WO2024099440A1

WO2024099440A1 - Fused ring compound, use thereof, and pharmaceutical composition containing same

Info

Publication number: WO2024099440A1
Application number: PCT/CN2023/131053
Authority: WO
Inventors: 胡永韩; 王仁林; 彭冲; 魏海阳; 吴政; 吴冬冬; 吴予川
Original assignee: Evopoint Biosciences Co Ltd
Current assignee: Evopoint Biosciences Co Ltd
Priority date: 2022-11-11
Filing date: 2023-11-10
Publication date: 2024-05-16
Anticipated expiration: 2025-05-11
Also published as: CN119768400A

Abstract

A fused ring compound, a use thereof, and a pharmaceutical composition containing same. The compound has a strong inhibitory effect on BRM ATPase, and has a good application prospect in BRG1 gene mutation tumors.

Description

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

Technical Field

本发明涉及一种稠环化合物、其用途及含其的药物组合物。The present invention relates to a condensed ring compound, application thereof and a pharmaceutical composition containing the condensed ring compound.

Background technique

癌症是全球人类死亡的主要原因之一，主要由遗传和表观遗传改变引起。这些改变会影响正常细胞的基因表达或信号通路，导致正常细胞转化为恶性肿瘤细胞。肿瘤样本的癌症基因组测序结果发现，人类ATP依赖性染色质重塑复合物SWI/SNF的亚基基因在＞20％的人类肿瘤中发生突变，且多为功能丧失型突变。Cancer is one of the leading causes of death worldwide and is mainly caused by genetic and epigenetic changes. These changes affect the gene expression or signaling pathways of normal cells, leading to the transformation of normal cells into malignant tumor cells. Cancer genome sequencing results of tumor samples found that subunit genes of the human ATP-dependent chromatin remodeling complex SWI/SNF are mutated in >20% of human tumors, and most of them are loss-of-function mutations.

BRM(Protein brahma homolog)为SWI/SNF复合物的ATPase亚基，与同是ATPase亚基的BRG1(Protein brahma homolog 1)相互排斥。ATPase水解ATP为SWI/SNF复合物提供能量，使其行使调控基因表达和关键细胞过程的功能，对维持细胞活力具有重要作用。BRM (Protein brahma homolog) is the ATPase subunit of the SWI/SNF complex and is mutually exclusive with BRG1 (Protein brahma homolog 1), which is 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, and plays an important role in maintaining cell vitality.

BRG1基因(SMARCA4)在多癌症种类中发生高突变，包括但不限于黑色素瘤、子宫内膜癌、非小细胞肺癌、食道胃腺癌、尿路上皮膀胱癌、结直肠癌。相比之下，BRM基因(SMARCA2)很少发生突变。BRM与BRG1在参与调控细胞周期与激素作用通路、DNA损伤修复应答等细胞活力相关的功能方面存在互补和冗余，因此在BRG1基因缺陷的肿瘤细胞中，BRM可以补偿BRG1的功能损失，维持SWI/SNF复合物的功能，以支持细胞活力。The BRG1 gene (SMARCA4) is highly mutated in many types of cancer, 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) rarely mutates. BRM and BRG1 are complementary and redundant in their functions related to cell viability, such as participating in the regulation of cell cycle and hormone action pathways, DNA damage repair response, etc. Therefore, in tumor cells with BRG1 gene defects, BRM can compensate for the functional loss of BRG1 and maintain the function of the SWI/SNF complex to support cell viability.

BRM与BRG1的合成致死性，在多种类型的肿瘤细胞的体外和体内疾病模型中都得到了验证：在BRG1基因缺陷的细胞中降解BRM、或沉默BRM基因表达，均会抑制体外肿瘤细胞增殖和体内肿瘤生长；BRG1基因缺陷的肿瘤细胞对BRM基因的shRNA极为敏感；抑制BRM的ATPase活性，能够抑制BRG1基因缺陷肿瘤的体内生长…因此，在BRG1基因突变肿瘤中，BRM是一个有潜力的药物治疗靶点。The synthetic lethality of BRM and BRG1 has been verified in in vitro and in vivo disease models of various types of tumor cells: degradation of BRM or silencing of 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 the ATPase activity of BRM can inhibit the in vivo growth of BRG1 gene-deficient tumors... Therefore, in BRG1 gene mutant tumors, BRM is a potential drug treatment target.

相比BRG1，药物干扰BRM毒性风险更低。BRM-SWI/SNF复合物的ATPase酶活性和染色质重塑能力远低于BRG1-SWI/SNF复合物，在正常细胞中，SWI/SNF复合物主要依赖BRG1行使功能。纯合敲除BRG1基因不会引起小鼠胚胎致死和影响成年小鼠的生殖能力，这与纯合敲除BRM基因的表现相反。Compared with BRG1, drug interference with BRM has a lower risk of toxicity. The ATPase activity and chromatin remodeling ability of the BRM-SWI/SNF complex are much lower than those of the BRG1-SWI/SNF complex. In normal cells, the SWI/SNF complex mainly relies on BRG1 to function. Homozygous knockout of the BRG1 gene does not cause embryonic lethality in mice or affect the reproductive capacity of adult mice, which is the opposite of the performance of homozygous knockout of the BRM gene.

因此，靶向抑制BRM ATPase活性有潜力成为BRG1基因突变肿瘤的新型治疗方案。Therefore, targeted inhibition of BRM ATPase activity has the potential to become a new treatment option for BRG1 gene mutant tumors.

目前还未有BRM ATPase抑制剂药物进入临床阶段，但已有BRM ATPase抑制剂正在临床前研发过程中，Foghorn近期披露的专利WO2022103899中公开了多个高选择性的BRM ATPase抑制剂，结构示例如下：
Currently, no BRM ATPase inhibitor drugs have entered the clinical stage, but some BRM ATPase inhibitors are in preclinical development. Foghorn’s recently disclosed patent WO2022103899 discloses a number of highly selective BRM ATPase inhibitors. The structural examples are as follows:

发明内容Summary of the invention

本发明所要解决的技术问题是现有的BRM ATPase抑制剂种类较少，为此，本发明提供了一种稠环化合物I或其药学上可接受的盐。该稠环化合物对BRM ATPase有较强的抑制作用，在BRG1基因突变肿瘤中有很好的应用前景。The technical problem to be solved by the present invention is that there are few types of existing BRM ATPase inhibitors. To this end, the present invention provides a condensed ring compound I or a pharmaceutically acceptable salt thereof. The condensed ring compound has a strong inhibitory effect on BRM ATPase and has a good application prospect in BRG1 gene mutation tumors.

本发明提供了一种如式I所示的化合物或其药学上可接受的盐，
The present invention provides a compound as shown in Formula I or a pharmaceutically acceptable salt thereof,

其中，in,

Y为C或N；Y is C or N;

R¹为羟基、氰基、卤素、氨基、氘、未取代或被1个或多个R^1-3取代的C₁-C₆的烷基、未取代或被1个或多个R^1-4取代的C₃-C₆的环烷基或未取代或被1个或多个R^1-5取代的3-6元的杂环烷基；所述3-6元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个； ^R1 is Hydroxyl, cyano, halogen, amino, deuterium, C ₁ -C ₆ alkyl which is unsubstituted or substituted by one or more R ^1-3 , C ₃ -C ₆ cycloalkyl which is unsubstituted or substituted by one or more R ^1-4 , or 3-6 membered heterocycloalkyl which is unsubstituted or substituted by one or more R ^1-5 ; 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为未取代或被1个或多个R^1-1-1取代的C₁-C₆的烷基、未取代或被1个或多个氘取代的C₃-C₆的环烷基或-NR^1-1-2R^1-1-3；R ^1-1 is C ₁ -C ₆ alkyl which is unsubstituted or substituted by one or more R ^1-1-1 , C ₃ -C ₆ cycloalkyl which is unsubstituted or substituted by one or more deuterium, or -NR ^1-1-2 R ^1-1-3 ;

R^1-2为O或NR^1-2-1；R^1-2-1为氢或未取代或被1个或多个氘取代的C₁-C₆的烷基；R ^1-2 is O or NR ^1-2-1 ; R ^1-2-1 is hydrogen or a C ₁ -C ₆ alkyl group which is unsubstituted or substituted with one or more deuteriums;

各个R^1-1-1独立地为OR^1-1-1-1、未取代或被1个或多个氘取代的C₁-C₆的烷基或氘；Each R ^1-1-1 is independently OR ^1-1-1-1 , C ₁ -C ₆ alkyl which is unsubstituted or substituted with one or more deuteriums, or deuterium;

R^1-1-1-1为氢或未取代或被1个或多个氘取代的C₁-C₆的烷基；R ^1-1-1-1 is hydrogen or C ₁ -C ₆ alkyl which is unsubstituted or substituted with one or more deuteriums;

R^1-1-2和R^1-1-3独立地为氢或未取代或被1个或多个氘取代的C₁-C₆的烷基；R ^1-1-2 and R ^1-1-3 are independently hydrogen or C ₁ -C ₆ alkyl which is unsubstituted or substituted with one or more deuteriums;

各个R^1-3独立地为羟基、氰基、卤素、氨基、未取代或被1个或多个氘取代的C₁-C₆的烷基或氘；Each R ^1-3 is independently hydroxy, cyano, halogen, amino, C ₁ -C ₆ alkyl which is unsubstituted or substituted with one or more deuteriums, or deuterium;

各个R^1-4和R^1-5独立地为羟基、氘或未取代或被1个或多个氘取代的C₁-C₆的烷基；Each of R ^1-4 and R ^1-5 is independently hydroxy, deuterium, or C ₁ -C ₆ alkyl which is unsubstituted or substituted with one or more deuteriums;

X为-CR^1-6R^1-7-或-NR^1-8-；X is -CR ^1-6 R ^1-7 - or -NR ^1-8 -;

R^1-6和R^1-7独立地为氢、氘、卤素或未取代或被1个或多个氘取代的C₁-C₆的烷基；R ^1-6 and R ^1-7 are independently hydrogen, deuterium, halogen, or C ₁ -C ₆ alkyl which is unsubstituted or substituted with one or more deuteriums;

R^1-8为氢或未取代或被1个或多个氘取代的C₁-C₆的烷基；R ^1-8 is hydrogen or C ₁ -C ₆ alkyl which is unsubstituted or substituted with one or more deuteriums;

R²和R³与其相连的原子形成未取代或被1个或多个R^2-1取代的5-6元的杂芳基、未取代或被1个或多个R^2-2取代的4-6元的杂环烷基、未取代或被1个或多个R^2-3取代的C₄-C₆的环烷基或未取代或被1个或多个R^2-4取代的C₆-C₁₀的芳基；所述5-6元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个；所述4-6元的杂环烷基中的杂原子独立地选自N、O 和S中的一种或多种，杂原子数为1个、2个或3个； ^R2 and ^R3 and the atoms connected thereto form a 5-6 membered heteroaryl group which is unsubstituted or substituted by one or more ^R2-1 , a 4-6 membered heterocycloalkyl group which is unsubstituted or substituted by one or more ^R2-2 , a C4-C6 cycloalkyl group which is unsubstituted or substituted by one or more ^R2-3 _, or a _C6 - _C10 aryl group which is unsubstituted or substituted by one or more ^R2-4 ; 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 N, _O and S, and the number of heteroatoms is 1, 2 or 3. and S, with one or more heteroatoms, 1, 2 or 3;

各个R^2-1独立地为氘、卤素、未取代或被1个或多个R^2-1-1取代的C₁-C₆的烷基、氧代基(＝O)，或者，两个R^2-1和与之相连的碳原子形成未取代或被1个或多个氘取代的C₃-C₆的环烷基；Each R ^2-1 is independently deuterium, halogen, C ₁ -C ₆ alkyl which is unsubstituted or substituted by one or more R ^2-1-1 , oxo (═O), or two R ^2-1 and the carbon atom to which they are attached form a C ₃ -C ₆ cycloalkyl which is unsubstituted or substituted by one or more deuterium;

各个R^2-2独立地为氘、卤素、未取代或被1个或多个R^2-2-1取代的C₁-C₆的烷基、氧代基(＝O)，或者，两个R^2-2和与之相连的碳原子形成未取代或被1个或多个氘取代的C₃-C₆的环烷基；Each R ^2-2 is independently deuterium, halogen, C ₁ -C ₆ alkyl which is unsubstituted or substituted by one or more R ^2-2-1 , oxo (═O), or two R ^2-2 and the carbon atom to which they are attached form a C ₃ -C ₆ cycloalkyl which is unsubstituted or substituted by one or more deuterium;

各个R^2-3独立地为氘、卤素、未取代或被1个或多个R^2-3-1取代的C₁-C₆的烷基、氧代基(＝O)，或者，两个R^2-3和与之相连的碳原子形成未取代或被1个或多个氘取代的C₃-C₆的环烷基；Each R ^2-3 is independently deuterium, halogen, C ₁ -C ₆ alkyl which is unsubstituted or substituted by one or more R ^2-3-1 , oxo (═O), or two R ^2-3 and the carbon atom to which they are attached form a C ₃ -C ₆ cycloalkyl which is unsubstituted or substituted by one or more deuterium;

各个R^2-4独立地为氘、卤素、未取代或被1个或多个R^2-4-1取代的C₁-C₆的烷基、氧代基(＝O)，或者，两个R^2-4和与之相连的碳原子形成未取代或被1个或多个氘取代的C₃-C₆的环烷基；Each R ^2-4 is independently deuterium, halogen, C ₁ -C ₆ alkyl which is unsubstituted or substituted by one or more R ^2-4-1 , oxo (═O), or two R ^2-4 and the carbon atom to which they are attached form a C ₃ -C ₆ cycloalkyl which is unsubstituted or substituted by one or more deuterium;

R^2-1-1、R^2-2-1、R^2-3-1和R^2-4-1独立地为氘或羟基；R ^2-1-1 , R ^2-2-1 , R ^2-3-1 and R ^2-4-1 are independently deuterium or hydroxyl;

A为未取代或被1个或多个氘取代的C₆-C₁₀的亚芳基、未取代或被1个或多个氘取代的5-12元的亚杂芳基或未取代或被1个或多个氘取代的5-12元的亚杂环烷基；所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个；所述5-12元的亚杂环烷基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个；A is a C ₆ -C ₁₀ arylene group which is unsubstituted or substituted by one or more deuteriums, a 5-12-membered heteroarylene group which is unsubstituted or substituted by one or more deuteriums, or a 5-12-membered heterocycloalkylene group which is unsubstituted or substituted by one or more deuteriums; 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;

L为连接健、未取代或被1个或多个氘取代的C₂-C₆的亚烯基或未取代或被1个或多个氘取代的C₁-C₆的亚烷基；L is a linking bond, a C ₂ -C ₆ alkenylene group which is unsubstituted or substituted by one or more deuterium groups, or a C ₁ -C ₆ alkylene group which is unsubstituted or substituted by one or more deuterium groups;

Q为未取代或被1个或多个R^3-1取代的C₆-C₁₀的亚芳基、未取代或被一个或多个R^3-1取代的5-12元的亚杂芳基或未取代或被一个或多个R^3-1取代的5-12元的亚杂环烷基；所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个；所述5-12元的亚杂环烷基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个；Q is a C ₆ -C ₁₀ arylene group which is unsubstituted or substituted by one or more R ^3-1 , a 5-12-membered heteroarylene group which is unsubstituted or substituted by one or more R ^3-1 , or a 5-12-membered heterocycloalkylene group which is unsubstituted or substituted by one or more R ^3-1 ; 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;

各个R^3-1独立地为卤素或氘；Each R ^3-1 is independently halogen or deuterium;

R⁴为未取代或被一个或多个R^4-1取代的C₁-C₆的烷基、未取代或被一个或多个R^4-2取代的C₂-C₆的烯基、未取代或被一个或多个R^4-3取代的C₂-C₆的炔基、未取代或被一个或多个R^4-4取代的C₃-C₆的环烷基、未取代或被一个或多个R^4-5取代的4-12元的杂环烷基、未取代或被一个或多个R^4-6取代的5-12元的杂芳基、未取代或被一个或多个R^4-7取代的C₁-C₆的烷氧基或-NR^4-9R^4-8；所述4-12元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个；所述5-12元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个；R ⁴ is C ₁ -C ₆ alkyl which is unsubstituted or substituted by one or more R ^4-1 , C 2 -C 6 alkenyl which is unsubstituted or substituted by one or more R ^4-2 , C ₂ -C ₆ alkynyl which _is unsubstituted or substituted by one or more R ^4-3 , C ₃ _-C ₆ cycloalkyl which is unsubstituted or substituted by one or more R ^4-4 , 4-12 membered heterocycloalkyl which is unsubstituted or substituted by one or more R ^4-5 , 5-12 membered heteroaryl which is unsubstituted or substituted by one or more R ^4-6 , C ₁ -C ₆ alkoxy which is unsubstituted or substituted by one or more R ^4-7 , or -NR ^4-9 R ^4-8 ; 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;

各个R^4-1独立地为氘、卤素、羟基、未取代或被1个或多个氘取代的C₁-C₆的烷基或未取代或被1个或多个氘取代的C₁-C₆的烷氧基；Each R ^4-1 is independently deuterium, halogen, hydroxyl, C ₁ -C ₆ alkyl which is unsubstituted or substituted by 1 or more deuterium, or C ₁ -C ₆ alkoxy which is unsubstituted or substituted by 1 or more deuterium;

各个R^4-2独立地为氘、卤素、羟基或未取代或被1个或多个氘取代的C₁-C₆的烷基；Each R ^4-2 is independently deuterium, halogen, hydroxyl, or C ₁ -C ₆ alkyl which is unsubstituted or substituted with one or more deuteriums;

各个R^4-3独立地为氘、卤素、羟基或未取代或被1个或多个氘取代的C₁-C₆的烷基；Each R ^4-3 is independently deuterium, halogen, hydroxyl, or C ₁ -C ₆ alkyl which is unsubstituted or substituted with one or more deuteriums;

各个R^4-4独立地为氘、卤素、羟基或未取代或被1个或多个氘取代的C₁-C₆的烷基；Each R ^4-4 is independently deuterium, halogen, hydroxyl, or C ₁ -C ₆ alkyl which is unsubstituted or substituted with one or more deuteriums;

各个R^4-5独立地为氘、卤素、羟基、未取代或被一个或多个R^4-5-1取代的C₁-C₆的烷基、-NR^4-5- ²R^4-5-3或未取代或被1个或多个氘取代的C₁-C₆的烷氧基； Each R ^4-5 is independently deuterium, halogen, hydroxyl, C ₁ -C ₆ alkyl which is unsubstituted or substituted with one or more R ^4-5-1 , -NR ^4-5- ² R ^4-5-3 , or C ₁ -C ₆ alkoxy which is unsubstituted or substituted with one or more deuterium;

各个R^4-5-1独立地为氘、羟基或卤素；Each R ^4-5-1 is independently deuterium, hydroxyl or halogen;

R^4-5-2和R^4-5-3独立地为氢或未取代或被1个或多个氘取代的C₁-C₆的烷基；R ^4-5-2 and R ^4-5-3 are independently hydrogen or C ₁ -C ₆ alkyl which is unsubstituted or substituted with one or more deuteriums;

各个R^4-6独立地为氘、卤素、氰基、羟基、未取代或被1个或多个氘取代的C₁-C₆的烷基或未取代或被1个或多个氘取代的C₁-C₆的烷氧基；Each R ^4-6 is independently deuterium, halogen, cyano, hydroxyl, C ₁ -C ₆ alkyl which is unsubstituted or substituted by 1 or more deuterium, or C ₁ -C ₆ alkoxy which is unsubstituted or substituted by 1 or more deuterium;

各个R^4-7独立地为氘、卤素、未取代或被1个或多个氘取代的C₁-C₆的烷基或未取代或被1个或多个氘取代的C₁-C₆的烷氧基；Each R ^4-7 is independently deuterium, halogen, C ₁ -C ₆ alkyl which is unsubstituted or substituted by 1 or more deuterium, or C ₁ -C ₆ alkoxy which is unsubstituted or substituted by 1 or more deuterium;

R^4-9和R^4-8独立地为氢、未取代或被一个或多个R^4-8-1取代的C₁-C₆的烷基或未取代或被1个或多个氘取代的4-6元的杂环烷基；所述4-6元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个；R ^4-9 and R ^4-8 are independently hydrogen, C ₁ -C ₆ alkyl which is unsubstituted or substituted by one or more R ^4-8-1, or 4-6 membered heterocycloalkyl which is unsubstituted or substituted by one or more deuteriums; 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;

各个R^4-8-1独立地为氘、羟基、未取代或被一个或多个R^4-8-1-1取代的C₁-C₆的烷氧基或OR^4-8-1-2；Each R ^4-8-1 is independently deuterium, hydroxy, C ₁ -C ₆ alkoxy which is unsubstituted or substituted by one or more R ^4-8-1-1 , or OR ^4-8-1-2 ;

各个R^4-8-1-1独立地为氘或未取代或被1个或多个氘取代的C₃-C₆的环烷基；Each R ^4-8-1-1 is independently deuterium or a C ₃ -C ₆ cycloalkyl group which is unsubstituted or substituted with one or more deuteriums;

各个R^4-8-1-2独立地为未取代或被1个或多个氘取代的C₃-C₆的环烷基。Each R ^4-8-1-2 is independently a C ₃ -C ₆ cycloalkyl group which is unsubstituted or substituted with one or more deuterium groups.

某一优选方案中，如式I化合物中，某些基团的定义可如下所述，其他基团的定义可如其他任一方案所述(以下简称“在某一方案中”)。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").

在某一方案中，R¹中，所述多个为2个、3个、4个、5个、6个或7个。In one embodiment, in R ¹ , the plurality is 2, 3, 4, 5, 6 or 7.

在某一方案中，R¹中，所述C₁-C₆的烷基为甲基、乙基、丙基、异丙基或异丁基。In one embodiment, in R ¹ , the C ₁ -C ₆ alkyl group is methyl, ethyl, propyl, isopropyl or isobutyl.

在某一方案中，R¹中，所述“未取代或被1个或多个R^1-4取代的C₃-C₆的环烷基”中；所述C₃-C₆的环烷基为环丁基，例如， In one embodiment, in R ¹ , in the "C ₃ -C ₆ cycloalkyl group which is unsubstituted or substituted by one or more R ^1-4 ", the C ₃ -C ₆ cycloalkyl group is cyclobutyl, for example,

在某一方案中，R¹中，所述3-6元的杂环烷基中的杂原子为N、O或S，优选为O，所述3-6元的杂环烷基中的杂原子数优选为1个。In a certain embodiment, in R ¹ , 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.

在某一方案中，R¹中，所述“未取代或被1个或多个R^1-5取代的3-6元的杂环烷基”中；所述3-6元的杂环烷基为4元杂环烷基，例如， In one embodiment, in R ¹ , in the “3-6 membered heterocycloalkyl group which is unsubstituted or substituted by one or more R ^1-5 ”, the 3-6 membered heterocycloalkyl group is a 4 membered heterocycloalkyl group, for example,

在某一方案中，R^1-1中，所述“未取代或被1个或多个R^1-1-1取代的C₁-C₆的烷基”中；所述多个为2个。In one embodiment, in R ^1-1 , the “C ₁ -C ₆ alkyl group which is unsubstituted or substituted with one or more R ^1-1-1 ”; the “plurality” is 2.

在某一方案中，R^1-1中，所述C₁-C₆的烷基为甲基、乙基或丙基。In one embodiment, in R ^1-1 , the C ₁ -C ₆ alkyl group is methyl, ethyl or propyl.

在某一方案中，R^1-1中，所述C₃-C₆的环烷基为环丙基。In one embodiment, in R ^1-1 , the C ₃ -C ₆ cycloalkyl group is cyclopropyl.

在某一方案中，R^1-1-1中，所述C₁-C₆的烷基为甲基。In one embodiment, in R ^1-1-1 , the C ₁ -C ₆ alkyl group is methyl.

在某一方案中，R^1-1-1-1中，所述C₁-C₆的烷基为甲基。In one embodiment, in R ^1-1-1-1 , the C ₁ -C ₆ alkyl group is methyl.

