H] + , purity: 99.3%. 1 H NMR (400MHz, DMSO-d6) δ9.57(t,J=6.0Hz,1H),9.41(s,1H),8.74(d,J=1.6Hz,1H),8.68 -8.61(m,2H),8.54(s,1H),8.51(d,J=1.6Hz,1H),7.89(d,J=7.2Hz,1H),7.83(s,1H),7 .72(t,J=8.0Hz,1H),7.02(d,J=8.4Hz,1H),4.85(d,J=5.6Hz,2H),4.31(d,J=12Hz,2H) ,4.20(s,3H),3.70-3.65(m,2H),3.51(s,3H),2.52-2.46(m,2H),1.21(d,J=6.4Hz,6H).

[0597] Example 31 EVO33160

[0598] The reference compound EVO33168 was separated by HPLC preparative column and freeze-dried to obtain a yellow solid EVO33160 (16.31 mg, yield: 29.1%), LCMS (ESI) m / z = 600.6 [M+H] + , purity: 90.5%. 1 H NMR (400MHz, DMSO-d6) δ9.60(t,J=5.9Hz,1H),9.40(s,1H),8.88(d,J=1.8Hz,1H),8.70–8.51(m,4H),7.92-7.82(m,2H),7.73(t,J=7.8Hz,1H ),7.02(d,J=8.5Hz,1H),4.84(d,J=5.8Hz,2H),4.44(s,3H),4.31(d,J=12.7Hz,2H),3.73-3.55(m,4H),2.46-2.41(m,2H),1.23-1.17(m,9H).

[0599] Example 32 EVO33232

[0600] The reference compound EVO33168 was separated by HPLC preparative column and freeze-dried to obtain a yellow solid EVO33232 (21.4 mg, yield: 32.6%), LCMS (ESI) m / z = 603.2 [M+H] + , purity: 92.06%. 1 H NMR(400MHz,DMSO-d6)δ9.84(s,1H),9.72(t,J=6.0Hz,1H),9.41(s,1H),9.21(d,J =1.6Hz,1H),8.69-8.62(m,3H),7.92-7.87(m,2H),7.74(t,J=8.0Hz,1H),7.03(d,J =8.4Hz,1H),4.86(d,J=5.6Hz,2H),4.31(d,J=12.8Hz,2H),3.78(t,J=7.2Hz,2H), 3.71-3.63(m,2H),2.53-2.47(m,2H),1.21(d,J=6.0Hz,6H),1.15(t,J=7.2Hz,3H).

[0601] Example 33 EVO33281

[0602] The reference compound EVO331168 was separated by HPLC preparative column and freeze-dried to obtain a yellow solid EVO33281 (2.3 mg, yield: 2.59%), LCMS (ESI) m / z = 603.2 [M+H] + , purity: 98.44%. 1 H NMR(400MHz,Chloroform-d)δ9.72(s,1H),9.30(s,1H),8.81(d,J=8.4Hz,1H),8.52- 8.42(m,2H),8.25(s,1H),8.16(s,1H),8.09(d,J=7.2Hz,1H),7.86(s,1H),7.74(t,J =8.0Hz,1H),6.84(d,J=8.4Hz,1H),5.05(d,J=5.6Hz,2H),4.70(s,2H),4.21(d,J=12 .4Hz,2H),3.83-3.75(m,2H),3.22(s,3H),2.69-2.59(m,2H),1.33(d,J=6.0Hz,6H).

[0603] Example 34 EVO33313

[0604] The reference compound EVO33168 was separated by HPLC preparative column and freeze-dried to give a yellow solid EVO33313 (15 mg, yield: 40%), LCMS (ESI) m / z = 575.4 [M+H] + , purity: 99.14%. 1 H NMR (400MHz, DMSO-d6) δ9.44-9.40(m,2H),8.64(q,J=8.4Hz,2H),8.53(d,J=1.6Hz,1 H),8.40(s,1H),8.00(d,J=1.6Hz,1H),7.89(d,J=7.2Hz,1H),7.82(s,1H),7.72(t,J =8.4Hz,1H),7.02(d,J=8.4Hz,1H),4.82(d,J=6.0Hz,2H),4.51(s,3H),4.31(d,J=12 .4Hz,2H),3.69-3.64(m,2H),2.52-2.46(m,2H),1.97(s,6H),1.21(d,J=6.4Hz,6H).

[0605] Example 35 EVO33323

[0606] The reference compound EVO33168 was separated by HPLC preparative column and freeze-dried to give a yellow solid EVO33323 (81 mg, yield: 95%), LCMS (ESI) m / z = 586.4 [M+H] + , purity: 95.6%. 1 H NMR (400MHz, DMSO-d6) δ13.80(bs,1H),9.63(t,J=6.0Hz,1H),9.43(s,1H),8.91(d,J=1.6Hz,1H),8.70-8.63(m,2H),8.54(d,J=1.2 Hz,1H),8.50(d,J=1.2Hz,1H),7.92(d,J=7.2Hz,1H),7.87(s,1H),7.73-7.77(m,1H),7.04(d,J=8.4Hz,1H),4.88(d,J=1.4Hz,2H),4.34(d, J=2.4Hz,1H),4.31(d,J=2.4Hz,1H),3.65-3.73(m,2H),3.49-3.55(m,2H),2.48-2.54(m,2H),1.24(d,J=6.4Hz,6H),1.21(t,J=7.2Hz,3H).

[0607] Example 36 EVO33324

[0608] The reference compound EVO33168 was separated by HPLC preparative column and freeze-dried to give a yellow solid EVO33324 (30 mg, yield: 51%), LCMS (ESI) m / z = 599.1 [M+H] + , purity: 88.4%. 1 H NMR(400MHz,Chloroform-d)δ9.34(s,1H),8.89-8.87(m,1H),8.58-8.57(m,1H),8.54-8.52 (m,1H),8.47-8.46(m,2H),8.29-8.23(m,1H),8.13-8.11(m,1H),7.78-7.74(m,1H),6.87(d ,J=8.8Hz,1H).6.81-6.80(m,2H),5.16-5.14(m,2H),4.73-4.67(m,2H),4.22-4.19(m,2H), 3.81-3.77(m,2H),3.38(s,3H),2.68-2.62(m,2H),1.50-1.58(m,3H),1.34(d,J=6.4Hz,6H).

[0609] Example 37 EVO33326

[0610] The reference compound EVO33168 was separated by HPLC preparative column and freeze-dried to obtain a yellow solid EVO33326 (17 mg, yield: 37%), LCMS (ESI) m / z = 585.1 [M+H] + , purity: 99.73%. 1 H NMR(400MHz,Chloroform-d)δ9.88(s,1H),9.24(s,1H),8.62-8.60(m,1H),8.47-8.46(m,1H),8.35 -8.33(m,1H),8.15-8.14(m,1H),8.02-7.99(m,2H),7.69(t,J=8.4Hz,1H),7.63-7.61(m,1H),7.38- 7.37(m,1H),6.76(d,J=8.4Hz,1H).6.73-6.71(m,1H),5.01(d,J=5.2Hz,2H),4.22-4.18(m,2H),3. 81-3.76(m,2H),3.25-3.19(m,2H),2.64-2.59(m,2H),1.32(d,J=6.4Hz,6H),1.26(t,J=7.6Hz,3H).

[0611] Example 38 EVO33327

[0612] The reference compound EVO33168 was separated by HPLC preparative column and then freeze-dried to obtain a yellow solid EVO33327 (5 mg, yield: 22%), LCMS (ESI) m / z = 599.1 [M+H] + , purity: 99.03%. 1 H NMR(400MHz,Chloroform-d)δ9.26(s,1H),8.63-8.61(m,1H),8.50-8.49(m,1H),8.38-8.34(m,2H),8.02-8.00(m,2H ),7.69(t,J=8.4Hz,1H),7.54-7.53(m,1H),7.17-7.16(m,1H),6.78-6.73(m,2H),5.02(d,J=5.6Hz,2H).4.24(s,3H), 4.23-4.19(m,2H),3.81-3.77(m,2H),3.39-3.33(m,2H),2.65-2.59(m,2H),1.37(d,J=7.2Hz,3H),1.32(d,J=6.4Hz,6H).

[0613] Example 39 EVO33330

[0614] The reference compound EVO33168 was separated by HPLC preparative column and freeze-dried to give a yellow solid EVO33330 (14.49 mg, yield: 25%), LCMS (ESI) m / z = 586.4 [M+H] + , purity: 98.6%. 1H NMR(400MHz,DMSO-d6)δ9.65(t,J=6.0Hz,1H),9.43(s,1H),8.74-8.73(m,1H),8.72-8.62(m,2H) ,8.41(d,J=1.6Hz,1H),8.38(d,J=2.4Hz,1H),7.94-7.92(m,1H),7.87(s,1H),7.78-7.74(m,1H) ,7.36(d,J=2.0Hz,1H),7.05(d,J=8.4Hz,1H),4.87(d,J=6.0Hz,2H),4.36-4.32(m,2H),3.74-3. 66(m,2H),3.56(q,J=7.6Hz,2H),2.56-2.48(m,2H),1.24(d,J=6.4Hz,6H),1.20(t,J=7.6Hz,3H).

[0615] Example 40 EVO33331

[0616] The reference compound EVO33168 was separated by HPLC preparative column and freeze-dried to give a yellow solid EVO33331 (9 mg, yield: 36%), LCMS (ESI) m / z = 602.4 [M+H] + , purity: 96.9%. 1 H NMR(400MHz,DMSO-d6)δ9.70(t,J=6Hz,1H),9.44(s,1H),8.92(d,J=1.6Hz,1H),8.73-8.61(m ,2H),8.51(d,J=1.6Hz,1H),8.13(d,J=5.6Hz,1H),7.93(d,J=7.2Hz,1H),7.95-7.88(m,2H),7 .82-7.73(m,2H),7.05(d,J=8.4Hz,1H),4.90(d,J=6.0Hz,2H),4.37-4.30(m,2H),3.76-3.64( m, 2H), 3.48 (d, J = 7.4Hz, 2H), 2.58-2.45 (m, 2H), 1.24 (d, J = 6.0Hz, 6H), 1.17 (t, J = 7.2Hz, 3H).

[0617] Example 41 EVO33356

[0618] The reference compound EVO33168 was separated by HPLC preparative column and freeze-dried to give a yellow solid EVO33356 (27.87 mg, yield: 30%), LCMS (ESI) m / z = 586.4 [M+H] + , purity: 98.4%. 1 H NMR (400MHz, DMSO-d6) δ9.64 (t, J = 6.0 Hz, 1H), 9.41 (s, 1H), 8.72-8.58 (m, 3H), 8.46 (d, J = 2. 0Hz,1H),8.42(d,J=1.2Hz,1H),7.90(d,J=7.6Hz,1H),7.86(s,1H),7.75-7.71(m,1H),7.35 -7.34(m,1H),7.02(d,J=8.4Hz,1H),4.85(d,J=5.6Hz,2H),4.33-4.29(m,2H),3.71-3.63(m ,2H),3.41(q,J=7.6Hz,2H),2.56-2.48(m,2H),1.21(d,J=6.4Hz,6H),1.14(t,J=7.2Hz,3H).

[0619] Example 42 EVO33395

[0620] The reference compound EVO33168 was separated by HPLC preparative column and freeze-dried to give a yellow solid EVO33395 (9.8 mg, yield: 48.8%), LCMS (ESI) m / z = 600.4 [M+H] + , purity: 99.9%. 1 H NMR(400MHz, DMSO-d6)δ9.53(t,J=5.8Hz,1H),9.40(s,1H),8.68-8.60(m,2H),8.59(d, J=1.6Hz,1H),8.45(d,J=1.6Hz,1H),7.90(d,J=7.2Hz,1H),7.82(s,1H),7.72(t,J=7.6H z,1H),7.02(d,J=8.4Hz,1H),4.84(d,J=6.0Hz,2H),4.31(d,J=12.4Hz,2H),4.14(s,3H) ,3.70-3.65(m,2H),3.50(s,3H),2.65(s,3H),2.52-2.47(m,2H),1.21(d,J=6.4Hz,6H).

[0621] Example 43 EVO33362

[0622] The reference compound EVO33173 was separated by HPLC preparative column and freeze-dried to give a yellow solid EVO33362 (15 mg, yield: 53%), LCMS (ESI) m / z = 520.9 [M+H] + , purity: 99.89%. 1 H NMR (400MHz, DMSO-d6) δ9.44-9.41(m,2H),8.72-8.61(m,2H),8.20(d,J=7.6Hz,1H),7.92-7.88(m,2H),7.81-7.80(m,2H),6.98(d,J=8. 4Hz, 1H), 6.35 (s, 2H), 4.78 (d, J = 5.6Hz, 2H), 4.51 (q, J = 7.2Hz, 2H), 3.38 (q, J = 7.2Hz, 2H), 1.41 (t, J = 7.2Hz, 3H), 1.18 (t, J = 7.2Hz, 3H).

[0623] Example 44 EVO33363

[0624] The reference compound EVO33173 was separated by HPLC preparative column and freeze-dried to give a yellow solid EVO33363 (9 mg, yield: 32%), LCMS (ESI) m / z = 516.9 [M+H] + , purity: 99.77%. 1 H NMR (400MHz, DMSO-d6) δ9.44-9.41(m,2H),8.70-8.60(m,2H),8.34(d,J=7.6Hz,1H),7.90-7.80(m,4H),7.47(d,J=8.0Hz,1 H), 6.35 (s, 2H), 4.78 (d, J = 5.6Hz, 2H), 3.38 (q, J = 7.2Hz, 2H), 2.26-2.20 (m, 1H), 1.18 (t, J = 7.2Hz, 3H), 1.12-1.03 (m, 4H).

[0625] Example 45 EVO33364

[0626] The reference compound EVO33173 was separated by HPLC preparative column and then freeze-dried to obtain a yellow solid EVO33364 (10.8 mg, yield: 20.5%), LCMS (ESI) m / z = 588.4 [M+H] + , purity: 92.7%. 1H NMR (400MHz, DMSO-d6) δ9.42-9.39 (m, 2H), 8.63 (q, J = 8.0Hz, 2H), 7.93-7.87 (m,2H),7.82-7.77(m,2H),7.73(t,J=8.0Hz,1H),6.91(d,J=8.4Hz,1H),6.3 5(s,2H),4.78(d,J=5.6Hz,2H),4.49(s,2H),4.00(d,J=12.4Hz,2H),3.38(q ,J=7.2Hz,2H),3.07-3.03(m,2H),1.93-1.74(m,4H),1.18(t,J=7.2Hz,3H).

[0627] Example 46 EVO33390

[0628] The reference compound EVO33173 was separated by HPLC preparative column and freeze-dried to obtain a yellow solid EVO33390 (18.8 mg, yield: 12.6%), LCMS (ESI) m / z = 556.7 [M+H] + , purity: 99.95%. 1 H NMR(400MHz,Chloroform-d)δ9.31(s,1H),8.75(d,J=8.7Hz,1H),8.45(d,J=8.7Hz,1 H),8.16(s,1H),8.09(d,J=7.4Hz,1H),7.83-7.73(m,2H),7.71(d,J=1.8Hz,1H),7.3 8(d,J=1.8Hz,1H),6.85(d,J=8.4Hz,1H),6.09(s,2H),5.04(d,J=5.5Hz,2H),4.29-4 .20(m,2H),3.88-3.78(m,2H),2.72-2.63(m,2H),1.67(s,6H),1.38(d,J=6.2Hz,6H).

[0629] Example 47 EVO33396

[0630] The reference compound EVO33173 was separated by HPLC preparative column and freeze-dried to give a yellow solid EVO33396 (17.4 mg, yield: 38%), LCMS (ESI) m / z = 590.4 [M+H] + , purity: 99.49%. 1H NMR(400MHz,DMSO-d6)δ9.45-9.34(m,2H),8.70-8.58(m,2H),7.92-7.87(m ,2H),7.81(d,J=1.6Hz,1H),7.79-7.78(m,1H),7.75-7.71(m,1H),7.01(d,J =8.4Hz,1H),6.35(s,2H),4.78(d,J=5.6Hz,2H),4.12-4.05(m,2H),3.76(d ,J=3.2Hz,1H),3.72(d,J=3.6Hz,1H),3.42-3.33(m,4H),1.25-1.14(m,9H).

[0631] Example 48 EVO33397

[0632] The reference compound EVO33173 was separated by HPLC preparative column and freeze-dried to give a yellow solid EVO33397 (13.09 mg, yield: 12%), LCMS (ESI) m / z = 590.2 [M+H] + , purity: 96.6%. 1 H NMR(400MHz,Chloroform-d)δ9.27(s,1H),8.68-8.66(m,1H),8.40-8.37(m,1 H),8.02-8.00(m,2H),7.82-7.81(m,1H),7.72-7.68(m,2H),7.61-7.56(m,1H ),6.76(d,J=8.4Hz,1H),6.24(s,2H),4.98(d,J=5.2Hz,2H),4.22-4.18(m,2H ),3.80-3.76(m,2H),3.81-3.77(m,2H),3.36-3.26(m,2H),1.35-1.30(m,9H).

[0633] Example 49 EVO33399

[0634] The reference compound EVO33173 was separated by HPLC preparative column and freeze-dried to give a yellow solid EVO33399 (24.5 mg, yield: 52%), LCMS (ESI) m / z = 576.4 [M+H] + , purity: 99.33%. 1H NMR(400MHz,Chloroform-d)δ9.27(s,1H),8.69(d,J=8.8Hz,1H),8.38(d,J=8.8 Hz,1H),8.06-8.01(m,2H),7.83(d,J=1.6Hz,1H),7.75-7.63(m,3H),6.75(d,J=8 .4Hz,1H),6.24(s,2H),4.98(d,J=5.2Hz,2H),4.47-4.41(m,1H),4.12-4.00(m, 2H),3.89-3.81(m,2H),3.73-3.65(m,1H),3.39-3.25(m,3H),1.37-1.30(m,6H).

[0635] Example 50 EVO33402

[0636] The reference compound EVO33173 was separated by HPLC preparative column and freeze-dried to give a yellow solid EVO33402 (4.18 mg, yield: 9.7%), LCMS (ESI) m / z = 556.3 [M+H] + , purity: 98.4%. 1 H NMR(400MHz,Chloroform-d)δ9.27(s,1H),8.61-8.60(m,1H),8.39(d,J=8.8Hz,1H),8.1 7-8.10(m,2H),8.08(s,1H),7.98-7.95(m,1H),7.83(d,J=1.6Hz,1H),7.70(d,J=1.6Hz,1 H),7.66(s,1H),7.59(t,J=7.6Hz,1H),7.44(d,J=2.4Hz,1H),6.67(d,J=2.4Hz,1H),6.24 (s, 2H), 4.99 (d, J = 5.2Hz, 2H), 4.00 (s, 3H), 3.29 (q, J = 7.6Hz, 2H), 1.34 (t, J = 7.2Hz, 3H).

[0637] Example 51 EVO33404

[0638] The reference compound EVO33173 was separated by HPLC preparative column and freeze-dried to give a yellow solid EVO33404 (18.2 mg, yield: 47%), LCMS (ESI) m / z = 573.4 [M+H] + , purity: 98.10%. 1H NMR(400MHz,Chloroform-d)δ9.53-9.33(m,1H),8.53-8.30(m,2H),8.05-7.94(m,1H),7.87-7.74(m,2H),7.69-7.30(m,5H),6.22 (s,2H),5.10(d,J=6.2Hz,2H),4.45-4.32(m,2H),3.82-3.72(m,2H),3.38-3.33(m,3H),3.30-3.25(m,2H),1.36-1.29(m,3H).

[0639] Example 52 EVO33502

[0640] The reference compound EVO33173 was separated by HPLC preparative column and freeze-dried to obtain a yellow solid EVO33502 (4.1 mg, yield: 12%), LCMS (ESI) m / z = 562.1 [M+H] + , purity: 99.43%. 1 H NMR (400MHz, DMSO-d6) δ9.39(q,J=2.8Hz,2H),8.71-8.55(m,2H),7.97-7.86(m,2H),7.82-7.74(m,3H),7.03(d,J=8.4Hz,1H ), 6.35 (s, 2H), 4.78 (d, J = 5.7Hz, 2H), 3.79-3.74 (m, 4H), 3.60 (t, J = 4.8Hz, 4H), 3.38 (q, J = 7.2Hz, 2H), 1.18 (t, J = 7.2Hz, 3H).

[0641] Example 53 EVO33503

[0642] The reference compound EVO33173 was separated by HPLC preparative column and freeze-dried to obtain a yellow solid EVO33503 (2.1 mg, yield: 4.5%), LCMS (ESI) m / z = 576.3 [M+H] + , purity: 99.35%. 1H NMR (400MHz, DMSO-d6) δ9.44-9.34 (m, 2H), 8.64 (q, J = 8.8Hz, 2H), 7.94-7. 87(m,2H),7.83-7.72(m,3H),7.03(d,J=8.4Hz,1H),6.35(s,2H),4.78(d, J=5.6Hz,2H),4.33-4.18(m,2H),4.01-3.93(m,1H),3.67-3.56(m,2H),3. 43-3.37(m,2H),2.97-2.85(m,1H),2.63-2.55(m,1H),1.23-1.16(m,6H).

[0643] Example 54 EVO33506

[0644] The reference compound EVO33173 was separated by HPLC preparative column and freeze-dried to obtain a yellow solid EVO33506 (21.6 mg, yield: 22.5%), LCMS (ESI) m / z = 576.2 [M+H] + , purity: 98.69%. 1 H NMR (400MHz, DMSO-d6) δ9.44-9.33(m,2H),8.65(d,J=8.6Hz,1H),8.59(d,J=8.6Hz ,1H),7.90(d,J=1.7Hz,1H),7.85-7.77(m,3H),7.73-7.66(m,1H),6.88(d,J=8.4Hz ,1H),6.35(s,2H),4.78(d,J=5.8Hz,2H),3.93-3.87(m,2H),3.86-3.77(m,4H),3.6 3(t,J=5.5Hz,2H),3.38(q,J=7.3Hz,2H),1.99-1.91(m,2H),1.19(t,J=7.3Hz,3H).

[0645] Example 55 EVO33179

[0646] The reference compound EVO33174 was separated by HPLC preparative column and freeze-dried to give a yellow solid EVO33179 (10 mg, yield: 26%), LCMS (ESI) m / z = 574.1 [M+H] + , purity: 99.73%. 1H NMR(400MHz,DMSO-d6)δ9.35(t,J=6.0Hz,1H),9.09(s,1H),8.29(d,J=9.2Hz,1H),8.1 9(d,J=8.2Hz,1H),7.88(d,J=1.6Hz,1H),7.79(d,J=1.6Hz,1H),7.47(s,1H),7.21(d,J =8.0Hz,1H),6.98(d,J=8.0Hz,1H),6.35(s,2H),4.69(d,J=6.0Hz,2H),4.31-4.27(m,4 H), 3.37 (q, J = 7.2Hz, 2H), 2.04-1.97 (m, 1H), 1.17 (t, J = 7.2Hz, 3H), 0.88-0.76 (m, 4H).

[0647] Example 56 EVO33361

[0648] The reference compound EVO33174 was separated by HPLC preparative column and then freeze-dried to obtain a yellow solid EVO33361 (16 mg, yield: 47.5%), LCMS (ESI) m / z=577.9 [M+H]+, purity: 99.3%. 1 H NMR(400MHz,DMSO-d6)δ9.36(t,J=5.9Hz,1H),9.10(s,1H),8.32(s,2H),7.88( d,J=1.6Hz,1H),7.79(d,J=1.7Hz,1H),7.48(s,1H),7.32(d,J=8.6Hz,1H),6.4 6(d,J=8.5Hz,1H),6.35(s,2H),4.70(d,J=5.8Hz,2H),4.28(s,4H),4.17(q,J= 7.0Hz, 2H), 3.37 (q, J = 7.4Hz, 2H), 1.28 (t, J = 7.0Hz, 3H), 1.18 (t, J = 7.4Hz, 3H).

[0649] Example 57 EVO33240

[0650] Step 1:

[0651] At room temperature, m-bromobenzylamine (1.0 g, 5.37 mmol), Na2CO3 (1.14 g, 10.75 mmol), Boc2O (1.29 g, 5.91 mmol) and THF (20 mL) were stirred at room temperature for 2 hours. The reaction was completed after LC-MS monitoring. Water (30 mL) was added and extracted with EA (30 mL*3). The organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to give EVO33240-A1 (1.15 g, crude) as a white solid. LCMS (ESI) m / z = 286.1 [M+H] + .