在某一方案中，R^1-1-2和R^1-1-3中，所述C₁-C₆的烷基为甲基。In one embodiment, in R ^1-1-2 and R ^1-1-3 , the C ₁ -C ₆ alkyl group is methyl.

在某一方案中，R^1-3中，所述卤素为F、Cl或Br，优选为F。In one embodiment, in R ^1-3 , the halogen is F, Cl or Br, preferably F.

在某一方案中，R^1-3中，所述“未取代或被1个或多个氘取代的C₁-C₆的烷基”中；所述多个为2个或3个。 In one embodiment, in R ^1-3 , the “C ₁ -C ₆ alkyl group which is unsubstituted or substituted with one or more deuteriums”; the “plurality” is 2 or 3.

在某一方案中，R^1-3中，所述C₁-C₆的烷基为甲基或乙基。In one embodiment, in R ^1-3 , the C ₁ -C ₆ alkyl group is a methyl group or an ethyl group.

在某一方案中，R^1-6和R^1-7中，所述C₁-C₆的烷基为甲基。In one embodiment, in R ^1-6 and R ^1-7 , the C ₁ -C ₆ alkyl group is methyl.

在某一方案中，R^1-8中，所述C₁-C₆的烷基为甲基。In one embodiment, in R ^1-8 , the C ₁ -C ₆ alkyl group is methyl.

在某一方案中，R²和R³中，所述5-6元的杂芳基中的杂原子独立地选自N、O和S的一种或两种，杂原子数为1个、2个或3个。In a certain embodiment, in R ² and R ³ , 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.

在某一方案中，R²和R³中，所述“R²和R³与其相连的原子形成未取代或被1个或多个R^2-1取代的5-6元的杂芳基”中；所述5-6元的杂芳基为5元的杂芳基，例如， In one embodiment, in ^R2 and ^R3 , in the " ^R2 and ^R3 and the atoms to which they are connected form a 5-6-membered heteroaryl group which is unsubstituted or substituted by one or more ^R2-1 ", the 5-6-membered heteroaryl group is a 5-membered heteroaryl group, for example,

在某一方案中，R²和R³中，所述4-6元的杂环烷基中的杂原子独立地选自N或O中的一种或两种，杂原子数优选为1个或2个。In a certain embodiment, in R ² and R ³ , 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 preferably 1 or 2.

在某一方案中，R²和R³中，所述“R²和R³与其相连的原子形成未取代或被1个或多个R^2-2取代的4-6元的杂环烷基”中；所述4-6元的杂环烷基为5-6元的杂环烷基，例如， In one embodiment, in ^R2 and ^R3 , in the " ^R2 and ^R3 and the atoms to which they are attached form a 4-6 membered heterocycloalkyl group which is unsubstituted or substituted by one or more ^R2-2 ", the 4-6 membered heterocycloalkyl group is a 5-6 membered heterocycloalkyl group, for example,

在某一方案中，R²和R³中，所述“R²和R³与其相连的原子形成未取代或被1个或多个R^2-3取代的C₄-C₆的环烷基”中；所述C₄-C₆的环烷基为环戊烷。In one embodiment, in R ² and R ³ , in the "R ² and R ³ and the atoms to which they are attached form a C ₄ -C ₆ cycloalkyl group which is unsubstituted or substituted with one or more R ^2-3 ", the C ₄ -C ₆ cycloalkyl group is cyclopentane.

在某一方案中，R²和R³中，所述C₆-C₁₀的芳基为苯基。In one embodiment, in R ² and R ³ , the C ₆ -C ₁₀ aryl group is phenyl.

在某一方案中，R^2-1中，所述卤素为F、Cl或Br，优选为F。In one embodiment, in R ^2-1 , the halogen is F, Cl or Br, preferably F.

在某一方案中，R^2-1中，所述C₁-C₆的烷基为甲基或乙基。In one embodiment, in R ^2-1 , the C ₁ -C ₆ alkyl group is a methyl group or an ethyl group.

在某一方案中，R^2-2中，所述卤素为F、Cl或Br，优选为F。In one embodiment, in R ^2-2 , the halogen is F, Cl or Br, preferably F.

在某一方案中，R^2-2中，所述C₃-C₆的环烷基为环丙基。In one embodiment, in R ^2-2 , the C ₃ -C ₆ cycloalkyl group is cyclopropyl.

在某一方案中，A中，所述亚芳基为亚苯基。In one embodiment, in A, the arylene group is a phenylene group.

在某一方案中，A中，所述5-12元的亚杂芳基中的杂原子独立地选自N和S中的一种或两种，杂原子数为1个、2个或3个。In a certain 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.

在某一方案中，A中，所述5-12元的亚杂芳基为6元亚杂芳基、6元亚杂芳基并5元亚杂芳基或6元亚杂芳基并6元亚杂芳基，例如， In one embodiment, in A, the 5-12-membered heteroarylene is a 6-membered heteroarylene, a 6-membered heteroarylene and a 5-membered heteroarylene, or a 6-membered heteroarylene and a 6-membered heteroarylene, for example,

在某一方案中，A中，所述5-12元的亚杂环烷基中的杂原子独立地为N；杂原子数优选为1个。In one embodiment, in A, the heteroatom in the 5-12-membered heterocycloalkylene group is independently N; the number of the heteroatom is preferably 1.

在某一方案中，A中，所述5-12元的亚杂环烷基为6元亚杂芳基并6元亚杂环烷基，例如， In one embodiment, in A, the 5-12 membered heterocycloalkylene is a 6-membered heteroarylene and a 6-membered heterocycloalkylene, for example,

在某一方案中，L中，所述C₂-C₆的亚烯基为乙烯基，例如， In one embodiment, in L, the C ₂ -C ₆ alkenylene group is vinyl, for example,

在某一方案中，Q中，所述C₆-C₁₀的亚芳基为亚苯基。In one embodiment, in Q, the C ₆ -C ₁₀ arylene group is a phenylene group.

在某一方案中，Q中，所述5-12元的亚杂芳基中的杂原子独立地选自N和O中的一种或两种，杂原子数为1个、2个或3个。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.

在某一方案中，Q中，所述“未取代或被一个或多个R^3-1取代的5-12元的亚杂芳基”中；所述5-12元的亚杂芳基为6元亚杂芳基、5元亚杂芳基并6元亚芳基或6元亚杂芳基并5元亚杂芳基，例如， In one embodiment, in Q, the “5-12-membered heteroarylene group which is unsubstituted or substituted by one or more R ^3-1 ”; the 5-12-membered heteroarylene group is a 6-membered heteroarylene group, a 5-membered heteroarylene group and a 6-membered heteroarylene group, or a 6-membered heteroarylene group and a 5-membered heteroarylene group, for example,

在某一方案中，Q中，所述5-12元的亚杂环烷基中的杂原子独立地选自N和O中的一种或两种，杂原子数为1个、2个或3个。In a certain 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 the heteroatoms is 1, 2 or 3.

在某一方案中，Q中，所述5-12元的亚杂环烷基为6元亚杂芳基并6元亚杂环烷基，例如， In one embodiment, in Q, the 5-12 membered heterocycloalkylene is a 6-membered heteroarylene and a 6-membered heterocycloalkylene, for example,

在某一方案中，R^3-1中，所述卤素为F、Cl或Br，优选为F。In one embodiment, in R ^3-1 , the halogen is F, Cl or Br, preferably F.

在某一方案中，R⁴中，所述“未取代或被一个或多个R^4-1取代的C₁-C₆的烷基”中；所述C₁-C₆的烷基为乙基，例如， In one embodiment, in R ⁴ , in the "C ₁ -C ₆ alkyl group which is unsubstituted or substituted by one or more R ^4-1 ", the C ₁ -C ₆ alkyl group is ethyl, for example,

在某一方案中，R⁴中，所述C₂-C₆的炔基为乙炔基。In one embodiment, in R ⁴ , the C ₂ -C ₆ alkynyl group is ethynyl.

在某一方案中，R⁴中，所述“未取代或被一个或多个R^4-4取代的C₃-C₆的环烷基”中；所述多个为两个。In one embodiment, in R ⁴ , the “C ₃ -C ₆ cycloalkyl which is unsubstituted or substituted by one or more R ^4-4 ”; the plurality is two.

在某一方案中，R⁴中，所述“未取代或被一个或多个R^4-4取代的C₃-C₆的环烷基”中；所述C₃-C₆的环烷基为环丙基或环丁基，例如， In one embodiment, in R ⁴ , the "C ₃ -C ₆ cycloalkyl group which is unsubstituted or substituted by one or more R ^4-4 "; the C ₃ -C ₆ cycloalkyl group is cyclopropyl or cyclobutyl, for example,

在某一方案中，R⁴中，所述4-12元的杂环烷基中的杂原子独立地选自N、O和S中的一种或两种，杂原子数优选为1个或2个。In a certain embodiment, in R ⁴ , the heteroatoms in the 4-12 membered heterocycloalkyl group are independently selected from one or two of N, O and S, and the number of heteroatoms is preferably 1 or 2.

在某一方案中，R⁴中，所述未取代或被一个或多个R^4-5取代的4-12元的杂环烷基中；所述多个为两个。In a certain embodiment, in R ⁴ , the 4-12 membered heterocycloalkyl group which is unsubstituted or substituted by one or more R ^4-5 ; the plurality is two.

在某一方案中，R⁴中，所述“未取代或被一个或多个R^4-5取代的4-12元的杂环烷基”中；所述 4-12元的杂环烷基为4-7元的杂环烷基或7-9元双桥环，例如， In one embodiment, in R ⁴ , the “4-12 membered heterocycloalkyl group which is unsubstituted or substituted by one or more R ^4-5 ”; The 4-12 membered heterocycloalkyl is a 4-7 membered heterocycloalkyl or a 7-9 membered double bridged ring, for example,

在某一方案中，R⁴中，所述5-12元的杂芳基中的杂原子为N，杂原子数优选为1个或2个。In one embodiment, in R ⁴ , the heteroatom in the 5-12 membered heteroaryl group is N, and the number of heteroatoms is preferably 1 or 2.

在某一方案中，R⁴中，所述“未取代或被一个或多个R^4-6取代的5-12元的杂芳基”中；所述多个为两个。In one embodiment, in R ⁴ , the “5-12 membered heteroaryl group which is unsubstituted or substituted by one or more R ^4-6 ”; the plurality is two.

在某一方案中，R⁴中，所述“未取代或被一个或多个R^4-6取代的5-12元的杂芳基”中；所述5-12元的杂芳基为5元或6元杂芳基，例如， In one embodiment, in R ⁴ , the “5-12 membered heteroaryl group which is unsubstituted or substituted by one or more R ^4-6 ”; the 5-12 membered heteroaryl group is a 5-membered or 6-membered heteroaryl group, for example,

在某一方案中，R⁴中，所述C₁-C₆的烷氧基为乙氧基，例如， In one embodiment, in R ⁴ , the C ₁ -C ₆ alkoxy group is an ethoxy group, for example,

在某一方案中，R^4-1中，所述C₁-C₆的烷氧基为甲氧基。In one embodiment, in R ^4-1 , the C ₁ -C ₆ alkoxy group is a methoxy group.

在某一方案中，R^4-4中，所述卤素为F、Cl或Br，优选为F。In one embodiment, in R ^4-4 , the halogen is F, Cl or Br, preferably F.

在某一方案中，R^4-5中，所述C₁-C₆的烷基为甲基。In one embodiment, in R ^4-5 , the C ₁ -C ₆ alkyl group is methyl.

在某一方案中，R^4-5中，所述C₁-C₆的烷氧基为甲氧基。In one embodiment, in R ^4-5 , the C ₁ -C ₆ alkoxy group is a methoxy group.

在某一方案中，R^4-5-2和R^4-5-3中，所述C₁-C₆的烷基为甲基。In one embodiment, in R ^4-5-2 and R ^4-5-3 , the C ₁ -C ₆ alkyl group is methyl.

在某一方案中，R^4-6中，所述卤素为F、Cl或Br，优选为F。 In one embodiment, in R ^4-6 , the halogen is F, Cl or Br, preferably F.

在某一方案中，R^4-6中，所述C₁-C₆的烷基为甲基。In one embodiment, in R ^4-6 , the C ₁ -C ₆ alkyl group is methyl.

在某一方案中，R^4-9和R^4-8中所述C₁-C₆的烷基为甲基或乙基。In one embodiment, the C ₁ -C ₆ alkyl group in R ^4-9 and R ^4-8 is methyl or ethyl.

在某一方案中，R^4-9和R^4-8中，所述4-6元的杂环烷基中的杂原子为O，杂原子数优选为1个。In one embodiment, in R ^4-9 and R ^4-8 , the heteroatom in the 4-6-membered heterocycloalkyl group is O, and the number of the heteroatom is preferably 1.

在某一方案中，R^4-9和R^4-8中，所述4-6元的杂环烷基为5元或6元杂环烷基。In one embodiment, in R ^4-9 and R ^4-8 , the 4-6-membered heterocycloalkyl is a 5-membered or 6-membered heterocycloalkyl.

在某一方案中，R^4-8-1-2中，所述C₃-C₆的环烷基为环丙基。In one embodiment, in R ^4-8-1-2 , the C ₃ -C ₆ cycloalkyl group is cyclopropyl.

在某一方案中，Y为C或N；较佳地为C。In one embodiment, Y is C or N; preferably C.

在某一方案中，R¹为被1个或多个R^1-3取代的C₁-C₆的烷基、未取代或被1个或多个R^1-4取代的C₃-C₆的环烷基或未取代或被1个或多个R^1-5取代的3-6元的杂环烷基；所述3-6元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个；较佳地为被1个或多个R^1-3取代的C₁-C₆的烷基或未取代或被1个或多个R^1-4取代的C₃-C₆的环烷基；进一步较佳地为或被1个或多个R^1-3取代的C₁-C₆的烷基；更进一步较佳地为 In one embodiment, ^R1 is C ₁ -C ₆ alkyl substituted by one or more R ^1-3 , C ₃ -C 6 cycloalkyl unsubstituted or substituted by one or more R ^1-4 , or _3-6 membered heterocycloalkyl unsubstituted or substituted by one or more R ^1-5 ; 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 C ₁ -C ₆ alkyl substituted by one or more R ^1-3 or C ₃ -C ₆ cycloalkyl unsubstituted or substituted by one or more R ^1-4 ; further preferably or a C ₁ -C ₆ alkyl group substituted by one or more R ^1-3 ; more preferably

在某一方案中，R^1-1为未取代或被1个或多个R^1-1-1取代的C₁-C₆的烷基、未取代的C₃-C₆的环烷基或-NR^1-1-2R^1-1-3；较佳地为未取代或被1个或多个R^1-1-1取代的C₁-C₆的烷基或-NR^1-1-2R^1-1-3；进一步较佳地为未取代或被1个或多个R^1-1-1取代的C₁-C₆的烷基；更进一步较佳地为未取代的C₁-C₆的烷基。In one embodiment, R ^1-1 is C ₁ -C ₆ alkyl, unsubstituted or substituted by one or more R ^1-1-1 , unsubstituted C 3 -C ₆ cycloalkyl, or -NR ^1-1-2 R ^1-1-3 ; preferably C ₁ -C 6 alkyl, unsubstituted or substituted by one or more R ^1-1-1 , or -NR ^1-1-2 R ^1-1-3 ; further preferably C ₁ -C ₆ alkyl, unsubstituted or substituted by one or more R ^1-1-1 ; further preferably unsubstituted C ₁ _-C ₆ _alkyl .

在某一方案中，R^1-2为O或NR^1-2-1；较佳地为O。In one embodiment, R ^1-2 is O or NR ^1-2-1 ; preferably, it is O.

在某一方案中，R^1-2-1为氢。In one embodiment, R ^1-2-1 is hydrogen.

在某一方案中，各个R^1-1-1独立地为OR^1-1-1-1、未取代的C₁-C₆的烷基或未取代的C₁-C₆的烷氧基；较佳地为OR^1-1-1-1或未取代的C₁-C₆的烷基；进一步较佳地为未取代的C₁-C₆的烷基。In one embodiment, each R ^1-1-1 is independently OR ^1-1-1-1 , unsubstituted C ₁ -C ₆ alkyl or unsubstituted C ₁ -C ₆ alkoxy; preferably OR ^1-1-1-1 or unsubstituted C ₁ -C ₆ alkyl; more preferably unsubstituted C ₁ -C ₆ alkyl.

在某一方案中，R^1-1-1-1为氢或未取代的C₁-C₆的烷基；较佳地为未取代的C₁-C₆的烷基。In one embodiment, R ^1-1-1-1 is hydrogen or unsubstituted C ₁ -C ₆ alkyl; preferably, it is unsubstituted C ₁ -C ₆ alkyl.

在某一方案中，R^1-1-2和R^1-1-3独立地为氢或未取代的C₁-C₆的烷基。In one embodiment, R ^1-1-2 and R ^1-1-3 are independently hydrogen or unsubstituted C ₁ -C ₆ alkyl.

在某一方案中，各个R^1-3独立地为羟基、氰基、卤素、氨基、未取代的C₁-C₆的烷基或氘；较佳地为羟基、氰基、卤素、未取代的C₁-C₆的烷基或氘；进一步较佳地为羟基、氰基、卤素或未取代的C₁-C₆的烷基；更进一步较佳地为羟基或卤素。In a certain embodiment, each R ^1-3 is independently hydroxyl, cyano, halogen, amino, unsubstituted C ₁ -C ₆ alkyl or deuterium; preferably hydroxyl, cyano, halogen, unsubstituted C ₁ -C ₆ alkyl or deuterium; further preferably hydroxyl, cyano, halogen or unsubstituted C ₁ -C ₆ alkyl; further preferably hydroxyl or halogen.

在某一方案中，各个R^1-3独立地为羟基、卤素、未取代的C₁-C₆的烷基或氘；较佳地为羟基、卤素或未取代的C₁-C₆的烷基。 In a certain embodiment, each R ^1-3 is independently hydroxyl, halogen, unsubstituted C ₁ -C ₆ alkyl or deuterium; preferably hydroxyl, halogen or unsubstituted C ₁ -C ₆ alkyl.

在某一方案中，各个R^1-4和R^1-5独立地为羟基。In one embodiment, each of R ^1-4 and R ^1-5 is independently hydroxy.

在某一方案中，X为-CR^1-6R^1-7-或-NR^1-8-；较佳地为-CR^1-6R^1-7-。In one embodiment, X is -CR ^1-6 R ^1-7 - or -NR ^1-8 -; preferably -CR ^1-6 R ^1-7 -.

在某一方案中，R^1-6和R^1-7独立地为氢或未取代的C₁-C₆的烷基；较佳地为氢。In one embodiment, R ^1-6 and R ^1-7 are independently hydrogen or unsubstituted C ₁ -C ₆ alkyl; preferably hydrogen.

在某一方案中，R^1-8为未取代的C₁-C₆的烷基。In one embodiment, R ^1-8 is an unsubstituted C ₁ -C ₆ alkyl group.

在某一方案中，R²和R³与其相连的原子形成未取代或被1个或多个R^2-1取代的5-6元的杂芳基、未取代或被1个或多个R^2-2取代的4-6元的杂环烷基、未取代或被1个或多个R^2-3取代的C₄-C₆的环烷基或未取代的C₆-C₁₀的芳基；较佳地为未取代或被1个或多个R^2-1取代的5-6元的杂芳基、未取代或被1个或多个R^2-2取代的4-6元的杂环烷基或未取代或被1个或多个R^2-3取代的C₄-C₆的环烷基；进一步较佳地为未取代或被1个或多个R^2-1取代的5-6元的杂芳基、未取代或被1个或多个R^2-2取代的4-6元的杂环烷基或未取代的C₄-C₆的环烷基；更进一步较佳地为未取代或被1个或多个R^2-1取代的5-6元的杂芳基、未取代的4-6元的杂环烷基或未取代的C₄-C₆的环烷基；还可更进一步较佳地为未取代的4-6元的杂环烷基或未取代的C₄-C₆的环烷基；所述5-6元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个；所述4-6元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个。In a certain embodiment, ^R2 and ^R3 and the atoms to which they are connected form a 5-6-membered heteroaryl group which is unsubstituted or substituted by one or more ^R2-1 , a 4-6-membered heterocycloalkyl group which is unsubstituted or substituted by one or more ^R2-2 , a _C4 - _C6 cycloalkyl group which is unsubstituted or substituted by one or more ^R2-3 , or an unsubstituted C6- _C10 aryl group; preferably, a 5-6-membered heteroaryl group which is unsubstituted or substituted by one or more _R2-1 , a 4-6- ^membered heterocycloalkyl group which is unsubstituted or substituted by one or more ^R2-2 , or a _C4 - _C6 cycloalkyl group which is unsubstituted or substituted by one or more ^R2-3 ; further preferably, a 5-6-membered heteroaryl group which is unsubstituted or substituted by one or more ^R2-1 , a 4-6-membered heterocycloalkyl group which is unsubstituted or substituted by one or more ^R2-2 , or an unsubstituted C4- _C6 cycloalkyl group R _2-1 ; preferably, a 5-6-membered heteroaryl, an unsubstituted 4-6-membered heterocycloalkyl or an unsubstituted C 4 -C 6 cycloalkyl which is unsubstituted or substituted _by one or more R ^2-1 ; and preferably, an unsubstituted 4-6-membered heterocycloalkyl or an unsubstituted C ₄ _-C ₆ 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 the 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 the heteroatoms is 1, 2 or 3.

在某一方案中，各个R^2-1独立地为卤素、未取代或被1个或多个R^2-1-1取代的C₁-C₆的烷基或氧代基(＝O)；较佳地为卤素或未取代的C₁-C₆的烷基；进一步较佳地为未取代的C₁-C₆的烷基。In one embodiment, each R ^2-1 is independently halogen, unsubstituted or substituted C ₁ -C 6 alkyl or oxo (═O) with one or more R ^2-1-1 ; preferably _halogen or unsubstituted C ₁ -C ₆ alkyl; more preferably unsubstituted C ₁ -C ₆ alkyl.

在某一方案中，各个R^2-2独立地为卤素、未取代的C₁-C₆的烷基、氧代基(＝O)，或者，两个R^2- ²和与之相连的碳原子形成C₃-C₆的环烷基；较佳地为氧代基(＝O)，或者，两个R^2-2和与之相连的碳原子形成C₃-C₆的环烷基；进一步较佳地为氧代基(＝O)。In a certain embodiment, each R ^2-2 is independently halogen, unsubstituted C ₁ -C ₆ alkyl, oxo (=O), or two ^R ^2-2 and the carbon atom to which they are attached form a C ₃ -C ₆ cycloalkyl; preferably oxo (=O), or two R ^2-2 and the carbon atom to which they are attached form a C ₃ -C ₆ cycloalkyl; further preferably oxo (=O).

在某一方案中，各个R^2-2独立地为卤素、未取代的C₁-C₆的烷基或氧代基(＝O)；较佳地为卤素。In one embodiment, each R ^2-2 is independently halogen, unsubstituted C ₁ -C ₆ alkyl or oxo (═O); preferably halogen.

在某一方案中，各个R^2-3独立地为氧代基(＝O)。In one embodiment, each R ^2-3 is independently oxo (=O).

在某一方案中，R^2-1-1为羟基。In one embodiment, R ^2-1-1 is hydroxy.

在某一方案中，A为未取代的C₆-C₁₀的亚芳基、未取代的5-12元的亚杂环烷基或未取代的5-12元的亚杂芳基；较佳地为未取代的5-12元的亚杂芳基；所述5-12元的亚杂环烷基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个；所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个。In a certain embodiment, A is an unsubstituted C ₆ -C ₁₀ arylene group, an unsubstituted 5-12 membered heterocycloalkylene group or an unsubstituted 5-12 membered heteroarylene group; preferably an unsubstituted 5-12 membered heteroarylene group; 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; 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.

在某一方案中，L为连接健或未取代的C₂-C₆的亚烯基；较佳地为连接健。In one embodiment, L is a linker or an unsubstituted C ₂ -C ₆ alkenylene; preferably, it is a linker.

在某一方案中，Q为未取代的C₆-C₁₀的亚芳基、未取代或被一个或多个R^3-1取代的5-12元的亚杂芳基或未取代的5-12元的亚杂环烷基；较佳地为未取代或被一个或多个R^3-1取代的5-12元的亚杂芳基或未取代的5-12元的亚杂环烷基；进一步较佳地为未取代的5-12元的亚杂芳基或未取代的5-12元的亚杂环烷基；所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个；所述5-12元的亚杂环烷基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个。In a certain embodiment, Q is an unsubstituted C ₆ -C ₁₀ arylene group, an unsubstituted or substituted ^5-12 -membered heteroarylene group, or an unsubstituted 5-12-membered heterocycloalkylene group; preferably, an unsubstituted or 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.

在某一方案中，各个R^3-1独立地为卤素。 In one embodiment, each R ^3-1 is independently halogen.

在某一方案中，R⁴为未取代或被一个或多个R^4-1取代的C₁-C₆的烷基、未取代的C₂-C₆的炔基、未取代或被一个或多个R^4-4取代的C₃-C₆的环烷基、未取代或被一个或多个R^4-5取代的4-12元的杂环烷基、未取代或被一个或多个R^4-6取代的5-12元的杂芳基、未取代的C₁-C₆的烷氧基或-NR^4-9R^4-8；较佳地为被一个或多个R^4-1取代的C₁-C₆的烷基、未取代的C₂-C₆的炔基、未取代的C₃-C₆的环烷基、未取代或被一个或多个R^4-5取代的4-12元的杂环烷基、未取代或被一个或多个R^4-6取代的5-12元的杂芳基或未取代的C₁-C₆的烷氧基；进一步较佳地为未取代的C₂-C₆的炔基、未取代的C₃-C₆的环烷基、被一个或多个R^4-5取代的4-12元的杂环烷基、被一个或多个R^4-6取代的5-12元的杂芳基或未取代的C₁-C₆的烷氧基；更进一步较佳地为未取代的C₂-C₆的炔基、未取代的C₃-C₆的环烷基或被一个或多个R^4-6取代的5-12元的杂芳基；所述4-12元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个；所述5-12元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个。In a certain embodiment, ^R4 is _C1 - _C6 alkyl which is unsubstituted or substituted by one or more ^R4-1 , unsubstituted _C2 - _C6 alkynyl, _C3 - _C6 cycloalkyl which is unsubstituted or substituted by one or more ^R4-4 , 4-12-membered heterocycloalkyl which is unsubstituted or substituted by one or more ^R4-5 , 5-12-membered heteroaryl which is unsubstituted or substituted by one or more ^R4-6 , unsubstituted C1- _C6 alkoxy or ^-NR4-9R4-8 ; preferably _C1 - _C6 alkyl which is substituted by one or more ^R4-1 , unsubstituted _C2 _-C6 _alkynyl , unsubstituted _C3 - _C6 cycloalkyl, 4-12-membered heterocycloalkyl which is unsubstituted or substituted by one or more ^R4-5 , ^5-12 -membered heteroaryl which is unsubstituted or substituted by one or more ^R4-6 , or unsubstituted _C1 -C The present invention is preferably an unsubstituted C2- _C6 alkoxy group; further preferably an unsubstituted _C2 - _C6 alkynyl group, an unsubstituted _C3 - _C6 cycloalkyl group, a 4-12-membered heterocycloalkyl group substituted by one or more ^R4-5 , a 5-12-membered heteroaryl group substituted by one or more ^R4-6 , or an unsubstituted _C1 - _C6 alkoxy group; further preferably an unsubstituted _C2 - _C6 alkynyl group, an unsubstituted _C3 - _C6 cycloalkyl group, or a 5-12-membered heteroaryl group substituted by one or more ^R4-6 ; 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.

在某一方案中，各个R^4-1独立地为未取代的C₁-C₆的烷氧基。In one embodiment, each R ^4-1 is independently an unsubstituted C ₁ -C ₆ alkoxy group.

在某一方案中，各个R^4-4独立地为卤素。In one embodiment, each R ^4-4 is independently halogen.

在某一方案中，各个R^4-5独立地为羟基、未取代或被一个或多个R^4-5-1取代的C₁-C₆的烷基、-NR^4-5-2R^4-5-3或未取代的C₁-C₆的烷氧基；较佳地为未取代或被一个或多个R^4-5-1取代的C₁-C₆的烷基或未取代的C₁-C₆的烷氧基；进一步较佳地为未取代的C₁-C₆的烷氧基。In a certain embodiment, each R ^4-5 is independently hydroxyl, C ₁ -C ₆ alkyl which is unsubstituted or substituted by one or more R ^4-5-1 , -NR ^4-5-2 R ^4-5-3 , or unsubstituted C ₁ -C ₆ alkoxy; preferably C ₁ -C ₆ alkyl which is unsubstituted or substituted by one or more R ^4-5-1 , or unsubstituted C ₁ -C ₆ alkoxy; further preferably unsubstituted C ₁ -C ₆ alkoxy.

在某一方案中，各个R^4-5-1独立地为羟基。In one embodiment, each R ^4-5-1 is independently hydroxyl.

在某一方案中，R^4-5-2和R^4-5-3独立地为未取代的C₁-C₆的烷基。In one embodiment, R ^4-5-2 and R ^4-5-3 are independently unsubstituted C ₁ -C ₆ alkyl.

在某一方案中，各个R^4-6独立地为氰基、卤素或未取代的C₁-C₆的烷基；较佳地为氰基或未取代的C₁-C₆的烷基。In one embodiment, each R ^4-6 is independently cyano, halogen or unsubstituted C ₁ -C ₆ alkyl; preferably cyano or unsubstituted C ₁ -C ₆ alkyl.

在某一方案中，R^4-9和R^4-8独立地为未取代或被一个或多个R^4-8-1取代的C₁-C₆的烷基或未取代的4-6元的杂环烷基；所述4-6元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个。In a certain embodiment, R ^4-9 and R ^4-8 are independently C ₁ -C ₆ alkyl or unsubstituted 4-6 membered heterocycloalkyl which is unsubstituted or substituted by one or more R ^4-8-1 ; 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.

在某一方案中，各个R^4-8-1独立地为OR^4-8-1-2。In one embodiment, each R ^4-8-1 is independently OR ^4-8-1-2 .

在某一方案中，各个R^4-8-1-2独立地为未取代的C₃-C₆的环烷基。In one embodiment, each R ^4-8-1-2 is independently an unsubstituted C ₃ -C ₆ cycloalkyl.

在某一方案中，In one plan,

Y为C或N；Y is C or N;

R¹为被1个或多个R^1-3取代的C₁-C₆的烷基、未取代或被1个或多个R^1-4取代的C₃-C₆的环烷基或未取代或被1个或多个R^1-5取代的3-6元的杂环烷基，所述3-6元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个； ^R1 is C ₁ -C ₆ alkyl substituted by one or more R ^1-3 , C ₃ -C 6 cycloalkyl unsubstituted or substituted by one or more R ^1-4 , or _3-6 membered heterocycloalkyl unsubstituted or substituted by one or more R ^1-5 , wherein 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为未取代或被1个或多个R^1-1-1取代的C₁-C₆的烷基、未取代的C₃-C₆的环烷基或-NR^1-1-2R^1-1- ³； R ^1-1 is C ₁ -C ₆ alkyl, unsubstituted C ₃ -C ₆ cycloalkyl or -NR ^1-1-2 R ^1-1- ³ which is unsubstituted or substituted by one or more R ^1-1-1 ;

R^1-2为O或NR^1-2-1；R^1-2-1为氢；R ^1-2 is O or NR ^1-2-1 ; R ^1-2-1 is hydrogen;

各个R^1-1-1独立地为OR^1-1-1-1、未取代的C₁-C₆的烷基或未取代的C₁-C₆的烷氧基；Each R ^1-1-1 is independently OR ^1-1-1-1 , an unsubstituted C ₁ -C ₆ alkyl group or an unsubstituted C ₁ -C ₆ alkoxy group;

R^1-1-1-1为氢或未取代的C₁-C₆的烷基；R ^1-1-1-1 is hydrogen or unsubstituted C ₁ -C ₆ alkyl;

R^1-1-2和R^1-1-3独立地为氢或未取代的C₁-C₆的烷基；R ^1-1-2 and R ^1-1-3 are independently hydrogen or unsubstituted C ₁ -C ₆ alkyl;

各个R^1-3独立地为羟基、氰基、卤素、氨基、未取代的C₁-C₆的烷基或氘；Each R ^1-3 is independently hydroxy, cyano, halogen, amino, unsubstituted C ₁ -C ₆ alkyl or deuterium;

各个R^1-4和R^1-5独立地为羟基；Each of R ^1-4 and R ^1-5 is independently hydroxyl;

X为-CR^1-6R^1-7-或-NR^1-8-；X is -CR ^1-6 R ^1-7 - or -NR ^1-8 -;

R^1-6和R^1-7独立地为氢或未取代的C₁-C₆的烷基；R ^1-6 and R ^1-7 are independently hydrogen or unsubstituted C ₁ -C ₆ alkyl;

R^1-8为未取代的C₁-C₆的烷基；R ^1-8 is an unsubstituted C ₁ -C ₆ alkyl group;

R²和R³与其相连的原子形成未取代或被1个或多个R^2-1取代的5-6元的杂芳基、未取代或被1个或多个R^2-2取代的4-6元的杂环烷基、未取代或被1个或多个R^2-3取代的C₄-C₆的环烷基或未取代的C₆-C₁₀的芳基；所述5-6元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个；所述4-6元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个； ^R2 and ^R3 and the atoms connected thereto form a 5-6 membered heteroaryl group which is unsubstituted or substituted by one or more ^R2-1 , a 4-6 membered heterocycloalkyl group which is unsubstituted or substituted by one or more ^R2-2 , a _C4 - _C6 cycloalkyl group which is unsubstituted or substituted by one or more ^R2-3 , or an unsubstituted _C6 - _C10 aryl group; 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 the 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 the heteroatoms is 1, 2 or 3;

各个R^2-1独立地为卤素、未取代或被1个或多个R^2-1-1取代的C₁-C₆的烷基或氧代基(＝O)；Each R ^2-1 is independently halogen, C ₁ -C ₆ alkyl which is unsubstituted or substituted by one or more R ^2-1-1 , or oxo (═O);

各个R^2-2独立地为卤素、未取代的C₁-C₆的烷基、氧代基(＝O)，或者，两个R^2-2和与之相连的碳原子形成C₃-C₆的环烷基；Each R ^2-2 is independently halogen, unsubstituted C ₁ -C ₆ alkyl, oxo (=O), or two R ^2-2 and the carbon atom to which they are attached form a C ₃ -C ₆ cycloalkyl;

各个R^2-3独立地为氧代基(＝O)；Each R ^2-3 is independently oxo (=O);

R^2-1-1为羟基；R ^2-1-1 is a hydroxyl group;

A为未取代的C₆-C₁₀的亚芳基、未取代的5-12元的亚杂环烷基或未取代的5-12元的亚杂芳基；所述5-12元的亚杂环烷基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个；所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个；A is an unsubstituted C ₆ -C ₁₀ arylene group, an unsubstituted 5-12-membered heterocycloalkylene group or an unsubstituted 5-12-membered heteroarylene group; 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; 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;

L为连接健或未取代的C₂-C₆的亚烯基；L is a linker or an unsubstituted C ₂ -C ₆ alkenylene group;

Q为未取代的C₆-C₁₀的亚芳基、未取代或被一个或多个R^3-1取代的5-12元的亚杂芳基或未取代的5-12元的亚杂环烷基；所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个；所述5-12元的亚杂环烷基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个；Q is an unsubstituted C ₆ -C ₁₀ arylene group, an unsubstituted or one or more R ^3-1 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;

各个R^3-1独立地为卤素；Each R ^3-1 is independently halogen;

R⁴为未取代或被一个或多个R^4-1取代的C₁-C₆的烷基、未取代的C₂-C₆的炔基、未取代或被一个或多个R^4-4取代的C₃-C₆的环烷基、未取代或被一个或多个R^4-5取代的4-12元的杂环烷基、未取代或被一个或多个R^4-6取代的5-12元的杂芳基、未取代的C₁-C₆的烷氧基或-NR^4-9R^4-8；所述4-12元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个；所述5-12元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个； R ⁴ is C ₁ -C ₆ alkyl which is unsubstituted or substituted by one or more R ^4-1 , unsubstituted C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl which is unsubstituted or substituted by one or more R ^4-4 , 4-12-membered heterocycloalkyl which is unsubstituted or substituted by one or more R ^4-5 , 5-12-membered heteroaryl which is unsubstituted or substituted by one or more R ^4-6 , unsubstituted C ₁ -C ₆ alkoxy or -NR ^4-9 R ^4-8 ; 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;

各个R^4-1独立地为未取代的C₁-C₆的烷氧基；Each R ^4-1 is independently an unsubstituted C ₁ -C ₆ alkoxy group;

各个R^4-4独立地为卤素；Each R ^4-4 is independently halogen;

各个R^4-5独立地为羟基、未取代或被一个或多个R^4-5-1取代的C₁-C₆的烷基、-NR^4-5-2R^4-5-3或未取代的C₁-C₆的烷氧基；Each R ^4-5 is independently hydroxy, C ₁ -C ₆ alkyl which is unsubstituted or substituted by one or more R ^4-5-1 , -NR ^4-5-2 R ^4-5-3 or unsubstituted C ₁ -C ₆ alkoxy;

各个R^4-5-1独立地为羟基；Each R ^4-5-1 is independently hydroxyl;

R^4-5-2和R^4-5-3独立地为未取代的C₁-C₆的烷基；R ^4-5-2 and R ^4-5-3 are independently unsubstituted C ₁ -C ₆ alkyl groups;

各个R^4-6独立地为氰基、卤素或未取代的C₁-C₆的烷基；较佳地为氰基或未取代的C₁-C₆的烷基；Each R ^4-6 is independently cyano, halogen or unsubstituted C ₁ -C ₆ alkyl; preferably cyano or unsubstituted C ₁ -C ₆ alkyl;

R^4-9和R^4-8独立地为未取代或被一个或多个R^4-8-1取代的C₁-C₆的烷基或未取代的4-6元的杂环烷基；所述4-6元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个；R ^4-9 and R ^4-8 are independently C ₁ -C ₆ alkyl or unsubstituted 4-6 membered heterocycloalkyl which is unsubstituted or substituted by one or more R ^4-8-1 ; 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;

各个R^4-8-1独立地为OR^4-8-1-2；Each R ^4-8-1 is independently OR ^4-8-1-2 ;

各个R^4-8-1-2独立地为未取代的C₃-C₆的环烷基。Each R ^4-8-1-2 is independently an unsubstituted C ₃ -C ₆ cycloalkyl group.

在某一方案中，In one plan,

Y为C或N；Y is C or N;

R¹为被1个或多个R^1-3取代的C₁-C₆的烷基或未取代或被1个或多个R^1-4取代的C₃-C₆的环烷基； ^R1 is C ₁ -C ₆ alkyl substituted by 1 or more R ^1-3 or C ₃ -C ₆ cycloalkyl unsubstituted or substituted by 1 or more R ^1-4 ;

R^1-1为未取代或被1个或多个R^1-1-1取代的C₁-C₆的烷基或-NR^1-1-2R^1-1-3；R ^1-1 is a C ₁ -C ₆ alkyl group which is unsubstituted or substituted by one or more R ^1-1-1 or -NR ^1-1-2 R ^1-1-3 ;

各个R^1-1-1独立地为OR^1-1-1-1或未取代的C₁-C₆的烷基；Each R ^1-1-1 is independently OR ^1-1-1-1 or an unsubstituted C ₁ -C ₆ alkyl group;

各个R^1-3独立地为羟基、氰基、卤素、未取代的C₁-C₆的烷基或氘；Each R ^1-3 is independently hydroxy, cyano, halogen, unsubstituted C ₁ -C ₆ alkyl or deuterium;

各个R^1-4为羟基；Each R ^1-4 is hydroxyl;

X为-CR^1-6R^1-7-或-NR^1-8-；X is -CR ^1-6 R ^1-7 - or -NR ^1-8 -;

R²和R³与其相连的原子形成未取代或被1个或多个R^2-1取代的5-6元的杂芳基、未取代或被1个或多个R^2-2取代的4-6元的杂环烷基或未取代或被1个或多个R^2-3取代的C₄-C₆的环烷基；所述5-6元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个；所述4-6元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个；较佳地，所述4-6元的杂环烷基中的杂原子为N或O，杂原子数为1个或2个； ^R2 and ^R3 and the atoms connected thereto form a 5-6 membered heteroaryl group which is unsubstituted or substituted by one or more ^R2-1 , a 4-6 membered heterocycloalkyl group which is unsubstituted or substituted by one or more ^R2-2 , or a _C4 - _C6 cycloalkyl group which is unsubstituted or substituted by one or more ^R2-3 ; 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; preferably, the heteroatoms in the 4-6 membered heterocycloalkyl group are N or O, and the number of heteroatoms is 1 or 2;

各个R^2-1独立地为卤素或未取代的C₁-C₆的烷基； Each R ^2-1 is independently halogen or unsubstituted C ₁ -C ₆ alkyl;

各个R^2-3独立地为氧代基(＝O)；Each R ^2-3 is independently oxo (=O);

A为未取代的5-12元的亚杂芳基，所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个；较佳地，所述5-12元的亚杂芳基中的杂原子独立地选自N和S中的一种或两种，杂原子数为1个、2个或3个；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;

Q为未取代或被一个或多个R^3-1取代的5-12元的亚杂芳基或未取代的5-12元的亚杂环烷基；所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个；所述5-12元的亚杂环烷基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个；较佳地，所述5-12元的亚杂芳基中的杂原子为N，杂原子数为1个、2个或3个；所述5-12元的亚杂环烷基中的杂原子独立地选自N和O中的一种或两种，杂原子数为1个、2个或3个；Q is a 5-12-membered heteroarylene group or an unsubstituted 5-12-membered heterocycloalkylene group which is unsubstituted or substituted by one or more R ^3-1 ; 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;

各个R^3-1独立地为卤素；Each R ^3-1 is independently halogen;

R⁴为被一个或多个R^4-1取代的C₁-C₆的烷基、未取代的C₂-C₆的炔基、未取代的C₃-C₆的环烷基、未取代或被一个或多个R^4-5取代的4-12元的杂环烷基、未取代或被一个或多个R^4-6取代的5-12元的杂芳基或未取代的C₁-C₆的烷氧基；所述4-12元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个；所述5-12元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个；较佳地，R⁴为被一个或多个R^4-1取代的C₁-C₆的烷基、未取代的C₂-C₆的炔基、未取代的C₃-C₆的环烷基、未取代或被一个或多个R^4-5取代的4-6元的杂环烷基、未取代或被一个或多个R^4-6取代的5-6元的杂芳基或未取代的C₁-C₆的烷氧基；所述4-6元的杂环烷基中的杂原子独立地选自N和O中的一种或两种，杂原子数为1个或2个；所述5-6元的杂芳基中的杂原子为N，杂原子数为1个或2个；R ⁴ is a C ₁ -C ₆ alkyl group substituted by one or more R ^4-1 , an unsubstituted C ₂ -C ₆ alkynyl group, an unsubstituted C ₃ -C ₆ cycloalkyl group, a 4-12-membered heterocycloalkyl group unsubstituted or substituted by one or more R ^4-5 , a 5-12-membered heteroaryl group unsubstituted or substituted by one or more R ^4-6 , or an unsubstituted C ₁ -C ₆ alkoxy group; 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; preferably, R ⁴ is a C ₁ -C ₆ alkyl group substituted by one or more R ^4-1 , an unsubstituted C ₂ -C ₆ alkynyl group, an unsubstituted C ₃ -C ₆ cycloalkyl group, an unsubstituted or substituted by one or more R ^4-5 substituted 4-6 membered heterocycloalkyl, unsubstituted or substituted by one or more R ^4-6 membered heteroaryl, or unsubstituted C ₁ -C ₆ alkoxy; the heteroatom in the 4-6 membered heterocycloalkyl is 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 or 2;

R^4-1独立地为未取代的C₁-C₆的烷氧基；R ^4-1 is independently an unsubstituted C ₁ -C ₆ alkoxy group;

各个R^4-5独立地为未取代或被一个或多个R^4-5-1取代的C₁-C₆的烷基或未取代的C₁-C₆的烷氧基；Each R ^4-5 is independently a C ₁ -C ₆ alkyl group or an unsubstituted C ₁ -C ₆ alkoxy group which is unsubstituted or substituted by one or more R ^4-5-1 ;

各个R^4-5-1独立地为羟基；Each R ^4-5-1 is independently hydroxyl;

各个R^4-6独立地为氰基、卤素或未取代的C₁-C₆的烷基。Each R ^4-6 is independently cyano, halogen or unsubstituted C ₁ -C ₆ alkyl.

在某一方案中，In one plan,

Y为C或N；Y is C or N;

R^1-2为O或NR^1-2-1；R^1-2-1为氢； R ^1-2 is O or NR ^1-2-1 ; R ^1-2-1 is hydrogen;

R^1-1-1-1为未取代的C₁-C₆的烷基；R ^1-1-1-1 is an unsubstituted C ₁ -C ₆ alkyl group;

各个R^1-3独立地为羟基、氰基、卤素或未取代的C₁-C₆的烷基；Each R ^1-3 is independently hydroxy, cyano, halogen or unsubstituted C ₁ -C ₆ alkyl;

各个R^1-4为羟基；Each R ^1-4 is hydroxyl;

X为-CR^1-6R^1-7-或-NR^1-8-；X is -CR ^1-6 R ^1-7 - or -NR ^1-8 -;

各个R^2-1独立地为未取代的C₁-C₆的烷基；Each R ^2-1 is independently an unsubstituted C ₁ -C ₆ alkyl group;

各个R^2-3独立地为氧代基(＝O)；Each R ^2-3 is independently oxo (=O);

各个R^3-1独立地为卤素；Each R ^3-1 is independently halogen;

R⁴为被一个或多个R^4-1取代的C₁-C₆的烷基、未取代的C₂-C₆的炔基、未取代的C₃-C₆的环烷基、未取代或被一个或多个R^4-5取代的4-12元的杂环烷基、未取代或被一个或多个R^4-6取代的5-12元的杂芳基或未取代的C₁-C₆的烷氧基；所述4-12元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个；所述5-12元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个；较佳地，R⁴为被一个或多个R^4-1取代的C₁-C₆的烷基、未取代的C₂-C₆的炔基、未取代的C₃-C₆的环烷基、未取代或被一个或多个R^4-5取代的4-6元的杂环烷基、未取代或被一个或多个R^4-6取代的5-6元的杂芳基或未取代的C₁-C₆的烷氧基；所述4-6元的杂环烷基中的杂原子独立地选自N和O中的一种或两种，杂原子数为1个或2个；所述5-6元的杂芳基中的杂原子为N，杂原子数为1个或2个；R ⁴ is a C ₁ -C ₆ alkyl group substituted by one or more R ^4-1 , an unsubstituted C ₂ -C ₆ alkynyl group, an unsubstituted C ₃ -C ₆ cycloalkyl group, a 4-12-membered heterocycloalkyl group unsubstituted or substituted by one or more R ^4-5 , a 5-12-membered heteroaryl group unsubstituted or substituted by one or more R ^4-6 , or an unsubstituted C ₁ -C ₆ alkoxy group; 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; preferably, R ⁴ is a C ₁ -C ₆ alkyl group substituted by one or more R ^4-1 , an unsubstituted C ₂ -C ₆ alkynyl group, an unsubstituted C ₃ -C ₆ cycloalkyl group, an unsubstituted or substituted by one or more R ^4-5 substituted 4-6 membered heterocycloalkyl, unsubstituted or 5-6 membered heteroaryl substituted by one or more R ^4-6 , or unsubstituted C ₁ -C ₆ alkoxy; the 4-6 membered The heteroatoms in the 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;

各个R^4-5-1独立地为羟基；Each R ^4-5-1 is independently hydroxyl;

在某一方案中，In one plan,

Y为C或N；Y is C or N;

各个R^1-4为羟基；Each R ^1-4 is hydroxyl;

X为-CR^1-6R^1-7-或-NR^1-8-；X is -CR ^1-6 R ^1-7 - or -NR ^1-8 -;

各个R^2-3独立地为氧代基(＝O)；Each R ^2-3 is independently oxo (=O);

A为未取代的5-12元的亚杂芳基，所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个；较佳地，所述5-12元的亚杂芳基中的杂原子独立地选自N和S中的一种或两种，杂原子数为1个、2个或3个； 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;

各个R^3-1独立地为卤素；Each R ^3-1 is independently halogen;

各个R^4-5-1独立地为羟基；Each R ^4-5-1 is independently hydroxyl;

各个R^4-6独立地为氰基或未取代的C₁-C₆的烷基。Each of R ^4-6 is independently cyano or unsubstituted C ₁ -C ₆ alkyl.