[0652] Step 2:

[0653] Under N2 protection, EVO33240-A1 (130 mg, 454.28 μmol), (2S, 6R)-2,6-dimethyl-4-(6-vinyl-2-pyridyl)morpholine (99.17 mg, 454.28 μmol), Pd(OAc)2 (10.20 mg, 45.43 μmol), tri-o-tolylphosphine (27.65 mg, 90.86 μmol), triethylamine (137.91 mg, 1.36 mmol) and DMF (2 mL) were added, and the mixture was heated to 40 ℃. The mixture was heated to 120°C. After 5 hours, a small amount of starting material remained. The mixture was cooled to room temperature and filtered through celite. Water (30 mL) was added to the filtrate, and the mixture was extracted with EA (30 mL*3). The organic phase was washed with saturated sodium chloride solution (30 mL*3), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated and purified by medium-pressure normal phase column chromatography (PE / EA=0-50%) to give EVO33240-A2 (50 mg, yield: 26%) as a light yellow solid. LCMS (ESI) m / z=424.3 [M+H] + .

[0654] Step 3:

[0655] EVO33240-A2 (50 mg, 118.05 μmol) was stirred in DCM (5 mL) and TFA (40.38 mg, 354.15 μmol) at room temperature for 2 hours. The reaction was monitored by LC-MS. The product was concentrated under reduced pressure to remove most of the TFA and lyophilized to obtain a yellow oil, EVO33240-A3 (50 mg, crude), which was directly used in the next step. LCMS (ESI) m / z = 324.1 [M+H] + .

[0656] Step 4:

[0657] At room temperature, 7-(Ethylsulfonyl)benzo[d][1,3]dioxolane-5-carboxylic acid (22.47 mg, 92.76 μmol) was dissolved in DMF (7.94 mL). DIPEA (59.94 mg, 463.78 μmol) and HATU (52.90 mg, 139.13 μmol) were added and stirred for 5 minutes. EVO33240-A3 (30 mg, 92.76 μmol) was added and stirred continuously for 3 hours. The reaction was completed after 3 hours. Water (20 mL) was added to the system and the mixture was extracted with ethyl acetate (30 mL*3). The combined organic phases were washed three times with brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was then prepared by preparative liquid chromatography, concentrated, and lyophilized to obtain the white product EVO33240 (5 mg, yield: 9.6%). LCMS (ESI) m / z = 564.1 [M+H] + ; Purity: 96.14%. 1 H NMR (400MHz, DMSO-d6) δ9.17(t,J=6.0Hz,1H),7.82(d,J=1.6Hz,1H),7.73(d,J=1.6Hz,1H),7.6 0-7.50(m,4H),7.35(t,J=7.6Hz,1H),7.25(d,J=7.6Hz,1H),7.17-7.09(m,1H),6.82(d,J=7.2H z,1H),6.75(d,J=8.4Hz,1H),6.33(s,2H),4.49(d,J=5.6Hz,2H),4.27-4.18(m,2H),3.67-3.61 (m,2H),3.36(t,J=7.2Hz,2H),2.45-2.37(m,2H),1.18(d,J=6.4Hz,6H),1.15(t,J=7.2Hz,3H).

[0658] Example 58 EVO33343

[0659] The reference compound EVO33240 was separated by HPLC preparative column and freeze-dried to give a yellow solid EVO33343 (2.6 mg, yield: 6.2%), LCMS (ESI) m / z = 665.6 [M+H] + , purity: 97.71%. 1H NMR (400MHz, DMSO-d6) δ9.22(t,J=5.8Hz,1H),8.49(d,J=5.0Hz,1H),7.84(d,J=1.6Hz,1H),7.76(d,J=1.6Hz,1H),7.60-7.50(m, 4H),7.42-7.34(m,1H),6.87(d,J=7.3Hz,1H),6.81(d,J=8.6Hz,1H),6.33(s,2H),4.57(d,J=5.8Hz, 2H),4.28-4.21(m,2H),3.67-3.56(m,2H),3.40-3.36(m,2H),2.45-2.35(m,2H),1.20-1.15(m,9H).

[0660] Example 59 & Example 60 EVO33338 & EVO33339

[0661] Step 1:

[0662] 5-Bromo-1,3-difluoro-2-nitrobenzene (10 g, 42.02 mmol), K2CO3 (29.04 g, 210.10 mmol), benzylamine (4.50 g, 42.02 mmol), and THF (500 mL) were stirred at room temperature for 3 hours. TLC (PE / DCM = 5 / 1) showed the disappearance of the starting benzylamine, with a small amount of bisfluoride remaining. The mixture was filtered, the filter cake washed with EA, and crude silica gel was added to the filtrate, which was then spin-dried. Purification by medium-pressure normal-phase column chromatography (PE / DCM = 0-20%) afforded EVO33338-A1 (10.3 g, yield: 75.39%) as a yellow solid. LCMS (ESI) m / z = 324.8 / 326.8 [M+H] + .

[0663] Step 2:

[0664] Under argon, EVO33338-A1 (9.9 g, 30.45 mmol), sodium ethanethiolate (3.84 g, 45.67 mmol), and THF (200 mL) were stirred in an oil bath at 25°C overnight. TLC (PE / DCM = 4 / 1) showed that a small amount of starting material had not reacted completely. Water (300 mL) and saturated sodium chloride solution (100 mL) were added, and the mixture was extracted three times with EA. The combined organic phases were washed once with water and once with saturated sodium chloride solution, dried over anhydrous Na2SO4, filtered, and the filtrate was spin-dried to give EVO33338-A2 (11.1 g, crude) as an orange-red solid. LCMS (ESI) m / z = 366.8 / 368.8 [M+H] + .

[0665] Step 3:

[0666] To a reaction flask, EVO33338-A2 (11.1 g, 30.22 mmol), CH3CN (200 mL), water (200 mL), and Oxone (55.74 g, 90.67 mmol) were added and stirred in an oil bath at 35°C over the weekend. LC-MS showed approximately 25% sulfoxide and 75% product. Additional Oxone (27.87 g, 45.34 mmol), CH3CN (100 mL), and water (100 mL) were added and stirred in an oil bath at 35°C overnight. LC-MS showed approximately 11% sulfoxide. The solvent was evaporated, and water (200 mL) was added. After stirring for a short time, the mixture was filtered and washed with water. The filter cake was collected, dissolved in DCM, and purified by medium-pressure normal-phase column chromatography (PE / EA = 0-40%) to afford EVO33338-A3 (10.3 g, crude) as an orange solid. LCMS(ESI)m / z=398.8 / 400.8[M+H] + .

[0667] Step 4:

[0668] To EVO33338-A3 (3 g, 7.51 mmol) was added Pd(dppf)Cl2-CH2Cl2 (613.61 mg, 751.39 μmol), DMF (50 mL), MeOH (50 mL), and TEA (2.28 g, 22.54 mmol, 3.14 mL) at room temperature. The reaction system was purged with CO3 three times and stirred in an oil bath at 80°C overnight. TLC (PE / EA = 3 / 1) showed near-complete conversion of the starting material. The MeOH was evaporated, water was added, and the mixture was extracted three times with EA. The combined organic phases were washed three times with water and once with saturated sodium chloride solution. The organic phase was then spin-dried and purified by medium-pressure normal-phase column chromatography (PE / EA = 0-25%) to afford EVO33338-A4 (980 mg, crude) as an orange-yellow oil.

[0669] Step 5:

[0670] MeOH (30 mL) and Pd(OH)2 (20%) (200 mg, 1.42 mmol) were added to EVO33338-A4 (980 mg, 2.59 mmol) at room temperature. After H2 substitution, the mixture was stirred at room temperature for 3 hours. LC-MS indicated the reaction was complete. The mixture was filtered through Celite, washed with MeOH, and the filtrate was dried. The mixture was then purified by medium-pressure normal-phase column chromatography (DCM / MeOH = 0-5%) to afford EVO33338-A5 (566 mg, yield: 84.61%) as an off-white solid. LCMS (ESI) m / z = 258.9 [M+H] + .

[0671] Step 6:

[0672] Under argon, EVO33338-A5 (565 mg, 2.19 mmol), CH3CN (18 mL), and isoamyl nitrite (384.38 mg, 3.28 mmol, 439.29 μL) were stirred in an oil bath at 60°C for 1 hour. LC-MS indicated the reaction was complete. The mixture was spin-dried, MTBE (30 mL) was added, and after sonication, the mixture was stirred for a short time. The mixture was filtered with suction, washed with a small amount of MTBE, and the filter cake collected. The filtrate was spin-dried, slurried with PE / EA (1 / 2), filtered with suction, washed with a small amount of PE / EA (1 / 1), and the filter cake collected. The two filter cakes were combined to give EVO33338-A6 (490 mg, yield: 83%) as a light gray solid. LCMS (ESI) m / z = 269.8 [M+H] + .

[0673] Step 7:

[0674] Under Ar protection, EVO33338-A6 (400 mg, 1.49 mmol) and anhydrous DMF (16 mL) were added to a three-necked flask under ice-water bath. NaH (60%) (76 mg, 1.9 mmol) was added and stirred for 1 hour. CHCl (560 mg, 3.95 mmol, 245.6 μL) was added dropwise and stirred under ice-water bath for 1 hour. TLC (PE / EA = 1 / 1) showed complete reaction. The product was quenched with saturated NH4Cl solution and extracted three times with EA. The combined organic phases were washed twice with water and once with saturated sodium chloride solution. The organic phase was evaporated to dryness to obtain the crude product. Purification by medium-pressure normal phase column chromatography (PE / EA = 0-50%) revealed two peaks. Fractions were collected and concentrated under reduced pressure to yield: A: EVO33338-A7 (38 mg) as a white solid. LCMS (ESI) m / z = 283.9 [M+H] + B: Off-white solid (109 mg), slurried with PE / EA = 1 / 1 (6 mL) at room temperature for 10 min, filtered, washed, and collected to obtain an off-white solid EVO33339-A1 (97 mg), LCMS (ESI) m / z = 283.9 [M+H] + .

[0675] Step 8:

[0676] At room temperature, EVO33338-A7 (35 mg, 123.54 μmol), THF (2 mL), MeOH (1 mL), and water (1 mL) were added. The mixture was stirred in an oil bath at 40°C until dissolved. NaOH (34.59 mg, 864.80 μmol) was added and stirring continued for 2 hours. TLC (PE / EA = 1 / 2) showed complete reaction of the starting material. The organic solvent was evaporated, water (6 mL) was added, and the pH was adjusted to ~1 with 2N dilute HCl solution. The precipitated solid was filtered, washed with water until neutral, and drained. The filter cake was collected to yield EVO33338-A8 (26 mg, yield: 78.16%) as a white solid. LCMS (ESI) m / z = 270.2 [M+H] + ,268.2[M+H] - .

[0677] Referring to EVO33338-A8, a white solid EVO33339-A2 (26 mg, yield: 68.39%) was obtained. LCMS (ESI) m / z = 270.2 [M+H] + ,268.2[M+H] - .

[0678] Step 9:

[0679] At room temperature, intermediate 1-A1 (25.95 mg, 67.26 μmol), EVO33338-A8 (20 mg, 74.27 μmol), DMF (3 mL), DIPEA (95.99 mg, 742.73 μmol, 129.37 μL), and HATU (33.89 mg, 89.13 μmol) were added and stirred in an oil bath at 30°C for 40 minutes. EA was added, and the mixture was washed sequentially with water and saturated sodium chloride solution. The organic phase was then spin-dried to dryness. The residue was purified by medium-pressure normal-phase column chromatography (DCM / MeOH = 0-3%) to afford a crude yellow solid (28 mg). CH3CN (4 mL) was added, the mixture was slurried at room temperature, and filtered with suction. A small amount of CH3CN was washed and dried, and the filter cake was collected to afford EVO33338 (25 mg, yield: 56.03%) as a yellow-green solid. LCMS (ESI) m / z = 601.1 [M+H] + .HPLC purity: 98.0%. 1H NMR (400MHz, DMSO-d6) δ9.75(t,J=6.0Hz,1H),9.41(s,1H),9.16(d,J=1.6Hz,1H),8.70-8.61(m,3H),7.94-7.86(m,2H),7.73(t,J=8.0Hz,1H ),7.03(d,J=8.4Hz,1H),4.87(d,J=5.8Hz,2H),4.62(s,3H),4.31(d,J=11.6Hz,2H),3.72-3.58(m,4H),2.54-2.46(m,2H),1.25-1.17(m,9H).

[0680] With reference to EVO33338, the product was separated by HPLC preparative column and freeze-dried to obtain a yellow solid EVO33339 (20 mg, yield: 44.83%). LCMS (ESI) m / z = 601.1 [M+H] + . Purity: 97.6%. 1 H NMR(400MHz,DMSO-d6)δ9.74(t,J=6.0Hz,1H),9.41(s,1H),9.03(s,1H),8.65( q,J=8.4Hz,2H),8.54(s,1H),7.94-7.86(m,2H),7.73(t,J=8.0Hz,1H),7.02(d ,J=8.4Hz,1H),4.87(d,J=6.0Hz,2H),4.67(s,3H),4.31(d,J=10.4Hz,2H),3.7 3-3.55(m,4H),2.54-2.46(m,2H),1.21(d,J=6.2Hz,6H),1.15(t,J=7.2Hz,3H).

[0681] Example 61 EVO33341

[0682] Step 1:

[0683] Compound EVO3337-A6 (790 mg, 3.06 mmol) and TEA (1.55 g, 15.29 mmol) were added to anhydrous DCM (5 mL), and SOCl2 (1.09 g, 9.18 mmol) was slowly added dropwise. The reaction was allowed to react at 50°C for 2 hours. After completion of the reaction, DCM and water were added to the reaction mixture, and the mixture was separated and extracted. The organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by medium-pressure normal-phase column chromatography (PE / EA = 5 / 1) to obtain the product EVO33341-A1 (650 mg, yield: 74%). 1H NMR (400MHz, Chloroform-d) δ9.03 (d, J = 1.6 Hz, 1H), 8.95 (d, J = 1.6 Hz, 1H), 4.06 (s, 3H), 3.67 (q, J = 7.6 Hz, 2H), 1.32 (t, J = 7.6 Hz, 3H).

[0684] Step 2:

[0685] To a 25 ml vial was added EVO33341-A1 (650 mg, 2.27 mmol), THF (5 mL), Methanol (5 mL), water (2 mL), and LiOH (476 mg, 11.35 mmol) and stirred at 25°C for 2 hours. After completion of the reaction, the pH was adjusted to 3 with dilute HCl (1 N) and the product was purified by medium-pressure reverse-phase column chromatography (H2O / CH3CN = 0-50%) and lyophilized to afford EVO3341-A2 (540 mg, yield: 87%) as a white solid. LCMS (ESI) m / z = 271.2 [MH] - .

[0686] Step 3:

[0687] EVO33341-A2 (30 mg, 0.109 mmol) and intermediate 1-A1 (38 mg, 0.109 mmol) were dissolved in DMF (3 mL) at room temperature. DIPEA (42 mg, 0.326 mmol) and HATU (62 mg, 0.163 mmol) were added sequentially, and the reaction system was stirred at room temperature for 1 hour. After completion of the reaction, the reaction system was quenched with water and extracted twice with EA. The organic phases were combined, washed once with water and once with saturated sodium chloride solution, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. After Prep-HPLC preparation, the product was lyophilized to obtain EVO33341 (18 mg, yield: 27%) as a pale yellow solid. LCMS (ESI) m / z = 604.4 [M+H] + . Purity: 99.16%. 1H NMR(400MHz,Chloroform-d)δ9.30(s,1H),8.91(d,J=1.6Hz,1H),8.85(d,J=1.6Hz,1 H),8.70(d,J=8.8Hz,1H),8.42(d,J=8.8Hz,1H),8.11-8.07(m,2H),8.06(d,J=7.6Hz ,1H),7.76-7.69(m,1H),6.80(d,J=8.4Hz,1H),5.07(d,J=5.2Hz,2H),4.25-4.17(m, 2H), 3.84-3.75 (m, 2H), 3.67 (q, J = 7.6Hz, 2H), 2.67-2.58 (m, 2H), 1.35-1.30 (m, 9H).

[0688] Example 62 EVO33349

[0689] Step 1:

[0690] Under Ar protection, methyl 8-bromo-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylate (800 mg, 3.12 mmol), ethyl S-methylthioate (1.41 g, 15.62 mmol), tris(dibenzylideneacetone)dipalladium (286 mg, 312 μmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (361 mg, 624 μmol), and potassium phosphate (1.99 g, 9.37 mmol) were added to a mixture of tert-butyl alcohol (0.5 mL) and toluene (5 mL) and reacted at 110°C for 24 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure and purified by medium-pressure normal phase flash column chromatography to afford EVO33349-A2 (350 mg, 50% yield) as a white solid. LCMS (ESI) m / z = 224.1 [M+H] + .

[0691] Step 2:

[0692] EVO33349-A2 (350 mg, 1.57 mmol) was dissolved in acetonitrile (5 mL) and water (5 mL) at room temperature, and solid Oxone (2.89 g, 4.70 mmol) was added. The reaction was stirred overnight. After completion of the reaction, the reaction solution was concentrated, EA and water were added, and the mixture was separated and extracted. The organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by medium-pressure normal phase column chromatography (PE / EA = 3 / 1) to obtain EVO33349-A3 (220 mg, yield: 54%) as a white solid. LCMS (ESI) m / z = 256.1 [M+H] + .

[0693] Step 3:

[0694] EVO33349-A3 (220 mg, 862 μmol), THF (2 mL), Methanol (2 mL), water (1 mL), and LiOH (108 mg, 2.59 mmol) were added to the reaction flask and stirred at 25°C for 2 hours. After completion of the reaction, the pH was adjusted to 3 with dilute HCl (1N). The product was purified by medium-pressure reverse-phase column chromatography (H2O / CH3CN = 0-50%) and lyophilized to obtain EVO3349-A4 (130 mg, yield: 62%) as a white solid. LCMS (ESI) m / z = 240.2 [MH] - .

[0695] Step 4:

[0696] EVO33349-A4 (25 mg, 0.103 mmol) and intermediate 1-A1 (36 mg, 0.103 mmol) were dissolved in DMF (3 mL) at room temperature. DIPEA (40 mg, 0.311 mmol) and HATU (59 mg, 0.155 mmol) were added sequentially and stirred at room temperature for 1 hour. After completion of the reaction, the mixture was quenched with water and extracted twice with EA. The organic phases were combined, washed once with water and once with saturated sodium chloride solution, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. After Prep-HPLC preparation, the product was lyophilized to obtain EVO33349 (6 mg, yield: 10%) as a pale yellow solid. LCMS (ESI) m / z = 572.9 [M+H] + . Purity: 99.90%. 1 H NMR(400MHz,Chloroform-d)δ9.54(d,J=1.6Hz,1H),9.28(s,1H),8.67(d,J=3.2Hz,1H),8 .66(d,J=3.6Hz,1H),8.59(s,1H),8.40(d,J=8.4Hz,1H),8.03(d,J=7.2Hz,1H),8.00(s,1 H),7.88-7.84(m,1H),7.74-7.69(m,1H),6.79(d,J=8.4Hz,1H),5.02(d,J=4.9Hz,2H),4. 25-4.17(m,2H),3.83-3.76(m,2H),3.53(s,3H),2.68-2.61(m,2H),1.33(d,J=6.4Hz,6H).

[0697] Example 63 EVO33350

[0698] The reference compound EVO33349 was separated by HPLC preparative column and freeze-dried to give a yellow solid EVO33350 (28 mg, yield: 36%), LCMS (ESI) m / z = 572.4 [M+H] + , purity: 99.97%, 1 H NMR (400MHz, DMSO-d6) δ9.69(s,1H),9.58(s,1H),9.41(s,1H),8.69-8.60(m,2H),8.42(s,1H),8.32(s,1H),7.92-7.84(m,3H),7.74(t,J=8.0 Hz,1H),7.02(d,J=8.0Hz,1H),4.88-4.80(m,2H),4.35-4.26(m,2H),3. 72-3.62(m,2H),3.58(s,3H),2.66-2.60(m,2H),1.21(d,J=5.6Hz,6H).

[0699] Example 64 EVO33383

[0700] Step 1:

[0701] At room temperature, a reaction flask was charged with 7-bromobenzo[D][1,3]dioxolane-5-carboxylic acid (900 mg, 3.67 mmol), K2CO3 (1.02 g, 7.35 mmol), and DMF (10 mL). CH3I (1.04 g, 7.35 mmol) was then added dropwise, and the mixture was stirred at room temperature for 16 hours. Saturated ammonium chloride solution was slowly added dropwise to the reaction mixture, resulting in the precipitation of a white solid. The solid was filtered, and the filter cake was rinsed with water (5 mL x 3). The filter cake was then dried to afford EVO33383-A1 (936 mg, 98.4% yield) as a white solid.

[0702] Step 2:

[0703] At room temperature, EVO33383-A1 (400 mg, 1.54 mmol), benzyl mercaptan (230.14 mg, 1.85 mmol), DIPEA (598.67 mg, 4.63 mmol, 806.84 μL) and anhydrous 1,4-dioxane (5 mL) were added to the reaction flask, and Ar substitution was performed. Xantphos (178.69 mg, 308.82 μmol) and Pd2(dba)3 (141.39 mg, 154.41 μmol) were added, and Ar substitution was performed again. The mixture was heated in an oil bath at 93°C for 6 hours. Water (30 mL) was added to the system, and EA was extracted (20 mL*3). The organic phase was washed with water and saturated sodium chloride solution, dried over anhydrous Na2SO4, filtered, and concentrated to obtain a crude product. The crude product was purified by medium-pressure normal phase column chromatography (PE / EA = 0–10%) to obtain EVO33383-A2 (570 mg, crude) as a yellow oil.

[0704] Step 3:

[0705] At room temperature, EVO33383-A2 (60 mg, 198.45 μmol) was dissolved in a mixed solvent (2 mL, ACN:H2O:AcOH = 80:2:1). 1,3-Dichloro-5,5-dimethylimidazoline-2,4-dione (58.65 mg, 297.67 μmol, 39.10 μL) was added and stirred at room temperature for 2.5 hours. The solvent was removed by concentration under reduced pressure to obtain EVO33383-A3 (60 mg, crude product), which was directly reacted in the next step.

[0706] Step 4:

[0707] At room temperature, EVO33383-A3 (60 mg, 215.31 μmol), TEA (0.2 mL), and DCM (2 mL) were added to the reaction flask, followed by methylamine solution (0.2 mL, 2 M in THF) and stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and passed through a column. Purification by medium-pressure normal phase column chromatography (PE / EA = 0–50%) afforded EVO33383-A4 (36 mg, yield: 61.2%) as a pale yellow solid. LCMS (ESI) m / z = 274.0 [M+H] + .

[0708] Step 5:

[0709] At room temperature, EVO33383-A4 (36 mg, 131.74 μmol) and MeOH (1.5 mL) were added to the reaction flask, followed by LiOH.H2O (22.11 mg, 526.97 μmol) and H2O (1.5 mL). The reaction was heated in an oil bath at 33°C for 1.5 hours. The methanol was removed by concentration under reduced pressure, and water (0.5 mL) was added. The pH was adjusted to 3 with 1N dilute hydrochloric acid to precipitate a white solid. The solid was filtered, and the filter cake was washed with water (1 mL x 3) and dried to obtain EVO33383-A5 (21 mg, yield: 61.5%) as an off-white solid. LCMS (ESI) m / z = 260.0 [M+H] + .

[0710] Step 6:

[0711] EVO33383-A5 (21 mg, 81.01 μmol), intermediate 1-A1 (28.31 mg, 81.01 μmol), DIPEA (52.35 mg, 405.04 μmol, 70.55 μL), HATU (46.20 mg, 121.51 μmol), and anhydrous DMF (2 mL) were added to a reaction flask at room temperature and reacted at 25°C for 3 hours. The mixture was quenched with water and extracted with EA. The organic phase was washed with water and saturated sodium chloride solution, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, separated by HPLC preparative column, and freeze-dried to obtain the product EVO33383 (26 mg, yield: 54.3%). LCMS (ESI) m / z = 591.0 [M+H] + . Purity: 99.7%. 1 H NMR (400MHz, DMSO-d6) δ9.39-9.35(m,2H),8.68-8.61(m,2H),7.91(d,J=7.2Hz,1H),7.86(d,J=1.6Hz,1H),7.78-7.72(m,3H),7.66(bs,1H),7.03 (d,J=8.4Hz,1H),6.32(s,2H),4.77(d,J=6.0Hz,2H),4.33-4.30(m,2H), 3.70-3.64(m,2H),2.54(s,3H),2.52-2.47(m,2H),1.21(d,J=6.4Hz,6H).

[0712] Example 65 EVO33381

[0713] The reference compound EVO33383 was separated by HPLC preparative column and freeze-dried to give a yellow solid EVO33381 (20 mg, yield: 69.4%), LCMS (ESI) m / z = 604.4 [M+H]+ , purity: 99.9%. 1 H NMR (400MHz, DMSO-d6) δ9.42-9.39(m,2H),8.68-8.61(m,2H),7.92-7.89(m,2H),7.80-7.72(m,3H),7.03(d,J=8.8Hz,1H),6.36(s, 2H),4.78(d,J=5.6Hz,2H),4.31(d,J=11.6Hz,2H),3.71-3.64(m,2H),3.37-3.35(m,2 H), 2.53-2.47 (m, 2H), 1.70-1.60 (m, 2H), 1.21 (d, J = 6.0Hz, 6H), 0.96 (t, J = 7.4Hz, 3H).