在某一方案中，In one plan,

Y为C；Y is C;

各个R^1-1-1独立地为未取代的C₁-C₆的烷基；Each R ^1-1-1 is independently an unsubstituted C ₁ -C ₆ alkyl group;

各个R^1-3独立地为羟基或卤素；Each R ^1-3 is independently hydroxy or halogen;

各个R^1-4为羟基；Each R ^1-4 is hydroxyl;

X为-CR^1-6R^1-7-或-NR^1-8-；X is -CR ^1-6 R ^1-7 - or -NR ^1-8 -;

R^1-6和R^1-7独立地为氢或未取代的C₁-C₆的烷基； R ^1-6 and R ^1-7 are independently hydrogen or unsubstituted C ₁ -C ₆ alkyl;

R²和R³与其相连的原子形成未取代或被1个或多个R^2-1取代的5-6元的杂芳基、未取代或被1个或多个R^2-2取代的4-6元的杂环烷基或未取代的C₄-C₆的环烷基；所述5-6元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个；所述4-6元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个；较佳地，所述5-6元的杂芳基中的杂原子独立地选自N和S中的一种或两种；杂原子数为1个或2个；所述4-6元的杂环烷基中的杂原子为N或O，杂原子数为1个或2个； ^R2 and ^R3 and the atoms connected thereto form a 5-6 membered heteroaryl group which is unsubstituted or substituted by one or more ^R2-1 , a 4-6 membered heterocycloalkyl group which is unsubstituted or substituted by one or more ^R2-2 , or an unsubstituted _C4 - _C6 cycloalkyl group; 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; preferably, the heteroatoms in the 5-6 membered heteroaryl group 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 group are N or O, and the number of heteroatoms is 1 or 2;

各个R^2-2独立地为氧代基(＝O)，或者，两个R^2-2和与之相连的碳原子形成C₃-C₆的环烷基；Each R ^2-2 is independently an oxo group (=O), or two R ^2-2 and the carbon atom to which they are attached form a C ₃ -C ₆ cycloalkyl group;

A为未取代的5-12元的亚杂芳基；所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个；较佳地，所述5-12元的亚杂芳基中的杂原子独立地选自N和S中的一种或两种，杂原子数为1个、2个或3个；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;

Q为未取代的5-12元的亚杂芳基或未取代的5-12元的亚杂环烷基；所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个；所述5-12元的亚杂环烷基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个；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;

R⁴为未取代的C₂-C₆的炔基、未取代的C₃-C₆的环烷基、被一个或多个R^4-5取代的4-12元的杂环烷基、被一个或多个R^4-6取代的5-12元的杂芳基或未取代的C₁-C₆的烷氧基；所述4-12元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个；所述5-12元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个；较佳地，R⁴为未取代的C₂-C₆的炔基、未取代的C₃-C₆的环烷基、被一个或多个R^4-5取代的4-6元的杂环烷基、被一个或多个R^4-6取代的5-6元的杂芳基或未取代的C₁-C₆的烷氧基；所述4-6元的杂环烷基中的杂原子独立地选自N和O中的一种或两种，杂原子数为1个或2个；所述5-6元的杂芳基中的杂原子为N，杂原子数为1个； ^R4 is an unsubstituted _C2 - _C6 alkynyl, an unsubstituted _C3 - _C6 cycloalkyl, a 4-12-membered heterocycloalkyl substituted by one or more ^R4-5 , a 5-12-membered heteroaryl substituted by one or more ^R4-6 , or an unsubstituted _C1 - _C6 alkoxyl group; 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, ^R4 is an unsubstituted _C2 - _C6 alkynyl, an unsubstituted C3- _C6 cycloalkyl, a _4-6 -membered heterocycloalkyl substituted by one or more ^R4-5 , a 5-6-membered heteroaryl substituted by one or more ^R4-6 , or an unsubstituted _C1 -C6 alkoxyl group; The heteroatom in _the 4-6 membered heterocycloalkyl is 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;

各个R^4-5独立地为未取代的C₁-C₆的烷基；Each R ^4-5 is independently an unsubstituted C ₁ -C ₆ alkyl group;

在某一方案中，In one plan,

Y为C；Y is C;

R^1-1为未取代或被1个或多个R^1-1-1取代的C₁-C₆的烷基；R ^1-1 is a C ₁ -C ₆ alkyl group which is unsubstituted or substituted by one or more R ^1-1-1 ;

R^1-2为O； R ^1-2 is O;

各个R^1-3独立地为卤素；Each R ^1-3 is independently halogen;

各个R^1-4为羟基；Each R ^1-4 is hydroxyl;

X为-CR^1-6R^1-7-或-NR^1-8-；X is -CR ^1-6 R ^1-7 - or -NR ^1-8 -;

R^1-6和R^1-7独立地为氢；R ^1-6 and R ^1-7 are independently hydrogen;

R²和R³与其相连的原子形成未取代或被1个或多个R^2-1取代的5-6元的杂芳基、未取代或被1个或多个R^2-2取代的4-6元的杂环烷基或未取代的C₄-C₆的环烷基；所述5-6元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个；所述4-6元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个；较佳地，所述5-6元的杂芳基中的杂原子为N；杂原子数为1个或2个；所述4-6元的杂环烷基中的杂原子为N或O，杂原子数为1个或2个； ^R2 and ^R3 and the atoms connected thereto form a 5-6 membered heteroaryl group which is unsubstituted or substituted by one or more ^R2-1 , a 4-6 membered heterocycloalkyl group which is unsubstituted or substituted by one or more ^R2-2 , or an unsubstituted _C4 - _C6 cycloalkyl group; 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; preferably, the heteroatom in the 5-6 membered heteroaryl group is N, and the number of heteroatoms is 1 or 2; the heteroatom in the 4-6 membered heterocycloalkyl group is N or O, and the number of heteroatoms is 1 or 2;

各个R^2-2独立地为氧代基(＝O)；Each R ^2-2 is independently oxo (=O);

Q为未取代的5-12元的亚杂芳基或未取代的5-12元的亚杂环烷基；所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个；所述5-12元的亚杂环烷基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个；较佳地，Q为未取代的5-6元的亚杂芳基或未取代的5-12元的亚杂环烷基；所述5-6元的亚杂芳基中的杂原子为N，杂原子数为1个；所述5-12元的亚杂环烷基中的杂原子独立地选自N和O中的一种或两种，杂原子数为1个、2个或3个；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;

各个R^4-6独立地为氰基或未取代的C₁-C₆的烷基。 Each of R ^4-6 is independently cyano or unsubstituted C ₁ -C ₆ alkyl.

在某一方案中，In one plan,

Y为C；Y is C;

R¹为或未取代或被1个或多个R^1-3取代的C₁-C₆的烷基； ^R1 is or C ₁ -C ₆ alkyl which is unsubstituted or substituted by one or more R ^1-3 ;

R^1-2为O；R ^1-2 is O;

各个R^1-1-1独立地为OR^1-1-1-1；Each R ^1-1-1 is independently OR ^1-1-1-1 ;

各个R^1-3独立地为羟基、卤素、未取代的C₁-C₆的烷基或氘；Each R ^1-3 is independently hydroxy, halogen, unsubstituted C ₁ -C ₆ alkyl or deuterium;

X为-CR^1-6R^1-7-；X is -CR ^1-6 R ^1-7 -;

R^1-6和R^1-7独立地为氢；R ^1-6 and R ^1-7 are independently hydrogen;

R²和R³与其相连的原子形成未取代或被1个或多个R^2-1取代的5-6元的杂芳基、未取代或被1个或多个R^2-2取代的4-6元的杂环烷基或未取代的C₄-C₆的环烷基；所述5-6元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个；所述4-6元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个；较佳地，所述4-6元的杂环烷基中的杂原子为O；杂原子数为1个或2个； ^R2 and ^R3 and the atoms connected thereto form a 5-6 membered heteroaryl group which is unsubstituted or substituted by one or more ^R2-1 , a 4-6 membered heterocycloalkyl group which is unsubstituted or substituted by one or more ^R2-2 , or an unsubstituted _C4 - _C6 cycloalkyl group; 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; preferably, the heteroatom in the 4-6 membered heterocycloalkyl group is O; the number of heteroatoms is 1 or 2;

各个R^2-1独立地为卤素或未取代的C₁-C₆的烷基；Each R ^2-1 is independently halogen or unsubstituted C ₁ -C ₆ alkyl;

各个R^2-2独立地为卤素、未取代的C₁-C₆的烷基或氧代基(＝O)；Each R ^2-2 is independently halogen, unsubstituted C ₁ -C ₆ alkyl or oxo (=O);

A为未取代的5-12元的亚杂芳基；所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个；较佳地，所述5-12元的亚杂芳基中的杂原子为N，杂原子数为1个或2个；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;

各个R^3-1独立地为卤素；Each R ^3-1 is independently halogen;

R⁴为未取代的C₂-C₆的炔基、未取代的C₃-C₆的环烷基、被一个或多个R^4-5取代的4-12元的杂环烷基、被一个或多个R^4-6取代的5-12元的杂芳基或未取代的C₁-C₆的烷氧基；所述4-12元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个；所述5-12元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个；较佳地， R⁴为未取代的C₂-C₆的炔基、未取代的C₃-C₆的环烷基、被一个或多个R^4-5取代的4-6元的杂环烷基、被一个或多个R^4-6取代的5-6元的杂芳基或未取代的C₁-C₆的烷氧基；所述4-6元的杂环烷基中的杂原子独立地选自N和O中的一种或两种，杂原子数为1个或2个；所述5-6元的杂芳基中的杂原子为N，杂原子数为1个；R ⁴ is an unsubstituted C ₂ -C ₆ alkynyl, an unsubstituted C ₃ -C ₆ cycloalkyl, a 4-12-membered heterocycloalkyl substituted by one or more R ^4-5 , a 5-12-membered heteroaryl substituted by one or more R ^4-6 , or an unsubstituted C ₁ -C ₆ 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, ^R4 is an unsubstituted _C2 - _C6 alkynyl, an unsubstituted _C3 - _C6 cycloalkyl, a 4-6-membered heterocycloalkyl substituted by one or more ^R4-5 , a 5-6-membered heteroaryl substituted by one or more ^R4-6 , or an unsubstituted _C1 - _C6 alkoxy; the heteroatom in the 4-6-membered heterocycloalkyl is independently selected from one or both of N and O, and the number of the heteroatoms is 1 or 2; the heteroatom in the 5-6-membered heteroaryl is N, and the number of the heteroatoms is 1;

在某一方案中，In one plan,

Y为C；Y is C;

R¹为或被1个或多个R^1-3取代的C₁-C₆的烷基； ^R1 is or a C ₁ -C ₆ alkyl group substituted by one or more R ^1-3 ;

R^1-2为O；R ^1-2 is O;

X为-CR^1-6R^1-7-；X is -CR ^1-6 R ^1-7 -;

R^1-6和R^1-7独立地为氢；R ^1-6 and R ^1-7 are independently hydrogen;

各个R^2-1独立地为卤素火或未取代的C₁-C₆的烷基；Each R ^2-1 is independently a halogen or an unsubstituted C ₁ -C ₆ alkyl group;

A为未取代的5-12元的亚杂芳基，所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个；较佳地，所述5-12元的亚杂芳基中的杂原子为N，杂原子数为1个或2个；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;

Q为未取代的5-12元的亚杂芳基或未取代的5-12元的亚杂环烷基；所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个；所述5-12元的亚杂环烷基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个；较佳地，Q为未取代的5-6元的亚杂芳基或未取代的5-12元的亚杂环烷基；所述5-6元的亚杂芳基中的杂原子为N，杂原子数为1个；所述5-12元的亚杂环烷基中的杂原子独立地选自N和O中的一种或两种，杂原子数为1个、2个或3个；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. The number of atoms is 1, 2 or 3;

各个R^3-1独立地为卤素；Each R ^3-1 is independently halogen;

在某一方案中，In one plan,

Y为C；Y is C;

R^1-2为O；R ^1-2 is O;

各个R^1-3独立地为羟基、卤素或未取代的C₁-C₆的烷基；Each R ^1-3 is independently hydroxy, halogen or unsubstituted C ₁ -C ₆ alkyl;

X为-CR^1-6R^1-7-；X is -CR ^1-6 R ^1-7 -;

R^1-6和R^1-7独立地为氢；R ^1-6 and R ^1-7 are independently hydrogen;

各个R^2-2独立地为卤素；Each R ^2-2 is independently halogen;

A为未取代的5-12元的亚杂芳基；所述5-12元的亚杂芳基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个；较佳地，所述5-12元的亚杂芳基中的杂原子为N，杂原子数为1个或2个； 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;

各个R^3-1独立地为卤素；Each R ^3-1 is independently halogen;

在某一方案中，In one plan,

Y为C；Y is C;

R^1-2为O；R ^1-2 is O;

X为-CR^1-6R^1-7-；X is -CR ^1-6 R ^1-7 -;

R^1-6和R^1-7独立地为氢；R ^1-6 and R ^1-7 are independently hydrogen;

R²和R³与其相连的原子形成未取代或被1个或多个R^2-1取代的5-6元的杂芳基、未取代的4-6元的杂环烷基或未取代的C₄-C₆的环烷基；所述5-6元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个；所述4-6元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个；较佳地，所述5-6元的杂芳基中的杂原子为N或 O，杂原子数为1个或2个；所述4-6元的杂环烷基中的杂原子为O，杂原子数为1个或2个； ^R2 and ^R3 and the atoms connected thereto form a 5-6 membered heteroaryl group, an unsubstituted 4-6 membered heterocycloalkyl group or an unsubstituted _C4 - _C6 cycloalkyl group, which is unsubstituted or substituted by one or more ^R2-1 ; 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; preferably, the heteroatoms in the 5-6 membered heteroaryl group are N or O, the number of heteroatoms is 1 or 2; the heteroatom in the 4-6 membered heterocycloalkyl is O, the number of heteroatoms is 1 or 2;

在某一方案中，In one plan,

Y为C；Y is C;

R¹为 ^R1 is

R^1-1为未取代的C₁-C₆的烷基；R ^1-1 is an unsubstituted C ₁ -C ₆ alkyl group;

R^1-2为O；R ^1-2 is O;

X为-CR^1-6R^1-7-；X is -CR ^1-6 R ^1-7 -;

R^1-6和R^1-7独立地为氢；R ^1-6 and R ^1-7 are independently hydrogen;

R²和R³与其相连的原子形成未取代的4-6元的杂环烷基或未取代的C₄-C₆的环烷基；所述4-6元的杂环烷基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个；较佳地，所述4-6元的杂环烷基中的杂原子为O；杂原子数为1个； ^R2 and ^R3 and the atoms to which they are connected form an unsubstituted 4-6 membered heterocycloalkyl or an unsubstituted _C4 - _C6 cycloalkyl; the heteroatom in the 4-6 membered heterocycloalkyl is 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;

L为连接健；L is the connection key;

R⁴为未取代的C₂-C₆的炔基、未取代的C₃-C₆的环烷基、或被一个或多个R^4-6取代的5-12元的杂芳基；所述5-12元的杂芳基中的杂原子独立地选自N、O和S中的一种或多种，杂原子数为1个、2个或3个；较佳地，R⁴为未取代的C₂-C₆的炔基、未取代的C₃-C₆的环烷基、或被一个或多个R^4-6取代的5-6元的杂芳基；所述5-6元的杂芳基中的杂原子为N，杂原子数为1个； ^R4 is an unsubstituted _C2 - _C6 alkynyl, an unsubstituted _C3 - _C6 cycloalkyl, or a 5-12-membered heteroaryl substituted by one or more ^R4-6 ; the heteroatom in the 5-12-membered heteroaryl is independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, ^R4 is an unsubstituted _C2 - _C6 alkynyl, an unsubstituted C3- _C6 cycloalkyl, or a _5-6 -membered heteroaryl substituted by one or more ^R4-6 ; the heteroatom in the 5-6-membered heteroaryl is N, and the number of heteroatoms is 1;

在某一方案中，R¹为 In one embodiment, ^R1 is

在某一方案中，X为亚甲基、 In one embodiment, X is methylene,

在某一方案中，为 In one plan, for

在某一方案中，A为 In one scheme, A is

在某一方案中，L为 In one scheme, L is

在某一方案中，Q为 In one scheme, Q is

在某一方案中，R⁴为 In one embodiment, ^R4 is

本发明提供了如下的化合物或其药学上可接受的盐：

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

本发明还提供了如上所示的化合物或其药学上可接受的盐在制备BRM ATPase抑制剂中的用途。The present invention also provides the use of the compound shown above or its pharmaceutically acceptable salt in the preparation of BRM ATPase inhibitors.

本发明还提供了一种药物组合物，其包含如上所示的化合物或其药学上可接受的盐、以及药学上可接受的载体。The present invention also provides a pharmaceutical composition, which comprises the compound shown above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

本发明还提供了如上所示的化合物或其药学上可接受的盐在制备药物中的用途，所述药物用于治疗BRM ATPase相关的疾病。The present invention also provides the use of the compound shown above or its pharmaceutically acceptable salt in the preparation of a drug for treating BRM ATPase-related diseases.

本发明还提供了如上所示的化合物或其药学上可接受的盐在制备药物中用途，所述药物用于治疗黑色素瘤、子宫内膜癌、非小细胞肺癌、食道胃腺癌、尿路上皮膀胱癌或结直肠癌。The present invention also provides the use of the compound shown above or a pharmaceutically acceptable salt thereof in preparing a drug for treating melanoma, endometrial cancer, non-small cell lung cancer, esophageal gastric adenocarcinoma, urothelial bladder cancer or colorectal cancer.

如本文所述，术语“药学上可接受的盐”是指本发明的化合物的药学上可接受的有机或无机盐。As used herein, the term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable organic or inorganic salt of a compound of the present invention.

术语“烷基”是指具有指定碳原子数(例如，C₁-C₆)的、直链或支链的、饱和的一价烃基；例如，C₁-C₆的烷基。The term "alkyl" refers to a linear or branched, saturated, monovalent hydrocarbon group having a specified number of carbon atoms (eg, C ₁ -C ₆ ); for example, C ₁ -C ₆ alkyl.

术语“炔基”是指具有至少一个不饱和位置即碳-碳sp三键的二到二十二个碳原子的直链或支链的一价烃基；例如，C₂-C₆的炔基。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.

术语“环烷基”是指具有指定的环碳原子数(例如，C_3-C₆或C₄-C₆)、环原子仅由碳原子组成的饱和的单环基团。例如，C_3-C₆的环烷基或C₄-C₆的环烷基。The term "cycloalkyl" refers to a saturated monocyclic group having a specified number of ring carbon atoms (e.g., C _{3 -} C ₆ or C ₄ -C ₆ ), wherein the ring atoms consist only of carbon atoms, for example, C ₃ - C ₆ cycloalkyl or C ₄ -C ₆ cycloalkyl.

术语“杂环烷基”是指具有指定环原子数(例如3-6元、4-6元或4-12元)的、指定杂原子数(例如1个、2个或3个)的、指定杂原子或杂原子基团种类(N、O和S中的1种、2种或3种)的饱和单环(例如，)、螺环(例如，)或桥环(例如，)，不饱和并环 The term "heterocycloalkyl" refers to a saturated monocyclic ring (e.g., 3-6, 4-6, or 4-12) with a specified number of ring atoms (e.g., 1, 2, or 3), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom or heteroatom group (1, 2, or 3 of N, O, and S). ), spirocyclic ring (e.g., ) or bridge ring (e.g. ), unsaturated and cyclic

术语“亚杂环烷基”是指二价基团，其通过两个单键与分子其余部分相连，其余定义同术语“杂环烷基”。术语“杂芳基”是指具有指定环原子数(例如，5-12元或5-6元)的、指定杂原子数(例如，1个、2个或3个)的、指定杂原子种类(例如，N、O和S中的一种、两种或多种)的环状基团，其为单环或双环。单环杂芳基包括但不限于呋喃基、吡咯基、噻吩基、吡唑基、咪唑基、三氮唑、呋咱噁唑基、噻唑基、吡啶基、嘧啶基、吲哚基，例如，双环杂芳基包括但不限于5元亚杂芳基并6元亚芳基或6元亚杂芳基并5元亚杂芳基；例如， 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 heteroatom type (e.g., one, two, or more of N, O, and S), which is monocyclic or bicyclic. Monocyclic heteroaryl includes, but is not limited to, furanyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, triazole, furazolidinyl, 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,

术语“芳基”是指具有指定环碳原子数(例如，C₆-C₁₀)的芳香基团。芳基的实例包括不限于苯基。The term "aryl" refers to an aromatic group having a specified number of ring carbon atoms (eg, C ₆ -C ₁₀ ). Examples of aryl groups include, but are not limited to, phenyl.

术语“亚芳基”是指二价基团，其通过两个单键与分子其余部分相连，其余定义同术语“芳基”。The term "arylene" refers to a divalent group which is attached to the rest of the molecule by two single bonds, and the rest is the same as the definition of the term "aryl".

术语“卤素”是指F、Cl或Br。The term "halogen" refers to F, Cl or Br.

术语“亚杂芳基”是指二价基团，其通过两个单键与分子其余部分相连，其余定义同术语“杂芳基”。The term "heteroarylene" refers to a divalent group which 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".

术语“烯基”是指具有至少一个不饱和位置即碳-碳sp2双键的二到二十二个碳原子的直链或支链的一价烃基(例如，C₁～C₆烯基)。The term "alkenyl" refers to a linear or branched monovalent hydrocarbon group of two to twenty-two carbon atoms (eg, C ₁ -C ₆ alkenyl) having at least one site of unsaturation, ie, a carbon-carbon sp 2 double bond.

术语“亚烯基”是指二价基团，其通过两个单键与分子其余部分相连，其余定义同术语“烯基”。The term "alkenylene" refers to a divalent group which 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".

术语“烷氧基”是指基团R^X-O-，其中，R^X为上文所定义的烷基。The term "alkoxy" refers to the group R ^X -O-, wherein R ^X is alkyl as defined above.

在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

本发明所用试剂和原料均市售可得。The reagents and raw materials used in the present invention are commercially available.

本发明的积极进步效果在于：本发明化合物对BRM ATPase有较强的抑制作用，在BRG1基因突变肿瘤中有很好的应用前景。The positive and progressive effect of the present invention is that the compounds of the present invention have a strong inhibitory effect on BRM ATPase and have good application prospects in BRG1 gene mutation tumors.

Detailed ways

下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

实施例1 EVO33109

Example 1 EVO33109

第1步：step 1:

室温下，将5-溴-7-氟-1-茚酮(1g,4.37mmol)溶于DMF(15mL)中，加入NaSCH₃(2.29g,6.55mmol,20％purity)的水溶液，反应体系在室温下搅拌过夜。反应体系中加水稀释，EA萃取1次，合并有机相，用水和饱和氯化钠溶液各洗涤1次，无水Na₂SO₄干燥，过滤，浓缩得粗品，中压正相柱层析纯化(PE/DCM＝5-50％)得白色固体EVO33109-A1(700mg,收率：62％)。At room temperature, 5-bromo-7-fluoro-1-indanone (1 g, 4.37 mmol) was dissolved in DMF (15 mL), and an aqueous solution of NaSCH ₃ (2.29 g, 6.55 mmol, 20% purity) was added, and the reaction system was stirred at room temperature overnight. Water was added to dilute the reaction system, and EA was extracted once. The organic phases were combined, washed once with water and saturated sodium chloride solution, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to obtain a crude product, which was purified by medium-pressure normal phase column chromatography (PE/DCM=5-50%) to obtain white solid EVO33109-A1 (700 mg, yield: 62%).

第2步：Step 2:

室温下，单口瓶中依次加入EVO33109-A1(257mg,1.0mmol)，Pd(dppf)Cl₂-DCM(81mg,0.1mmol)，TEA(303mg,3.0mmol)，DMF(6mL)和MeOH(3mL)，反应体系用CO置换3次，80℃加热搅拌过夜。反应结束后，体系冷却到室温，加入水(30mL)和EA(30mL)，水相用EA萃取1次，合并有机相，用水和饱和氯化钠溶液各洗涤1次，无水Na₂SO₄干燥，过滤，浓缩得粗品，中压正相柱层析纯化(PE/DCM＝10-50％)得白色固体EVO33109-C1(160mg,收率：67％)，LCMS(ESI)m/z＝237.1[M+H]⁺。At room temperature, EVO33109-A1 (257 mg, 1.0 mmol), Pd(dppf)Cl ₂ -DCM (81 mg, 0.1 mmol), TEA (303 mg, 3.0 mmol), DMF (6 mL) and MeOH (3 mL) were added to a single-mouth bottle in sequence, and the reaction system was replaced with CO 3 times, and heated at 80°C with stirring overnight. After the reaction was completed, the system was cooled to room temperature, and water (30 mL) and EA (30 mL) were added. The aqueous phase was extracted once with EA, and the organic phases were combined, washed once with water and saturated sodium chloride solution, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to obtain a crude product, which was purified by medium-pressure normal phase column chromatography (PE/DCM=10-50%) to obtain white solid EVO33109-C1 (160 mg, yield: 67%), LCMS (ESI) m/z=237.1[M+H] ⁺ .

第3步：Step 3:

室温下，将EVO33109-C1(160mg,0.68mmol)悬浮在MeOH(10mL)，H₂O(10mL)和CH₃CN(10mL)中，加入固体Oxone(1.24g,2.03mmol)，反应体系在室温下搅拌过夜。反应结束后，反应体系浓缩，加入水(30mL)和EA(30mL)，水相用EA萃取1次，有机相合并后，用水和饱和氯化钠溶液各洗涤1次，无水Na₂SO₄干燥，过滤，浓缩得粗品，中压正相柱层析纯化(DCM/EA＝0-10％)得白色固体EVO33109-C2(150mg,收率：82％)，¹H 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)。At room temperature, EVO33109-C1 (160 mg, 0.68 mmol) was suspended in MeOH (10 mL), H ₂ O (10 mL) and CH ₃ CN (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 saturated sodium chloride solution, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to obtain a crude product. The crude product was purified by medium-pressure normal phase column chromatography (DCM/EA=0-10%) to obtain a white solid EVO33109-C2 (150 mg, yield: 82%), ¹ H NMR (400 MHz, CDCl ₃ )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).

第4步：Step 4:

室温下，将EVO33109-C2(20mg,0.075mmol)悬浮于MeOH(1mL)、H₂O(0.5mL)和THF(1mL)中，加入固体LiOH·H₂O(9mg,0.22mmol)，反应体系从白色浑浊液，慢慢变为淡黄色浑浊液，再变为深绿色澄清液，反应体系在室温下搅拌1小时。反应结束后，反应体系用稀HCl(1M)调pH＝3–5，反应体系浓缩后得黑色固体EVO33109-C3(25mg,粗品)，LCMS(ESI)m/z＝253.1[M-H]^-。 At room temperature, EVO33109-C2 (20 mg, 0.075 mmol) was suspended in MeOH (1 mL), H ₂ O (0.5 mL) and THF (1 mL), and solid LiOH·H ₂ O (9 mg, 0.22 mmol) was added. The reaction system 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 was completed, the reaction system was adjusted to pH 3-5 with dilute HCl (1 M). The reaction system was concentrated to obtain a black solid EVO33109-C3 (25 mg, crude product), LCMS (ESI) m/z = 253.1 [MH] ^- .

第5步：Step 5:

室温下，将中间体1(30mg,0.067mmol)溶于1,4-二氧六环(0.5mL)中，再加入氯化氢的1,4-二氧六环溶液(3mL),反应体系在室温下搅拌1小时。反应体系浓缩得粗品黄色固体中间体1-A1(22mg,收率：95％)，LCMS(ESI)m/z＝350.4[M+H]⁺。At room temperature, intermediate 1 (30 mg, 0.067 mmol) was dissolved in 1,4-dioxane (0.5 mL), and then a solution of hydrogen chloride in 1,4-dioxane (3 mL) was added, and the reaction system was stirred at room temperature for 1 hour. The reaction system was concentrated to obtain a crude yellow solid intermediate 1-A1 (22 mg, yield: 95%), LCMS (ESI) m/z = 350.4 [M+H] ⁺ .

第6步：Step 6:

室温下，将EVO33109-C3(20mg,0.078mmol)和中间体1-A1(22mg,0.063mmol)溶于DMF(3mL)中，依次加入TEA(40mg,0.39mmol)和HATU(45mg,0.12mmol)，反应体系在室温下搅拌1小时。反应加水淬灭，用EA萃取2次，合并有机相，用水和饱和氯化钠溶液各洗涤1次，无水Na₂SO₄干燥，过滤，浓缩，中压正相柱层析纯化(DCM/EA＝10-50％；然后DCM/10％MeOH＝10-30％)得粗品，再用Prep-HPLC制备，冻干得淡黄色固体EVO33109(7mg,收率：15％)，LCMS(ESI)m/z＝586.1[M+H]⁺，纯度：99.3％，¹H 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)。At room temperature, EVO33109-C3 (20 mg, 0.078 mmol) and intermediate 1-A1 (22 mg, 0.063 mmol) were dissolved in DMF (3 mL), and TEA (40 mg, 0.39 mmol) and HATU (45 mg, 0.12 mmol) were added in sequence, and the reaction system was stirred at room temperature for 1 hour. The reaction was quenched with water, extracted twice with EA, the organic phases were combined, washed once with water and 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 a crude product, which was then prepared by Prep-HPLC and lyophilized to obtain a light yellow solid EVO33109 (7 mg, yield: 15%), LCMS (ESI) m/z=586.1 [M+H] ⁺ , purity: 99.3%, ¹ H NMR (400 MHz, DMSO-d ₆ )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).

实施例2 EVO33127
Example 2 EVO33127

第1步：step 1:

室温下，将EVO33109-A1(180mg,0.70mmol)溶于TFA(5mL)中，再加入Et₃SiH(406mg,3.50mmol)。反应体系在室温下搅拌过夜。反应结束后，浓缩，加入EA(30mL)和水(30mL)稀释，有机相用饱和NaHCO₃溶液、水和饱和氯化钠溶液各洗涤1次，无水Na₂SO₄干燥，过滤，浓缩得粗品，中压正相柱层析纯化得无色油状物EVO33127-A1(150mg，收率：88％)，久置变为白色固体。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)。At room temperature, EVO33109-A1 (180 mg, 0.70 mmol) was dissolved in TFA (5 mL), and Et ₃ SiH (406 mg, 3.50 mmol) was added. The reaction system was stirred at room temperature overnight. After the reaction was completed, it was concentrated, and EA (30 mL) and water (30 mL) were added to dilute it. The organic phase was washed with saturated NaHCO ₃ solution, water and saturated sodium chloride solution once each, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to obtain a crude product. The crude product was purified by medium-pressure normal phase column chromatography to obtain a colorless oil EVO33127-A1 (150 mg, yield: 88%), which turned into a white solid after long standing. ¹ H NMR (400 MHz, CDCl ₃ )δ7.14 (s, 1H), 7.04 (s, 1H), 2.91 (t, J＝7.2 Hz, 2H), 2.77 (t, J＝7.2 Hz, 2H), 2.46 (s, 3H), 2.12-2.05 (m, 2H).

第2步：Step 2:

室温下，将EVO33127-A1(150mg,0.62mmol)溶于CH₃CN(6mL)和H₂O(6mL)，再加入Oxone(1.13g,1.85mmol)，有固体析出。反应体系在室温下搅拌过夜。反应结束后，浓缩，加入EA(30mL)和水(30mL)稀释，水相用EA萃取1次。有机相合并后，用水和饱和氯化钠溶液各洗涤1次，无水Na₂SO₄干燥，过滤，浓缩得粗品白色固体EVO33127-A2(140mg，收率：82％)，¹H 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)。At room temperature, EVO33127-A1 (150 mg, 0.62 mmol) was dissolved in CH ₃ CN (6 mL) and H ₂ O (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, and EA (30 mL) and water (30 mL) were added to dilute it, and the aqueous phase was extracted once with EA. The organic phases were combined, washed once with water and saturated sodium chloride solution, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give a crude white solid EVO33127-A2 (140 mg, yield: 82%), ¹ H NMR (400 MHz, CDCl ₃ ) δ7.89 (s, 1H), 7.61 (s, 1H), 3.22 (t, J＝7.6 Hz, 2H), 3.04 (s, 3H), 2.97 (t, J＝7.6 Hz, 2H), 2.21-2.13 (m, 2H).

第3步：Step 3:

室温下，向单口瓶中依次加入EVO33127-A2(90mg,0.33mmol)，Pd(OAc)₂(7mg,0.033mmol)，DCCP-2HBF₄(20mg,0.033mmol)，K₂CO₃(135mg,0.99mmol)，H₂O(0.1mL)和DMSO(3mL)，反应体系用CO置换3次后，加热到100℃搅拌过夜。反应结束后，反应体系冷却到室温并过滤，滤饼用水洗涤2次。滤液用EA萃取1次，有机相丢弃，水相用稀HCl(1M)调pH＝3，用DCM/MeOH＝10/1萃取3次，有机相合并，浓缩得粗品，用中压反相柱层析纯化(H₂O/CH₃CN＝0-50％)，冻干得淡粉色固体EVO33127-A3(60mg，收率：80％)，LCMS(ESI)m/z＝239.2[M-H]^-。At room temperature, EVO33127-A2 (90 mg, 0.33 mmol), Pd(OAc) ₂ (7 mg, 0.033 mmol), DCCP-2HBF ₄ (20 mg, 0.033 mmol), K ₂ CO ₃ (135 mg, 0.99 mmol), H ₂ O (0.1 mL) and DMSO (3 mL) were added to a single-mouth bottle in sequence. The reaction system was replaced with CO 3 times, and then heated to 100°C and stirred overnight. After the reaction was completed, the reaction system was cooled to room temperature and filtered, and the filter cake was washed with water twice. The filtrate was extracted once with EA, the organic phase was discarded, the aqueous phase was adjusted to pH = 3 with dilute HCl (1M), 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 light pink solid EVO33127-A3 (60 mg, yield: 80%), LCMS (ESI) m/z = 239.2 [MH] ^- .

第4步：Step 4:

室温下，将EVO33127-A3(15mg,0.062mmol)和中间体1-A1(22mg,0.062mmol)溶于DMF(3mL)中，依次加入TEA(32mg,0.31mmol)和HATU(35mg,0.093mmol)，反应体系在室温下搅拌1小时。反应体系加水淬灭，用EA萃取2次，合并有机相，用水和饱和氯化钠溶液各洗涤1次，无水Na₂SO₄干燥，过滤，浓缩得粗品，Prep-HPLC制备后，冻干得淡黄色固体EVO33127(15mg，收率：42％)，LCMS(ESI)m/z＝572.37[M+H]⁺。纯度：99.17％。¹H 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),3.30-3.25(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)。At room temperature, EVO33127-A3 (15 mg, 0.062 mmol) and intermediate 1-A1 (22 mg, 0.062 mmol) were dissolved in DMF (3 mL), and TEA (32 mg, 0.31 mmol) and HATU (35 mg, 0.093 mmol) were added in sequence. The reaction system was stirred at room temperature for 1 hour. The reaction system was quenched with water, extracted twice with EA, and the organic phases were combined, washed once with water and saturated sodium chloride solution, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to obtain a crude product. After Prep-HPLC preparation, the crude product was freeze-dried to obtain a light yellow solid EVO33127 (15 mg, yield: 42%), LCMS (ESI) m/z = 572.37 [M+H] ⁺ . Purity: 99.17%. ¹ H NMR (400 MHz, DMSO-d ₆ )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),3.30-3.25(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).

实施例3 EVO33314
Example 3 EVO33314

参照化合物EVO33127，经高效液相制备柱分离，再冷冻干燥得到黄色固体EVO33314(15mg，收率：38％)，LCMS(ESI)m/z＝586.4[M+H]⁺，纯度：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)。The reference compound EVO33127 was separated by HPLC preparative column and freeze-dried to obtain yellow solid EVO33314 (15 mg, yield: 38%), LCMS (ESI) m/z=586.4 [M+H] ⁺ , purity: 99.13%, ¹ H NMR (400 MHz, DMSO-d ₆ )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 = 7.4 Hz, 2H), 2.56-2.50 (m, 2H), 2.18-2.08 (m, 2H), 1.21 (d, J = 6.2 Hz, 6H), 1.13 (t, J = 7.4 Hz, 3H).

实施例4 EVO33319
Example 4 EVO33319

参照化合物EVO33127，经高效液相制备柱分离，再冷冻干燥得到得黄色固体EVO33319(25mg,收率：46％)，LCMS(ESI)m/z＝600.5[M+H]⁺，纯度：97.9％，¹H NMR(400MHz,DMSO-d₆)δ9.49(t,J＝5.6Hz,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)。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-d ₆ )δ9.49(t, J=5.6Hz,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).

实施例5 EVO33168
Example 5 EVO33168

第1步：step 1:

Ar保护下，化合物5-溴-7-氟吲唑(1.03g,4.80mmol)和甲硫醇钠(0.93g,12mmol)的DMF(5mL)溶液在80℃下反应12小时。反应液加冰水淬灭，加入EA萃取，合并有机相，无水Na₂SO₄干燥，过滤，减压浓缩得到白色固体EVO33168-A1(1.28g，收率：98％)，LCMS(ESI)m/z＝245.04[M+H]⁺。Under Ar protection, a DMF (5 mL) solution of compound 5-bromo-7-fluoroindazole (1.03 g, 4.80 mmol) and sodium thiomethoxide (0.93 g, 12 mmol) was reacted at 80°C for 12 hours. The reaction solution was quenched with ice water, extracted with EA, and the organic phases were combined, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to obtain a white solid EVO33168-A1 (1.28 g, yield: 98%), LCMS (ESI) m/z=245.04 [M+H] ⁺ .

第2步：Step 2:

Ar保护，冰水浴条件下，向化合物EVO33168-A1(300mg,1.23mmol)的DMF(5mL)溶液中加入NaH(200mg,4.94mmol)，搅拌10分钟，再滴入CH₃I(350mg，2.46mmol)，继续搅拌15分钟。反应液加冰水淬灭，加入EA萃取，合并有机相，无水Na₂SO₄干燥，过滤，减压浓缩得到白色固体 EVO33168-A2(380mg，收率：98％)，LCMS(ESI)m/z＝259.07[M+H]⁺。Ar protection, under ice-water bath conditions, NaH (200 mg, 4.94 mmol) was added to a DMF (5 mL) solution of compound EVO33168-A1 (300 mg, 1.23 mmol), stirred for 10 minutes, and then CH ₃ I (350 mg, 2.46 mmol) was added dropwise, and stirring continued for 15 minutes. The reaction solution was quenched with ice water, extracted with EA, and the organic phases were combined, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to obtain a white solid. EVO33168-A2 (380 mg, yield: 98%), LCMS (ESI) m/z=259.07 [M+H] ⁺ .

第3步：Step 3:

室温下，将EVO33168-A2(380mg,1.23mmol)溶于乙腈(5mL)和水(5mL)溶液中，加入固体Oxone(1.60g,2.46mmol)，反应搅拌过夜。将反应液浓缩，加入EA和水，分层萃取，合并有机相，无水Na₂SO₄干燥，过滤，减压浓缩得粗品，中压正相柱层析纯化(PE/EA＝3/1)，得到白色固体EVO33168-A3(210mg，收率：60％)，LCMS(ESI)m/z＝291.10[M+H]⁺。At room temperature, EVO33168-A2 (380 mg, 1.23 mmol) was dissolved in acetonitrile (5 mL) and water (5 mL) solution, 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 organic phases were combined, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by medium-pressure normal phase column chromatography (PE/EA=3/1) to obtain a white solid EVO33168-A3 (210 mg, yield: 60%), LCMS (ESI) m/z=291.10 [M+H] ⁺ .

第4步：Step 4:

室温下，向反应瓶中加入化合物EVO33168-A3(195mg,0.68mmol)、Pd(OAc)₂(15mg,0.068mmol)、1,3-双(二环己基膦)丙烷双(四氟硼酸盐)(41mg,0.068mmol)、K₂CO₃(281mg,2.04mmol)、DMSO(2mL)和水(0.2mL)，CO置换3次后，反应液在100℃下搅拌4小时。反应液中加入水，过滤，少量水洗涤滤饼，滤液酸化至pH＝1-2，EA萃取，合并有机相，无水Na₂SO₄干燥，过滤，减压浓缩得到淡黄色固体EVO33168-A4(140mg，收率：80％)，LCMS(ESI)m/z＝255.17[M+H]⁺。At room temperature, 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), K ₂ CO ₃ (281 mg, 2.04 mmol), DMSO (2 mL) and water (0.2 mL) were added to the reaction bottle. After CO replacement 3 times, the reaction solution was stirred at 100° C. for 4 hours. Water was added to the reaction solution, filtered, the filter cake was washed with a small amount of water, the filtrate was acidified to pH=1-2, extracted with EA, the organic phases were combined, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to obtain a light yellow solid EVO33168-A4 (140 mg, yield: 80%), LCMS (ESI) m/z=255.17 [M+H] ⁺ .

第5步：Step 5:

室温下，向化合物中间体1-A1(40mg,0.11mmol)的DCM(5mL)溶液中加入化合物EVO33168-A4(42mg,0.15mmol)、HOBt(22mg,0.16mmol)、EDCI(31mg，0.16mmol)和DIPEA(28.7mg，0.22mmol)，反应搅拌1小时。依次用水和饱和氯化钠溶液各洗涤1次，无水Na₂SO₄干燥，过滤，浓缩，粗品经Prep-HPLC制备，冷冻干燥得到黄色固体EVO33168(25.6mg，收率：42％)，纯度：97％，LCMS(ESI)m/z＝586.44[M+H]⁺，¹H 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)。At room temperature, 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) were added to a DCM (5 mL) solution of compound intermediate 1-A1 (40 mg, 0.11 mmol) and the reaction was stirred for 1 hour. The mixture was washed with water and saturated sodium chloride solution once each, dried over anhydrous Na ₂ SO ₄ , filtered, concentrated, and the crude product was prepared by Prep-HPLC and freeze-dried to obtain yellow solid EVO33168 (25.6 mg, yield: 42%), purity: 97%, LCMS (ESI) m/z=586.44 [M+H] ⁺ , ¹ H NMR (400 MHz, DMSO-d ₆ )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).

实施例6 EVO33135
Example 6 EVO33135

参照化合物EVO33168，经高效液相制备柱分离，再冷冻干燥得到黄色固体EVO33135(15.5mg，收率：16.3％)，LCMS(ESI)m/z＝571.05[M+H]⁺，¹H NMR(400MHz,DMSO-d₆)δ11.62(s,1H),9.47-9.40(m,1H),9.40(s,1H),8.70-8.59(m,3H),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)。The reference compound EVO33168 was separated by HPLC preparative column and freeze-dried to obtain yellow solid EVO33135 (15.5 mg, yield: 16.3%), LCMS (ESI) m/z=571.05 [M+H] ⁺ , ¹ H NMR (400 MHz, DMSO-d ₆ )δ11.62(s,1H),9.47-9.40(m,1H),9.40(s,1H),8.70-8.59(m,3H),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).

实施例7 EVO33136
Example 7 EVO33136

参照化合物EVO33168，经高效液相制备柱分离，再冷冻干燥得到黄色固体EVO33136(13.58mg，收率：31％)，LCMS(ESI)m/z＝585.46[M+H]⁺，¹H 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)。The reference compound EVO33168 was separated by HPLC preparative column and freeze-dried to obtain yellow solid EVO33136 (13.58 mg, yield: 31%), LCMS (ESI) m/z=585.46 [M+H] ⁺ , ¹ H NMR (400 MHz, DMSO-d ₆ )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).

实施例8 EVO33165
Example 8 EVO33165

参照化合物EVO33168，经高效液相制备柱分离，再冷冻干燥得到黄色固体EVO33165(5.6mg，收率：12％，纯度：97.3％)，LCMS(ESI)＝572.43[M+H]⁺，¹H 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)。The 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 (400 MHz, DMSO-d ₆ )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).

实施例9 EVO33070

Example 9 EVO33070

第1步：step 1:

室温下，往反应瓶中加入二氟溴乙酸乙酯(7.96g,39.20mmol)和DMSO(50mL)，溶清后加入Cu(2.49g,39.20mmol)，反应液在室温下搅拌1小时，再加入2,6-二氟-4-溴碘苯(5g,16mmol)，油浴75℃搅拌过夜。反应体系冷却到室温，加入EA(300mL)和水(300mL)，有大量固体析出，过滤，滤饼用EA洗涤，分液，合并有机相，用水和饱和氯化钠溶液各洗涤1次，无水Na₂SO₄干燥，过滤，浓缩得粗品，中压正相柱层析纯化(PE/DCM＝0-15％)得无色油状物EVO33070-A1(4g,收率：81％)，¹H NMR(400MHz,DMSO-d₆)δ7.78–7.75(m,2H),4.37(q,J＝6.8Hz,2H),1.24(t,J＝7.2Hz,3H)。At room temperature, ethyl difluorobromoacetate (7.96 g, 39.20 mmol) and DMSO (50 mL) were added to the reaction bottle. After dissolving, Cu (2.49 g, 39.20 mmol) was added. The reaction solution was stirred at room temperature for 1 hour. 2,6-difluoro-4-bromoiodobenzene (5 g, 16 mmol) was added and stirred in an oil bath at 75°C overnight. The reaction system was cooled to room temperature, EA (300 mL) and water (300 mL) were added, a large amount of solid precipitated, filtered, the filter cake was washed with EA, separated, the organic phases were combined, washed once with water and saturated sodium chloride solution, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to obtain a crude product, which was purified by medium-pressure normal phase column chromatography (PE/DCM=0-15%) to obtain a colorless oil EVO33070-A1 (4 g, yield: 81%), ¹ H NMR (400 MHz, DMSO-d ₆ )δ7.78–7.75 (m, 2H), 4.37 (q, J=6.8 Hz, 2H), 1.24 (t, J=7.2 Hz, 3H).

第2步：Step 2:

室温下，反应瓶中加入EVO33070-A1(1g,3.17mmol)、CH₃CN(50mL)和NaSCH₃(222mg,3.17mmol)，搅拌过夜。反应体系浓缩后，加入EA(50mL)和水(50mL)稀释，分液，水相用EA萃取2次，有机相合并，无水Na₂SO₄干燥，过滤，浓缩得粗品，中压正相柱层析纯化(PE/DCM＝0-10％)得无色油状物EVO33070-A2(600mg,收率：55％)，¹H 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)。At room temperature, EVO33070-A1 (1 g, 3.17 mmol), CH ₃ CN (50 mL) and NaSCH ₃ (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, and the liquid was separated. The aqueous phase was extracted twice with EA, and the organic phases were combined, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to obtain a crude product, which was purified by medium-pressure normal phase column chromatography (PE/DCM=0-10%) to obtain a colorless oil EVO33070-A2 (600 mg, yield: 55%), ¹ H NMR (400 MHz, CDCl ₃ )δ7.13 (s, 1H), 7.09–7.06 (m, 1H), 4.11 (t, J=13.2 Hz, 2H), 2.47 (t, J=4.4 Hz, 3H).