[0714] Example 66 EVO33382

[0715] The reference compound EVO33383 was separated by HPLC preparative column and freeze-dried to give a yellow solid EVO33382 (37 mg, yield: 63.9%), LCMS (ESI) m / z = 602.4 [M+H] + , purity: 99.9%. 1 H NMR(400MHz,DMSO-d6)δ9.43-9.39(m,2H),8.64(q,J=8.6Hz,2H),7.92-7.90( m,2H),7.80-7.79(m,2H),7.74(t,J=8.0Hz,1H),7.03(d,J=8.8Hz,1H),6.36( s,2H),4.78(d,J=5.6Hz,2H),4.31(dd,J=13.2,2.4Hz,2H),3.71-3.64(m,2H) ,2.97-2.91(m,1H),2.52-2.47(m,2H),1.22-1.19(m,8H),1.13-1.07(m,2H).

[0716] Example 67 EVO33384

[0717] The reference compound EVO33383 was separated by HPLC preparative column and freeze-dried to give a yellow solid EVO33384 (24 mg, yield: 57.6%), LCMS (ESI) m / z = 605.0 [M+H] + , purity: 98.4%. 1H NMR (400MHz, DMSO-d6) δ9.41-9.38(m,2H),8.68-8.61(m,2H),7.91(d,J=7.6Hz,1H),7.82-7.73(m,4H),7.03(d,J=8.4Hz,1H),6.3 0(s,2H),4.78(d,J=6.0Hz,2H),4.31(d,J=11.6Hz,2H),3.70-3.65(m,2H),2.75(s,6H),2.53-2.47(m,2H),1.21(d,J=6.0Hz,6H).

[0718] Example 68 EVO33500

[0719] Step 1:

[0720] At room temperature, 4-amino-5-bromo-2-chloropyridine (1 g, 4.85 mmol) and potassium O-ethyldithiocarbonate (3.1 g, 19.41 mmol) were mixed in DMF (10 mL) and stirred in an oil bath at 130°C. The reaction was monitored by LC-MS. The mixture was quenched with water, extracted with EA (50 mL x 3), concentrated under reduced pressure, and purified by medium-pressure normal-phase column chromatography (PE / EA = 0-100%) to afford EVO33500-A1 (850 mg, yield: 87%) as an off-white solid. LCMS (ESI) m / z = 202.9 [M+H] + .

[0721] Step 2:

[0722] EVO33500-A1 (850 mg, 4.21 mmol) and SOCl2 (10 mL) were stirred at room temperature. The reaction was monitored by LC-MS. Water (20 mL) was added to quench the mixture, and the product precipitated and was filtered to obtain an off-white solid, EVO33500-A2 (800 mg, yield: 93%). LCMS (ESI) m / z = 204.9 [M+H] + .

[0723] Step 3:

[0724] Under N2 protection, EVO33500-A2 (700 mg, 3.46 mmol), (2S,6R)-2,6-dimethyl-4-(6-(trimethyltinyl)pyridin-2-yl)morpholine (1.2 g, 3.46 mmol), Pd(dppf)Cl2 (253 mg, 0.34 mmol) and anhydrous 1,4-dioxane (10 mL) were stirred in an oil bath at 100°C. LC-MS monitored the completion of the reaction. Water was added to quench the mixture, and the mixture was extracted with EA (50 mL x 3) and concentrated under reduced pressure. Purification by medium-pressure normal phase column chromatography (DCM / EA = 0-30%) gave an off-white solid EVO33500-A3 (510 mg, yield: 41%), LCMS (ESI) m / z = 361.1 [M+H] + .

[0725] Step 4:

[0726] Under N2 protection, EVO33500-A3 (480 mg, 1.33 mmol), potassium N-tert-butylcarbonylmethyltrifluoroborate (474 ​​mg, 2 mmol), cataCXium A-Pd-G2 (87 mg, 0.13 mmol), K3PO4 (564 mg, 2.66 mmol), 1,4-dioxane (10 mL), and water (1 mL) were stirred in an oil bath at 80°C. LC-MS monitored the reaction completion, with a small amount of starting material remaining. The product was quenched with water, extracted with EA (50 mL x 3), concentrated under reduced pressure, and purified by medium-pressure normal-phase column chromatography (DCM / EA = 0-30%) to afford EVO33500-A4 (212 mg, yield: 35%) as a white solid. LCMS (ESI) m / z = 456.2 [M+H] + .

[0727] Step 5:

[0728] At 0°C, a solution of hydrogen chloride in 1,4-dioxane (3 mL) was added dropwise to a solution of EVO33500-A4 (212 mg, 0.46 mmol) in DCM (5 mL). LC-MS monitored the reaction completion. The product was directly concentrated to afford a crude solid, EVO33500-A5 (151 mg, crude product). LCMS (ESI) m / z = 356.1 [M+H] + .

[0729] Step 6:

[0730] Under nitrogen protection, EVO33500-A5 (60 mg, 0.17 mmol), EVO33138-A4 (41 mg, 0.17 mmol), DMF (3 mL), EDCl (65 mg, 0.34 mmol), HOBt (46 mg, 0.34 mmol), and DIEA (44 mg, 0.34 mmol) were stirred at room temperature overnight. LC-MS monitored the reaction, indicating the product. The product was quenched with water, extracted with EA (50 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The product was separated by HPLC preparative column chromatography and lyophilized to afford EVO33500 (22.6 mg, yield: 20%). LCMS (ESI) m / z = 582.1 [M+H] + ; Purity: 99.36%. 1 H NMR (400MHz, DMSO-d6) δ9.38-9.27(m,2H),7.90(t,J=1.6Hz,2H),7.82-7.75(m,2H),7.62(d,J=7.2Hz,1H),7.13(d,J=8.8Hz,1H) ,6.36(s,2H),4.71(d,J=5.6Hz,2H),4.30-4.21(m,2H),3.72-3.60(m,2H),3.30(s,3H),2.60-2.53(m,2H),1.20(d,J=6.0Hz,6H).

[0731] Example 69 EVO33408

[0732] The reference compound EVO33168 was separated by HPLC preparative column and freeze-dried to give a yellow solid EVO33408 (7 mg, yield: 27%), LCMS (ESI) m / z = 604.0 [M+H] + , purity: 98.1%. 1 H NMR (400MHz, DMSO-d6) δ9.43 (s, 1H), 9.19 (d, J = 7.6Hz, 1H), 8.70-8.62 (m, 2H), 7.96-7 .89(m,3H),7.86(d,J=1.6Hz,1H),7.80-7.76(m,1H),7.07(d,J=8.4Hz,1H),6.37(s,2 H),5.47-5.36(m,1H),4.39-4.29(m,2H),3.76-3.64(m,2H),3.44-3.38(m,2H),2.57- 3.47(m,2H),1.67(d,J=6.8Hz,3H),1.25(d,J=6.0Hz,6H),1.22-1.18(t,J=7.2Hz,3H).

[0733] Example 70 EVO33411

[0734] The reference compound EVO33138 was separated by HPLC preparative column and then freeze-dried to obtain the product EVO33411 (4.5 mg, yield: 5.07%), LCMS (ESI) m / z = 602.27 [M+H] + , purity: 96.99%. 1 H NMR (400MHz, DMSO-d6) δ9.84(t,J=5.6Hz,1H),9.41(s,1H),8.71-8.59(m,2H),8.57(d,J=8.4,2H),7.90(d,J=7.2H z,1H),7.86(s,1H),7.75(t,J=8.4,1H),7.03(d,J=8.4Hz,1H),5.58(s,2H),4.85(d,J=6Hz,2H),4.37-4.20(m,2H), 3.73(q,J=7.6Hz,2H),3.69-3.65(m,2H),2.54-2.45(m,2H),1.22(d,J=6.4Hz,6H),1.17(t,J=7.2Hz,3H).

[0735] Example 71 EVO33412

[0736] The reference compound EVO33138 was separated by HPLC preparative column and freeze-dried to give a yellow solid EVO33412 (5.5 mg, yield: 8.23%), LCMS (ESI) m / z = 602.25 [M+H] + , purity: 98.62%. 1 H NMR (400MHz, DMSO-d6) δ9.81 (t, J = 6Hz, 1H), 9.41 (s, 1H), 8.80 (s, 1H), 8.71-8. 65(m,3H),7.94-7.85(m,2H),7.74(t,J=8.0Hz,1H),7.03(d,J=8.4Hz,1H),5.75 (s,2H),4.86(d,J=5.6Hz,2H),4.31(d,J=10.8Hz,2H),3.72-3.62(m,2H),3.48 (q, J=7.6Hz, 2H), 2.55-2.44 (m, 2H), 1.22 (d, J=6Hz, 6H), 1.18 (t, J=7.6Hz, 3H).

[0737] Example 72 EVO33376

[0738] The reference compound EVO33173 was separated by HPLC preparative column and freeze-dried to give a white solid EVO33376 (17.1 mg, yield: 50.5%), LCMS (ESI) m / z = 592.44 [M+H] + , 1 H NMR(400MHz, DMSO-d6)δ9.39(s,1H),9.36(t,J=5.9Hz,1H),8.70-8.59(m,2H),8.05(d,J=1.7Hz,1H),7.93-7.85(m,2H),7.81-7.70(m,2H),7.03( d,J=8.5Hz,1H),5.58(s,1H),4.79(d,J=5.8Hz,2H),4.35-4.28(m,2H),3 .72-3.63(m,2H),2.54-2.44(m,2H),1.53(s,6H),1.21(d,J=6.2Hz,6H).

[0739] Example 73 EVO33398

[0740] The reference compound EVO33173 was separated by HPLC preparative column and freeze-dried to give a yellow solid EVO33398 (24.6 mg, yield: 50.2%), LCMS (ESI) m / z = 576.18 [M+H] + , 1 H NMR(400MHz,Chloroform-d)δ9.27(s,1H),8.67(d,J=8.6Hz,1H),8.44-8.31(m,1H) ,8.08-7.98(m,2H),7.82(d,J=1.6Hz,1H),7.76-7.68(m,2H),7.62-7.53(m,1H),6.7 5(d,J=8.5Hz,1H),6.25(s,2H),4.98(d,J=5.2Hz,2H),4.53-4.39(m,1H),4.15-4.01 (m,2H),3.95-3.80(m,2H),3.78-3.64(m,1H),3.40-3.25(m,3H),1.41-1.28(m,6H).

[0741] Example 74 EVO33403

[0742] The reference compound EVO33138 was separated by HPLC preparative column and then freeze-dried to obtain the product EVO33403 (18.2 mg, yield: 31%), LCMS (ESI) m / z = 582.12 [M+H] + , purity: 99.41%. 1 H NMR(400MHz,Chloroform-d)δ9.32(s,1H),8.90(d,J=8.4Hz,1H),8.75(d,J=8.0Hz ,1H),8.47(d,J=8.4Hz,1H),8.06-8.01(m,2H),7.93(d,J=8.0Hz,1H),7.80(d,J=1 .6Hz,1H),7.77(br,2H),7.69(d,J=1.6Hz,1H),7.40(t,J=4.8Hz,1H),6.25(s,2H) ,4.98(d,J=5.2Hz,2H),3.31(q,J=7.6Hz,2H),2.73(s,6H),1.35(t,J=7.6Hz,3H).

[0743] Example 75 EVO33416

[0744] The reference compound EVO33138 was separated by HPLC preparative column and then freeze-dried to obtain the product EVO33416 (32.8 mg, yield: 45%), LCMS (ESI) m / z = 558.26 [M+H] + , purity: 86.1%. 1 H NMR(400MHz,Chloroform-d)δ9.46(s,1H),8.99(t,1H),8.92(d,J=8.7Hz,1H),8.59-8.5 1(m,2H),8.14(d,J=7.4Hz,1H),7.82-7.73(m,1H),7.64-7.56(m,1H),7.37(d,J=1.7Hz, 1H),6.89(d,J=8.5Hz,1H),6.04(s,2H),5.05(d,J=6.1Hz,2H),4.21(d,J=12.6Hz,2H),3 .80(d,J=6.6Hz,2H),2.75-2.60(m,2H),1.76(s,3H),1.70(s,3H),1.35(d,J=6.2Hz,6H).

[0745] Example 76 EVO33432

[0746] The reference compound EVO33138 was separated by HPLC preparative column and then freeze-dried to obtain the product EVO33432 (78.8 mg, yield: 54%), LCMS (ESI) m / z = 542.23 [M+H] + , purity: 99.55%. 1 H NMR(400MHz,Chloroform-d)δ9.19(s,1H),8.62(d,J=8.6Hz,1H),8.35(d,J=8.7Hz, 1H),7.98(d,J=8.0Hz,2H),7.73-7.63(m,2H),7.60(s,1H),7.29(d,J=1.5Hz,1H),6. 78(d,J=8.4Hz,1H),6.12-6.01(m,2H),5.11-4.78(m,3H),4.21(d,J=12.5Hz,2H),3. 80(d,J=4.0Hz,2H),2.70-2.58(m,2H),1.52(d,J=6.5Hz,3H),1.34(d,J=6.2Hz,6H).

[0747] Example 77 EVO33458

[0748] The reference compound EVO33138 was separated by HPLC preparative column and then freeze-dried to obtain the product EVO33458 (3.88 mg, yield: 16%), LCMS (ESI) m / z = 555.26 [M+H] + , purity: 97.2%. 1 H NMR (400MHz, Chloroform-d) δ9.26 (s, 1H), 8.63 (d, J = 8.5 Hz, 1H), 8.37 (d, J = 8. 7Hz,1H),8.08-7.95(m,2H),7.76-7.67(m,1H),7.59-7.50(m,1H),7.30-7.27( m,1H),6.79(d,J=8.4Hz,1H),6.07(s,2H),4.96(d,J=4.8Hz,2H),4.33-4.16(m ,2H),3.92-3.73(m,2H),2.73-2.56(m,2H),1.55(s,6H),1.34(d,J=6.2Hz,6H).

[0749] Example 78 EVO33467

[0750] The reference compound EVO33138 was separated by HPLC preparative column and then freeze-dried to obtain the product EVO33467 (9.28 mg, yield: 24%), LCMS (ESI) m / z = 570.19 [M+H] + , purity: 98.4%. 1 H NMR (400MHz, DMSO-d6) δ9.39 (s, 1H), 9.20 (t, J = 6.0Hz, 1H), 8.69-8.59 (m, 2H), 7.90 (d, J = 7 .2Hz,1H),7.77-7.69(m,2H),7.65(d,J=1.6Hz,1H),7.49(d,J=1.6Hz,1H),7.03(d,J=8.4H z,1H),6.45(s,1H),6.17(s,2H),5.02(d,J=6.8Hz,2H),4.76(d,J=5.6Hz,2H),4.67(d,J=6 .8Hz,2H),4.35-4.27(m,2H),3.71-3.62(m,2H),2.55-2.45(m,2H),1.21(d,J=6.0Hz,6H).

[0751] Example 79 EVO33486

[0752] The reference compound EVO33138 was separated by HPLC preparative column and then freeze-dried to obtain the product EVO33486 (14.81 mg, yield: 42%), LCMS (ESI) m / z = 588.20 [M+H] + , purity: 99.06%. 1 H NMR(400MHz,Chloroform-d)δ9.82(d,J=2.0Hz,1H),9.56(s,1H),8.78(d,J=2.0Hz,1H),8.33(s ,1H),8.30-8.25(m,1H),8.14(s,1H),8.08(s,1H),7.75-7.71(m,1H),7.36(d,J=8.0Hz,1H),6. 82(d,J=8.0Hz,1H),5.46-5.45(m,2H),5.23(s,2H),5.07(d,J=5.6Hz,2H),4.29-4.26(m,2H),3 .85-3.79(m,2H),3.24-3.19(m,2H),2.72-2.66(m,2H),1.38(d,J=6.4Hz,6H)1.37-1.33(m,3H).

[0753] Example 80 EVO33490

[0754] The reference compound EVO33138 was separated by HPLC preparative column and then freeze-dried to obtain the product EVO33490 (16 mg, yield: 48%), LCMS (ESI) m / z = 580.43 [M+H] + , purity: 99.13%. 1 H NMR(400MHz,DMSO-d6)δ9.61(t,J=6.0Hz,1H),9.47(s,1H),8.90(d,J=8.4Hz ,1H),8.78(d,J=8.4Hz,1H),8.65(d,J=7.8Hz,1H),8.33(s,1H),8.29-8.23(m ,2H),8.16(t,J=7.8Hz,1H),7.92-7.89(m,3H),5.33(s,2H),5.15(s,2H),4.8 5(d,J=5.6Hz,2H), 3.38(q,J=7.2Hz,2H), 2.57(s,6H), 1.15(t,J=7.2Hz,3H).

[0755] Example 81 EVO33504

[0756] The reference compound EVO33138 was separated by HPLC preparative column and then freeze-dried to obtain the product EVO33504 (27.8 mg, yield: 36%), LCMS (ESI) m / z = 576.2 [M+H] + , purity: 99.31%. 1 H NMR (400MHz, DMSO-d6) δ9.44-9.36 (m, 2H), 8.64 (q, J = 8.4Hz, 2H), 7.94-7.8 7(m,2H),7.82-7.73(m,3H),7.03(d,J=8.4Hz,1H),6.35(s,2H),4.78(d,J= 5.6Hz,2H),4.32-4.20(m,2H),3.97(d,J=10Hz,1H),3.70-3.52(m,2H),3.4 0(q,J=7.2Hz,2H),2.95-2.88(m,1H),2.62-2.52(m,1H),1.23-1.16(m,6H).

[0757] Example 82 EVO33507

[0758] The reference compound EVO33138 was separated by HPLC preparative column and then freeze-dried to obtain the product EVO33507 (14.7 mg, yield: 19.1%), LCMS (ESI) m / z = 576.22 [M+H] + , purity: 98.65%. 1 H NMR (400MHz, DMSO-d6) δ9.41-9.38 (m, 2H), 8.66 (s, 2H), 7.90 (d, J = 1.6Hz, 1H), 7.83-7.79(m,3H),7.69(t,J=8.4Hz,1H),6.64(d,J=8.4Hz,1H),6.35(s,2H),4. 78(d,J=5.6Hz,2H),4.15-4.11(m,1H),3.64-3.59(m,3H),3.50(q,J=8.6Hz,1H ), 3.38 (q, J = 7.4Hz, 2H), 3.30 (s, 3H), 2.14-2.09 (m, 2H), 1.18 (t, J = 7.2Hz, 3H).

[0759] Example 83 EVO33508

[0760] The reference compound EVO33138 was separated by HPLC preparative column and then freeze-dried to obtain the product EVO33508 (17.8 mg, yield: 12.14%), LCMS (ESI) m / z = 548.51 [M+H] + , purity: 95.67%. 1 H NMR (400MHz, DMSO-d6) δ9.41-9.38(m,2H),8.66(d,J=8.4Hz,1H),8.60(d,J=8.8Hz ,1H),7.91-7.85(m,2H),7.82-7.78(m,2H),7.70(t,J=8Hz,1H),6.56(d,J=8.4Hz, 1H),6.35(s,2H),5.67(d,J=6.4Hz,1H),4.78(d,J=5.6Hz,2H),4.65-4.61(m,1H), 4.32-4.23(m,2H),3.81-3.78(m,2H),3.38(q,J=7.2Hz,2H),1.18(t,J=7.6Hz,3H).

[0761] Example 84 EVO33509

[0762] The reference compound EVO33138 was separated by HPLC preparative column and then freeze-dried to obtain the product EVO33509 (8.7 mg, yield: 12.6%), LCMS (ESI) m / z = 574.57 [M+H] + , purity: 85.2%. 1 H NMR (400MHz, DMSO) δ9.42-9.36(m,2H),8.67(d,J=8.8Hz,1H),8.60(d,J=8.4Hz,1H),7.92-7.87(m,2H),7.83-7.77(m,2H),7.72 (t,J=8.0Hz,1H),6.58(d,J=8.0Hz,1H),6.35(s,2H),4.78-4.75(m,6H),4.24(s,4H),3.39-3.35(m,2H),1.18(t,J=7.2Hz,3H).

[0763] Example 85 EVO33511

[0764] The reference compound EVO33138 was separated by HPLC preparative column and then freeze-dried to obtain the product EVO33511 (15.7 mg, yield: 22.3%), LCMS (ESI) m / z = 590.2 [M+H] + , purity: 96.33%. 1 H NMR(400MHz,DMSO-d6)δ9.41-9.38(m,2H),8.64(dd,J=24.4,8.4Hz,2H),7.90(d,J =1.6Hz,1H),7.84-7.79(m,3H),7.71(t,J=8.0Hz,1H),6.88(d,J=8.4Hz,1H),6.35( s,2H),4.79-4.71(m,3H),4.01-3.94(m,2H),3.55(d,J=11.6Hz,2H),3.38(q,J=7. 6Hz, 2H), 2.98 (s, 3H), 1.90-1.79 (m, 2H), 1.65-1.61 (m, 2H), 1.18 (t, J = 7.2Hz, 3H).

[0765] Example 86 EVO33512

[0766] The reference compound EVO33138 was separated by HPLC preparative column and then freeze-dried to obtain the product EVO33512 (20.7 mg, yield: 30.2%), LCMS (ESI) m / z = 576.24 [M+H] +, purity: 97.94%. 1 H NMR (400MHz, DMSO-d6) δ9.41-9.39(m,2H),8.68-8.63(m,2H),7.90(d,J=1.6Hz,1 H),7.85(d,J=7.6Hz,1H),7.81-7.80(m,2H),7.72(t,J=8.4Hz,1H),6.87(d,J=8. 4Hz,1H),6.35(s,2H),5.51-5.44(m,1H),4.78(d,J=6.0Hz,2H),4.03-3.97(m,1H ),3.87-3.82(m,1H),3.79-3.75(m,1H),3.70(q,J=8.0Hz,1H),3.38(q,J=7.2Hz, 2H), 3.00 (s, 3H), 2.33-2.25 (m, 1H), 1.96-1.88 (m, 1H), 1.19 (t, J = 7.6Hz, 3H).

[0767] Example 87 EVO33513

[0768] The reference compound EVO33138 was separated by HPLC preparative column and then freeze-dried to obtain the product EVO33513 (2.1 mg, yield: 3.8%), LCMS (ESI) m / z = 590.7 [M+H] + , purity: 95.27%. 1 H NMR (400MHz, DMSO-d6) δ9.40-9.38(m,2H),8.68-8.59(m,2H),7.90(d,J=1. 6Hz,1H),7.83-7.79(m,3H),7.69(t,J=7.6Hz,1H),6.81(d,J=8.4Hz,1H),6. 35(s,2H),4.78(d,J=6.4Hz,2H),3.81(t,J=6.0Hz,2H),3.70(t,J=5.6Hz,2H ),3.41-3.34(m,3H),3.13(s,3H),1.18(t,J=7.2Hz,3H),0.45-0.40(m,4H).

[0769] Example 88 EVO33522

[0770] The reference compound EVO33138 was separated by HPLC preparative column and then freeze-dried to obtain the product EVO33522 (10.7 mg, yield: 23.48%), LCMS (ESI) m / z = 591.24 [M+H] +, purity: 91.3%. 1 H NMR (400MHz, DMSO-d6) δ10.74(s,1H),9.06(s,1H),8.84(s,1H),8.44(d,J=8.4Hz, 1H),8.29(d,J=8.8Hz,1H),7.90(d,J=1.6Hz,1H),7.86-7.80(m,2H),7.73-7.69(m ,1H),7.00(d,J=8.4Hz,1H),6.86(s,1H),6.38(s,2H),4.29(dd,J=12.8,2.4Hz,2H ),3.71-3.64(m,2H),3.40(d,J=7.2Hz,2H),2.52-2.46(m,2H),1.22-1.18(m,9H).

[0771] Example 89 EVO33525

[0772] The reference compound EVO33138 was separated by HPLC preparative column and then freeze-dried to obtain the product EVO33525 (13.5 mg, yield: 29.4%), LCMS (ESI) m / z = 588.06 [M+H] + , purity: 99.38%. 1 H NMR (400MHz, DMSO-d6) δ9.46(t,J=5.6Hz,1H),9.40(s,1H),8.64(q,J=8.4Hz,2H),7.99(s,1H),7.91 (d,J=7.2Hz,1H),7.80(s,1H),7.75(t,J=8.0Hz,1H),7.69(s,1H),7.03(d,J=8.8Hz,1H),4.80(d,J=5 .6Hz,2H),4.62(t,J=8.0Hz,1H),4.41(dd,J=8.4,2.0Hz,1H),4.31(d,J=12.8Hz,2H),3.97-3.90(m, 1H), 3.72-3.64 (m, 2H), 3.31 (s, 3H), 2.53-2.47 (m, 2H), 1.34 (d, J = 7.2Hz, 3H), 1.22 (d, J = 6.0Hz, 6H).