第3步：Step 3:

室温下，反应瓶中加入EVO33070-A2(600mg,1.75mmol)、CH₃OH(6mL)和THF(6mL)，在0℃搅拌5-10分钟后，加入NaBH₄(133mg,3.50mmol)，继续搅拌1小时后，升至室温搅拌过夜。反应体系加水淬灭，浓缩，用EA萃取2次，有机相合并，无水Na₂SO₄干燥，过滤，浓缩，中压正相柱层析纯化(PE/DCM＝50％-70％)得白色固体EVO33070-A3(440mg,收率：83％)，¹H NMR(400MHz,DMSO-d₆)δ7.58(d,J＝5.6Hz,1H),7.49(s,1H),4.34(q,J＝7.2Hz,2H),2.55(s,3H),1.23(t,J＝6.8Hz,3H)。At room temperature, EVO33070-A2 (600 mg, 1.75 mmol), CH ₃ OH (6 mL) and THF (6 mL) were added to the reaction flask. After stirring at 0° C. for 5-10 minutes, NaBH ₄ (133 mg, 3.50 mmol) was added. After stirring for 1 hour, the mixture was heated to room temperature and stirred overnight. The reaction system was quenched with water, concentrated, extracted twice with EA, the organic phases were combined, dried over anhydrous Na ₂ SO ₄ , filtered, concentrated, and purified by medium pressure normal phase column chromatography (PE/DCM=50%-70%) to give a white solid EVO33070-A3 (440 mg, yield: 83%), ¹ H NMR (400 MHz, DMSO-d ₆ )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).

第4步： Step 4:

室温下，反应瓶中加入Cs₂CO₃(953mg,2.92mmol)、TBAB(47mg,0.15mmol)和CH₃CN(50mL)，加热到85℃，然后向反应体系中滴加EVO33070-A3(440mg,1.46mmol)的CH₃CN(5mL)溶液，滴毕，油浴90℃搅拌过夜。反应体系冷却到室温，过滤，滤液浓缩得粗品，中压正相柱层析纯化(PE/DCM＝0-2％)得白色固体EVO33070-A4(160mg,收率：39％)，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)。At room temperature, Cs ₂ CO ₃ (953 mg, 2.92 mmol), TBAB (47 mg, 0.15 mmol) and CH ₃ CN (50 mL) were added to the reaction flask and heated to 85°C. Then, a CH ₃ CN (5 mL) solution of EVO33070-A3 (440 mg, 1.46 mmol) was added dropwise to the reaction system. After the addition was completed, the mixture was stirred in an oil bath at 90°C overnight. The reaction system was cooled to room temperature, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by medium-pressure normal phase column chromatography (PE/DCM=0-2%) to obtain a white solid EVO33070-A4 (160 mg, yield: 39%), ¹ H NMR (400 MHz, DMSO-d ₆ )δ7.14(q, J=1.6 Hz, 1H), 7.06(d, J=1.2 Hz, 1H), 4.81(t, J=16.8 Hz, 2H), 2.57(s, 3H).

第5步：Step 5:

室温下，反应瓶中加入EVO33070-A4(160mg,0.57mmol)、CH₃OH(5mL)和H₂O(5mL)，然后加入Oxone(1.05g,1.71mmol)，反应液在室温下搅拌2-4小时。反应体系加水稀释，用EA萃取2次，合并有机相，无水Na₂SO₄干燥，过滤，浓缩得粗品，中压正相柱层析纯化(PE/DCM＝0-50％)得白色固体EVO33070-A5(140mg,收率：78％)，¹H 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)。At room temperature, EVO33070-A4 (160 mg, 0.57 mmol), CH ₃ OH (5 mL) and H ₂ O (5 mL) were added to the reaction flask, and then Oxone (1.05 g, 1.71 mmol) was added, and the reaction solution was stirred at room temperature for 2-4 hours. The reaction system was diluted with water, extracted twice with EA, and the organic phases were combined, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to obtain a crude product, which was purified by medium-pressure normal phase column chromatography (PE/DCM=0-50%) to obtain a white solid EVO33070-A5 (140 mg, yield: 78%), ¹ H NMR (400 MHz, CDCl ₃ )δ7.82(d, J=1.2 Hz, 1H),7.43(q, J=1.6 Hz, 1H),4.74(t, J=16.0 Hz, 2H),3.19(s, 3H).

第6步：Step 6:

室温下，依次向单口瓶中加入EVO33070-A5(140mg,0.45mmol)，Pd(OAc)₂(10mg,0.045mmol)，DCCP-2HBF₄(27mg,0.045mmol)，K₂CO₃(185mg,1.34mmol)，DMSO(5mL)和H₂O(0.2mL)，反应体系用CO置换3次，加热到100℃搅拌过夜。反应体系冷却到室温，过滤，滤饼用水洗涤，水相用EA萃取1次，有机相丢弃，水相用稀HCl(1M)调pH＝3-5，用DCM/MeOH(10/1)萃取3次，有机相合并，无水Na₂SO₄干燥，过滤，浓缩得粗品，反相柱层析纯化(H₂O/CH₃CN＝5-50％)，冷冻干燥得白色固体EVO33070-A6(65mg，收率：52％)，LCMS(ESI)m/z＝277.0[M-H]^-。At room temperature, EVO33070-A5 (140 mg, 0.45 mmol), Pd(OAc) ₂ (10 mg, 0.045 mmol), DCCP-2HBF ₄ (27 mg, 0.045 mmol), K ₂ CO ₃ (185 mg, 1.34 mmol), DMSO (5 mL) and H ₂ O (0.2 mL) were added to a single-necked bottle in sequence. The reaction system was replaced with CO three 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. The aqueous phase was extracted once with EA. The organic phase was discarded. The aqueous phase was adjusted to pH 3-5 with dilute HCl (1 M), extracted three times with DCM/MeOH (10/1), the organic phases were combined, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to obtain a crude product. The crude product was purified by reverse phase column chromatography (H ₂ O/CH ₃ CN=5-50%) and freeze-dried to obtain a white solid EVO33070-A6 (65 mg, yield: 52%), LCMS (ESI) m/z=277.0 [MH] ^- .

第7步：Step 7:

室温下，将EVO33070-A6(20mg,0.072mmol)和中间体1-A1(25mg,0.072mmol)溶于DMF(2mL)中，依次加入TEA(36mg,0.36mmol)和HATU(55mg,0.14mmol)。反应体系在室温下搅拌2小时。反应体系加入水淬灭，用EA萃取2次，有机相合并，用水和饱和氯化钠溶液各洗涤1次，无水Na₂SO₄干燥，过滤，浓缩得粗品，用Prep-HPLC纯化后，冷冻干燥得EVO33070(5mg，收率：11％)。LCMS(ESI)m/z＝610.34[M+H]⁺，纯度：98％，¹H 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＝12.4Hz,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)。At room temperature, EVO33070-A6 (20 mg, 0.072 mmol) and intermediate 1-A1 (25 mg, 0.072 mmol) were dissolved in DMF (2 mL), and TEA (36 mg, 0.36 mmol) and HATU (55 mg, 0.14 mmol) were added in sequence. The reaction system was stirred at room temperature for 2 hours. Water was added to the reaction system to quench, and EA was extracted twice. The organic phases were combined, washed once with water and saturated sodium chloride solution, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to obtain a crude product. After purification by Prep-HPLC, EVO33070 (5 mg, yield: 11%) was obtained by freeze drying. LCMS (ESI) m/z = 610.34 [M+H] ⁺ , purity: 98%, ¹ H NMR (400 MHz, DMSO-d ₆ )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＝12.4Hz,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).

实施例10 EVO33074
Example 10 EVO33074

参照化合物EVO33070，经高效液相制备柱分离，再冷冻干燥得到淡黄色固体EVO33074(10mg,收率：35％)，LCMS(ESI)m/z＝589.9[M+H]⁺，纯度：88.7％，¹H NMR(400MHz,DMSO-d₆)δ9.68(t,J＝6.0Hz,1H),9.40(s,1H),8.77(d,J＝4.0Hz,1H),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)。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%, ¹ H NMR (400 MHz, DMSO-d ₆ )δ9.68(t,J＝6.0Hz,1H),9.40(s,1H),8.77(d,J＝4.0Hz,1H),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).

实施例11 EVO33137
Example 11 EVO33137

第1步：step 1:

室温下，将1-溴-3-羟基萘(3.8g,17.04mmol)溶于CH₃CN(80mL)中，依次加入K₂CO₃(7.05g,51.11mmol)和CH₃I(7.36g,51.11mmol)，反应体系在室温下搅拌过夜。反应体系过滤，滤液浓缩后，加水稀释，用EA萃取，有机相用水和饱和氯化钠溶液各洗涤1次，无水Na₂SO₄干燥，过滤，浓缩得粗品棕色油状物EVO33137-A1(4g)，¹H NMR(400MHz,DMSO-d₆)δ8.02(d,J＝8.8Hz,1H),7.89(d,J＝8.4Hz,1H),7.58-7.48(m,3H),7.43(d,J＝2.4Hz,1H),3.89(s,3H)。At room temperature, 1-bromo-3-hydroxynaphthalene (3.8 g, 17.04 mmol) was dissolved in CH ₃ CN (80 mL), K ₂ CO ₃ (7.05 g, 51.11 mmol) and CH ₃ I (7.36 g, 51.11 mmol) were added in sequence, and the reaction system was stirred at room temperature overnight. The reaction system was filtered, the filtrate was concentrated, diluted with water, extracted with EA, the organic phase was washed with water and saturated sodium chloride solution once each, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to obtain a crude brown oil EVO33137-A1 (4 g), ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

第2步：Step 2:

室温下，向单口瓶中依次加入EVO33137-A1(3.5g,14.76mmol)，Pd₂(dba)₃(1.35g,1.48mmol)，Xantphos(1.71g,2.95mmol)，Cs₂CO₃(14.44g,44.29mmol)，t-BuOH(6mL)和toluene(60mL)，用氩气置换3次后，加入硫代乙酸甲酯(6.65g,73.81mmol)，再用氩气置换1次，反应体系加热到100℃搅拌过夜。反应体系过滤，滤饼用EA洗涤，滤液浓缩得粗品，中压正相柱层析纯化(PE/DCM＝0- 5％)得无色油状物EVO33137-A2(2g,收率：66％)，¹H 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)。At room temperature, EVO33137-A1 (3.5 g, 14.76 mmol), Pd ₂ (dba) ₃ (1.35 g, 1.48 mmol), Xantphos (1.71 g, 2.95 mmol), Cs ₂ CO ₃ (14.44 g, 44.29 mmol), t-BuOH (6 mL) and toluene (60 mL) were added to a single-mouth bottle in sequence. After replacing with argon for 3 times, methyl thioacetate (6.65 g, 73.81 mmol) was added, and then replaced with argon once. 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 a crude product, which was purified by medium-pressure normal phase column chromatography (PE/DCM=0- 5%) to give colorless oil EVO33137-A2 (2 g, yield: 66%), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.98 (d, J = 8.4 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.51-7.47 (m, 1H), 7.41-7.37 (m, 1H), 7.13 (d, J = 2.4 Hz, 1H), 6.98 (d, J = 2.4 Hz, 1H), 3.87 (s, 3H), 2.57 (s, 3H).

第3步：Step 3:

室温下，将EVO33137-A2(1g,4.90mmol)悬浮于CH₃CN(30mL)和H₂O(30mL)中，再加入Oxone(8.99g,14.69mmol)，反应体系在室温下搅拌过夜。反应体系浓缩后，加水稀释，用EA萃取1次，有机相用水和饱和氯化钠溶液各洗涤1次，无水Na₂SO₄干燥，过滤，浓缩得粗品淡黄色固体EVO33137-A3(1g,收率：86％)，¹H 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)。At room temperature, EVO33137-A2 (1 g, 4.90 mmol) was suspended in CH ₃ CN (30 mL) and H ₂ O (30 mL), and Oxone (8.99 g, 14.69 mmol) was added, and the reaction system was stirred at room temperature overnight. After the reaction system was concentrated, it was diluted with water and extracted once with EA, and the organic phase was washed once with water and saturated sodium chloride solution, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to obtain a crude light yellow solid EVO33137-A3 (1 g, yield: 86%), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ8.51 (d, J＝8.4 Hz, 1H), 7.82 (d, J＝8.8 Hz, 1H), 7.80-7.77 (m, 2H), 7.67-7.58 (m, 2H), 3.95 (s, 3H), 3.36 (s, 3H).

第4步：Step 4:

在充满氩气的三口瓶中，加入EVO33137-A3(200mg,0.85mmol)和DCM(5mL)，反应体系冷却到-70℃，缓慢滴加BBr₃(2.54mL,2.54mmol,1M in DCM)，滴毕，反应体系缓慢升温到室温，搅拌2小时。反应体系冷却到0℃，加水淬灭，用DCM萃取2次，合并有机相，无水Na₂SO₄干燥，过滤，浓缩得粗品，中压正相柱层析纯化(DCM/10％MeOH＝0-30％)得淡黄色固体EVO33137-A4(130mg,收率：69％)，LCMS(ESI)m/z＝221.1[M-H]^-。In a three-necked flask filled with argon, EVO33137-A3 (200 mg, 0.85 mmol) and DCM (5 mL) were added, the reaction system was cooled to -70°C, BBr ₃ (2.54 mL, 2.54 mmol, 1 M in DCM) was slowly added dropwise, 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, extracted twice with DCM, the organic phases were combined, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to obtain a crude product, which was purified by medium-pressure normal phase column chromatography (DCM/10% MeOH=0-30%) to obtain a light yellow solid EVO33137-A4 (130 mg, yield: 69%), LCMS (ESI) m/z=221.1 [MH] ^- .

第5步：Step 5:

在0℃下，将EVO33137-A4(130mg,0.58mmol)溶于吡啶(3mL)中，再缓慢滴加Tf₂O(495mg,1.75mmol)，滴毕，反应体系升到室温，搅拌过夜。反应体系浓缩后，加入EA稀释，用饱和NaHCO₃溶液、水和饱和氯化钠溶液各洗涤1次，无水Na₂SO₄干燥，过滤，浓缩得粗品，中压正相柱层析纯化(PE/DCM＝0-50％)得无色油状物EVO33137-A5(120mg,收率：58％)，¹HNMR(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)。At 0°C, EVO33137-A4 (130 mg, 0.58 mmol) was dissolved in pyridine (3 mL), and Tf ₂ O (495 mg, 1.75 mmol) was slowly added dropwise. After the addition was completed, the reaction system was warmed to room temperature and stirred overnight. After the reaction system was concentrated, EA was added to dilute it, and it was washed once with saturated NaHCO ₃ solution, water and saturated sodium chloride solution respectively, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to obtain a crude product, which was purified by medium-pressure normal phase column chromatography (PE/DCM=0-50%) to obtain a colorless oil EVO33137-A5 (120 mg, yield: 58%), ¹ HNMR (400 MHz, DMSO-d ₆ )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).

第6步：Step 6:

室温下，向单口瓶中依次加入EVO33137-A5(120mg,0.34mmol)，Pd(OAc)₂(7.6mg,0.034mmol)，DCCP-2HBF₄(21mg,0.034mmol)，K₂CO₃(140mg,1.02mmol)，H₂O(0.1mL)和DMSO(3mL)，反应体系用CO置换3次后，加热到100℃搅拌过夜。反应体系过滤，滤饼用水洗涤，滤液用EA萃取1次，有机相丢弃，水相用稀HCl(2M)调pH＝3-5，用DCM/MeOH(10/1)萃取3次后，有机相合并，浓缩得粗品，中压反相柱层析纯化(H₂O/CH₃CN＝5-50％)，冻干得白色固体EVO33137-A6(60mg,收率：70％)，LCMS(ESI)m/z＝249.1[M-H]^-。At room temperature, EVO33137-A5 (120 mg, 0.34 mmol), Pd(OAc) ₂ (7.6 mg, 0.034 mmol), DCCP-2HBF ₄ (21 mg, 0.034 mmol), K ₂ CO ₃ (140 mg, 1.02 mmol), H ₂ O (0.1 mL) and DMSO (3 mL) were added to a single-necked bottle in sequence. The reaction system was replaced with CO three times and heated to 100° C. with stirring overnight. The reaction system was filtered, the filter cake was washed with water, the filtrate was extracted once with EA, the organic phase was discarded, the aqueous phase was adjusted to pH = 3-5 with dilute HCl (2M), extracted three times with DCM/MeOH (10/1), the organic phases were combined and concentrated to obtain a crude product, purified by medium-pressure reverse phase column chromatography ( _H2O / _CH3CN = 5-50%), and freeze-dried to obtain a white solid EVO33137-A6 (60 mg, yield: 70%), LCMS (ESI) m/z = 249.1 [MH] ^- .

第7步：Step 7:

室温下，将EVO33137-A6(25mg,0.1mmol)和中间体1-A1(35mg,0.1mmol)溶于DMF(3mL)中，再依次加入TEA(51mg,0.5mmol)和HATU(76mg,0.2mmol)，反应体系在室温下搅拌1小时。反应体系加水淬灭，用EA萃取1次，有机相用水和饱和氯化钠溶液各洗涤1次，无水Na₂SO₄干燥，过滤，浓缩得粗品，用Prep-HPLC制备，冻干得黄色固体EVO33137(25mg,收率：43％)，LCMS (ESI)m/z＝582.4[M+H]⁺，纯度：98.6％，¹H 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)。At room temperature, EVO33137-A6 (25 mg, 0.1 mmol) and intermediate 1-A1 (35 mg, 0.1 mmol) were dissolved in DMF (3 mL), and TEA (51 mg, 0.5 mmol) and HATU (76 mg, 0.2 mmol) were added in sequence, and the reaction system was stirred at room temperature for 1 hour. The reaction system was quenched with water, extracted once with EA, and the organic phase was washed once with water and saturated sodium chloride solution, dried with anhydrous Na ₂ SO ₄ , filtered, and concentrated to obtain a crude product, which was prepared by Prep-HPLC and freeze-dried to obtain a yellow solid EVO33137 (25 mg, yield: 43%), LCMS (ESI) m/z = 582.4 [M + H] ⁺ , purity: 98.6%, ¹ H NMR (400 MHz, DMSO-d ₆ )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).

实施例12 EVO33167
Example 12 EVO33167

参照化合物EVO33168、EVO33137，经高效液相制备柱分离，再冷冻干燥得到黄色固体EVO33167(20.11mg,收率：31.3％)，LCMS(ESI)m/z＝572.4[M+H]⁺，纯度：99.0％，¹H 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)。The reference compounds EVO33168 and EVO33137 were separated by HPLC preparative column and freeze-dried to obtain yellow solid EVO33167 (20.11 mg, yield: 31.3%), LCMS (ESI) m/z=572.4 [M+H] ⁺ , purity: 99.0%, ¹ H NMR (400 MHz, DMSO-d ₆ )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,J ₁ ＝2.4Hz,J ₂ ＝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).

实施例13 EVO33111
Example 13 EVO33111

第一步：first step:

冰水浴条件下，反应瓶中加入5-溴-2,3-二氢苯并呋喃(1.00g,5.02mmol)和氯磺酸(2mL)，2小时后，将反应液倒入冰水中，DCM(20mL*3)萃取，有机相浓缩，中压制备纯化得EVO33111-A1(1.00g,收率：67.1％)。Under ice-water bath conditions, 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 to obtain EVO33111-A1 (1.00 g, yield: 67.1%).

第二步： Step 2:

室温下，反应瓶中加入EVO33111-A1(1.00g,3.36mmol)，亚硫酸钠(667.74mg,5.38mmol)，碳酸氢钠(451.74mg,5.38mmol)，水(10mL)和1,4-二氧六环(10mL)，油浴加热至80℃。反应结束后，中压反相制备得EVO33111-A2(1.20g,收率:>99％)。At room temperature, 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) were added to the reaction flask and heated to 80°C in an oil bath. After the reaction was completed, EVO33111-A2 (1.20 g, yield: >99%) was prepared by medium pressure reverse phase.

第三步：third step:

室温下，反应瓶中加入EVO33111-A2(1.10g,1.93mmol)和DMF(5mL)，室温下滴加CH₃I(821.50mg,5.79mmol)。反应结束后，中压制备得EVO33111-A3(290mg,收率:27.1％)。At room temperature, EVO33111-A2 (1.10 g, 1.93 mmol) and DMF (5 mL) were added to the reaction flask, and CH ₃ I (821.50 mg, 5.79 mmol) was added dropwise at room temperature. After the reaction was completed, EVO33111-A3 (290 mg, yield: 27.1%) was prepared under medium pressure.

第四步：the fourth step:

室温下，反应瓶中加入EVO33111-A3(290.00mg,1.05mmol)，醋酸钯(23.49mg,0.10mmol)，1,3-双(二环己基膦)丙烷双(四氟硼酸盐)(63.86mg,0.10mmol)，碳酸钾(433.88mg,3.14mmol)，DMSO(3mL)和水(0.3mL)，CO置换3次后，升温至80℃。反应结束后，中压制备得EVO33111-A4(20mg,收率：7.9％)。At room temperature, EVO33111-A3 (290.00 mg, 1.05 mmol), palladium acetate (23.49 mg, 0.10 mmol), 1,3-bis(dicyclohexylphosphine)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) were added to the reaction flask, CO was replaced 3 times, and the temperature was raised to 80°C. After the reaction was completed, EVO33111-A4 (20 mg, yield: 7.9%) was prepared under medium pressure.

第五步：the fifth step:

室温下，反应瓶中加入EVO33111-A4(20.00mg,0.08mmol)，中间体1-A1(28.85mg,0.08mmol)，HATU(47.09mg,0.12mmol)和DMF(5mL),室温下，加入DIPEA(42.68mg,0.33mmol)。反应结束后，用Prep-HPLC纯化，冷冻干燥得EVO33111(13mg,收率：27.5％)，LCMS(ESI)m/z＝574.36[M+H]⁺，纯度：99.80％，¹H NMR(400MHz,DMSO-d₆)δ9.41(d,J＝6.5Hz,2H),8.72-8.61(m,2H),8.27–8.19(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)。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. At room temperature, DIPEA (42.68 mg, 0.33 mmol) was added. After the reaction was completed, it 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 (400 MHz, DMSO-d ₆ )δ9.41(d,J＝6.5Hz,2H),8.72-8.61(m,2H),8.27–8.19(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).

实施例14 EVO33138
Example 14 EVO33138

第1步：step 1:

室温下，将5-溴-3-氟苯-1,2-二醇(1g,4.83mmol)溶于DMF(30mL)中，再依次加入K₂CO₃(3.34g,24.15mmol)和二溴甲烷(4.20g,24.15mmol)，反应体系加热到80℃搅拌过夜。反应结束后，冷却到室温，加入EA和水稀释，有机相用水和饱和氯化钠溶液各洗涤1次，无水Na₂SO₄干燥，过滤，浓缩得粗品，中压正相柱层析纯化(PE/DCM＝2-5％)得无色油状物EVO33138-A1(300mg，收率：28％)，¹H NMR(400MHz,DMSO-d₆)δ7.16(dd,J1,J2＝1.6Hz,9.6Hz,1H),7.12-7.11(m,1H),6.16(s,2H)。At room temperature, 5-bromo-3-fluorobenzene-1,2-diol (1 g, 4.83 mmol) was dissolved in DMF (30 mL), and K ₂ CO ₃ (3.34 g, 24.15 mmol) and dibromomethane (4.20 g, 24.15 mmol) were added in sequence. The reaction system was heated to 80°C and stirred overnight. After the reaction was completed, the mixture was cooled. The mixture was cooled to room temperature, and EA and water were added for dilution. The organic phase was washed once with water and saturated sodium chloride solution, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to obtain a crude product. The crude product was purified by medium-pressure normal phase column chromatography (PE/DCM=2-5%) to obtain a colorless oil EVO33138-A1 (300 mg, yield: 28%), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ7.16 (dd, J1, J2=1.6 Hz, 9.6 Hz, 1H), 7.12-7.11 (m, 1H), 6.16 (s, 2H).