[0773] Example 90 EVO33535

[0774] The reference compound EVO33138 was separated by HPLC preparative column and then freeze-dried to obtain the product EVO33535 (15.5 mg, yield: 22.12%), LCMS (ESI) m / z = 560.24 [M+H] + , purity: 98.57%. 1 H NMR(400MHz,Chloroform-d)δ9.30(s,1H),8.75(d,J=8.8Hz,1H),8.40(d,J=8.8Hz,1H),8.06(s,1H),8.00(d,J=7.2Hz,1H),7.82(d,J=1.6Hz,1H),7.87-7 .58(m,3H),6.85(d,J=8.4Hz,1H),6.27(s,2H),5.01(d,J=5.2Hz,2H),3.70- 3.66(m,4H),3.33(q,J=7.6Hz,2H),1.75-1.68(m,6H),1.37(t,J=7.6Hz,3H).

[0775] Example 91 EVO33536

[0776] The reference compound EVO33138 was separated by HPLC preparative column and then freeze-dried to obtain the product EVO33536 (23 mg, yield: 19%), LCMS (ESI) m / z = 546.19 [M+H] + , purity: 95.02%. 1 H NMR (400MHz, DMSO-d6) δ9.43-9.35(m,2H),8.65(s,2H),7.90(d,J=1.6Hz,1H),7.82-7.78(m,3H),7.68(dd,J=8.4,7.2Hz,1H),6.62(d ,J=8.0Hz,1H),6.35(s,2H),4.78(d,J=6.0Hz,2H),3.57-3.47(m,4H),3.38(q,J=7.6Hz,2H),2.04-1.96(m,4H),1.18(t,J=7.2Hz,3H).

[0777] Example 92 EVO33540

[0778] The reference compound EVO33138 was separated by HPLC preparative column and then freeze-dried to obtain the product EVO33540 (21.8 mg, yield: 31.19%), LCMS (ESI) m / z = 562.21 [M+H] + , purity: 98.33%.1 H NMR(400MHz,DMSO-d6)δ9.43-9.36(m,2H),8.65(s,2H),7.90(d,J=1.6Hz,1H),7.81- 7.79(m,3H),7.68(t,J=7.6Hz,1H),6.61(d,J=8.4,1H),6.35(s,2H),4.98(d,J=3.6H z,1H),4.78(d,J=5.8Hz,2H),4.44(s,1H),3.66-3.55(m,3H),3.46(d,J=11.2Hz,1H) ,3.38(q,J=7.4Hz,2H),2.12-2.03(m,1H),1.99-1.93(m,1H),1.18(t,J=7.4Hz,3H).

[0779] Example 93 EVO33546

[0780] The reference compound EVO33138 was separated by HPLC preparative column and then freeze-dried to obtain the product EVO33546 (7.1 mg, yield: 16.5%), LCMS (ESI) m / z = 578.2 [M+H] + , purity: 98.31%. 1 H NMR (400MHz, DMSO-d6) δ9.40-9.39 (m, 2H), 8.66 (d, J = 8.4Hz, 1H), 8.59 (d, J=8.4Hz,1H),7.90-7.86(m,2H),7.81-7.80(m,2H),7.40(t,J=8.0Hz,1H), 7.03(d,J=8.4Hz,1H),6.35(s,2H),4.78(d,J=5.6Hz,2H),4.06-4.03(m,4 H), 3.38 (dd, J = 14.8, 7.2Hz, 2H), 2.69-2.67 (m, 4H), 1.18 (t, J = 7.2Hz, 3H).

[0781] Example 94 EVO33600

[0782] The reference compound EVO33138 was separated by HPLC preparative column and then freeze-dried to obtain the product EVO33600 (8.58 mg, yield: 20%), LCMS (ESI) m / z = 556.2 [M+H] + , purity: 98.8%. 1H NMR(400MHz,Chloroform-d)δ9.77(d,J=2.0Hz,1H),9.55(s,1H),8.73(d,J=2.0Hz,1H), 8.00(s,1H),7.74-7.72(m,1H),7.72-7.70(m,1H),7.67(d,J=2.0Hz,1H),7.36(d,J=2.0H z,1H),7.35-7.33(m,1H),6.79(d,J=8.8Hz,1H),6.10(d,2H),5.01(d,J=6.0Hz,2H),4.3 0-4.26(m,2H),3.85-3.80(m,2H),2.72-2.64(m,2H),1.67(s,6H),1.38(d,J=6.4Hz,6H).

[0783] Example 95 EVO33415

[0784] Reference compound EVO33174 was separated by HPLC preparative column and freeze-dried to obtain brown solid EVO33415 (8.19 mg, yield: 17.25%, purity: 94%), LCMS (ESI) m / z = 580.38 [M+H] + . 1 H NMR(400MHz,Methanol-d4)δ8.57(s,1H),7.97-7.95(m,1H),7.86(s,1H),7.68 -7.67(m,1H),7.46-7.44(m,1H),6.34(s,2H),4.84(s,2H),4.57(q,J=6.8Hz,1 H),4.11-4.07(m,2H),3.95-3.92(m,2H),3.75-3.67(m,2H),3.28(s,3H),3.11 -3.08(m,2H),2.45-2.40(m,2H),1.70(d,J=7.2Hz,3H),1.25(d,J=6.0Hz,6H).

[0785] Example 96 EVO33426

[0786] The reference compound EVO33240 was separated by HPLC preparative column and freeze-dried to obtain a yellow solid EVO33426 (14.14 mg, yield: 36.89%, purity: 98.1%, LCMS (ESI) m / z = 551.38 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ9.22(t,J=6.0Hz,1H),8.54-8.45(m,1H),7.88(d,J=1.6Hz,1H),7.75(d,J=1.6Hz,1H),7.59-7.49(m, 4H),7.38(d,J=16.0Hz,1H),6.87(d,J=7.2Hz,1H),6.81(d,J=8.8Hz,1H),6.35(s,2H),4.58(d,J=5.6 Hz, 2H), 4.30-4.19 (m, 2H), 3.66-3.59 (m, 2H), 3.29 (s, 3H), 2.44-2.38 (m, 2H), 1.18 (d, J = 6.0Hz, 6H).

[0787] Example 97 EVO33342

[0788] The reference compound EVO33341 was separated by HPLC preparative column and then freeze-dried to obtain the product EVO33342 (15.8 mg, yield: 28%), LCMS (ESI) m / z = 588.39 [M+H] + , purity: 98.8%. 1 H NMR(400MHz,Chloroform-d)δ9.65-9.59(m,1H),9.51(s,1H),9.03(d,J=0.8Hz,1H),8.91(d,J=8.8Hz,1H),8.72(d,J=0.8Hz,1H),8.62(d,J=8.8Hz,1H ),8.45(s,1H),8.13(d,J=7.2Hz,1H),7.76(d,J=8.0Hz,1H),6.88(d,J=8.4 Hz,1H),5.18(d,J=6.0Hz,2H),4.24-4.19(m,2H),3.82-3.74(m,2H),3.50(q J=7.2Hz,2H),2.68-2.63(m,2H),1.35-1.29(m,9H).

[0789] Example 98 EVO33430

[0790] The reference compound EVO33341 was separated by HPLC preparative column and then freeze-dried to obtain the product EVO33430 (10.3 mg, yield: 22%), LCMS (ESI) m / z = 590.10 [M+H] + , purity: 95.7%. 1H NMR (400MHz, Chloroform-d) δ9.28(s,1H),8.89(s,1H),8.86(s,1H),8.68(d,J=8.4Hz,1H),8.40(d,J=8.8Hz,1H),8.06-8.00(m,3H),7.72(t,J=8. 0Hz,1H),6.80(d,J=8.4Hz,1H),5.06(d,J=4.8Hz,2H),4.24-4.19(m,2H), 3.83-3.76(m,2H),3.48(s,3H),2.69-2.59(m,2H),1.33(d,J=6.0Hz,6H).

[0791] Example 99 EVO33389

[0792] Step 1:

[0793] At room temperature, methyl 7-bromobenzo[d][1,3]dioxo-5-carboxylate (500 mg, 1.93 mmol), tributyltin carbinol (929.59 mg, 2.90 mmol), XPhosPd G2 (151.86 mg, 193.01 μmol), and anhydrous 1,4-dioxane (20 mL) were added to the reaction flask. Ar was replaced three times, and the mixture was heated in an oil bath at 100°C for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain the crude product. The crude product was purified by medium-pressure normal phase column chromatography (EA / PE = 0-100%) to obtain EVO33389-A1 (364 mg, yield: 89.7%) as an off-white solid. LCMS (ESI) m / z = 211.0 [M+H] + .

[0794] Step 2:

[0795] At room temperature, under Ar protection, EVO33389-A1 (364 mg, 1.73 mmol) and anhydrous DCM (10 mL) were added to the reaction flask and cooled to -10°C in a cold bath. PBr3 (937.57 mg, 3.46 mmol, 325.55 μL) was added with a temperature control of ±5°C. After addition, the mixture was naturally warmed to room temperature and stirred for 2 hours. The reaction solution was directly concentrated under reduced pressure to obtain the crude product, which was then purified by medium-pressure normal-phase column chromatography (EA / PE = 0-20%) to obtain EVO33389-A2 (322 mg, yield: 68.1%) as an off-white solid. LCMS (ESI) m / z = 273.1 / 275.1 [M+H] + .

[0796] Step 3:

[0797] At room temperature, EVO33389-A2 (322 mg, 1.18 mmol), anhydrous ACN (10 mL), and TMSCN (233.97 mg, 2.36 mmol, 295.04 μL) were added to the reaction flask. The temperature was lowered to 0-5°C in an ice-water bath, and TBAF solution (1.0 M in THF, 2.5 mL) was slowly added dropwise. The mixture was allowed to warm to room temperature and reacted for 2 hours. The crude product was concentrated under reduced pressure and purified by medium-pressure normal-phase column chromatography (EA / PE = 0-30%) to afford EVO33389-A3 (229 mg, yield: 88.6%) as an off-white solid. LCMS (ESI) m / z = 220.0 [M+H] + .

[0798] Step 4:

[0799] EVO33389-A3 (50 mg, 228.11 μmol), LiOH.H2O (19.14 mg, 456.22 μmol), MeOH (1 mL), and H2O (1 mL) were added to the reaction flask at room temperature and stirred at room temperature for 16 hours. The solvent was removed by evaporation under reduced pressure, and the pH was adjusted to 3-4 with 1N dilute hydrochloric acid. A white solid precipitated and was filtered. The filter cake was rinsed with ice water and dried to obtain an off-white solid, EVO33389-A4 (44 mg, yield: 94.0%). LCMS (ESI) m / z = 204.10 [MH] - , containing about 15% cyano hydrolysis by-products.

[0800] Step 5:

[0801] At room temperature, EVO33389-A4 (21 mg, 102.36 μmol), EVO33070A7 (35.77 mg, 102.36 μmol), anhydrous DMF (2 mL), and TEA (51.79 mg, 511.78 μmol, 71.33 μL) were added to the reaction flask in sequence. HATU (58.38 mg, 153.53 μmol) was then added and stirred at room temperature for 2 hours. The mixture was quenched with water and then processed. The product was separated by HPLC preparative column and freeze-dried to obtain EVO33389 (36 mg, yield: 65.6%) as a pale yellow solid. LCMS (ESI) m / z = 537.4 [M+H] + , purity: 99.5%. 1H NMR(400MHz,DMSO-d6)δ9.39(d,J=1.2Hz,1H),9.20(t,J=6.0Hz,1H),8.68-8.61(m ,2H),7.91(d,J=7.2Hz,1H),7.77-7.72(m,2H),7.61(d,J=1.6Hz,1H),7.54(d,J=1. 6Hz, 1H), 7.03 (d, J = 8.4Hz, 1H), 6.21 (s, 2H), 4.77 (d, J = 6.0Hz, 2H), 4.31 (d, J = 12. 0Hz, 2H), 4.04 (s, 2H), 3.70-3.65 (m, 2H), 2.53-2.47 (m, 2H), 1.21 (d, J = 6.4Hz, 6H).

[0802] Example 100 EVO33414

[0803] The reference compound EVO33389 was separated by HPLC preparative column and freeze-dried to obtain a yellow solid EVO33414 (42 mg, yield: 43.4%), LCMS (ESI) m / z = 565.4 [M+H] + , purity: 97.6%. 1 H NMR(400MHz, DMSO-d6)δ9.39(d,J=0.8Hz,1H),9.24(t,J=5.8Hz,1H),8.67-8.60(m, 2H),7.91(d,J=7.6Hz,1H),7.78-7.72(m,2H),7.64(d,J=1.6Hz,1H),7.58(d,J=1.6H z,1H),7.03(d,J=8.4Hz,1H),6.22(s,2H),4.77(d,J=6.0Hz,2H),4.31(dd,J=12.8,2 .4Hz,2H),3.71-3.64(m,2H),2.53-2.47(m,2H),1.76(s,6H),1.21(d,J=6.4Hz,6H).

[0804] Example 101 EVO33392

[0805] Step 1:

[0806] At room temperature, EVO33381-B1 (124 mg, 415.67 μmol) and THF (3 mL) were added to the reaction flask, followed by a methanol solution of NaOMe (5.4 M in methanol, 623.51 μmol). The mixture was stirred at room temperature for 2 h. The starting material disappeared, but no corresponding molecular ion peak of EVO33381-B2 appeared. The mother liquor was directly used in the next reaction.

[0807] Step 2:

[0808] 2-Bromoethanol (155.83 mg, 1.25 mmol) was added to the reaction mixture at room temperature and stirred at room temperature for 1 hour. The reaction mixture was directly concentrated under reduced pressure to obtain the crude product, which was purified by medium-pressure normal phase column chromatography (EA / PE = 0-60%) to obtain EVO33392-A1 (50 mg, yield: 46.9%) as a colorless oil. LCMS (ESI) m / z = 257.0 [M+H] + .

[0809] Step 3:

[0810] At room temperature, Oxone (431.79 mg, 702.37 μmol) and H2O (2 mL) were added to the reaction flask. The pH was adjusted to 7-8 with saturated sodium bicarbonate solution. EVO33392-A1 (60 mg, 234.12 μmol) and ACN (3.5 mL) were then added and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product, which was purified by medium-pressure normal-phase column chromatography (MeOH / DCM = 0-10%) to obtain EVO33392-A2 (60 mg, yield: 88.9%) as a colorless oil. LCMS (ESI) m / z = 289.0 [M+H] + .

[0811] Step 4:

[0812] At room temperature, EVO33392-A2 (60 mg, 208.14 μmol) and MeOH (1 mL) were added to a reaction flask. Lithium hydroxide (17.47 mg, 416.27 μmol) was dissolved in water (1 mL) and then added. The mixture was heated in an oil bath at 33°C for 1 hour. The reaction solution was concentrated under reduced pressure and then dissolved in DMF (2 mL). The product was passed through a reverse-phase column (acetonitrile: 0.1% formic acid in water) and freeze-dried to afford an off-white solid, EVO33392-A3 (29 mg, yield: 50.8%). LCMS (ESI) m / z = 273.0 [MH] - .

[0813] Step 5:

[0814] At room temperature, EVO33392-A3 (29 mg, 105.74 μmol), intermediate 1-A1 (36.95 mg, 105.74 μmol), anhydrous DMF (2 mL), DIPEA (68.33 mg, 528.72 μmol, 92.09 μL), and finally HATU (60.31 mg, 158.62 μmol) were added to the reaction flask in sequence. The mixture was stirred at room temperature for 1 hour. After quenching with water, the product was separated by HPLC preparative column and freeze-dried to obtain EVO33392 (36 mg, yield: 56.2%) as a pale yellow solid. LCMS (ESI) m / z = 606.4 [M+H] + , purity: 99.9%. 1 H NMR(400MHz,DMSO-d6)δ9.41-9.38(m,2H),8.68-8.61(m,2H),7.92-7.89(m,2 H),7.79-7.73(m,3H),7.03(d,J=8.4Hz,1H),6.35(s,2H),4.90(t,J=5.4Hz,1 H),4.78(d,J=5.6Hz,2H),4.32(d,J=12.8Hz,2H),3.76(q,J=5.6Hz,2H),3.70 -3.65(m,2H),3.54(t,J=6.2Hz,2H),2.53-2.47(m,2H),1.21(d,J=6.4Hz,6H).

[0815] Example 102 EVO33523

[0816] Step 1:

[0817] At room temperature, EVO33522-A2 (30 mg, 84.55 μmol), DMSO (1.0 mL), methylhydrazine sulfate (243 mg, 1.69 mmol), K2CO3 (350 mg, 2.54 mmol), and water (1.0 mL) were added to a microwave tube. The tube was sealed and eight batches of the reaction mixture were added. The mixture was stirred for 0.5 h, then heated to 110°C and stirred for 48 h. After cooling to room temperature, methylhydrazine sulfate (243 mg, 1.69 mmol) and K2CO3 (350 mg, 2.54 mmol) were added to each microwave tube. The tube was sealed and stirred at room temperature for 0.5 h, then heated to 110°C and stirred for 48 h. LC-MS analysis revealed 60% product and 30% starting material in each reaction. The reaction mixture was diluted with EA (10 mL) and H2O (10 mL). The organic phase was collected, and the aqueous phase was back-extracted three times with EA. The organic phases were combined, washed with saturated sodium chloride solution (50 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (DCM / MeOH: 10 / 1) to afford EVO33523-A1 (150 mg, purity: 70%) as a yellow oil. Purification on a preparative plate (DCM / MeOH: 10 / 1) afforded EVO33523-A1 (100 mg, yield: 36.51%, purity: 90%). LCMS (ESI) m / z = 365.46 [M+H] + .

[0818] Step 2:

[0819] In an ice-water bath, EVO33522-A1 (56 mg, 137.40 μmol), DMF (1 mL) and DIPEA (88 mg, 687.00 μmol) were stirred for 10 minutes, 7-ethylsulfonebenzo[d][1,3]dioxo-5-carboxylic acid (28 mg, 109.92 μmol) was added, and stirring was continued for 10 minutes. Then, EDCI (53 mg, 275.00 μmol) and HOBt (19 mg, 140.74 μmol) were added, and the mixture was stirred at room temperature for 1 hour. EA (30 mL) was added, and the mixture was washed with water (50 mL x 2). The aqueous phase was reversed and extracted. The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and separated by HPLC preparative column. The mixture was freeze-dried to obtain a light yellow solid EVO33523 (28 mg, yield: 32.71%). LCMS (ESI) m / z = 605.24 [M+H] + , purity: 97.02%. 1H NMR (400MHz, DMSO-d6) δ11.11(s,1H),9.11(s,1H),8.45(d,J=8.4Hz,1H),8.29(d,J=8. 8Hz,1H),7.91(d,J=1.6Hz,1H),7.85-7.81(m,2H),7.70(t,J=8.4Hz,1H),7.00(m,2H), 6.39(s,2H),4.29(dd,J=12.8,2.4Hz,2H),3.71-3.63(m,2H),3.48(s,3H),3.41(dd,J= 14.8, 7.2Hz, 2H), 2.47 (d, J = 12.0Hz, 2H), 1.22 (d, J = 4.8Hz, 3H), 1.20 (t, J = 3.6Hz, 6H).

[0820] Example 103 EVO33031

[0821] The reference compound EVO33138 was separated by HPLC preparative column and then freeze-dried to obtain EVO33031 (26 mg, yield: 43%), LCMS (ESI) m / z = 556.51 [M+H] + , purity: 98.8%. 1 H NMR(400MHz,Chloroform-d)δ9.28(s,1H),8.74(d,J=8.6Hz,1H),8.43(d,J=8.6Hz,1H), 8.17(s,1H),8.06(d,J=7.2Hz,1H),7.98-7.91(m,1H),7.76-7.68(m,3H),6.82(d,J=8.4H z,1H),5.29-5.24(m,2H),5.11(s,2H),5.04(d,J=5.6Hz,2H),4.21(d,J=11.2Hz,2H),3. 82-3.76(m,2H),2.64(t,J=11.6Hz,2H),1.75(s,3H),1.70(s,3H),1.33(d,J=6.0Hz,6H).

[0822] Example 104 EVO33036

[0823] The reference compound EVO33138 was separated by HPLC preparative column and then freeze-dried to obtain EVO33036 (3 mg, yield: 3%), LCMS (ESI) m / z = 546.21 [M+H] + , purity: 98.1%. 1H NMR(400MHz,Chloroform-d)δ9.31(s,1H),8.87(d,J=8.4Hz,1H),8.76(d,J=7.6Hz,1H),8.46(d,J=8.4Hz,1H),8.08-8.01(m,2H),7.94(d,J= 7.6Hz,1H),7.83-7.76(m,3H),7.62(s,1H),7.42(t,J=5.4Hz,1H),5.3 6(s,2H),5.10(s,2H),5.01(d,J=5.4Hz,2H),2.77(s,6H),1.62(s,6H).

[0824] Example 105 EVO33038

[0825] The reference compound EVO33138 was separated by HPLC preparative column and then freeze-dried to obtain EVO33038 (23 mg, yield: 30%), LCMS (ESI) m / z = 548.42 [M+H] + , purity: 99.23%. 1 H NMR(400MHz,Chloroform-d)δ9.32(s,1H),8.88(d,J=8.4Hz,1H),8.77(d,J=7.6Hz,1H),8.47(d,J=8.4Hz,1H),8.08-8.03(m,2H),7.95(d,J=7.6Hz,1H), 7.82(s,2H),7.68(s,1H),7.65(s,1H),7.46-7.40(m,1H),5.30-5.25(m,2H) ,5.13(s,2H),5.01(d,J=4.8Hz,2H),2.78(s,6H),1.75(s,3H),1.70(s,3H).

[0826] Example 106 EVO33041

[0827] Reference compound EVO33138 was separated by HPLC preparative column and freeze-dried to give brown solid EVO33041 (5.22 mg, yield: 14.04%), LCMS (ESI) m / z = 562.22 [M+H] + , purity: 99.47%. 1H NMR(400MHz, DMSO-d6)δ9.38(s,1H),9.10(t,J=6.0Hz,1H),8.70-8.57(m,2H),7.91(d,J=7.6Hz,1H),7.82(d,J= 1.6Hz,1H),7.78-7.69(m,2H),7.43(d,J=1.6Hz,1H),7.02(d,J=8.4Hz,1H),6.10(s,2H),5.24(s,1H),4.76(d,J= 5.6Hz, 2H), 4.31 (dd, J = 13.2, 2.4Hz, 2H), 3.71-3.63 (m, 2H), 2.45-2.39 (m, 2H), 1.21 (d, J = 6.4Hz, 6H).

[0828] Example 107 EVO33140

[0829] The reference compound EVO33138 was separated by HPLC preparative column and then freeze-dried to obtain EVO33140 (24.1 mg, yield: 36.3%), LCMS (ESI) m / z = 573.68 [M+H] + , purity: 92.5%. 1 H NMR(400MHz,Chloroform-d)δ9.29(s,1H),8.72(d,J=8.7Hz,1H),8.43(d,J=8.7Hz,1 H),8.13(s,1H),8.06(d,J=7.4Hz,1H),7.98(s,1H),7.86(s,1H),7.76-7.70(m,2H), 6.82(d,J=8.5Hz,1H),5.87(s,1H),5.01(d,J=5.5Hz,2H),4.27-4.16(m,2H),3.88-3 .70(m,4H),3.21-3.09(m,2H),3.05(s,3H),2.70-2.54(m,2H),1.34(d,J=6.2Hz,6H).

[0830] Example 108 EVO33412-B

[0831] The reference compound EVO33138 was separated by HPLC preparative column and then freeze-dried to obtain EVO33412-B (34 mg, yield: 14.83%), LCMS (ESI) m / z = 588.31 [M+H] + , purity: 98.83%. 1H NMR(400MHz,DMSO-d6)δ9.80(t,J=5.6Hz,1H),9.42(s,1H),8.77(dd,J=13.2, 1.2Hz,2H),8.71-8.61(q,J=8.8Hz,2H),7.91(d,J=7.2Hz,2H),7.75(t,J=7.2H z,1H),7.03(d,J=8.4Hz,1H),5.78(s,2H),4.87(d,J=5.6Hz,2H),4.31(d,J=11 .2Hz,2H),3.67(m,2H),3.39(s,3H),2.53-2.47(m,2H),1.22(d,J=6.0Hz,6H).

[0832] Example 109 EVO33435

[0833] Reference compound EVO33138 was separated by HPLC preparative column and freeze-dried to obtain EVO33435 (23 mg, yield: 22%), LCMS (ESI) m / z = 554.49 [M+H] + , purity: 97.5%. 1 H NMR(400MHz,Chloroform-d)δ9.28(s,1H),8.74(d,J=8.6Hz,1H),8.42(d,J=8.6Hz,1H),8. 17(s,1H),8.06(d,J=7.2Hz,1H),7.99-7.92(m,1H),7.85(s,1H),7.72(t,J=8.0Hz,1H),7.6 6(s,1H),6.82(d,J=8.4Hz,1H),5.34(s,2H),5.09(s,2H),5.03(d,J=5.6Hz,2H),4.21(d,J= 11.2Hz, 2H), 3.82-3.77 (m, 2H), 2.64 (t, J = 11.6Hz, 2H), 1.62 (s, 6H), 1.33 (d, J = 6.0Hz, 6H).