第2步：Step 2:

室温下，将EVO33138-A1(100mg,0.46mmol)溶于DMF(3mL)中，加入NaSCH₃(479.44mg,1.37mmol,20％purity in H₂O)，反应体系在室温下搅拌过夜。反应体系加水淬灭，用EA萃取，合并有机相，用水和饱和氯化钠溶液各洗涤1次，无水Na₂SO₄干燥，过滤，浓缩得粗品无色油状物EVO33138-A2(100mg)。At room temperature, EVO33138-A1 (100 mg, 0.46 mmol) was dissolved in DMF (3 mL), and NaSCH ₃ (479.44 mg, 1.37 mmol, 20% purity in H ₂ O) was added, and the reaction system was stirred at room temperature overnight. The reaction system was quenched with water, extracted with EA, and the organic phases were combined, washed with water and saturated sodium chloride solution once each, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to obtain a crude colorless oil EVO33138-A2 (100 mg).

第3步：Step 3:

室温下，将EVO33138-A2(100mg,0.40mol)悬浮于CH₃CN(3mL)和H₂O(3mL)中，再加入Oxone(745mg,1.21mmol)，反应体系在室温下搅拌过夜。反应体系浓缩后，用EA和水稀释，合并有机相，用水和饱和氯化钠溶液各洗涤1次，无水Na₂SO₄干燥，过滤，浓缩得粗品，中压正相柱层析纯化(PE/DCM＝20-50％,DCM/10％MeOH＝10％)得白色固体EVO33138-A3(50mg，收率：44％)。At room temperature, EVO33138-A2 (100 mg, 0.40 mol) was suspended in CH ₃ CN (3 mL) and H ₂ O (3 mL), and then Oxone (745 mg, 1.21 mmol) was added, and the reaction system was stirred at room temperature overnight. After the reaction system was concentrated, it was diluted with EA and water, and the organic phases were combined, washed with water and saturated sodium chloride solution once each, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to obtain a crude product, which was purified by medium pressure normal phase column chromatography (PE/DCM=20-50%, DCM/10%MeOH=10%) to obtain a white solid EVO33138-A3 (50 mg, yield: 44%).

第4步：Step 4:

室温下，向单口瓶中依次加入EVO33138-A3(50mg,0.18mmol)，Pd(OAc)₂(4mg,0.018mol)，DCCP-2HBF₄(11mg,0.018mmol)，K₂CO₃(74mg,0.54mmol)，H₂O(0.1mL)和DMSO(3mL)，反应体系用CO置换3次后，加热到100℃搅拌过夜。反应体系冷却到室温，过滤，滤饼用水洗涤，滤液用EA洗涤1次，有机相丢弃，水相用稀HCl(1M)调pH＝3-5，再DCM/MeOH(10/1)萃取3次，合并有机相，无水Na₂SO₄干燥，过滤，浓缩得粗品，用反相柱层析纯化(H₂O/CH₃CN＝5-50％)后，冻干得白色固体EVO33138-A4(26mg，收率：59％)，LCMS(ESI)m/z＝243.1[M-H]^-。At room temperature, EVO33138-A3 (50 mg, 0.18 mmol), Pd(OAc) ₂ (4 mg, 0.018 mol), DCCP-2HBF ₄ (11 mg, 0.018 mmol), K ₂ CO ₃ (74 mg, 0.54 mmol), H ₂ O (0.1 mL) and DMSO (3 mL) were added to a single-necked bottle in sequence. The reaction system was replaced with CO three 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. The filtrate was washed once with EA. The organic phase was discarded. The aqueous phase was adjusted to pH 3-5 with dilute HCl (1 M), and then extracted with DCM/MeOH (10/1) for 3 times. The organic phases were combined, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to obtain a crude product. The crude product was purified by reverse phase column chromatography (H ₂ O/CH ₃ CN=5-50%) and freeze-dried to obtain a white solid EVO33138-A4 (26 mg, yield: 59%), LCMS (ESI) m/z=243.1 [MH] ^- .

第5步：Step 5:

室温下，将EVO33138-A4(16mg,0.065mmol)和中间体1-A1(23mg,0.065mmol)溶于DMF(3mL)中，再依次加入TEA(33mg,0.33mol)和HATU(50mg,0.13mmol)。反应在室温下搅拌1小时。反应体系用水淬灭后，用EA萃取2次，合并有机相，用水和饱和氯化钠溶液各洗涤1次，无水Na₂SO₄干燥，过滤，浓缩得粗品，中压正相柱层析纯化(DCM/EA＝10-50％,DCM/10％MeOH＝10-50％)后，冻干得黄色固体EVO33138(20mg，收率：53％)，LCMS(ESI)m/z＝576.0[M+H]⁺，纯度：98.6％，¹H 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)。At room temperature, EVO33138-A4 (16 mg, 0.065 mmol) and intermediate 1-A1 (23 mg, 0.065 mmol) were dissolved in DMF (3 mL), and TEA (33 mg, 0.33 mol) and HATU (50 mg, 0.13 mmol) were added in sequence. The reaction was stirred at room temperature for 1 hour. After the reaction system was quenched with water, it was extracted twice with EA, the organic phases were combined, washed once with water and saturated sodium chloride solution, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to obtain a crude product, which was purified by medium pressure normal phase column chromatography (DCM/EA=10-50%, DCM/10%MeOH=10-50%) and freeze-dried to obtain a yellow solid EVO33138 (20 mg, yield: 53%), LCMS (ESI) m/z=576.0 [M+H] ⁺ , purity: 98.6%, ¹ H NMR (400 MHz, DMSO-d ₆ )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).

实施例15 EVO33157
Example 15 EVO33157

参照化合物EVO33138，经高效液相制备柱分离，再冷冻干燥得到黄色固体EVO33157(10mg，收率：36％)，LCMS(ESI)m/z＝590.1[M+H]⁺，纯度：99.94％，¹H 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＝8.8Hz,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)。The reference compound EVO33138 was separated by HPLC preparative column and freeze-dried to obtain yellow solid EVO33157 (10 mg, yield: 36%), LCMS (ESI) m/z=590.1 [M+H] ⁺ , purity: 99.94%, ¹ H NMR (400 MHz, DMSO-d ₆ )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＝8.8Hz,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).

实施例16 EVO33173
Example 16 EVO33173

第1步：step 1:

室温下，向单口瓶中依次加入2,6-二溴吡啶(1g,4.22mmol)，环丙基硼酸(725mg,8.44mmol)，Pd(dppf)Cl₂·DCM(345mg,0.42mmol)，K₂CO₃(1.75g,12.66mmol)和1,4-二氧六环(20mL)，反应体系用氩气置换3次后，加热到100℃搅拌过夜。反应体系过滤，滤饼用EA洗涤，滤液浓缩后，中压正相柱层析纯化(PE/DCM＝1-5％)得无色油状物EVO33173-A1(500mg，收率：59％)，LCMS(ESI)m/z＝197.9/199.9[M+H]+。At room temperature, 2,6-dibromopyridine (1 g, 4.22 mmol), cyclopropylboronic acid (725 mg, 8.44 mmol), Pd(dppf)Cl ₂ ·DCM (345 mg, 0.42 mmol), K ₂ CO ₃ (1.75 g, 12.66 mmol) and 1,4-dioxane (20 mL) were added to a single-mouth bottle in sequence. The reaction system was replaced with argon three times, and then heated to 100°C and stirred overnight. The reaction system was filtered, 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 obtain a colorless oil EVO33173-A1 (500 mg, yield: 59%), LCMS (ESI) m/z=197.9/199.9 [M+H]+.

第2步： Step 2:

室温下，向单口瓶中依次加入EVO33173-A1(180mg,0.91mmol)，六甲基二锡(596mg,1.82mmol)，Pd(PPh₃)₄(105mg,0.091mmol)和1,4-二氧六环(5mL)，反应体系用氩气置换3次后，加热到100℃搅拌3小时。反应结束后，将反应体系冷却到室温，加入KF(aq.)搅拌30分钟，过滤，滤饼用EA洗涤，分液，合并有机相，用水和饱和氯化钠溶液各洗涤1次，无水Na₂SO₄干燥，过滤，浓缩得粗品棕色油状物EVO33173-A2(300mg)。At room temperature, EVO33173-A1 (180 mg, 0.91 mmol), hexamethyltin (596 mg, 1.82 mmol), Pd(PPh ₃ ) ₄ (105 mg, 0.091 mmol) and 1,4-dioxane (5 mL) were added to a single-mouth bottle in sequence. The reaction system was replaced with argon three times and heated to 100°C and stirred for 3 hours. After the reaction was completed, the reaction system was cooled to room temperature, KF (aq.) was added and stirred for 30 minutes, filtered, the filter cake was washed with EA, separated, the organic phases were combined, washed once with water and saturated sodium chloride solution, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to obtain a crude brown oil EVO33173-A2 (300 mg).

第3步：Step 3:

室温下，向单口瓶中依次加入中间体2(120mg,0.41mmol)，EVO33173-A2(230mg,0.82mmol)，Pd(PPh₃)₂Cl₂(58mg,0.082mol)和1,4-二氧六环(5mL)。反应体系用氩气置换3次后，加热到110℃搅拌过夜。反应体系冷却到室温，浓缩得粗品，中压正相柱层析纯化(PE/EA＝0-50％)得淡黄色油状物EVO33173-A3(100mg，收率：65％)，LCMS(ESI)m/z＝377.2[M+H]⁺。At room temperature, intermediate 2 (120 mg, 0.41 mmol), EVO33173-A2 (230 mg, 0.82 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (58 mg, 0.082 mol) and 1,4-dioxane (5 mL) were added to a single-mouth bottle in sequence. The reaction system was replaced with argon three times, heated to 110°C and stirred overnight. The reaction system was cooled to room temperature and concentrated to obtain a crude product, which was purified by medium-pressure normal phase column chromatography (PE/EA=0-50%) to obtain a light yellow oil EVO33173-A3 (100 mg, yield: 65%), LCMS (ESI) m/z=377.2[M+H] ⁺ .

第4步：Step 4:

室温下，将EVO33173-A3(30mg,0.08mmol)溶于DCM(3mL)中，加入TFA(1.5mL)，反应体系在室温下搅拌1小时。反应体系浓缩得粗品淡黄色油状物EVO33173-A4(25mg)，LCMS(ESI)m/z＝277.2[M+H]⁺。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 a crude light yellow oil EVO33173-A4 (25 mg), LCMS (ESI) m/z = 277.2 [M+H] ⁺ .

第5步：Step 5:

室温下，将EVO33127-A3(20mg,0.083mmol)和EVO33173-A4(23mg,0.083mol)溶于DMF(3mL)中，再依次加入TEA(42mg,0.42mmol)和HATU(63mg,0.17mmol)，反应体系在室温下搅拌1小时。反应加水淬灭，用EA萃取1次，合并有机相，用水和饱和氯化钠溶液各洗涤1次，无水Na₂SO₄干燥，过滤，浓缩得粗品，用Prep-HPLC制备，冻干得白色固体EVO33173(20mg，收率：48％)，LCMS(ESI)m/z＝499.0[M+H]⁺，纯度：99.68％，¹H NMR(400MHz,DMSO-d₆)δ9.47(t,J＝6.0Hz,1H),9.40(s,1H),8.69-8.60(m,2H),8.33(d,J＝8.0Hz,1H),8.27(s,1H),8.18(s,1H),7.86-7.81(m,2H),7.47-7.45(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)。At room temperature, EVO33127-A3 (20 mg, 0.083 mmol) and EVO33173-A4 (23 mg, 0.083 mol) were dissolved in DMF (3 mL), and TEA (42 mg, 0.42 mmol) and HATU (63 mg, 0.17 mmol) were added in sequence, and the reaction system was stirred at room temperature for 1 hour. The reaction was quenched with water, extracted once with EA, and the organic phases were combined, washed once with water and saturated sodium chloride solution, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to obtain a crude product, which was prepared by Prep-HPLC and freeze-dried to obtain white solid EVO33173 (20 mg, yield: 48%), LCMS (ESI) m/z=499.0 [M+H] ⁺ , purity: 99.68%, ¹ H NMR (400 MHz, DMSO-d ₆ )δ9.47(t,J＝6.0Hz,1H),9.40(s,1H),8.69-8.60(m,2H),8.33(d,J＝8.0Hz,1H),8.27(s,1H),8.18(s,1H),7.86-7.81(m,2H),7.47-7.45(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).

实施例17 EVO33175
Example 17 EVO33175

参照化合物EVO33173，经高效液相制备柱分离，再冷冻干燥得到白色固体EVO33175(17mg，收率：43％)，LCMS(ESI)m/z＝503.0[M+H]⁺，纯度：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)。 The reference compound EVO33173 was separated by HPLC preparative column and freeze-dried to obtain white solid EVO33175 (17 mg, yield: 43%), LCMS (ESI) m/z=503.0 [M+H] ⁺ , purity: 99.74%, ¹ H NMR (400 MHz, DMSO-d ₆ )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).

实施例18 EVO33174
Example 18 EVO33174

第1步：step 1:

25mL反应瓶中，加入中间体2(100mg,340.62μmol)，EVO33174-A1(54mg,283.85μmol)，新烘干的Cs₂CO₃固体(277mg,851.55μmol)，Ruphos(26mg,56.77μmol，Ruphos-pd-G₃(24mg,28.39μmol)，无水二氧六环(5mL)，Ar气置换3次，油浴110℃反应2.5小时。冷却至室温，过滤，滤饼用EA淋洗，滤液减压浓缩过中压柱(PE:EA＝0-30％),得淡黄色粘稠物EVO33174-A2(44mg,收率：34.6％)，¹H 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＝8.0Hz,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)。In a 25 mL reaction bottle, intermediate 2 (100 mg, 340.62 μmol), EVO33174-A1 (54 mg, 283.85 μmol), freshly dried Cs ₂ CO ₃ solid (277 mg, 851.55 μmol), Ruphos (26 mg, 56.77 μmol, Ruphos-pd-G ₃ (24 mg, 28.39 μmol), anhydrous dioxane (5 mL) were added, and the Ar gas was replaced three times. The reaction was carried out at 110 ° C in an oil bath for 2.5 hours. Cool to room temperature, filter, rinse the filter cake with EA, and concentrate the filtrate under reduced pressure 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 (400 MHz, DMSO-d ₆ )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＝8.0Hz,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).

第2步：Step 2:

25mL反应瓶，加入EVO33174-A2(39mg,87.15μmol)，DCM(1.0mL)，冰水浴，Ar保护，加入TFA(0.5mL)，冰水浴搅拌20分钟，转室温搅拌1.5小时。减压浓缩，加入EA(10mL)，用饱和碳酸氢钠溶液调pH＝7～8，EA萃取(10mL*2)，合并有机相，用水和饱和氯化钠溶液各洗1次，无水Na₂SO₄干燥，过滤，减压浓缩得淡黄色粘稠物EVO33174-A3(粗品36mg,收率:>99％)，LCMS(ESI)m/z＝348.2[M+H]⁺。In a 25 mL reaction bottle, add EVO33174-A2 (39 mg, 87.15 μmol), DCM (1.0 mL), ice-water bath, Ar protection, add TFA (0.5 mL), stir in ice-water bath for 20 minutes, and stir at room temperature for 1.5 hours. Concentrate under reduced pressure, add EA (10 mL), adjust pH to 7-8 with saturated sodium bicarbonate solution, extract with EA (10 mL*2), combine the organic phases, wash once with water and saturated sodium chloride solution, dry over anhydrous Na ₂ SO ₄ , filter, and concentrate under reduced pressure to obtain a light yellow viscous EVO33174-A3 (crude product 36 mg, yield:> 99%), LCMS (ESI) m/z = 348.2 [M+H] ⁺ .

第3步：Step 3:

50mL反应瓶，加入EVO33127-A3(21mg,87.40μmol)，EVO33174-A3(30mg,87.40μmol)，TEA(44mg,437.00μmol,60.91μL)和无水DMF(2mL)，Ar保护，最后加入HATU(66mg,174.80μmol)，室温搅拌1.5小时。向反应体系加水，用EA萃取(15mL*3)，合并有机相，用水和饱和氯化钠溶液各洗1次，无水Na₂SO₄干燥，过滤，滤液减压浓缩得黄色粘稠物，用Prep-HPLC纯化，冷冻干燥，得到类白色固体EVO33174(22mg,收率:44.2％)，LCMS(ESI)m/z＝570.0[M+H]⁺，纯度：93.9％，¹H 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＝8.0Hz,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)。In a 50 mL reaction bottle, add 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 protection, and finally add HATU (66 mg, 174.80 μmol), stir at room temperature for 1.5 hours. Add water to the reaction system, extract with EA (15 mL*3), combine the organic phases, and use water and saturated chloride to remove the residue. The mixture was washed once with sodium solution, dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure to obtain a yellow viscous product, which was purified by Prep-HPLC and freeze-dried to obtain an off-white solid EVO33174 (22 mg, yield: 44.2%), LCMS (ESI) m/z=570.0[M+H] ⁺ , purity: 93.9%, ¹ H NMR (400 MHz, DMSO-d6) δ9.42 (t, J=2.0 Hz, 1H), 9.10 (s, 1H), 8.46 (d, J=9.2 Hz, 1H), 8.32 (d, J=9.2 Hz, 1H), 8.27 (d, J=1.6 Hz, 1H), 8.17 (d, J=1.6 Hz, 1H), 7.49 (s, 1H), 7.24 (d, J=8.0 Hz, 1H), 6.89 (d, J=8.0 Hz, 1H). z, 1H), 4.73 (d, J = 6.0 Hz, 2H), 4.40-4.26 (m, 4H), 3.59-3.48 (m, 1H), 3.28 (t, J = 7.2 Hz, 2H), 3.23 (s, 3H), 3.02 (t, J = 7.6 Hz, 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).

实施例19 EVO33071
Example 19 EVO33071

参照化合物EVO33174，经高效液相制备柱分离，再冷冻干燥得到淡黄色固体EVO33071(8mg，收率：17％)，LCMS(ESI)m/z＝629.9[M+H]⁺，纯度：97.9％，¹H 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)。The reference compound EVO33174 was separated by HPLC preparative column and then freeze-dried to obtain a light yellow solid EVO33071 (8 mg, yield: 17%), LCMS (ESI) m/z=629.9 [M+H] ⁺ , purity: 97.9%, ¹ H NMR (400 MHz, DMSO-d ₆ )δ9.61(t, J=6.0 Hz, 1H), 9.11(s, 1H), 8.31(d, J=9.2 Hz, 1H), 8.19(d, J=9.6 Hz, 1H), 8.15(d, J=1.2 Hz, 1H), 8.01(s, 1H), 7.53(s, 1H), 7.33(d, J=8.0 Hz, 1H), 7.12(d, J=8.0 Hz, 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).

实施例20 EVO33176
Example 20 EVO33176

参照化合物EVO33174，经高效液相制备柱分离，再冷冻干燥得到白色固体EVO33176(10mg，收率：21％)，LCMS(ESI)m/z＝554.0[M+H]⁺，纯度：93.4％，¹H NMR(400MHz,DMSO-d₆)δ9.40(t,J＝6.0Hz,1H),9.05(s,1H),8.26(s,1H),8.18-8.16(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,2H),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)。The reference compound EVO33174 was separated by HPLC preparative column and freeze-dried to obtain white solid EVO33176 (10 mg, yield: 21%), LCMS (ESI) m/z=554.0 [M+H] ⁺ , purity: 93.4%, ¹ H NMR (400 MHz, DMSO-d ₆ )δ9.40(t,J＝6.0Hz,1H),9.05(s,1H),8.26(s,1H),8.18-8.16(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,2H),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).

实施例21 EVO33177
Example 21 EVO33177

参照化合物EVO33174，经高效液相制备柱分离，再冷冻干燥得到淡黄色固体EVO33177(6mg，收率：14％)，LCMS(ESI)m/z＝556.4[M+H]⁺，纯度：97.7％，¹H 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)。The reference compound EVO33174 was separated by HPLC preparative column and freeze-dried to obtain a light yellow solid EVO33177 (6 mg, yield: 14%), LCMS (ESI) m/z=556.4 [M+H] ⁺ , purity: 97.7%, ¹ H NMR (400 MHz, DMSO-d ₆ )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).

实施例22 EVO33321
Example 22 EVO33321

参照化合物EVO33174，经高效液相制备柱分离，再冷冻干燥得到白色固体EVO33321(21.52mg,收率44.9％)，LCMS(ESI)m/z＝568.42[M+H]⁺，HPLC纯度：99.65％，¹H 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＝5.2Hz,2H),4.54–4.48(m,2H),4.43–4.36(m,2H),3.32(t,J＝7.5Hz,2H),3.15(q,J＝7.4Hz,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)。The reference compound EVO33174 was separated by HPLC preparative column and freeze-dried to obtain white solid EVO33321 (21.52 mg, yield 44.9%), LCMS (ESI) m/z=568.42 [M+H] ⁺ , HPLC purity: 99.65%, ¹ H NMR (400 MHz, CDCl ₃ )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＝5.2Hz,2H),4.54–4.48(m,2H),4.43–4.36(m,2H),3.32(t,J＝7.5Hz,2H),3.15(q,J＝7.4Hz,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).

实施例23 EVO33162
Example 23 EVO33162

参照化合物EVO33138，得黄色固体EVO33162(25mg,收率：49％)。LCMS(ESI)m/z＝590.4[M+H]⁺。纯度：99.42％。¹H 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)。 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 (400 MHz, DMSO-d ₆ ) δ 9.42-9.39 (m, 2H), 8.64 (q, J=8.8 Hz, 2H), 7.91-7.89 (m, 2H), 7.80-7.73 (m, 3H), 7.03 (d, J=8.4 Hz, 1H), 6.35 (s, 2H), 4.77 (d, J=5.6 Hz, 2H), 4.32 (d, J=12.4 Hz, 2H), 3.70-3.65 (m, 2H), 3.38 (q, J=7.2 Hz, 2H), 2.53-2.46 (m, 2H), 1.22-1.16 (m, 9H).

实施例24 EVO33163
Example 24 EVO33163

参照化合物EVO33138，用prep-HPLC制备后，冻干得黄色固体EVO33163(30mg,收率：75％)。LCMS(ESI)m/z＝604.4[M+H]⁺。纯度：99.20％。¹H 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)。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 (400 MHz, DMSO-d ₆ ) δ 9.42-9.39 (m, 2H), 8.64 (q, J=8.8 Hz, 2H), 7.92-7.86 (m, 2H), 7.81-7.73 (m, 3H), 7.03 (d, J=8.4 Hz, 1H), 6.33 (s, 2H), 4.77 (d, J=5.6 Hz, 2H), 4.32 (d, J=12.4 Hz, 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).

实施例25 EVO33110
Example 25 EVO33110

第1步：step 1:

室温下，4-溴-2,6-二氟苯乙酸(3g,11.95mmol,1.69mL)溶于THF(30mL)，加入CDI(2.91g,17.93mmol)，监测原料消失后，加入硼氢化钠(904.27mg,23.90mmol)，搅拌过夜。反应结束后，加入甲醇淬灭反应，蒸干溶剂，加入水(50mL)，EA(3*30mL)萃取，有机相浓缩中压制备得EVO33110-A1(1.6g,收率：56.84％)。¹H NMR(400MHz,Chloroform-d)δ7.10-7.02(m,2H),3.82(t,J＝6.7Hz,2H),2.90(d,J＝1.3Hz,2H)。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, and after monitoring the disappearance of the starting material, sodium borohydride (904.27 mg, 23.90 mmol) was added and stirred overnight. After the reaction was completed, methanol was added to quench the reaction, the solvent was evaporated, water (50 mL) was added, and EA (3*30 mL) was extracted. The organic phase was concentrated and medium pressure was used to prepare EVO33110-A1 (1.6 g, yield: 56.84%). ¹ H NMR (400 MHz, Chloroform-d) δ7.10-7.02 (m, 2H), 3.82 (t, J = 6.7 Hz, 2H), 2.90 (d, J = 1.3 Hz, 2H).