[0834] Example 110 EVO33453

[0835] The reference compound EVO33138 was separated by HPLC preparative column and then freeze-dried to obtain EVO33453 (5 mg, yield: 8.3%), LCMS (ESI) m / z = 575.16 [M+H] + , purity: 96.70%. 1H NMR(400MHz,Chloroform-d)δ9.24(s,1H),8.63(d,J=8.4Hz,1H),8.35(d,J=8.4Hz,1H),8.01 (d,J=7.2Hz,1H),7.97(s,1H),7.86(d,J=1.6Hz,1H),7.70(t,J=8.0Hz,1H),7.64(d,J=1.6Hz, 1H),7.54(t,J=4.8Hz,1H),6.77(d,J=8.4Hz,1H),6.24(s,2H),4.95(d,J=5.2Hz,2H),4.21(d, J=11.2Hz,2H),3.85-3.75(m,2H),3.25(s,3H),2.63(t,J=11.6Hz,2H),1.33(d,J=6.0Hz,6H).

[0836] Example 111 EVO33461

[0837] The reference compound EVO33138 was separated by HPLC preparative column and then freeze-dried to obtain EVO33461 (3.32 mg, yield: 23%), LCMS (ESI) m / z = 562.47 [M+H] + , purity: 96.7%. 1 H NMR(400MHz,DMSO-d6)δ9.33(s,1H),8.77(d,J=8.8Hz,1H),8.47(d,J=8.8Hz,1H),8 .18(s,1H),8.11(d,J=7.2Hz,1H),7.89-7.73(m,2H),7.67-7.66(m,1H),7.53-7.52( m,1H),6.86(d,J=8.4Hz,1H),6.16(s,2H),5.05(d,J=5.6Hz,2H),4.27-4.26(m,2H), 3.86-3.83(m,2H),2.71-2.65(m,2H),2.05(t,J=18.4Hz,3H),1.38(d,J=6.0Hz,6H).

[0838] Example 112 EVO33485

[0839] The reference compound EVO33138 was separated by HPLC preparative column and then freeze-dried to obtain EVO33485 (20 mg, yield: 27%), LCMS (ESI) m / z = 570.47 [M+H] + , purity: 99.64%. 1H NMR (400MHz, DMSO-d6) δ9.41 (s, 1H), 9.12 (t, J = 6.0Hz, 1H), 8.73-8.60 (m, 2H), 7.93 (d, J = 7.2Hz, 1 H),7.83(d,J=2.0Hz,1H),7.80-7.73(m,2H),7.46(d,J=2.0Hz,1H),7.05(d,J=8.4Hz,1H),6.10(s ,2H),5.09(s,1H),4.78(d,J=6.0Hz,2H),4.39-4.28(m,2H),3.78-3.64(m,2H),2.57-2.55(m,2H) ,1.94-1.85(m,1H),1.80-1.71(m,1H),1.50(s,3H),1.24(d,J=6.0Hz,6H),0.76(t,J=7.2Hz,3H).

[0840] Example 113 EVO33488

[0841] Reference compound EVO33138 was separated by HPLC preparative column and freeze-dried to obtain a light yellow solid EVO33488 (33 mg, yield: 46.5%), LCMS (ESI) m / z = 587.5 [M+H] + , purity: 98.4%. 1 H NMR (400MHz, DMSO-d6) δ9.55(t,J=6.0Hz,1H),9.38(s,1H),8.63(d,J=8.4Hz,1H),8.32-8.26(m, 3H),7.85(s,1H),7.79(t,J=2.2Hz,1H),7.69(d,J=7.6Hz,1H),7.40(t,J=8.0Hz,1H),7.13(dd,J =8.4,2.4Hz,1H),5.32(t,J=2.0Hz,2H),5.14(s,2H),4.82(d,J=6.0Hz,2H),3.76-3.70(m,4H),3 .37(q,J=7.2Hz,2H), 2.33(dd,J=12.2,10.6Hz,2H), 1.18(d,J=6.0Hz,6H), 1.15(t,J=7.2Hz,3H).

[0842] Example 114 EVO33526

[0843] The reference compound EVO33138 was separated by HPLC preparative column and then freeze-dried to obtain EVO33526 (10.3 mg, yield: 18.4%), LCMS (ESI) m / z = 600.15 [M+H] + , purity: 98.6%. 1 H NMR(400MHz,DMSO-d6)δ9.46(t,J=6.0Hz,1H),9.39(s,1H),8.64(q,J=8.4Hz,2H),7.98 (d,J=1.6Hz,1H),7.91(d,J=7.6Hz,1H),7.80-7.71(m,3H),7.03(d,J=8.4Hz,1H),4.80 (d,J=5.6Hz,2H),4.50(s,2H),4.31(d,J=13.2Hz,2H),3.71-3.64(m,2H),3.28(s,3H), 2.53-2.47(m,2H),1.79(q,J=4.4Hz,2H),1.22(d,J=6.4Hz,6H),1.10(q,J=4.4Hz,2H).

[0844] Example 115 EVO33530

[0845] The reference compound EVO33138 was separated by HPLC preparative column and then freeze-dried to obtain EVO33530 (26 mg, yield: 22%), LCMS (ESI) m / z = 588.5 [M+H] + , purity: 98.56%. 1 H NMR (400MHz, DMSO-d6) δ9.55(t,J=6.0Hz,1H),9.40(s,1H),8.69-8.59(m,2H),8.39(s,1H),8.23(s, 1H),7.90(d,J=7.2Hz,1H),7.83(s,1H),7.75(t,J=8.4Hz,1H),7.03(d,J=8.8Hz,1H),5.80-5.75(m, 1H),5.15(d,J=12.4Hz,1H),5.05(d,J=13.6Hz,1H),4.82(d,J=4.8Hz,2H),4.31(dd,J=12.8,2.4Hz, 2H), 3.70-3.65 (m, 2H), 3.32 (s, 3H), 2.52-2.48 (m, 2H), 1.50 (d, J = 6.4Hz, 3H), 1.21 (d, J = 6.4Hz, 6H).

[0846] Example 116 EVO33605

[0847] The reference compound EVO33138 was separated by HPLC preparative column and freeze-dried to give a yellow solid EVO33605 (8 mg, yield: 33%), LCMS (ESI) m / z = 548.15 [M+H] + , purity: 99.07%. 1 H NMR(400MHz, DMSO-d6)δ9.45(s,1H),9.14(t,J=6.0Hz,1H),8.89(d,J=8.4H z,1H),8.77(d,J=8.4Hz,1H),8.66(d,J=7.6Hz,1H),8.24(d,J=8.0Hz,1H),8 .14(t,J=7.6Hz,1H),7.91(s,2H),7.86-7.80(m,2H),7.45(d,J=1.6Hz,1H) ,6.10(s,2H),5.29(s,1H),4.78(d,J=5.6Hz,2H),2.57(s,6H),1.49(s,6H).

[0848] Example 117 EVO33607

[0849] The reference compound EVO33138 was separated by HPLC preparative column and then freeze-dried to obtain EVO33607 (11 mg, yield: 36%), LCMS (ESI) m / z = 550.14 [M+H] + , purity: 97.40%. 1 H NMR (400MHz, DMSO-d6) δ9.46 (s, 1H), 9.24 (t, J = 6.0Hz, 1H), 8.89 (d, J = 8.4Hz, 1H ),8.77(d,J=8.4Hz,1H),8.66(d,J=7.6Hz,1H),8.25(d,J=7.6Hz,1H),8.15(t,J =7.6Hz,1H),7.91(s,2H),7.83(s,1H),7.65(d,J=1.6Hz,1H),7.52(d,J=1.6Hz, 1H), 6.16 (s, 2H), 4.79 (d, J = 5.6Hz, 2H), 2.57 (s, 6H), 1.75 (s, 3H), 1.70 (s, 3H).

[0850] Example 118 EVO33537

[0851] The reference compound EVO33173 was separated by HPLC preparative column and then freeze-dried to obtain EVO33537 (5.4 mg, yield: 11.8%), LCMS (ESI) m / z = 532.2 [M+H] + , purity: 99.48%. 1 H NMR (400MHz, DMSO-d6) δ9.41-9.38(m,2H),8.66(d,J=8.6Hz,1H),8.59(d,J=8.6Hz,1H),7.90-7.81(m,2H),7.80(d,J=6.0Hz,2H),7.70(t,J=8.0Hz,1 H),6.53(d,J=8.0Hz,1H),6.35(s,2H),4.78(d,J=5.6Hz,2H),4.07(t,J=7 .2Hz, 4H), 3.37 (q, J = 7.2Hz, 2H), 2.42-2.34 (m, 2H), 1.18 (t, J = 7.2Hz, 3H).

[0852] Example 119 EVO33541

[0853] The reference compound EVO33173 was separated by HPLC preparative column and then freeze-dried to obtain EVO33541 (7.6 mg, yield: 17.2%), LCMS (ESI) m / z = 589.2 [M+H] + , purity: 97.08%. 1 H NMR (400MHz, DMSO-d6) δ9.41-9.38(m,2H),8.66(d,J=8.8Hz,1H),8.59(d,J=8.8Hz,1H),7.8 9(d,J=1.6Hz,1H),7.85(d,J=7.2Hz,1H),7.81-7.79(m,2H),7.70(t,J=8.4Hz,1H),6.99(d, J=8.4Hz,1H),6.35(s,2H),4.78(d,J=5.6Hz,2H),4.30(dd,J=8.4,2.0Hz,2H),3.38(q,J=7. 2Hz, 2H), 2.82-2.77 (m, 2H), 2.37-2.31 (m, 2H), 1.18 (t, J = 7.2Hz, 3H), 1.08 (d, J = 6.4Hz, 6H).

[0854] Example 120 EVO33544

[0855] The reference compound EVO33173 was separated by HPLC preparative column and then freeze-dried to obtain EVO33544 (11.1 mg, yield: 9.18%), LCMS (ESI) m / z = 592.66 [M+H] + , purity: 98.31%. 1 H NMR(400MHz,DMSO-d6)δ9.42-9.39(m,2H),8.68-8.60(m,2H),7.94-7.90(m,2H),7.81-7.7 5(m,3H),7.01(d,J=8.4Hz,1H),6.35(s,2H),4.86-4.81(m,1H),4.78(d,J=5.6Hz,2H),4.3 4(d,J=12.8Hz,1H),4.23(d,J=12.8Hz,1H),4.02-3.99(m,1H),3.65-3.59(m,1H),3.57-3. 48(m,3H),3.40-3.35(m,2H),2.98-2.91(m,1H),2.73-2.66(m,1H),1.18(t,J=7.6Hz,3H).

[0856] Example 121 EVO33547

[0857] The reference compound EVO33173 was separated by HPLC preparative column and then freeze-dried to obtain EVO33547 (13.3 mg, yield: 15.1%), LCMS (ESI) m / z = 554.55 [M+H] + , purity: 98.26%. 1 H NMR (400MHz, DMSO-d6) δ9.46 (s, 1H), 9.43 (t, J = 6.0Hz, 1H), 8.91 (d, J = 8.8Hz, 1H ),8.79-8.77(m,3H),8.69(d,J=8.0Hz,1H),8.32(d,J=8.0Hz,1H),8.27(d,J=6.4 Hz,2H),8.20(t,J=8.0Hz,1H),7.91(s,1H),7.87(s,1H),7.82(d,J=1.6Hz,1H), 6.36 (s, 2H), 4.81 (d, J = 5.6Hz, 2H), 3.39 (q, J = 7.2Hz, 2H), 1.19 (t, J = 7.2Hz, 3H).

[0858] Example 122 EVO33561

[0859] The reference compound EVO33173 was separated by HPLC preparative column and freeze-dried to obtain a yellow solid EVO33561 (7 mg, yield: 22.22%), LCMS (ESI) m / z = 589.55 [M+H] + , purity: 96.44%. 1 H NMR (400MHz, DMSO-d6) δ9.46-9.33(m,2H),8.73-8.62(m,2H),7.95-7.86(m,2H),7.82-7.72(m,3H),6.74(d,J= 8.0Hz,1H),6.36(s,2H),4.78(d,J=5.6Hz,2H),4.08-3.96(m,2H),3.83-3.78(m,1H),3.75-3.64(m,1H),3.55- 3.51(m,1H),3.41-3.35(m,2H),2.90(dd,J=10.0,4.4Hz,6H),2.47-2.44(m,1H),2.27(m,1H),1.18(t,J=7.2Hz,3H).

[0860] Example 123 EVO33077

[0861] The reference compound EVO33240 was separated by HPLC preparative column and freeze-dried to obtain a yellow solid EVO33077 (3.45 mg, yield: 13.26%), LCMS (ESI) m / z = 563.18 [M+H] + , purity: 95.8%. 1 H NMR (400MHz, DMSO-d6) δ9.39(t,J=5.6Hz,1H),8.51(d,J=5.2Hz,1H),8.27(d,J=1.6Hz,1H),8.21( d,J=1.6Hz,1H),7.61-7.49(m,4H),7.39(d,J=16.0Hz,1H),6.87(d,J=7.2Hz,1H),6.81(d,J=8.8Hz ,1H),5.30(d,J=2.0Hz,2H),5.12(s,2H),4.62(d,J=6.0Hz,2H),4.24(dd,J=13.2,2.4Hz,2H),3.6 6-3.58(m,2H),3.38-3.32(m,2H),2.43-2.37(m,2H),1.18(d,J=6.0Hz,6H),1.13(t,J=7.2Hz,3H).

[0862] Example 124 EVO33466

[0863] The reference compound EVO33392 was separated by HPLC preparative column and freeze-dried to obtain a yellow solid EVO33466 (6 mg, yield: 11.0%), LCMS (ESI) m / z = 618.2 [M+H] + , purity: 98.6%. 1 H NMR(400MHz,DMSO-d6)δ9.78(t,J=6.0Hz,1H),9.41(s,1H),8.75(dd,J=16.8,1 .4Hz,2H),8.65(q,J=8.8Hz,2H),7.92-7.89(m,2H),7.75(t,J=8.0Hz,1H),7.0 3(d,J=8.4Hz,1H),5.75(s,2H),4.90-4.85(m,3H),4.31(d,J=12.4Hz,2H),3.7 8(q,J=5.6Hz,2H),3.70-3.63(m,4H),2.53-2.47(m,2H),1.21(d,J=6.0Hz,6H).

[0864] Example 125 EVO33493

[0865] The reference compound EVO33392 was separated by HPLC preparative column and freeze-dried to obtain a yellow solid EVO33493 (85.35 mg, yield: 69.7%), LCMS (ESI) m / z = 620.2 [M+H] + , purity: 99.8%. 1 H NMR (400MHz, DMSO-d6) δ9.41-9.38(m,2H),8.64(q,J=8.8Hz,2H),7.91-7.89(m,2H),7.79-7.73(m,3H),7.03(d,J=8.4Hz,1H),6.35( s,2H),4.78(d,J=5.6Hz,2H),4.31(dd,J=13.0,2.4Hz,2H),3.71-3.63(m,6H),3.14(s,3H),2.53-2.47(m,2H),1.21(d,J=6.4Hz,6H).

[0866] Example 126 EVO33602

[0867] The reference compound EVO33392 was separated by HPLC preparative column and then freeze-dried to obtain EVO33602 (8.54 mg, yield: 25%), LCMS (ESI) m / z = 598.43 [M+H]+ , purity: 99.78%. 1 H NMR (400MHz, DMSO-d6) δ9.50 (s, 1H), 9.44 (t, J = 5.6Hz, 1H), 8.93 (d, J = 8.4Hz, 1H), 8.8 0(d,J=8.4Hz,1H),8.70(d,J=7.2Hz,1H),8.28(d,J=7.2Hz,1H),8.19(t,J=7.6Hz,1H) ,7.95-7.93(m,3H),7.90(s,1H),7.83(d,J=1.6Hz,1H),6.39(s,2H),4.93(t,J=5.6Hz ,1H),4.83(d,J=5.6Hz,2H),3.80(q,J=6.0Hz,2H),3.58(t,J=6.0Hz,2H),2.60(s,6H).

[0868] Example 127 EVO33037

[0869] The reference compound EVO33138 was separated by HPLC preparative column and then freeze-dried to obtain EVO33037 (4.72 mg, yield: 32.7%), LCMS (ESI) m / z = 568.49 [M+H] + , purity: 90.9%. 1 H NMR (400MHz, DMSO-d6) δ9.38 (s, 1H), 9.15 (t, J = 5.9Hz, 1H), 8.69-8.58 (m, 2H), 7.90 (d, J = 7.4Hz ,1H),7.78-7.70(m,2H),7.66(d,J=1.7Hz,1H),7.44(d,J=1.7Hz,1H),7.03(d,J=8.5Hz,1H),6.1 3(s,2H),5.56(s,1H),4.76(d,J=5.8Hz,2H),4.31(dd,J=13.0,2.4Hz,2H),3.74-3.61(m,3H),2. 71-2.59(m,2H),2.28-2.14(m,2H),2.03-1.89(m,1H),1.71-1.59(m,1H),1.24(d,J=6.2Hz,6H).

[0870] Example 128 EVO33185

[0871] The reference compound EVO33138 was separated by HPLC preparative column and then freeze-dried to obtain the product EVO33185 (27 mg, yield: 58%), LCMS (ESI) m / z = 587.2 [M+H] + , purity: 94.8%. 1 H NMR(400MHz,DMSO-d6)δ9.79-9.71(m,1H),9.40(s,1H),9.06(s,1H),8.7 0-8.57(m,4H),7.93-7.87(m,1H),7.86(s,1H),7.74(t,J=7.9Hz,1H),7.0 2(d,J=8.5Hz,1H),4.85(d,J=5.7Hz,2H),4.79(s,2H),4.38-4.24(m,2H), 3.74-3.61(m,2H),3.35(s,3H),2.57-2.42(m,2H),1.21(d,J=6.2Hz,6H).

[0872] Example 129 EVO33438

[0873] The reference compound EVO33138 was separated by HPLC preparative column and then freeze-dried to obtain the product EVO33438 (60 mg, yield: 86%), LCMS (ESI) m / z = 615.23 [M+H] + , purity: 98.1%. 1 H NMR (400MHz, Chloroform-d) δ9.42 (s, 1H), 9.17-9.03 (m, 1H), 8.88 (d, J = 8.8Hz, 1H), 8.61-8.52 ( m,2H),8.48-8.38(m,2H),8.12(d,J=7.4Hz,1H),7.79-7.71(m,1H),7.30(d,J=3.2Hz,1H),6.90-6 .83(m,1H),6.75(d,J=3.2Hz,1H),5.14(d,J=5.8Hz,2H),4.79(t,J=5.1Hz,2H),4.24-4.18(m,2H) ,3.97(t,J=5.1Hz,2H),3.84-3.75(m,2H),3.44(s,3H),2.70-2.59(m,2H),1.34(d,J=6.2Hz,6H).

[0874] Example 130 EVO33080

[0875] The reference compound EVO33173 was separated by HPLC preparative column and freeze-dried to obtain a yellow solid EVO33080 (16.86 mg, yield: 26.15%), LCMS (ESI) m / z = 628.30 [M+H] + , purity: 98.54%. 1 H NMR(400MHz,DMSO-d6)δ9.56(t,J=6.0Hz,1H),9.30(s,1H),8.57(d,J=8.8Hz,2H),8.32 (s,1H),8.29(d,J=8.6Hz,1H),8.26(s,1H),7.96(s,1H),7.78(s,1H),7.73(s,1H),5.3 2(s,2H),5.14(s,2H),4.80(d,J=5.8Hz,2H),4.71(d,J=12.9Hz,2H),3.74-3.64(m,2H) ,3.37(q,J=7.2Hz,2H),3.01-2.86(m,2H),1.22(d,J=6.2Hz,6H),1.15(t,J=7.3Hz,3H).

[0876] Example 131 EVO33081

[0877] The reference compound EVO33173 was separated by HPLC preparative column and freeze-dried to obtain a yellow solid EVO33081 (23.13 mg, yield: 37.94%), LCMS (ESI) m / z = 630.30 [M+H] + , purity: 99.89%. 1 H NMR(400MHz,DMSO-d6)δ9.38(t,J=5.9Hz,1H),9.29(s,1H),8.59-8.53(m,2H),8.29(d ,J=8.6Hz,1H),7.96(s,1H),7.90(d,J=1.7Hz,1H),7.80(d,J=1.6Hz,1H),7.76-7.72( m,2H),6.35(s,2H),4.75(d,J=5.8Hz,2H),4.72(d,J=13.2Hz,2H),3.72-3.67(m,2H), 3.38 (q, J=7.4Hz, 2H), 3.01-2.87 (m, 2H), 1.22 (d, J=6.2Hz, 6H), 1.18 (t, J=7.4Hz, 3H).

[0878] Example 132 EVO33229

[0879] The reference compound EVO33173 was separated by HPLC preparative column and freeze-dried to obtain a white solid EVO33229 (12.97 mg, yield: 16.3%), LCMS (ESI) m / z = 559.26 [M+H] + , purity: 99.89%. 1 H NMR (400MHz, DMSO-d6) δ9.47(s,1H),9.13(t,J=5.9Hz,1H),8.97(d,J=8.6Hz,1 H),8.78(d,J=8.6Hz,1H),8.75-8.70(m,2H),8.50(d,J=1.6Hz,1H),8.40(dd,J =7.9,1.0Hz,1H),8.21(t,J=7.9Hz,1H),7.85-7.79(m,2H),7.45(d,J=1.8Hz,1 H), 6.10 (s, 2H), 5.27 (s, 1H), 4.78 (d, J = 5.7Hz, 2H), 2.69 (s, 3H), 1.50 (s, 6H).

[0880] Example 133 EVO33566

[0881] The reference compound EVO33173 was separated by HPLC preparative column and freeze-dried to obtain a yellow solid EVO33566 (9.8 mg, yield: 19.85%), LCMS (ESI) m / z = 608.4 [M+H] + , purity: 99.66%. 1 H NMR(400MHz,DMSO-d6)δ9.40(d,J=4.0Hz,2H),8.73-8.65(m,1H),8.55(d,J=8.6Hz,1 H),8.09(dd,J=8.2,2.9Hz,1H),7.89(d,J=1.6Hz,1H),7.82-7.78(m,2H),7.71(dd,J =13.1,8.2Hz,1H),6.35(s,2H),4.78(d,J=5.8Hz,2H),4.01(d,J=12.1Hz,2H),3.83- 3.71 (m, 2H), 3.37 (q, J = 7.4Hz, 2H), 2.67 (dd, J = 12.8, 10.5Hz, 2H), 1.21-1.16 (m, 9H).

[0882] Example 134 EVO33571

[0883] The reference compound EVO33173 was separated by HPLC preparative column and freeze-dried to obtain a white solid EVO33571 (16.87 mg, yield: 20.1%), LCMS (ESI) m / z = 591.3 [M+H] + , purity: 99.65%. 1 H NMR(400MHz,DMSO-d6)δ9.60(t,J=5.9Hz,1H),9.49(s,1H),8.99(d,J=8.6Hz,1H),8.79 (d,J=8.7Hz,1H),8.75-8.70(m,2H),8.51(d,J=1.7Hz,1H),8.41(d,J=7.8Hz,1H),8.33 (s,1H),8.28(s,1H),8.24(t,J=7.9Hz,1H),7.91(s,1H),5.32(d,J=2.1Hz,2H),5.15(s ,2H),4.85(d,J=5.8Hz,2H),3.38(q,J=7.3Hz,2H),2.69(s,3H),1.16(t,J=7.3Hz,3H).

[0884] Example 135 EVO33012

[0885] The reference compound EVO33240 was separated by HPLC preparative column and freeze-dried to obtain a yellow solid EVO33012 (23 mg, yield: 28.8%), LCMS (ESI) m / z = 529.53 [M+H] + , purity: 97.40%. 1 H NMR(400MHz,Chloroform-d)δ8.51(d,J=5.2Hz,1H),7.79(s,2H),7.61(s,1H),7.5 6-7.49(m,3H),7.42(d,J=4.4Hz,1H),7.28-7.24(m,1H),6.76(d,J=7.2Hz,1H),6.6 2(d,J=8.4Hz,1H),5.34(s,2H),5.09(s,2H),4.80(d,J=5.2Hz,2H),4.17(d,J=11. 2Hz, 2H), 3.80-3.70 (m, 2H), 2.60-2.54 (m, 2H), 1.61 (s, 6H), 1.31 (d, J = 6.0Hz, 6H).

[0886] Example 136 EVO33024

[0887] The reference compound EVO33240 was separated by HPLC preparative column and freeze-dried to obtain a yellow solid EVO33012 (9.3 mg, yield: 58.8%), LCMS (ESI) m / z = 531.50 [M+H] + , purity: 98.50%. 1 H NMR(400MHz,Chloroform-d)δ8.53(d,J=5.2Hz,1H),7.83-7.78(m,1H),7.68(s,1H),7. 65(s,1H),7.57-7.49(m,3H),7.43(d,J=4.8Hz,1H),7.30-7.25(m,1H),6.77(d,J=7.2Hz ,1H),6.63(d,J=8.4Hz,1H),5.27(s,2H),5.12(s,2H),4.81(d,J=5.2Hz,2H),4.17(d,J =11.2Hz,2H),3.79-3.74(m,2H),2.61-2.55(m,2H),1.70(s,6H),1.32(d,J=6.0Hz,6H).

[0888] Example 137 EVO33608

[0889] The reference compound EVO33240 was separated by HPLC preparative column and then freeze-dried to obtain EVO33608 (21.26 mg, yield: 30.7%), LCMS (ESI) m / z = 549.49 [M+H] + , purity: 97.2%. 1 H NMR (400MHz, DMSO-d6) δ9.26(t,J=5.9Hz,1H),8.50(d,J=5.1Hz,1H),7.90(d,J=1.4Hz,1H) ,7.62(d,J=1.4Hz,1H),7.61-7.48(m,4H),7.38(d,J=16.0Hz,1H),6.87(d,J=7.2Hz,1H),6 .81(d,J=8.6Hz,1H),4.70(t,J=8.8Hz,2H),4.59(d,J=5.8Hz,2H),4.24(dd,J=13.0,2.4Hz ,2H),3.64-3.54(m,4H),3.24(s,3H),2.41(dd,J=12.8,10.5Hz,2H),1.18(d,J=6.2Hz,6H).

[0890] Example 138 EVO33039

[0891] The reference compound EVO33138 was separated by HPLC preparative column and then freeze-dried to obtain EVO33039 (13.26 mg, yield: 13%), LCMS (ESI) m / z = 594.2 [M+H] + , purity: 98.67%. 1 H NMR (400MHz, DMSO-d6) δ9.39(s,1H),9.25(t,J=5.9Hz,1H),8.64(q,J=8.6Hz,2H),7.91(d,J=7.4 Hz,1H),7.78(s,1H),7.74(t,J=7.9Hz,1H),7.67(d,J=1.7Hz,1H),7.61(d,J=1.6Hz,1H),7.03(d, J=8.5Hz,1H),6.43(td,J=54.0,8.0Hz,1H),6.18(s,2H),4.77(d,J=5.8Hz,2H),4.31(dd,J=12.9 ,2.4Hz,2H),3.70-3.65(m,2H),2.53-2.47(m,2H),1.84(d,J=23.8Hz,3H),1.22(d,J=6.2Hz,6H).

[0892] Example 139 EVO33484

[0893] The reference compound EVO33138 was separated by HPLC preparative column and then freeze-dried to obtain EVO33484 (22.93 mg, yield: 41.8%), LCMS (ESI) m / z = 610.4 [M+H] + , purity: 98.88%. 1 H NMR (400MHz, DMSO-d6) δ9.38 (s, 1H), 9.18 (t, J = 5.9Hz, 1H), 8.67-8.60 (m, 2H), 7.92-7.90(m,2H),7.76-7.72(m,2H),7.58(d,J=1.8Hz,1H),7.03(d,J=8.5Hz, 1H),6.80(s,1H),6.13(s,2H),4.76(d,J=5.8Hz,2H),4.31(dd,J=13.0,2.4Hz, 2H), 3.70-3.65 (m, 2H), 2.53-2.47 (m, 2H), 1.80 (s, 3H), 1.21 (d, J = 6.2Hz, 6H).

[0894] Example 140 EVO33492

[0895] The reference compound EVO33138 was separated by HPLC preparative column and then freeze-dried to obtain EVO33492 (14.92 mg, yield: 14.5%), LCMS (ESI) m / z = 592.3 [M+H] + , purity: 99.97%. 1 H NMR (400MHz, DMSO-d6) δ9.39 (s, 1H), 9.15 (t, J=5.9Hz, 1H), 8.69-8.59 (m, 2H), 7.91 (d, J= 7.4Hz,1H),7.83(d,J=1.7Hz,1H),7.78-7.70(m,2H),7.52(d,J=1.7Hz,1H),7.03(d,J=8. 5Hz,1H),6.15-6.09(m,3H),6.06(t,J=55.7Hz,1H),4.76(d,J=5.8Hz,2H),4.31(dd,J=13 .0,2.4Hz,2H),3.74-3.60(m,2H),2.53-2.47(m,2H),1.60(s,3H),1.22(d,J=6.2Hz,6H).

[0896] Example 141 EVO33604

[0897] The reference compound EVO33138 was separated by HPLC preparative column and then freeze-dried to obtain EVO33604 (20.54 mg, yield: 23.5%), LCMS (ESI) m / z = 612.2 [M+H] + , purity: 99.95%. 1 H NMR (400MHz, DMSO-d6) δ9.39 (s, 1H), 9.29 (t, J = 5.9Hz, 1H), 8.64 (q, J = 8.6Hz, 2H), 7.91(d,J=7.4Hz,1H),7.78-7.71(m,3H),7.67(d,J=1.6Hz,1H),7.03(d,J=8.5Hz, 1H),6.20(d,J=4.9Hz,2H),4.77(d,J=5.8Hz,2H),4.31(dd,J=12.9,2.3Hz,2H),3. 71-3.64(m,2H),2.53-2.47(m,2H),2.03(d,J=24.4Hz,3H),1.21(d,J=6.2Hz,6H).

[0898] Example 142 EVO33082

[0899] The reference compound EVO33173 was separated by HPLC preparative column and then freeze-dried to obtain EVO33082 (8.71 mg, yield: 14.24%), LCMS (ESI) m / z = 596.37 [M+H] + , purity: 99.68%. 1 H NMR (400MHz, DMSO-d6) δ9.28 (s, 1H), 9.08 (t, J = 6.0Hz, 1H), 8.59-8.53 (m, 2H), 8 .28(d,J=8.6Hz,1H),7.96(s,1H),7.82(d,J=1.8Hz,1H),7.73(d,J=1.6Hz,1H), 7.70(s,1H),7.43(d,J=1.7Hz,1H),6.10(s,2H),5.26(s,1H),4.79-4.66(m,4H) ,3.74-3.63(m,2H),2.93(t,J=10.2Hz,2H),1.49(s,6H),1.22(d,J=6.1Hz,6H).

[0900] Example 143 EVO33083

[0901] The reference compound EVO33173 was separated by HPLC preparative column and then freeze-dried to obtain EVO33083 (9.16 mg, yield: 36.52%), LCMS (ESI) m / z = 598.36 [M+H] + , purity: 95.82%. 1 H NMR (400MHz, DMSO-d6) δ9.28 (s, 1H), 9.19 (t, J = 6.0Hz, 1H), 8.60-8.53 (m, 2H), 8.28(d,J=8.7Hz,1H),7.96(s,1H),7.74(d,J=1.7Hz,1H),7.71(s,1H),7.64(d, J=1.7Hz,1H),7.50(d,J=1.7Hz,1H),6.16(s,2H),4.82-4.64(m,4H),3.76-3.6 3(m,2H),2.93(t,J=11.0Hz,2H),1.72(d,J=22.3Hz,6H),1.22(d,J=6.1Hz,6H).

[0902] Example 144 EVO33253

[0903] The reference compound EVO33173 was separated by HPLC preparative column and then freeze-dried to obtain EVO33253 (11.27 mg, yield: 16.67%), LCMS (ESI) m / z = 584.24 [M+H] + , purity: 99.56%. 1 H NMR(400MHz, DMSO-d6)δ9.60(t,J=5.9Hz,1H),9.47(s,1H),8.92(d,J=8.6Hz,1H), 8.77(d,J=8.6Hz,1H),8.69(d,J=7.8Hz,1H),8.35–8.30(m,2H),8.27(s,1H),8.20 (t,J=7.9Hz,1H),8.12(s,1H),7.90(s,1H),7.82(s,1H),5.33(s,2H),5.15(s,2H) ,4.85(d,J=5.7Hz,2H),3.37(q,J=7.3Hz,2H),2.58(s,3H),1.16(t,J=7.3Hz,3H).

[0904] Example 145 EVO33254

[0905] The reference compound EVO33173 was separated by HPLC preparative column and then freeze-dried to obtain EVO33254 (6.95 mg, yield: 10.96%), LCMS (ESI) m / z = 552.20 [M+H] + , purity: 94.91%. 1 H NMR(400MHz,DMSO-d6)δ9.46(s,1H),9.13(t,J=5.9Hz,1H),8.91(d,J=8.6H z,1H),8.77(d,J=8.6Hz,1H),8.71(d,J=7.9Hz,1H),8.33(d,J=7.8Hz,1H),8 .19(t,J=7.9Hz,1H),8.12(s,1H),7.86-7.79(m,3H),7.45(d,J=1.8Hz,1H) ,6.10(s,2H),5.27(s,1H),4.78(d,J=5.8Hz,2H),2.58(s,3H),1.50(s,6H).

[0906] Example 146 EVO33573

[0907] The reference compound EVO33173 was separated by HPLC preparative column and then freeze-dried to obtain EVO33573 (8.03 mg, yield: 10.4%), LCMS (ESI) m / z = 567.24 [M+H] + , purity: 99.15%. 1 H NMR (400MHz, DMSO-d6) δ9.96 (d, J = 2.2Hz, 1H), 9.60 (t, J = 5.8Hz, 1H), 9.48 (s, 1H), 8. 97(d,J=8.6Hz,1H),8.79(d,J=8.6Hz,1H),8.72(d,J=7.9Hz,1H),8.43-8.39(m,2H),8 .34(d,J=1.4Hz,1H),8.28-8.22(m,2H),7.91(s,1H),5.32(d,J=2.1Hz,2H),5.15(s, 2H), 4.85 (d, J = 5.7Hz, 2H), 3.38 (q, J = 7.3Hz, 2H), 2.78 (s, 3H), 1.16 (t, J = 7.3Hz, 3H).

[0908] Example 147 EVO33610

[0909] The reference compound EVO33240 was separated by HPLC preparative column and then freeze-dried to obtain EVO33610 (25 mg, yield: 32.7%), LCMS (ESI) m / z = 531.53 [M+H] + , purity: 99.0%. 1 H NMR(400MHz,Chloroform-d)δ8.50(d,J=5.4Hz,1H),7.82-7.73(m,1H),7.62(d,J=1.7Hz,1H),7.58-7.48(m,3H),7.44(dd,J=5 .4,1.6Hz,1H),7.32-7.27(m,1H),6.76(d,J=7.2Hz,1H),6.62(d,J=8.5Hz,1H),6.04(s,2H),4.80(d,J=5.3Hz,2H),4.16(dd,J =13.1,2.2Hz,2H),3.80-3.70(m,2H),2.62-2.53(m,2H),1.62(s,6H),1.31(d,J=6.2Hz,6H).

[0910] Effect Example 1 Inhibitory Activity Detection Experiment of Compounds on BRM and BRG1 ATPase

[0911] To characterize the ATPase inhibitory activity of compounds against BRM and BRG1, ADP-Glo TM Kinase Assay (Promega, #V9101) detects the amount of ADP in the ATPase reaction endpoint system to evaluate ATPase activity. It is carried out in two steps: first, after the ATPase reaction, ADP-Glo ​​Reagent is added to terminate the reaction and deplete the remaining ATP; then, Kinase Detection Reagent is added to convert ADP into ATP, and ATP is consumed by the luciferase / luciferin reaction to produce a chemiluminescent signal. The signal is proportional to the concentration of ATP (converted from ADP generated by the ATPase reaction). Compared with the control wells without compound treatment, the ATPase inhibitory activity of the compound is evaluated by the reduction of the luminescent signal. The IC is calculated based on the data relationship between the compound concentration and the percentage of ATPase activity. 50 value.

[0912] The specific procedure is as follows: Test compounds (dissolved in DMSO, concentrations ranging from 10 μM to 1 nM, 50 nL / well) are added to a 384-well plate (Greiner #781280). A mixture of a BRM truncated protein (expressed and purified BRM ATPase-SnAC Domain, described in the literature DOI: 10.1021 / acs.jmedchem.8b01318) or a BRG1 truncated protein (expressed and purified BRG1 ATPase-SnAC Domain, described in the literature DOI: 10.1021 / acs.jmedchem.8b01318) and DNA (Invitrogen #15632011) is added to each well (final protein concentration: 30 nM, final DNA concentration: 80 nM). The enzyme reaction is initiated by adding 2.5 μL of ATP (Promega #V9101, final concentration: 400 μM) to each well. The system buffer was 20 mM Tris, pH 8.0, 50 mM NaCl, 20 mM MgCl2, 0.1% Tween-20, and 1 mM DTT in a total volume of 5 μL. The reaction was incubated at 25°C for 60 minutes. ADP-Glo ​​reagent (5 μL) was then added, and the reaction was incubated at 25°C for 90 minutes. Kinase Detection Reagent (10 μL) was then added, and the reaction was incubated at 25°C for 60 minutes. Chemiluminescence was then detected.

[0913] The results of enzyme activity determination are listed in the following table:

[0914] Where A represents IC 50≤100nM; B means 100nM<IC 50 ≤500nM; C means 500nM<IC 50 ≤1000nM; D means 1000nM<IC 50 ≤5000nM; E means 5000nM<IC 50 ≤10000nM; F represents IC 50 >10000 nM; NA means not detected.

[0915] Although the above describes specific embodiments of the present invention, it should be understood by those skilled in the art that these are merely illustrative and that various changes or modifications may be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.

Claims

1. A compound as shown in formula I or a pharmaceutically acceptable salt thereof, characterized in that: in, Y is C or N; R 1 for Hydroxyl, cyano, halogen, amino, deuterium, unsubstituted or replaced by one or more R 1-3 Substituted C1-C6 alkyl, unsubstituted or substituted by one or more R 1-4 Substituted C3-C6 cycloalkyl or unsubstituted or substituted by one or more R 1-5 Substituted 3-6 membered heterocycloalkyl; the heteroatoms in the 3-6 membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; R 1-1 is unsubstituted or substituted with one or more R 1-1-1 Substituted C1-C6 alkyl, unsubstituted or C3-C6 cycloalkyl substituted by one or more deuteriums, or -NR 1-1-2 R 1-1-3 ; R 1-2 O or NR 1-2-1 ; R 1-2-1 is hydrogen or C1-C6 alkyl which is unsubstituted or substituted by one or more deuterium groups; Each R 1-1-1 Independently OR 1-1-1-1 , C1-C6 alkyl or deuterium, unsubstituted or substituted with one or more deuterium groups; R 1-1-1-1 is hydrogen or C1-C6 alkyl which is unsubstituted or substituted by one or more deuterium groups; R 1-1-2 and R 1-1-3 are independently hydrogen or C1-C6 alkyl which is unsubstituted or substituted with one or more deuterium groups; Each R 1-3 are independently hydroxy, cyano, halogen, amino, C1-C6 alkyl which is unsubstituted or substituted with one or more deuterium groups, or deuterium; Each R 1-4 and R 1-5 are independently hydroxy, deuterium, or C1-C6 alkyl which is unsubstituted or substituted with one or more deuterium groups; X is -CR 1-6 R 1-7 -or-NR 1-8 -; R 1-6 and R 1-7 are independently hydrogen, deuterium, halogen, or C1-C6 alkyl which is unsubstituted or substituted with one or more deuterium groups; R 1-8 is hydrogen or C1-C6 alkyl which is unsubstituted or substituted by one or more deuterium groups; R 2 and R 3 The atoms to which it is attached are unsubstituted or replaced by one or more R 2-1 substituted 5-6 membered heteroaryl, unsubstituted or substituted by one or more R 2-2 substituted 4-6 membered heterocycloalkyl, unsubstituted or substituted by one or more R 2-3 Substituted C4-C6 cycloalkyl or unsubstituted or substituted by one or more R 2-4 Substituted C6-C 10 The heteroatoms in the 5-6 membered heteroaryl group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 4-6 membered heterocycloalkyl group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; Each R 2-1 are independently deuterium, halogen, unsubstituted or substituted with one or more R 2-1-1 Substituted C1-C6 alkyl, oxo (=O), or two R 2-1 Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl group which is unsubstituted or substituted with one or more deuteriums; Each R 2-2 are independently deuterium, halogen, unsubstituted or substituted with one or more R 2-2-1 Substituted C1-C6 alkyl, oxo (=O), Or, two R 2-2 Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl group which is unsubstituted or substituted with one or more deuteriums; Each R 2-3 are independently deuterium, halogen, unsubstituted or substituted with one or more R 2-3-1 Substituted C1-C6 alkyl, oxo (=O), or two R 2-3 Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl group which is unsubstituted or substituted with one or more deuteriums; Each R 2-4 are independently deuterium, halogen, unsubstituted or substituted with one or more R 2-4-1 Substituted C1-C6 alkyl, oxo (=O), or two R 2-4 Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl group which is unsubstituted or substituted with one or more deuteriums; R 2-1-1 、R 2-2-1 、R 2-3-1 and R 2-4-1 are independently deuterium or hydroxyl; A is unsubstituted or substituted with one or more deuteriums C6-C 10 substituted arylene, a 5-12 membered heteroarylene which is unsubstituted or substituted by one or more deuteriums, or a 5-12 membered heterocycloalkylene which is unsubstituted or substituted by one or more deuteriums; the heteroatoms in the 5-12 membered heteroarylene are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heterocycloalkylene are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; L is a linker, a C2-C6 alkenylene group which is unsubstituted or substituted with one or more deuterium groups, or a C1-C6 alkylene group which is unsubstituted or substituted with one or more deuterium groups; Q is unsubstituted or substituted with one or more R 3-1 Substituted C6-C 10 arylene, unsubstituted or replaced by one or more R 3-1 Substituted 5-12 membered heteroarylene or unsubstituted or replaced by one or more R 3-1 Substituted 5-12 membered heterocycloalkylene; the heteroatoms in the 5-12 membered heteroarylene are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heterocycloalkylene are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; Each R 3-1 are independently halogen or deuterium; R 4 is unsubstituted or replaced by one or more R 4-1 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more R 4-2 Substituted C2-C6 alkenyl, unsubstituted or replaced by one or more R 4-3 Substituted C2-C6 alkynyl, unsubstituted or replaced by one or more R 4-4 Substituted C3-C6 cycloalkyl, unsubstituted or replaced by one or more R 4-5 substituted 4-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 4-6 substituted 5-12 membered heteroaryl, unsubstituted or replaced by one or more R 4-7 Substituted C1-C6 alkoxy or -NR 4-9 R 4-8 The heteroatoms in the 4-12 membered heterocycloalkyl group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heteroaryl group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; Each R 4-1 are independently deuterium, halogen, hydroxy, C1-C6 alkyl which is unsubstituted or substituted by one or more deuterium groups, or C1-C6 alkoxy which is unsubstituted or substituted by one or more deuterium groups; Each R 4-2 are independently deuterium, halogen, hydroxyl, or C1-C6 alkyl which is unsubstituted or substituted with one or more deuterium groups; Each R 4-3 are independently deuterium, halogen, hydroxyl, or C1-C6 alkyl which is unsubstituted or substituted with one or more deuterium groups; Each R 4-4 are independently deuterium, halogen, hydroxyl, or C1-C6 alkyl which is unsubstituted or substituted with one or more deuterium groups; Each R 4-5 are independently deuterium, halogen, hydroxyl, unsubstituted or replaced by one or more R 4-5-1 Substituted C1-C6 alkyl, -NR 4-5- 2 R 4-5-3 or C1-C6 alkoxy which is unsubstituted or substituted with one or more deuterium groups; Each R 4-5-1 are independently deuterium, hydroxyl or halogen; R 4-5-2 and R 4-5-3 are independently hydrogen or C1-C6 alkyl which is unsubstituted or substituted with one or more deuterium groups; Each R 4-6 are independently deuterium, halogen, cyano, hydroxy, C1-C6 alkyl which is unsubstituted or substituted by one or more deuterium groups, or C1-C6 alkoxy which is unsubstituted or substituted by one or more deuterium groups; Each R 4-7 are independently deuterium, halogen, C1-C6 alkyl which is unsubstituted or substituted by one or more deuterium groups, or C1-C6 alkoxy which is unsubstituted or substituted by one or more deuterium groups; R 4-9 and R 4-8 are independently hydrogen, unsubstituted or replaced by one or more R 4-8-1 Substituted C1-C6 alkyl or unsubstituted or substituted by one or more deuterium-substituted 4-6 membered heterocycloalkyl; the heteroatoms in the 4-6 membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; Each R 4-8-1 are independently deuterium, hydroxy, unsubstituted or replaced by one or more R 4-8-1-1 Substituted C1-C6 alkoxy or OR 4-8-1-2 ; Each R 4-8-1-1 is independently deuterium or a C3-C6 cycloalkyl group which is unsubstituted or substituted with one or more deuteriums; Each R 4-8-1-2 and independently C3-C6 cycloalkyl, which is unsubstituted or substituted with one or more deuterium groups.

2. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein: The compound as shown in Formula I satisfies one or more of the following conditions: (1)R 1 , wherein the plurality is 2, 3, 4, 5, 6 or 7; (2)R 1 wherein the C1-C6 alkyl group is methyl, ethyl, propyl, isopropyl or isobutyl; (3)R 1 wherein the "unsubstituted or replaced by one or more R 1-4 In the "substituted C3-C6 cycloalkyl", the C3-C6 cycloalkyl is cyclobutyl, for example, (4)R 1 wherein the heteroatom in the 3-6 membered heterocycloalkyl group is N, O or S, preferably O, and the number of heteroatoms in the 3-6 membered heterocycloalkyl group is preferably 1; (5)R 1 wherein the "unsubstituted or replaced by one or more R 1-5 substituted 3-6 membered heterocycloalkyl"; the 3-6 membered heterocycloalkyl is a 4 membered heterocycloalkyl, for example, (6)R 1-1 wherein the "unsubstituted or replaced by one or more R 1-1-1 substituted C1-C6 alkyl"; the plurality is 2; (7)R 1-1 wherein the C1-C6 alkyl group is a methyl group, an ethyl group or a propyl group; (8)R 1-1 wherein the C3-C6 cycloalkyl group is a cyclopropyl group; (9)R 1-1-1 wherein the C1-C6 alkyl group is a methyl group; (10)R 1-1-1-1 wherein the C1-C6 alkyl group is a methyl group; (11)R 1-1-2 and R 1-1-3 wherein the C1-C6 alkyl group is a methyl group; (12)R 1-3 wherein the halogen is F, Cl or Br, preferably F; (13)R 1-3 In the "C1-C6 alkyl group which is unsubstituted or substituted with one or more deuterium groups", the number of the "multiple" groups is 2 or 3; (14)R 1-3 wherein the C1-C6 alkyl group is a methyl group or an ethyl group; (15)R 1-6 and R 1-7 wherein the C1-C6 alkyl group is a methyl group; (16)R 1-8 wherein the C1-C6 alkyl group is a methyl group; (17)R 2 and R 3 wherein the heteroatoms in the 5-6 membered heteroaryl group are independently selected from one or two of N, O and S, and the number of heteroatoms is 1, 2 or 3; (18)R 2 and R 3 In the above, the "R 2 and R 3 The atoms to which it is attached are unsubstituted or replaced by one or more R 2-1 substituted 5-6 membered heteroaryl”; the 5-6 membered heteroaryl is a 5 membered heteroaryl, for example, (19)R 2 and R 3 In the 4-6 membered heterocycloalkyl group, the heteroatoms are independently selected from one or both of N and O, and the number of heteroatoms is preferably 1 or 2; (20)R 2 and R 3 In the above, the "R 2 and R 3 The atoms to which it is attached are unsubstituted or replaced by one or more R 2-2 substituted 4-6 membered heterocycloalkyl"; the 4-6 membered heterocycloalkyl is a 5-6 membered heterocycloalkyl, for example, (21)R 2 and R 3 In the above, the "R 2 and R 3 The atoms to which it is attached are unsubstituted or replaced by one or more R 2-3 substituted C4-C6 cycloalkyl"; the C4-C6 cycloalkyl is cyclopentane; (22)R 2 and R 3 In the C6-C 10 The aryl group is phenyl; (23)R 2-1 wherein the halogen is F, Cl or Br, preferably F; (24)R 2-1 wherein the C1-C6 alkyl group is a methyl group or an ethyl group; (25)R 2-2 wherein the halogen is F, Cl or Br, preferably F; (26)R 2-2 wherein the C3-C6 cycloalkyl group is a cyclopropyl group; (27) In A, the arylene group is a phenylene group; (28) In A, the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or both of N and S; the number of heteroatoms is 1, 2 or 3; (29) In A, the 5-12 membered heteroarylene group is a 6-membered heteroarylene group, a 6-membered heteroarylene combined with a 5-membered heteroarylene group, or a 6-membered heteroarylene combined with a 6-membered heteroarylene group, for example, (30) In A, the heteroatom in the 5-12 membered heterocycloalkylene group is independently N; the number of heteroatoms is preferably 1; (31) In A, the 5-12 membered heterocycloalkylene group is a 6-membered heteroarylene group and a 6-membered heterocycloalkylene group, for example, (32) In L, the C2-C6 alkenylene group is a vinyl group, for example, (33) In Q, the C6-C 10 The arylene group is phenylene; (34) In Q, the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or both of N and O. 1, 2 or 3; (35) In Q, the "unsubstituted or replaced by one or more R 3-1 wherein the 5-12-membered heteroarylene is a 6-membered heteroarylene, a 5-membered heteroarylene and a 6-membered heteroarylene, or a 6-membered heteroarylene and a 5-membered heteroarylene, for example, (36) In Q, the heteroatoms in the 5-12 membered heterocycloalkylene group are independently selected from one or both of N and O, and the number of heteroatoms is 1, 2 or 3; (37) In Q, the 5- to 12-membered heterocycloalkylene group is a 6-membered heteroarylene group and a 6-membered heterocycloalkylene group, for example, (38)R 3-1 wherein the halogen is F, Cl or Br, preferably F; (39)R 4 wherein the “unsubstituted or replaced by one or more R 4-1 wherein the C1-C6 alkyl group is ethyl, for example, (40)R 4 wherein the C2-C6 alkynyl group is an ethynyl group; (41)R 4 wherein the “unsubstituted or replaced by one or more R 4-4 substituted C3-C6 cycloalkyl"; the plurality is two; (42)R 4 wherein the "unsubstituted or replaced by one or more R 4-4 wherein the C3-C6 cycloalkyl is cyclopropyl or cyclobutyl, for example, (43)R 4 In the 4-12 membered heterocycloalkyl group, the heteroatoms are independently selected from one or two of N, O and S, and the number of heteroatoms is preferably 1 or 2; (44)R 4 wherein said unsubstituted or replaced by one or more R 4-5 In the substituted 4-12 membered heterocycloalkyl group, the plurality is two; (45)R 4 wherein the "unsubstituted or replaced by one or more R 4-5 wherein the 4-12 membered heterocycloalkyl is a 4-7 membered heterocycloalkyl or a 7-9 membered double bridged ring, for example, (46)R 4 In the 5-12 membered heteroaryl group, the heteroatom is N, and the number of heteroatoms is preferably 1 or 2; (47)R 4 wherein the "unsubstituted or replaced by one or more R 4-6 substituted 5-12 membered heteroaryl"; the plurality is two; (48)R 4 wherein the “unsubstituted or replaced by one or more R 4-6 substituted 5-12 membered heteroaryl”; the 5-12 membered heteroaryl is a 5-membered or 6-membered heteroaryl, for example, (49)R 4 In the embodiment, the C1-C6 alkoxy group is an ethoxy group, for example, (50)R 4-1 wherein the C1-C6 alkoxy group is a methoxy group; (51)R 4-4 wherein the halogen is F, Cl or Br, preferably F; (52)R 4-5 wherein the C1-C6 alkyl group is a methyl group; (53)R 4-5 wherein the C1-C6 alkoxy group is a methoxy group; (54)R 4-5-2 and R 4-5-3 wherein the C1-C6 alkyl group is a methyl group; (55)R 4-6 wherein the halogen is F, Cl or Br, preferably F; (56)R 4-6 wherein the C1-C6 alkyl group is a methyl group; (57)R 4-9 and R 4-8 wherein the C1-C6 alkyl group is a methyl group or an ethyl group; (58)R 4-9 and R 4-8 In the 4-6 membered heterocycloalkyl group, the heteroatom is O, and the number of heteroatoms is preferably 1; (59)R 4-9 and R 4-8 wherein the 4-6 membered heterocycloalkyl group is a 5-membered or 6-membered heterocycloalkyl group; (60)R 4-8-1-2 wherein the C3-C6 cycloalkyl group is a cyclopropyl group.

3. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein: The compound as shown in Formula I satisfies one or more of the following conditions: (1) Y is C or N; preferably C; (2)R 1 for By one or more R 1-3 Substituted C1-C6 alkyl, unsubstituted or substituted by one or more R 1-4 Substituted C3-C6 cycloalkyl or unsubstituted or substituted by one or more R 1-5 Substituted 3-6 membered heterocycloalkyl; the heteroatoms in the 3-6 membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably By one or more R 1-3 Substituted C1-C6 alkyl or unsubstituted or substituted by one or more R 1-4 Substituted C3-C6 cycloalkyl; further preferably or by one or more R 1-3 Substituted C1-C6 alkyl; further preferably (3)R 1-1 is unsubstituted or substituted with one or more R 1-1-1 Substituted C1-C6 alkyl, unsubstituted C3-C6 cycloalkyl or -NR 1- 1-2 R 1-1-3 ; preferably unsubstituted or substituted with one or more R 1-1-1 Substituted C1-C6 alkyl or -NR 1-1-2 R 1-1-3 ; Further preferably, it is unsubstituted or substituted with one or more R 1-1-1 Substituted C1-C6 alkyl; further preferably unsubstituted C1-C6 alkyl; (4)R 1-2 O or NR 1-2-1 ; Preferably O; (5)R 1-2-1 is hydrogen; (6) Each R 1-1-1 Independently OR 1-1-1-1 , unsubstituted C1-C6 alkyl or unsubstituted C1-C6 alkoxy; preferably OR 1-1-1-1 or an unsubstituted C1-C6 alkyl group; further preferably an unsubstituted C1-C6 alkyl group; (7)R 1-1-1-1 is hydrogen or unsubstituted C1-C6 alkyl; preferably unsubstituted C1-C6 alkyl; (8)R 1-1-2 and R 1-1-3 are independently hydrogen or unsubstituted C1-C6 alkyl; (9) Each R 1-3 is independently hydroxy, cyano, halogen, amino, unsubstituted C1-C6 alkyl or deuterium; preferably hydroxy, cyano, halogen, unsubstituted C1-C6 alkyl or deuterium; further preferably hydroxy, cyano, halogen or unsubstituted C1-C6 alkyl; further preferably hydroxy or halogen; (10) Each R 1-3 are independently hydroxy, halogen, unsubstituted C1-C6 alkyl or deuterium; preferably hydroxy, halogen or unsubstituted C1-C6 alkyl; (11) Each R 1-4 and R 1-5 are independently hydroxyl groups; (12)X is -CR 1-6 R 1-7 -or-NR 1-8 -; preferably -CR 1-6 R 1-7 -; (13)R 1-6 and R 1-7 are independently hydrogen or unsubstituted C1-C6 alkyl; preferably hydrogen; (14)R 1-8 is an unsubstituted C1-C6 alkyl group; (15)R 2 and R 3 The atoms to which it is attached are unsubstituted or replaced by one or more R 2-1 substituted 5-6 membered heteroaryl, unsubstituted or substituted by one or more R 2-2 substituted 4-6 membered heterocycloalkyl, unsubstituted or substituted by one or more R 2-3 Substituted C4-C6 cycloalkyl or unsubstituted C6-C 10 Preferably, it is unsubstituted or substituted with one or more R 2-1 substituted 5-6 membered heteroaryl, unsubstituted or 1 One or more R 2-2 Substituted 4-6 membered heterocycloalkyl or unsubstituted or substituted by one or more R 2-3 Substituted C4-C6 cycloalkyl; further preferably unsubstituted or substituted by one or more R 2-1 substituted 5-6 membered heteroaryl, unsubstituted or substituted by one or more R 2-2 Substituted 4-6 membered heterocycloalkyl or unsubstituted C4-C6 cycloalkyl; further preferably unsubstituted or substituted by one or more R 2-1 a substituted 5-6 membered heteroaryl, an unsubstituted 4-6 membered heterocycloalkyl or an unsubstituted C4-C6 cycloalkyl; further preferably, an unsubstituted 4-6 membered heterocycloalkyl or an unsubstituted C4-C6 cycloalkyl; the heteroatoms in the 5-6 membered heteroaryl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 4-6 membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; (16) Each R 2-1 are independently halogen, unsubstituted or substituted with one or more R 2-1-1 Substituted C1-C6 alkyl or oxo (=O); preferably halogen or unsubstituted C1-C6 alkyl; further preferably unsubstituted C1-C6 alkyl; (17) Each R 2-2 are independently halogen, unsubstituted C1-C6 alkyl, oxo (=O), or two R 2-2 and the carbon atom connected thereto form a C3-C6 cycloalkyl group; preferably an oxo group (=O), or two R 2-2 and the carbon atom to which it is connected forms a C3-C6 cycloalkyl group; further preferably an oxo group (=O); (18) Each R 2-2 are independently halogen, unsubstituted C1-C6 alkyl or oxo (=O); preferably halogen; (19) Each R 2-3 are independently oxo (=O); (20)R 2-1-1 is hydroxyl group; (21) A is an unsubstituted C6-C 10 arylene, unsubstituted 5-12 membered heterocycloalkylene or unsubstituted 5-12 membered heteroarylene; preferably unsubstituted 5-12 membered heteroarylene; the heteroatoms in the 5-12 membered heterocycloalkylene are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heteroarylene are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; (22) L is a linker or an unsubstituted C2-C6 alkenylene group; preferably, it is a linker; (23)Q is an unsubstituted C6-C 10 arylene, unsubstituted or replaced by one or more R 3-1 Substituted 5-12 membered heteroaryl or unsubstituted 5-12 membered heterocycloalkyl; preferably unsubstituted or substituted by one or more R 3-1 A substituted 5-12 membered heteroarylene group or an unsubstituted 5-12 membered heterocycloalkylene group; further preferably an unsubstituted 5-12 membered heteroarylene group or an unsubstituted 5-12 membered heterocycloalkylene group; the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heterocycloalkylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; (24) Each R 3-1 are independently halogen; (25)R 4 is unsubstituted or replaced by one or more R 4-1 Substituted C1-C6 alkyl, unsubstituted C2-C6 alkynyl, unsubstituted or substituted with one or more R 4-4 Substituted C3-C6 cycloalkyl, unsubstituted or replaced by one or more R 4-5 substituted 4-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 4-6 Substituted 5-12 membered heteroaryl, unsubstituted C1-C6 alkoxy or -NR 4-9 R 4-8 ; preferably by one or more R 4-1 Substituted C1-C6 alkyl, unsubstituted C2-C6 alkynyl, unsubstituted C3-C6 cycloalkyl, unsubstituted or replaced by one or more R 4-5 substituted 4-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 4-6 substituted 5-12 membered heteroaryl or unsubstituted C1-C6 alkoxy; further preferably unsubstituted C2-C6 alkynyl, unsubstituted C3-C6 cycloalkyl, substituted by one or more R 4-5 substituted 4-12 membered heterocycloalkyl, substituted by one or more R 4-6 Substituted 5-12 membered heteroaryl or unsubstituted C1- C6 alkoxy; further preferably unsubstituted C2-C6 alkynyl, unsubstituted C3-C6 cycloalkyl or one or more R 4- 6 substituted 5-12 membered heteroaryl; the heteroatoms in the 4-12 membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heteroaryl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; (26) Each R 4-1 are independently unsubstituted C1-C6 alkoxy; (27) Each R 4-4 are independently halogen; (28) Each R 4-5 are independently hydroxy, unsubstituted or substituted with one or more R 4-5-1 Substituted C1-C6 alkyl, -NR 4-5-2 R 4-5-3 or unsubstituted C1-C6 alkoxy; preferably unsubstituted or substituted by one or more R 4-5-1 Substituted C1-C6 alkyl or unsubstituted C1-C6 alkoxy; further preferably unsubstituted C1-C6 alkoxy; (29) Each R 4-5-1 are independently hydroxyl groups; (30)R 4-5-2 and R 4-5-3 are independently unsubstituted C1-C6 alkyl; (31) Each R 4-6 are independently cyano, halogen or unsubstituted C1-C6 alkyl; preferably cyano or unsubstituted C1-C6 alkyl; (32)R 4-9 and R 4-8 are independently unsubstituted or substituted with one or more R 4-8-1 Substituted C1-C6 alkyl or unsubstituted 4-6 membered heterocycloalkyl; the heteroatoms in the 4-6 membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; (33) Each R 4-8-1 Independently OR 4-8-1-2 ; and (34) each R 4-8-1-2 and independently unsubstituted C3-C6 cycloalkyl.

4. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein: The compound shown in formula I satisfies any of the following schemes: Option 1: Y is C or N; R 1 for By one or more R 1-3 Substituted C1-C6 alkyl, unsubstituted or substituted by one or more R 1-4 Substituted C3-C6 cycloalkyl or unsubstituted or substituted by one or more R 1-5 Substituted 3-6 membered heterocycloalkyl; the heteroatoms in the 3-6 membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; R 1-1 is unsubstituted or substituted with one or more R 1-1-1 Substituted C1-C6 alkyl, unsubstituted C3-C6 cycloalkyl or -NR 1-1-2 R 1-1- 3 ; R 1-2 O or NR 1-2-1 ; R 1-2-1 is hydrogen; Each R 1-1-1 Independently OR 1-1-1-1 , unsubstituted C1-C6 alkyl or unsubstituted C1-C6 alkoxy; R 1-1-1-1 is hydrogen or unsubstituted C1-C6 alkyl; R 1-1-2 and R 1-1-3 are independently hydrogen or unsubstituted C1-C6 alkyl; Each R 1-3 are independently hydroxy, cyano, halogen, amino, unsubstituted C1-C6 alkyl or deuterium; Each R 1-4 and R 1-5 are independently hydroxyl groups; X is -CR 1-6 R 1-7 -or-NR 1-8 -; R 1-6 and R 1-7 are independently hydrogen or unsubstituted C1-C6 alkyl; R 1-8 is an unsubstituted C1-C6 alkyl group; R 2 and R 3 The atoms to which it is attached are unsubstituted or replaced by one or more R 2-1 substituted 5-6 membered heteroaryl, unsubstituted or substituted by one or more R 2-2 substituted 4-6 membered heterocycloalkyl, unsubstituted or substituted by one or more R 2-3 Substituted C4-C6 cycloalkyl or unsubstituted C6-C 10 The heteroatoms in the 5-6 membered heteroaryl group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 4-6 membered heterocycloalkyl group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; Each R 2-1 are independently halogen, unsubstituted or substituted with one or more R 2-1-1 Substituted C1-C6 alkyl or oxo (=O); Each R 2-2 are independently halogen, unsubstituted C1-C6 alkyl, oxo (=O), or two R 2-2 Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl group; Each R 2-3 are independently oxo (=O); R 2-1-1 is hydroxyl group; A is unsubstituted C6-C 10 arylene, unsubstituted 5-12 membered heterocycloalkylene or unsubstituted 5-12 membered heteroarylene; the heteroatoms in the 5-12 membered heterocycloalkylene are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heteroarylene are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; L is a linker or unsubstituted C2-C6 alkenylene; Q is an unsubstituted C6-C 10 arylene, unsubstituted or replaced by one or more R 3-1 a substituted 5-12 membered heteroarylene group or an unsubstituted 5-12 membered heterocycloalkylene group; the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heterocycloalkylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; Each R 3-1 are independently halogen; R 4 is unsubstituted or replaced by one or more R 4-1 Substituted C1-C6 alkyl, unsubstituted C2-C6 alkynyl, unsubstituted or substituted with one or more R 4-4 Substituted C3-C6 cycloalkyl, unsubstituted or replaced by one or more R 4-5 substituted 4-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 4-6 Substituted 5-12 membered heteroaryl, unsubstituted C1-C6 alkoxy or -NR 4-9 R 4-8 The heteroatoms in the 4-12 membered heterocycloalkyl group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heteroaryl group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; Each R 4-1 are independently unsubstituted C1-C6 alkoxy; Each R 4-4 are independently halogen; Each R 4-5 are independently hydroxy, unsubstituted or substituted with one or more R 4-5-1 Substituted C1-C6 alkyl, -NR 4-5-2 R 4-5-3 or unsubstituted C1-C6 alkoxy; Each R 4-5-1 are independently hydroxyl groups; R 4-5-2 and R 4-5-3 are independently unsubstituted C1-C6 alkyl; Each R 4-6 are independently cyano, halogen or unsubstituted C1-C6 alkyl; preferably cyano or unsubstituted C1-C6 alkyl; R 4-9 and R 4-8 are independently unsubstituted or substituted with one or more R 4-8-1 Substituted C1-C6 alkyl or unsubstituted 4-6 membered heterocycloalkyl; the heteroatoms in the 4-6 membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; Each R 4-8-1 Independently OR 4-8-1-2 ; Each R 4-8-1-2 are independently unsubstituted C3-C6 cycloalkyl; Option 2: Y is C or N; R 1 for By one or more R 1-3 Substituted C1-C6 alkyl or unsubstituted or substituted by one or more R 1-4 Substituted C3-C6 cycloalkyl; R 1-1 is unsubstituted or substituted with one or more R 1-1-1 Substituted C1-C6 alkyl or -NR 1-1-2 R 1-1-3 ; R 1-2 O or NR 1-2-1 ; R 1-2-1 is hydrogen; Each R 1-1-1 Independently OR 1-1-1-1 or unsubstituted C1-C6 alkyl; R 1-1-1-1 is hydrogen or unsubstituted C1-C6 alkyl; R 1-1-2 and R 1-1-3 are independently hydrogen or unsubstituted C1-C6 alkyl; Each R 1-3 are independently hydroxy, cyano, halogen, unsubstituted C1-C6 alkyl or deuterium; Each R 1-4 is hydroxyl group; X is -CR 1-6 R 1-7 -or-NR 1-8 -; R 1-6 and R 1-7 are independently hydrogen or unsubstituted C1-C6 alkyl; R 1-8 is an unsubstituted C1-C6 alkyl group; R 2 and R 3 The atoms to which it is attached are unsubstituted or replaced by one or more R 2-1 substituted 5-6 membered heteroaryl, unsubstituted or substituted by one or more R 2-2 Substituted 4-6 membered heterocycloalkyl or unsubstituted or substituted by one or more R 2-3 substituted C4-C6 cycloalkyl; the heteroatoms in the 5-6 membered heteroaryl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 4-6 membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatoms in the 4-6 membered heterocycloalkyl are N or O, and the number of heteroatoms is 1 or 2; Each R 2-1 are independently halogen or unsubstituted C1-C6 alkyl; Each R 2-2 are independently halogen, unsubstituted C1-C6 alkyl, oxo (=O), or two R 2-2 and the carbon atom to which it is attached to form a C3-C6 cycloalkyl group; Each R 2-3 are independently oxo (=O); A is an unsubstituted 5-12 membered heteroarylene group, wherein the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or more of One or both of N and S, with 1, 2 or 3 heteroatoms; L is a linker or unsubstituted C2-C6 alkenylene; Q is unsubstituted or replaced by one or more R 3-1 a substituted 5-12 membered heteroarylene group or an unsubstituted 5-12 membered heterocycloalkylene group; the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heterocycloalkylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatom in the 5-12 membered heteroarylene group is N, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heterocycloalkylene group are independently selected from one or both of N and O, and the number of heteroatoms is 1, 2 or 3; Each R 3-1 are independently halogen; R 4 For one or more R 4-1 Substituted C1-C6 alkyl, unsubstituted C2-C6 alkynyl, unsubstituted C3-C6 cycloalkyl, unsubstituted or replaced by one or more R 4-5 substituted 4-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 4-6 substituted 5-12 membered heteroaryl or unsubstituted C1-C6 alkoxy; the heteroatoms in the 4-12 membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heteroaryl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, R 4 For one or more R 4-1 Substituted C1-C6 alkyl, unsubstituted C2-C6 alkynyl, unsubstituted C3-C6 cycloalkyl, unsubstituted or replaced by one or more R 4-5 substituted 4-6 membered heterocycloalkyl, unsubstituted or replaced by one or more R 4-6 a substituted 5-6 membered heteroaryl or an unsubstituted C1-C6 alkoxy group; the heteroatoms in the 4-6 membered heterocycloalkyl group are independently selected from one or both of N and O, and the number of heteroatoms is 1 or 2; the heteroatom in the 5-6 membered heteroaryl group is N, and the number of heteroatoms is 1 or 2; R 4-1 are independently unsubstituted C1-C6 alkoxy; Each R 4-5 are independently unsubstituted or substituted with one or more R 4-5-1 Substituted C1-C6 alkyl or unsubstituted C1-C6 alkoxy; Each R 4-5-1 are independently hydroxyl groups; Each R 4-6 are independently cyano, halogen or unsubstituted C1-C6 alkyl; Option 3: Y is C or N; R 1 for By one or more R 1-3 Substituted C1-C6 alkyl or unsubstituted or substituted by one or more R 1-4 Substituted C3-C6 cycloalkyl; R 1-1 is unsubstituted or substituted with one or more R 1-1-1 Substituted C1-C6 alkyl or -NR 1-1-2 R 1-1-3 ; R 1-2 O or NR 1-2-1 ; R 1-2-1 is hydrogen; Each R 1-1-1 Independently OR 1-1-1-1 or unsubstituted C1-C6 alkyl; R 1-1-1-1 is an unsubstituted C1-C6 alkyl group; R 1-1-2 and R 1-1-3 are independently hydrogen or unsubstituted C1-C6 alkyl; Each R 1-3 are independently hydroxy, cyano, halogen or unsubstituted C1-C6 alkyl; Each R 1-4 is hydroxyl group; X is -CR 1-6 R 1-7 -or-NR 1-8 -; R 1-6 and R 1-7 are independently hydrogen or unsubstituted C1-C6 alkyl; R 1-8 is an unsubstituted C1-C6 alkyl group; R 2 and R 3 The atoms to which it is attached are unsubstituted or replaced by one or more R 2-1 substituted 5-6 membered heteroaryl, unsubstituted or substituted by one or more R 2-2 Substituted 4-6 membered heterocycloalkyl or unsubstituted or substituted by one or more R 2-3 substituted C4-C6 cycloalkyl; the heteroatoms in the 5-6 membered heteroaryl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 4-6 membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatoms in the 4-6 membered heterocycloalkyl are N or O, and the number of heteroatoms is 1 or 2; Each R 2-1 are independently unsubstituted C1-C6 alkyl; Each R 2-2 are independently halogen, unsubstituted C1-C6 alkyl, oxo (=O), or two R 2-2 Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl group; Each R 2-3 are independently oxo (=O); A is an unsubstituted 5-12 membered heteroarylene group; the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or both of N and S, and the number of heteroatoms is 1, 2 or 3; L is a linker or unsubstituted C2-C6 alkenylene; Q is unsubstituted or replaced by one or more R 3-1 a substituted 5-12 membered heteroarylene group or an unsubstituted 5-12 membered heterocycloalkylene group; the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heterocycloalkylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatom in the 5-12 membered heteroarylene group is N, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heterocycloalkylene group are independently selected from one or both of N and O, and the number of heteroatoms is 1, 2 or 3; Each R 3-1 are independently halogen; R 4 For one or more R 4-1 Substituted C1-C6 alkyl, unsubstituted C2-C6 alkynyl, unsubstituted C3-C6 cycloalkyl, unsubstituted or replaced by one or more R 4-5 substituted 4-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 4-6 substituted 5-12 membered heteroaryl or unsubstituted C1-C6 alkoxy; the heteroatoms in the 4-12 membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heteroaryl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, R 4 For one or more R 4-1 Substituted C1-C6 alkyl, unsubstituted C2-C6 alkynyl, unsubstituted C3-C6 cycloalkyl, unsubstituted or replaced by one or more R 4-5 substituted 4-6 membered heterocycloalkyl, unsubstituted or replaced by one or more R 4-6 a substituted 5-6 membered heteroaryl or an unsubstituted C1-C6 alkoxy group; the heteroatoms in the 4-6 membered heterocycloalkyl group are independently selected from one or both of N and O, and the number of heteroatoms is 1 or 2; the heteroatom in the 5-6 membered heteroaryl group is N, and the number of heteroatoms is 1 or 2; R 4-1 are independently unsubstituted C1-C6 alkoxy; Each R 4-5 are independently unsubstituted or substituted with one or more R 4-5-1 Substituted C1-C6 alkyl or unsubstituted C1-C6 alkoxy; Each R 4-5-1 are independently hydroxyl groups; Each R 4-6 are independently cyano, halogen or unsubstituted C1-C6 alkyl; Option 4: Y is C or N; R 1 for By one or more R 1-3 Substituted C1-C6 alkyl or unsubstituted or substituted by one or more R 1-4 Substituted C3-C6 cycloalkyl; R 1-1 is unsubstituted or substituted with one or more R 1-1-1 Substituted C1-C6 alkyl or -NR 1-1-2 R 1-1-3 ; R 1-2 O or NR 1-2-1 ; R 1-2-1 is hydrogen; Each R 1-1-1 Independently OR 1-1-1-1 or unsubstituted C1-C6 alkyl; R 1-1-1-1 is an unsubstituted C1-C6 alkyl group; R 1-1-2 and R 1-1-3 are independently hydrogen or unsubstituted C1-C6 alkyl; Each R 1-3 are independently hydroxy, cyano, halogen or unsubstituted C1-C6 alkyl; Each R 1-4 is hydroxyl group; X is -CR 1-6 R 1-7 -or-NR 1-8 -; R 1-6 and R 1-7 are independently hydrogen or unsubstituted C1-C6 alkyl; R 1-8 is an unsubstituted C1-C6 alkyl group; R 2 and R 3 The atoms to which it is attached are unsubstituted or replaced by one or more R 2-1 substituted 5-6 membered heteroaryl, unsubstituted or substituted by one or more R 2-2 Substituted 4-6 membered heterocycloalkyl or unsubstituted or substituted by one or more R 2-3 substituted C4-C6 cycloalkyl; the heteroatoms in the 5-6 membered heteroaryl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 4-6 membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatoms in the 4-6 membered heterocycloalkyl are N or O, and the number of heteroatoms is 1 or 2; Each R 2-1 are independently unsubstituted C1-C6 alkyl; Each R 2-2 are independently halogen, unsubstituted C1-C6 alkyl, oxo (=O), or two R 2-2 Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl group; Each R 2-3 are independently oxo (=O); A is an unsubstituted 5-12 membered heteroarylene group; the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or both of N and S, and the number of heteroatoms is 1, 2 or 3; L is a linker or unsubstituted C2-C6 alkenylene; Q is unsubstituted or replaced by one or more R 3-1 A substituted 5-12 membered heteroarylene group or an unsubstituted 5-12 membered heterocycloalkylene group; the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heterocycloalkylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatom in the 5-12 membered heteroarylene group is N, and the number of heteroatoms is 1, 2 or 3; The heteroatoms in the 5-12 membered heterocycloalkylene group are independently selected from one or both of N and O, and the number of heteroatoms is 1, 2 or 3; Each R 3-1 are independently halogen; R 4 For one or more R 4-1 Substituted C1-C6 alkyl, unsubstituted C2-C6 alkynyl, unsubstituted C3-C6 cycloalkyl, unsubstituted or replaced by one or more R 4-5 substituted 4-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 4-6 substituted 5-12 membered heteroaryl or unsubstituted C1-C6 alkoxy; the heteroatoms in the 4-12 membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heteroaryl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, R 4 For one or more R 4-1 Substituted C1-C6 alkyl, unsubstituted C2-C6 alkynyl, unsubstituted C3-C6 cycloalkyl, unsubstituted or replaced by one or more R 4-5 substituted 4-6 membered heterocycloalkyl, unsubstituted or replaced by one or more R 4-6 a substituted 5-6 membered heteroaryl or an unsubstituted C1-C6 alkoxy group; the heteroatoms in the 4-6 membered heterocycloalkyl group are independently selected from one or both of N and O, and the number of heteroatoms is 1 or 2; the heteroatom in the 5-6 membered heteroaryl group is N, and the number of heteroatoms is 1 or 2; R 4-1 are independently unsubstituted C1-C6 alkoxy; Each R 4-5 are independently unsubstituted or substituted with one or more R 4-5-1 Substituted C1-C6 alkyl or unsubstituted C1-C6 alkoxy; Each R 4-5-1 are independently hydroxyl groups; Each R 4-6 are independently cyano or unsubstituted C1-C6 alkyl; Option 5: Y is C; R 1 for By one or more R 1-3 Substituted C1-C6 alkyl or unsubstituted or substituted by one or more R 1-4 Substituted C3-C6 cycloalkyl; R 1-1 is unsubstituted or substituted with one or more R 1-1-1 Substituted C1-C6 alkyl or -NR 1-1-2 R 1-1-3 ; R 1-2 O or NR 1-2-1 ; R 1-2-1 is hydrogen; Each R 1-1-1 are independently unsubstituted C1-C6 alkyl; R 1-1-2 and R 1-1-3 are independently hydrogen or unsubstituted C1-C6 alkyl; Each R 1-3 are independently hydroxy or halogen; Each R 1-4 is hydroxyl group; X is -CR 1-6 R 1-7 -or-NR 1-8 -; R 1-6 and R 1-7 are independently hydrogen or unsubstituted C1-C6 alkyl; R 1-8 is an unsubstituted C1-C6 alkyl group; R 2 and R 3 The atoms to which it is attached are unsubstituted or replaced by one or more R 2-1 substituted 5-6 membered heteroaryl, unsubstituted or substituted by one or more R 2-2 substituted 4-6 membered heterocycloalkyl or unsubstituted C4-C6 cycloalkyl; the heteroatoms in the 5-6 membered heteroaryl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 4-6 membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the 5-6 membered The heteroatoms in the heteroaryl are independently selected from one or both of N and S; the number of heteroatoms is 1 or 2; the heteroatoms in the 4-6 membered heterocycloalkyl are N or O; the number of heteroatoms is 1 or 2; Each R 2-1 are independently unsubstituted C1-C6 alkyl; Each R 2-2 are independently oxo (=O), or two R 2-2 and the carbon atom to which it is attached to form a C3-C6 cycloalkyl group; A is an unsubstituted 5-12 membered heteroarylene group, wherein the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or more of N, O and S; the number of heteroatoms is 1, 2 or 3; preferably, the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or both of N and S, and the number of heteroatoms is 1, 2 or 3; L is a linker or unsubstituted C2-C6 alkenylene; Q is an unsubstituted 5-12 membered heteroarylene group or an unsubstituted 5-12 membered heterocycloalkylene group; the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heterocycloalkylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, Q is an unsubstituted 5-6 membered heteroarylene group or an unsubstituted 5-12 membered heterocycloalkylene group; the heteroatom in the 5-6 membered heteroarylene group is N, and the number of heteroatoms is 1; the heteroatoms in the 5-12 membered heterocycloalkylene group are independently selected from one or both of N and O, and the number of heteroatoms is 1, 2 or 3; R 4 is an unsubstituted C2-C6 alkynyl, an unsubstituted C3-C6 cycloalkyl, or one or more R 4-5 substituted 4-12 membered heterocycloalkyl, substituted by one or more R 4-6 substituted 5-12 membered heteroaryl or unsubstituted C1-C6 alkoxy; the heteroatoms in the 4-12 membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heteroaryl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, R 4 is an unsubstituted C2-C6 alkynyl, an unsubstituted C3-C6 cycloalkyl, or one or more R 4-5 substituted 4-6 membered heterocycloalkyl, one or more R 4-6 a substituted 5-6 membered heteroaryl or an unsubstituted C1-C6 alkoxy group; the heteroatoms in the 4-6 membered heterocycloalkyl group are independently selected from one or both of N and O, and the number of heteroatoms is 1 or 2; the heteroatom in the 5-6 membered heteroaryl group is N, and the number of heteroatoms is 1; Each R 4-5 are independently unsubstituted C1-C6 alkyl; Each R 4-6 are independently cyano or unsubstituted C1-C6 alkyl; Option 6: Y is C; R 1 for By one or more R 1-3 Substituted C1-C6 alkyl or unsubstituted or substituted by one or more R 1-4 Substituted C3-C6 cycloalkyl; R 1-1 is unsubstituted or substituted with one or more R 1-1-1 Substituted C1-C6 alkyl; R 1-2 is O; Each R 1-1-1 are independently unsubstituted C1-C6 alkyl; Each R 1-3 are independently halogen; Each R 1-4 is hydroxyl group; X is -CR 1-6 R 1-7 -or-NR 1-8 -; R 1-6 and R 1-7 are independently hydrogen; R 1-8 is an unsubstituted C1-C6 alkyl group; R 2 and R 3 The atoms to which it is attached are unsubstituted or replaced by one or more R 2-1 substituted 5-6 membered heteroaryl, unsubstituted or substituted by one or more R 2-2 a substituted 4-6 membered heterocycloalkyl or an unsubstituted C4-C6 cycloalkyl; the heteroatoms in the 5-6 membered heteroaryl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 4-6 membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatom in the 5-6 membered heteroaryl is N, and the number of heteroatoms is 1 or 2; the heteroatom in the 4-6 membered heterocycloalkyl is N or O, and the number of heteroatoms is 1 or 2; Each R 2-1 are independently unsubstituted C1-C6 alkyl; Each R 2-2 are independently oxo (=O); A is an unsubstituted 5-12 membered heteroarylene group; the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or both of N and S, and the number of heteroatoms is 1, 2 or 3; L is a linker or unsubstituted C2-C6 alkenylene; Q is an unsubstituted 5-12 membered heteroarylene group or an unsubstituted 5-12 membered heterocycloalkylene group; the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heterocycloalkylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, Q is an unsubstituted 5-6 membered heteroarylene group or an unsubstituted 5-12 membered heterocycloalkylene group; the heteroatom in the 5-6 membered heteroarylene group is N, and the number of heteroatoms is 1; the heteroatoms in the 5-12 membered heterocycloalkylene group are independently selected from one or both of N and O, and the number of heteroatoms is 1, 2 or 3; R 4 is an unsubstituted C2-C6 alkynyl, an unsubstituted C3-C6 cycloalkyl, or one or more R 4-5 substituted 4-12 membered heterocycloalkyl, substituted by one or more R 4-6 substituted 5-12 membered heteroaryl or unsubstituted C1-C6 alkoxy; the heteroatoms in the 4-12 membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heteroaryl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, R 4 is an unsubstituted C2-C6 alkynyl, an unsubstituted C3-C6 cycloalkyl, or one or more R 4-5 substituted 4-6 membered heterocycloalkyl, one or more R 4-6 a substituted 5-6 membered heteroaryl or an unsubstituted C1-C6 alkoxy group; the heteroatoms in the 4-6 membered heterocycloalkyl group are independently selected from one or both of N and O, and the number of heteroatoms is 1 or 2; the heteroatom in the 5-6 membered heteroaryl group is N, and the number of heteroatoms is 1; Each R 4-5 are independently unsubstituted C1-C6 alkyl; Each R 4-6 are independently cyano or unsubstituted C1-C6 alkyl; Option 7: Y is C; R 1 for or unsubstituted or substituted by one or more R 1-3 Substituted C1-C6 alkyl; R 1-1 is unsubstituted or substituted with one or more R 1-1-1 Substituted C1-C6 alkyl; R 1-2 is O; Each R 1-1-1 Independently OR 1-1-1-1 ; R 1-1-1-1 is hydrogen or unsubstituted C1-C6 alkyl; Each R 1-3 are independently hydroxy, halogen, unsubstituted C1-C6 alkyl or deuterium; X is -CR 1-6 R 1-7 -; R 1-6 and R 1-7 are independently hydrogen; R 2 and R 3 The atoms to which it is attached are unsubstituted or replaced by one or more R 2-1 substituted 5-6 membered heteroaryl, unsubstituted or substituted by one or more R 2-2 a substituted 4-6 membered heterocycloalkyl or an unsubstituted C4-C6 cycloalkyl; the heteroatoms in the 5-6 membered heteroaryl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 4-6 membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatom in the 4-6 membered heterocycloalkyl is O, and the number of heteroatoms is 1 or 2; Each R 2-1 are independently halogen or unsubstituted C1-C6 alkyl; Each R 2-2 are independently halogen, unsubstituted C1-C6 alkyl or oxo (=O); A is an unsubstituted 5-12 membered heteroarylene group, wherein the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatom in the 5-12 membered heteroarylene group is N, and the number of heteroatoms is 1 or 2; L is a linker or unsubstituted C2-C6 alkenylene; Q is an unsubstituted 5-12 membered heteroarylene group or an unsubstituted 5-12 membered heterocycloalkylene group; the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heterocycloalkylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, Q is an unsubstituted 5-6 membered heteroarylene group or an unsubstituted 5-12 membered heterocycloalkylene group; the heteroatom in the 5-6 membered heteroarylene group is N, and the number of heteroatoms is 1; the heteroatoms in the 5-12 membered heterocycloalkylene group are independently selected from one or both of N and O, and the number of heteroatoms is 1, 2 or 3; Each R 3-1 are independently halogen; R 4 is an unsubstituted C2-C6 alkynyl, an unsubstituted C3-C6 cycloalkyl, or one or more R 4-5 substituted 4-12 membered heterocycloalkyl, substituted by one or more R 4-6 substituted 5-12 membered heteroaryl or unsubstituted C1-C6 alkoxy; the heteroatoms in the 4-12 membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heteroaryl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, R 4 is an unsubstituted C2-C6 alkynyl, an unsubstituted C3-C6 cycloalkyl, or one or more R 4-5 substituted 4-6 membered heterocycloalkyl, one or more R 4-6 substituted 5-6 membered heteroaryl or unsubstituted C1-C6 alkoxy; the heteroaryl in the 4-6 membered heterocycloalkyl The atoms are independently selected from one or both of N and O, and the number of heteroatoms is 1 or 2; the heteroatom in the 5-6 membered heteroaryl is N, and the number of heteroatoms is 1; Each R 4-5 are independently unsubstituted C1-C6 alkyl; Each R 4-6 are independently cyano, halogen or unsubstituted C1-C6 alkyl; Option 8: Y is C; R 1 for or by one or more R 1-3 Substituted C1-C6 alkyl; R 1-1 is unsubstituted or substituted with one or more R 1-1-1 Substituted C1-C6 alkyl; R 1-2 is O; Each R 1-1-1 Independently OR 1-1-1-1 ; R 1-1-1-1 is hydrogen or unsubstituted C1-C6 alkyl; Each R 1-3 are independently hydroxy, halogen, unsubstituted C1-C6 alkyl or deuterium; X is -CR 1-6 R 1-7 -; R 1-6 and R 1-7 are independently hydrogen; R 2 and R 3 The atoms to which it is attached are unsubstituted or replaced by one or more R 2-1 substituted 5-6 membered heteroaryl, unsubstituted or substituted by one or more R 2-2 a substituted 4-6 membered heterocycloalkyl or an unsubstituted C4-C6 cycloalkyl; the heteroatoms in the 5-6 membered heteroaryl are independently selected from one or more of N, O and S; the number of heteroatoms is 1, 2 or 3, the heteroatoms in the 4-6 membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatom in the 4-6 membered heterocycloalkyl is O, and the number of heteroatoms is 1 or 2; Each R 2-1 are independently halogen or unsubstituted C1-C6 alkyl; Each R 2-2 are independently halogen, unsubstituted C1-C6 alkyl or oxo (=O); A is an unsubstituted 5-12 membered heteroarylene group; the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatom in the 5-12 membered heteroarylene group is N, and the number of heteroatoms is 1 or 2; L is a linker or unsubstituted C2-C6 alkenylene; Q is an unsubstituted 5-12 membered heteroarylene group or an unsubstituted 5-12 membered heterocycloalkylene group; the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heterocycloalkylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, Q is an unsubstituted 5-6 membered heteroarylene group or an unsubstituted 5-12 membered heterocycloalkylene group; the heteroatom in the 5-6 membered heteroarylene group is N, and the number of heteroatoms is 1; the heteroatoms in the 5-12 membered heterocycloalkylene group are independently selected from one or both of N and O, and the number of heteroatoms is 1, 2 or 3; Each R 3-1 are independently halogen; R 4 is an unsubstituted C2-C6 alkynyl, an unsubstituted C3-C6 cycloalkyl, or one or more R 4-5 substituted 4-12 membered heterocycloalkyl, substituted by one or more R 4-6 substituted 5-12 membered heteroaryl or unsubstituted C1-C6 alkoxy; the heteroatoms in the 4-12 membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heteroaryl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, R 4 is an unsubstituted C2-C6 alkynyl, an unsubstituted C3-C6 cycloalkyl, or one or more R 4-5 substituted 4-6 membered heterocycloalkyl, one or more R 4-6 a substituted 5-6 membered heteroaryl or an unsubstituted C1-C6 alkoxy group; the heteroatoms in the 4-6 membered heterocycloalkyl group are independently selected from one or both of N and O, and the number of heteroatoms is 1 or 2; the heteroatom in the 5-6 membered heteroaryl group is N, and the number of heteroatoms is 1; Each R 4-5 are independently unsubstituted C1-C6 alkyl; Each R 4-6 are independently cyano, halogen or unsubstituted C1-C6 alkyl; Option 9: Y is C; R 1 for or by one or more R 1-3 Substituted C1-C6 alkyl; R 1-1 is unsubstituted or substituted with one or more R 1-1-1 Substituted C1-C6 alkyl; R 1-2 is O; Each R 1-1-1 Independently OR 1-1-1-1 ; R 1-1-1-1 is an unsubstituted C1-C6 alkyl group; Each R 1-3 are independently hydroxy, halogen or unsubstituted C1-C6 alkyl; X is -CR 1-6 R 1-7 -; R 1-6 and R 1-7 are independently hydrogen; R 2 and R 3 The atoms to which it is attached are unsubstituted or replaced by one or more R 2-1 substituted 5-6 membered heteroaryl, unsubstituted or substituted by one or more R 2-2 a substituted 4-6 membered heterocycloalkyl or an unsubstituted C4-C6 cycloalkyl; the heteroatoms in the 5-6 membered heteroaryl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 4-6 membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatom in the 4-6 membered heterocycloalkyl is O, and the number of heteroatoms is 1 or 2; Each R 2-1 are independently unsubstituted C1-C6 alkyl; Each R 2-2 are independently halogen; A is an unsubstituted 5-12 membered heteroarylene group; the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatom in the 5-12 membered heteroarylene group is N, and the number of heteroatoms is 1 or 2; L is a linker or unsubstituted C2-C6 alkenylene; Q is an unsubstituted 5-12 membered heteroarylene group or an unsubstituted 5-12 membered heterocycloalkylene group; the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heterocycloalkylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, Q is an unsubstituted 5-6 membered heteroarylene group or an unsubstituted 5-12 membered heterocycloalkylene group; the heteroatom in the 5-6 membered heteroarylene group is N, and the number of heteroatoms is 1; the heteroatoms in the 5-12 membered heterocycloalkylene group are independently selected from one or both of N and O, and the number of heteroatoms is 1, 2 or 3; Each R 3-1 are independently halogen; R 4 is an unsubstituted C2-C6 alkynyl, an unsubstituted C3-C6 cycloalkyl, or one or more R 4-5 substituted 4-12 membered heterocycloalkyl, substituted by one or more R 4-6 substituted 5-12 membered heteroaryl or unsubstituted C1-C6 alkoxy; the heteroatoms in the 4-12 membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heteroaryl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, R 4 is an unsubstituted C2-C6 alkynyl, an unsubstituted C3-C6 cycloalkyl, or one or more R 4-5 substituted 4-6 membered heterocycloalkyl, one or more R 4-6 a substituted 5-6 membered heteroaryl or an unsubstituted C1-C6 alkoxy group; the heteroatoms in the 4-6 membered heterocycloalkyl group are independently selected from one or both of N and O, and the number of heteroatoms is 1 or 2; the heteroatom in the 5-6 membered heteroaryl group is N, and the number of heteroatoms is 1; Each R 4-5 are independently unsubstituted C1-C6 alkyl; Each R 4-6 are independently cyano, halogen or unsubstituted C1-C6 alkyl; Option 10: Y is C; R 1 for or by one or more R 1-3 Substituted C1-C6 alkyl; R 1-1 is unsubstituted or substituted with one or more R 1-1-1 Substituted C1-C6 alkyl; R 1-2 is O; Each R 1-1-1 Independently OR 1-1-1-1 ; R 1-1-1-1 is an unsubstituted C1-C6 alkyl group; Each R 1-3 are independently hydroxy, halogen or unsubstituted C1-C6 alkyl; X is -CR 1-6 R 1-7 -; R 1-6 and R 1-7 are independently hydrogen; R 2 and R 3 The atoms to which it is attached are unsubstituted or replaced by one or more R 2-1 a substituted 5-6 membered heteroaryl, an unsubstituted 4-6 membered heterocycloalkyl or an unsubstituted C4-C6 cycloalkyl; the heteroatoms in the 5-6 membered heteroaryl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 4-6 membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatom in the 5-6 membered heteroaryl is N or O, and the number of heteroatoms is 1 or 2; the heteroatom in the 4-6 membered heterocycloalkyl is O, and the number of heteroatoms is 1 or 2; Each R 2-1 are independently unsubstituted C1-C6 alkyl; A is an unsubstituted 5-12 membered heteroarylene group; the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatom in the 5-12 membered heteroarylene group is N, and the number of heteroatoms is 1 or 2; L is a linker or unsubstituted C2-C6 alkenylene; Q is an unsubstituted 5-12 membered heteroarylene group or an unsubstituted 5-12 membered heterocycloalkylene group; the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heterocycloalkylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, Q is an unsubstituted 5-6 membered heteroarylene group or an unsubstituted 5-12 membered heterocycloalkylene group; the heteroatom in the 5-6 membered heteroarylene group is N, and the number of heteroatoms is 1; the heteroatoms in the 5-12 membered heterocycloalkylene group are independently selected from one or both of N and O, and the number of heteroatoms is 1, 2 or 3; R 4 is an unsubstituted C2-C6 alkynyl, an unsubstituted C3-C6 cycloalkyl, or one or more R 4-5 substituted 4-12 membered heterocycloalkyl, substituted by one or more R 4-6 substituted 5-12 membered heteroaryl or unsubstituted C1-C6 alkoxy; the heteroatoms in the 4-12 membered heterocycloalkyl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heteroaryl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, R 4 is an unsubstituted C2-C6 alkynyl, an unsubstituted C3-C6 cycloalkyl, or one or more R 4-5 substituted 4-6 membered heterocycloalkyl, one or more R 4-6 a substituted 5-6 membered heteroaryl or an unsubstituted C1-C6 alkoxy group; the heteroatoms in the 4-6 membered heterocycloalkyl group are independently selected from one or both of N and O, and the number of heteroatoms is 1 or 2; the heteroatom in the 5-6 membered heteroaryl group is N, and the number of heteroatoms is 1; Each R 4-5 are independently unsubstituted C1-C6 alkyl; Each R 4-6 are independently cyano or unsubstituted C1-C6 alkyl; Option 11: Y is C; R 1 for R 1-1 is an unsubstituted C1-C6 alkyl group; R 1-2 is O; X is -CR 1-6 R 1-7 -; R 1-6 and R 1-7 are independently hydrogen; R 2 and R 3 The atoms connected thereto form an unsubstituted 4-6 membered heterocycloalkyl group or an unsubstituted C4-C6 cycloalkyl group; the heteroatoms in the 4-6 membered heterocycloalkyl group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatom in the 4-6 membered heterocycloalkyl group is O, and the number of heteroatoms is 1; A is an unsubstituted 5-12 membered heteroarylene group; the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatom in the 5-12 membered heteroarylene group is N, and the number of heteroatoms is 1 or 2; L is the connection key; Q is an unsubstituted 5-12 membered heteroarylene group or an unsubstituted 5-12 membered heterocycloalkylene group; the heteroatoms in the 5-12 membered heteroarylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 5-12 membered heterocycloalkylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, Q is an unsubstituted 5-6 membered heteroarylene group or an unsubstituted 5-12 membered heterocycloalkylene group; the heteroatom in the 5-6 membered heteroarylene group is N, and the number of heteroatoms is 1; the heteroatoms in the 5-12 membered heterocycloalkylene group are independently selected from one or both of N and O, and the number of heteroatoms is 1, 2 or 3; R 4 is an unsubstituted C2-C6 alkynyl, an unsubstituted C3-C6 cycloalkyl, or is replaced by one or more R 4-6 substituted 5-12 membered heteroaryl; the heteroatoms in the 5-12 membered heteroaryl are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, R 4 is an unsubstituted C2-C6 alkynyl, an unsubstituted C3-C6 cycloalkyl, or is replaced by one or more R 4-6 A substituted 5-6 membered heteroaryl group; wherein the heteroatom in the 5-6 membered heteroaryl group is N, and the number of heteroatoms is 1; Each R 4-6 are independently cyano or unsubstituted C1-C6 alkyl.

5. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein: The compound as shown in Formula I satisfies one or more of the following conditions: (1)R 1 for (2) X is a methylene group, (3) for (4) A is (5) L is (6) Q is (7)R 4 for 6. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein: The compound shown in formula I is any of the following structures, 7. Use of the compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 in the preparation of a BRM ATPase inhibitor.

8. A pharmaceutical composition, characterized in that It comprises a compound as shown in formula I according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

9. Use of a compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 in the preparation of a medicament, characterized in that: The drug is used to treat BRM ATPase-related diseases or the drug is used to treat melanoma, endometrial cancer, non-small cell lung cancer, esophageal and gastric adenocarcinoma, urothelial bladder cancer or colorectal cancer.

10. The use according to claim 9, characterized in that The BRM ATPase-related disease is melanoma, endometrial cancer, non-small cell lung cancer, esophageal and gastric adenocarcinoma, urothelial bladder cancer or colorectal cancer.

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