第2步：Step 2:

室温下，EVO33110-A1(1.2g,5.06mmol)溶于THF(20mL)，加入叔丁醇钾(1.70g,15.19mmol)，反应结束后，饱和氯化钠溶液(20mL)洗涤，有机相浓缩，中压制备得EVO33110-A2(400mg,收率：36.41％)。¹H NMR(400MHz,Chloroform-d)δ6.77-6.71(m,2H),4.63(t,J＝8.7Hz,2H),3.19(td,J＝8.8,1.1Hz,2H)。At room temperature, EVO33110-A1 (1.2 g, 5.06 mmol) was dissolved in THF (20 mL), potassium tert-butoxide (1.70 g, 15.19 mmol) was added, and after the reaction was completed, it was washed with saturated sodium chloride solution (20 mL), and the organic phase was concentrated and EVO33110-A2 (400 mg, yield: 36.41%) was prepared under medium pressure. ¹ H NMR (400 MHz, Chloroform-d) δ 6.77-6.71 (m, 2H), 4.63 (t, J = 8.7 Hz, 2H), 3.19 (td, J = 8.8, 1.1 Hz, 2H).

第3步： Step 3:

室温下，EVO33110-A2(240mg,1.11mmol)溶于DMF(5mL)，加入甲硫醇钠(116.26mg,1.66mmol)，升温至120℃过夜。反应结束后，加入水(50mL)，EA(3*30mL)萃取，有机相浓缩，中压制备得EVO33110-A3(184mg，收率：67.88％)。At room temperature, EVO33110-A2 (240 mg, 1.11 mmol) was dissolved in DMF (5 mL), sodium thiomethoxide (116.26 mg, 1.66 mmol) was added, and the temperature was raised to 120°C overnight. After the reaction was completed, water (50 mL) was added, EA (3*30 mL) was extracted, the organic phase was concentrated, and EVO33110-A3 (184 mg, yield: 67.88%) was prepared under medium pressure.

第4步：Step 4:

室温下，EVO33110-A3(184mg,750.60μmol)溶于乙腈(10mL)和水(10mL)，加入Oxone(460.87mg,750.60μmol)，30℃过夜。反应结束后，过滤，蒸出乙腈，加入水(50mL)，EA(3*30mL)萃取，有机相浓缩得EVO33110-A4(110mg，收率：52.88％)，粗品直接用于下一步。At room temperature, EVO33110-A3 (184 mg, 750.60 μmol) was dissolved in acetonitrile (10 mL) and water (10 mL), and Oxone (460.87 mg, 750.60 μmol) was added, and the mixture was kept at 30°C overnight. After the reaction was completed, the mixture was filtered, acetonitrile was evaporated, water (50 mL) was added, and EA (3*30 mL) was added for extraction. The organic phase was concentrated to obtain EVO33110-A4 (110 mg, yield: 52.88%), and the crude product was used directly in the next step.

第5步：Step 5:

室温下，EVO33110-A4(110mg,396.92μmol)溶于DMSO(5mL)和水(0.5mL)，再加入醋酸钯(17.82mg,79.38μmol)、1,3-双(二环己基膦)丙烷双(四氟硼酸盐)(48.44mg,79.38μmol)和碳酸钾(164.57mg,1.19mmol)，CO氛围下，110℃过夜。反应结束后，反相制备得EVO33110-A5(41mg，收率：42.64％)。At room temperature, EVO33110-A4 (110 mg, 396.92 μmol) was dissolved in DMSO (5 mL) and water (0.5 mL), and palladium acetate (17.82 mg, 79.38 μmol), 1,3-bis(dicyclohexylphosphine)propane bis(tetrafluoroborate) (48.44 mg, 79.38 μmol) and potassium carbonate (164.57 mg, 1.19 mmol) were added, and the mixture was heated at 110 ° C overnight under CO atmosphere. After the reaction, EVO33110-A5 (41 mg, yield: 42.64%) was prepared by reverse phase.

第6步：Step 6:

室温下，EVO33110-A5(20mg,82.56μmol)溶于DMF(2mL),再加入中间体1-A1(28.85mg,82.56μmol)、三乙胺(41.69mg,412.80μmol)和HATU(69.06mg,181.63μmol)，搅拌过夜。反应结束后，反应液中加入水(50mL)，EA(3*30mL)萃取，有机相浓缩高压制备，得EVO33110(14mg,收率：29.56％)。LCMS(ESI)m/z＝574.01[M+H]⁺。纯度：99.25％。¹H NMR(400MHz,DMSO-d₆)δ9.46(t,J＝6.0Hz,1H),9.39(s,1H),8.64(q,J＝8.8Hz,2H),7.96(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),3.72-3.63(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)。At room temperature, EVO33110-A5 (20 mg, 82.56 μmol) was dissolved in DMF (2 mL), and then intermediate 1-A1 (28.85 mg, 82.56 μmol), triethylamine (41.69 mg, 412.80 μmol) and HATU (69.06 mg, 181.63 μmol) were added and stirred overnight. After the reaction, water (50 mL) was added to the reaction solution, and EA (3*30 mL) was used for extraction. The organic phase was concentrated and prepared under high pressure to obtain EVO33110 (14 mg, yield: 29.56%). LCMS (ESI) m/z = 574.01 [M+H] ⁺ . Purity: 99.25%. ¹ H NMR (400 MHz, DMSO-d ₆ )δ9.46(t,J＝6.0Hz,1H),9.39(s,1H),8.64(q,J＝8.8Hz,2H),7.96(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),3.72-3.63(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).

实施例26 EVO33357
Example 26 EVO33357

参照化合物EVO33110，经高效液相制备柱分离，再冷冻干燥得到黄色固体EVO33357(1.8mg，收率：5.45％)，LCMS(ESI)m/z＝588.41[M+H]⁺，纯度：92.5％。¹H 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＝8.8Hz,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)。The reference compound EVO33110 was separated by HPLC preparative column and then freeze-dried to obtain yellow solid EVO33357 (1.8 mg, yield: 5.45%), LCMS (ESI) m/z=588.41 [M+H] ⁺ , purity: 92.5%. ¹ H NMR (400 MHz, DMSO-d ₆ )δ9.46 (t, J=5.6 Hz, 1H), 9.39 (s, 1H), 8.64 (q, J=8.8 Hz, 2H), 7.91 (t, J=4.4 Hz, 2H), 7.80 (s, 1H), 7.75 (t, J=8.0 Hz, 1H), 7.68 (s, 1H), 7.03 (d, J=8.4 Hz, 1H), 4.79 (d, J=5.6 Hz , 2H), 4.71(t, J＝8.8Hz, 2H), 4.38-4.27(m, 2H), 3.71-3.62(m, 2H), 3.56(t, J＝8.8Hz, 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).

实施例27 EVO33115
Example 27 EVO33115

第1步：step 1:

室温下，4-溴-2-氟-6-甲基苯甲酸(4g,17.16mmol)溶于水(40mL)，再加入KMnO₄(8.14g,51.49mmol)和NaOH(2.75g,68.66mmol)，80℃过夜。反应结束后，过滤，滤液用1N盐酸酸化至pH＝3，EA(3*50mL)萃取，合并有机相，无水Na₂SO₄干燥，过滤，蒸干滤液得EVO33115-A1(4g,收率：88.60％)。¹H NMR(400MHz,DMSO-d₆)δ7.95(dd,J＝8.9,1.8Hz,1H),7.85(d,J＝1.8Hz,1H).At room temperature, 4-bromo-2-fluoro-6-methylbenzoic acid (4 g, 17.16 mmol) was dissolved in water (40 mL), and KMnO ₄ (8.14 g, 51.49 mmol) and NaOH (2.75 g, 68.66 mmol) were added, and the mixture was heated at 80°C overnight. After the reaction was completed, the mixture was filtered, and the filtrate was acidified to pH = 3 with 1N hydrochloric acid, extracted with EA (3*50 mL), and the organic phases were combined, dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was evaporated to obtain EVO33115-A1 (4 g, yield: 88.60%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ7.95 (dd, J = 8.9, 1.8 Hz, 1H), 7.85 (d, J = 1.8 Hz, 1H).

第2步：Step 2:

EVO33115-A1(8g,30.42mmol)溶于甲醇(150mL)和浓硫酸(14.92g,152.08mmol)，回流过夜。反应结束后，蒸去溶剂后，加入水(100mL)，EA(3*50mL)萃取，合并有机相，无水Na₂SO₄干燥，过滤，有机相浓缩，中压制备得EVO33115-A2(8.5g,收率：96.01％)。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 was completed, the solvent was evaporated, water (100 mL) was added, EA (3*50 mL) was extracted, the organic phases were combined, dried over anhydrous Na ₂ SO ₄ , filtered, the organic phase was concentrated, and EVO33115-A2 (8.5 g, yield: 96.01%) was prepared under medium pressure.

第3步：Step 3:

0℃下，EVO33115-A2(8.5g,29.20mmol)溶于无水THF(50mL)，加入四氢铝锂(2.44g,64.25mmol)，反应结束后，加水(5mL)淬灭，过滤，滤液加入水(100mL)，EA(3*50mL)萃取，有机相浓缩，中压制备得EVO33115-A3(4.5g,收率：65.56％)。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.

第4步：Step 4:

室温下，EVO33115-A3(4.6g,19.57mmol)溶于二氯甲烷(50mL)，加入二氧化锰(8.17g,93.94mmol)，原料消失后，过滤，取滤液，加入三乙基硅烷(6.83g,58.71mmol)和三氟乙酸(10.71g,93.94mmol)，2小时后，反应结束，蒸去溶剂后，加入水(100mL)，EA(3*50mL)萃取，有机相浓缩，中压制备得EVO33115-A4(3.6g,收率：84.76％)。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 raw 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 evaporating the solvent, water (100 mL) was added, and EA (3*50 mL) was used for extraction. The organic phase was concentrated and EVO33115-A4 (3.6 g, yield: 84.76%) was prepared under medium pressure.

第5步：Step 5:

室温下，EVO33115-A4(220mg,1.01mmol)溶于DMF(5mL)，加入甲硫醇钠(355.24mg,5.07mmol)，反应升温至100℃，2小时后反应结束，加入水(30mL)，EA(3*50mL)萃取，有机相蒸干得EVO33115-A5(90mg,收率：36.22％)，直接用于下一步。At room temperature, EVO33115-A4 (220 mg, 1.01 mmol) was dissolved in DMF (5 mL), sodium thiomethoxide (355.24 mg, 5.07 mmol) was added, and the reaction temperature was raised to 100 ° C. After 2 hours, the reaction was completed, water (30 mL) was added, and EA (3*50 mL) was extracted. The organic phase was evaporated to dryness to obtain EVO33115-A5 (90 mg, yield: 36.22%), which was directly used in the next step.

第6步：Step 6:

室温下，EVO33115-A5(260mg,1.06mmol)溶于乙腈(10mL)和水(10mL)，加入Oxone(3.26g, 5.30mmol)，然后升温至60℃，1小时后反应结束，蒸去乙腈，加入水(30mL)，EA(3*50mL)萃取，有机相蒸干得EVO33115-A6(290mg,收率：98.66％)，直接用于下一步。At room temperature, EVO33115-A5 (260 mg, 1.06 mmol) was dissolved in acetonitrile (10 mL) and water (10 mL), and Oxone (3.26 g, 5.30mmol), then heated to 60°C. After 1 hour, the reaction was completed, acetonitrile was evaporated, water (30mL) was added, and EA (3*50mL) was extracted. The organic phase was evaporated to dryness to obtain EVO33115-A6 (290mg, yield: 98.66%), which was directly used in the next step.

第7步：Step 7:

室温下，EVO33115-A6(90mg,324.75μmol)，加入DMSO(5mL)、水(0.5mL)、醋酸钯(14.58mg,64.95μmol)、1,3-双(二环己基膦)丙烷双(四氟硼酸盐)(39.64mg,64.95μmol)和碳酸钾(134.65mg,974.26μmol)，CO氛围下，100℃反应过夜。结束后，反相制备得EVO33115-A7(10mg，收率：12.71％)。At room temperature, EVO33115-A6 (90 mg, 324.75 μmol) was added with DMSO (5 mL), water (0.5 mL), palladium acetate (14.58 mg, 64.95 μmol), 1,3-bis(dicyclohexylphosphine)propane bis(tetrafluoroborate) (39.64 mg, 64.95 μmol) and potassium carbonate (134.65 mg, 974.26 μmol), and reacted at 100 °C overnight under CO atmosphere. After completion, EVO33115-A7 (10 mg, yield: 12.71%) was prepared by reverse phase.

第8步：Step 8:

室温下，EVO33115-A7(10mg,41.28μmol)溶于DMF(2mL)，再加入中间体1-A1(21.64mg,61.92μmol)、DIPEA(21.34mg,165.12μmol)和HATU(23.54mg,61.92μmol)，搅拌过夜。反应结束后，加入水(50mL)，EA(3*30mL)萃取，有机相浓缩高压制备，得EVO33115(14mg,收率：59.12％)。LCMS(ESI)m/z＝574.4[M+H]⁺。纯度：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)。At room temperature, EVO33115-A7 (10 mg, 41.28 μmol) was dissolved in DMF (2 mL), and then intermediate 1-A1 (21.64 mg, 61.92 μmol), DIPEA (21.34 mg, 165.12 μmol) and HATU (23.54 mg, 61.92 μmol) were added and stirred overnight. After the reaction was completed, water (50 mL) was added, EA (3*30 mL) was extracted, and the organic phase was concentrated and prepared under high pressure to obtain EVO33115 (14 mg, yield: 59.12%). LCMS (ESI) m/z = 574.4 [M+H] ⁺ . Purity: 98.4%. ¹ H NMR (400 MHz, DMSO-d ₆ )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).

实施例28 EVO33369
Example 28 EVO33369

参照化合物EVO33115，经高效液相制备柱分离，再冷冻干燥得到黄色固体EVO33369(10mg，收率：36.34％)，LCMS(ESI)m/z＝588.4[M+H]⁺，纯度：95.8％。¹H 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,2H),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)。The reference compound EVO33115 was separated by HPLC preparative column and freeze-dried to obtain yellow solid EVO33369 (10 mg, yield: 36.34%), LCMS (ESI) m/z=588.4 [M+H] ⁺ , purity: 95.8%. ¹ H NMR (400 MHz, DMSO-d ₆ )δ9.59 (t, J=6.0 Hz, 1H), 9.40 (s, 1H), 8.65 (q, J=8.4 Hz, 2H), 8.32 (s, 1H), 8.27 (s, 1H), 7.90 (d, J=7.2 Hz, 1H), 7.83 (s, 1H), 7.77-7.73 (m, 1H), 7.03 (d, J=8.4 Hz, 1H), 5.32 (s, 2H), 5.14 (s, 2H), 4.82 (d, J = 5.6 Hz, 2H), 4.34-4.28 (m, 2H), 3.75-3.62 (m, 2H), 3.38 (q, J = 7.2 Hz, 2H), 2.53-2.47 (m, 2H), 1.21 (d, J = 6.0 Hz, 6H), 1.15 (t, J = 7.2 Hz, 3H).

实施例29 EVO33124

Example 29 EVO33124

第1步：step 1:

将8-氟-2,3-二氢苯并吡喃-4-酮(900mg,5.42mmol)及三乙基硅烷(2.52g,21.67mmol)加入到三氟乙酸(5mL)中，在25℃下反应72小时。TLC监测反应完毕，反应液减压浓缩，中压正相快速柱层析得到无色油状物EVO33124-A1(670mg，收率：81％)。8-Fluoro-2,3-dihydrobenzopyran-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. After the reaction was completed by TLC monitoring, the reaction solution was concentrated under reduced pressure, and medium-pressure normal phase flash column chromatography was used to obtain a colorless oil EVO33124-A1 (670 mg, yield: 81%).

第2步：Step 2:

将化合物EVO33124-A1(530mg,3.49mmol)加入到乙酸(5mL)中，再加入溴素(613mg,3.84mmol)，在25℃下反应15分钟。TLC监测反应完毕，反应液减压浓缩，中压正相快速柱层析得到无色油状物EVO33124-A2(450mg，收率：55％)。Compound EVO33124-A1 (530 mg, 3.49 mmol) was added to acetic acid (5 mL), and then bromine (613 mg, 3.84 mmol) was added, and the mixture was reacted at 25°C for 15 minutes. After the reaction was completed by TLC monitoring, the reaction solution was concentrated under reduced pressure, and medium-pressure normal phase flash column chromatography was performed to obtain a colorless oil EVO33124-A2 (450 mg, yield: 55%).

第3步：Step 3:

将化合物EVO33124-A2(176mg,0.76mmol)及甲硫醇钠(80mg,1.14mmol)加入到DMF(2mL)中，在50℃下反应2小时。反应完毕，将反应中加入EA和水，分层萃取，合并有机相，无水Na₂SO₄干燥，过滤，减压浓缩得粗品，中压正相柱层析纯化(PE/EA＝50/1)，得到产物EVO33124-A3(165mg，收率：83％)。¹H 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).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 the reaction was completed, EA and water were added to the reaction mixture, and the organic phases were separated and extracted. The organic phases were combined, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to obtain a crude product, which 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 (400 MHz, Chloroform-d) δ7.00 (s, 1H), 6.97 (s, 1H), 4.26 (t, J=5.2 Hz 2H), 2.75 (t, J=6.4 Hz, 2H), 2.41 (s, 3H), 2.05-1.94 (m, 2H).

第4步：Step 4:

室温下，将EVO33124-A3(165mg,0.64mmol)溶于乙腈(2mL)和水(2mL)溶液中，加入固体Oxone(1.17g,1.91mmol)，反应搅拌过夜。反应完毕，将反应液浓缩，加入EA和水，分层萃取，合并有机相，无水Na₂SO₄干燥，过滤，减压浓缩得粗品，中压正相柱层析纯化(PE/EA＝10/1)，得到产物EVO33124-A4(176mg，收率：94％)。At room temperature, EVO33124-A3 (165 mg, 0.64 mmol) was dissolved in acetonitrile (2 mL) and water (2 mL) solution, solid Oxone (1.17 g, 1.91 mmol) was added, and the reaction was stirred overnight. After the reaction was completed, the reaction solution was concentrated, EA and water were added, and the organic phases were combined, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by medium pressure normal phase column chromatography (PE/EA=10/1) to obtain the product EVO33124-A4 (176 mg, yield: 94%).

第5步：Step 5:

室温下，向单口瓶中依次加入EVO33124-A4(176mg,0.604mmol)，Pd(OAc)₂(14mg,0.06mmol)，DCCP-2HBF₄(74mg,0.121mmol)，K₂CO₃(167mg,1.21mmol)，H₂O(0.1mL)和DMSO(3mL)，反应体系用CO置换3次后，加热到100℃搅拌过夜。反应结束后，用稀HCl(1M)调pH＝3，用中压反相柱层析纯化(H₂O/CH₃CN＝0-50％)，冻干得白色固体EVO33124-A5(65mg，收率：41％)，LCMS(ESI)m/z＝255.2[M-H]^-。At room temperature, EVO33124-A4 (176 mg, 0.604 mmol), Pd(OAc) ₂ (14 mg, 0.06 mmol), DCCP-2HBF ₄ (74 mg, 0.121 mmol), K ₂ CO ₃ (167 mg, 1.21 mmol), H ₂ O (0.1 mL) and DMSO (3 mL) were added to a single-mouth bottle in sequence. The reaction system was replaced with CO 3 times, and then heated to 100°C and stirred overnight. After the reaction was completed, the pH was adjusted to 3 with dilute HCl (1 M), and the product was purified by medium-pressure reverse phase column chromatography (H ₂ O/CH ₃ CN=0-50%) and freeze-dried to obtain white solid EVO33124-A5 (65 mg, yield: 41%), LCMS (ESI) m/z=255.2 [MH] ^- .

第6步： Step 6:

室温下，将EVO33124-A5(23mg,0.089mmol)和中间体1-A1(31mg,0.089mmol)溶于DMF(3mL)中，依次加入DIPEA(35mg,0.267mmol)和HATU(51mg,0.134mmol)，反应体系在室温下搅拌1小时。反应完毕，反应体系加水淬灭，用EA萃取2次，合并有机相，水和饱和氯化钠溶液各洗涤1次，无水Na₂SO₄干燥，过滤，浓缩得粗品，Prep-HPLC制备后，冻干得淡黄色固体EVO33124(11mg，收率：20％)，LCMS(ESI)m/z＝588.1[M+H]⁺。纯度：99.67％。¹H 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)。At room temperature, EVO33124-A5 (23 mg, 0.089 mmol) and intermediate 1-A1 (31 mg, 0.089 mmol) were dissolved in DMF (3 mL), and DIPEA (35 mg, 0.267 mmol) and HATU (51 mg, 0.134 mmol) were added in sequence. The reaction system was stirred at room temperature for 1 hour. After the reaction was completed, the reaction system was quenched with water, extracted twice with EA, the organic phases were combined, washed once with water and saturated sodium chloride solution, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to obtain a crude product. After Prep-HPLC preparation, the crude product was freeze-dried to obtain a light yellow solid EVO33124 (11 mg, yield: 20%), LCMS (ESI) m/z = 588.1 [M+H] ⁺ . Purity: 99.67%. ¹ H NMR (400 MHz, DMSO-d ₆ )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).

实施例30 EVO33025
Example 30 EVO33025

参照化合物EVO33168，经高效液相制备柱分离，再冷冻干燥得到黄色固体EVO33025(10mg，收率：43.4％)，LCMS(ESI)m/z＝586.1[M+H]⁺，纯度：99.3％。¹H 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)。The reference compound EVO33168 was separated by HPLC preparative column and freeze-dried to obtain yellow solid EVO33025 (10 mg, yield: 43.4%), LCMS (ESI) m/z=586.1 [M+H] ⁺ , purity: 99.3%. ¹ H NMR (400 MHz, DMSO-d ₆ )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).

实施例31 EVO33160
Example 31 EVO33160

参照化合物EVO33168，经高效液相制备柱分离，再冷冻干燥得到黄色固体EVO33160(16.31mg，收率：29.1％)，LCMS(ESI)m/z＝600.6[M+H]⁺，纯度：90.5％。¹H 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)。The reference compound EVO33168 was separated by HPLC preparative column and freeze-dried to obtain yellow solid EVO33160 (16.31 mg, yield: 29.1%), LCMS (ESI) m/z=600.6 [M+H] ⁺ , purity: 90.5%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.60 (t, J = 5.9 Hz, 1H), 9.40 (s, 1H), 8.88 (d, J = 1.8 Hz, 1H), 8.70–8.51 (m, 4H), 7.92-7.82 (m, 2H), 7.73 (t, J = 7.8 Hz, 1H), 7.02 (d, J = 8.5 Hz, 1H), 4.84 (d, J = 5.8 Hz, 2H), 4.44 (s, 3H), 4.31 (d, J = 12.7 Hz, 2H), 3.73-3.55 (m, 4H), 2.46-2.41 (m, 2H), 1.23-1.17 (m, 9H).

实施例32 EVO33232
Example 32 EVO33232

参照化合物EVO33168，经高效液相制备柱分离，再冷冻干燥得到黄色固体EVO33232(21.4mg，收率：32.6％)，LCMS(ESI)m/z＝603.2[M+H]⁺，纯度：92.06％。¹H 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)。The reference compound EVO33168 was separated by HPLC preparative column and freeze-dried to obtain yellow solid EVO33232 (21.4 mg, yield: 32.6%), LCMS (ESI) m/z=603.2 [M+H] ⁺ , purity: 92.06%. ¹ H NMR (400 MHz, DMSO-d ₆ )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).

实施例33 EVO33281
Example 33 EVO33281

参照化合物EVO331168，经高效液相制备柱分离，再冷冻干燥得到黄色固体EVO33281(2.3mg，收率：2.59％)，LCMS(ESI)m/z＝603.2[M+H]⁺，纯度：98.44％。¹H 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)。The reference compound EVO331168 was separated by HPLC preparative column and freeze-dried to obtain yellow solid EVO33281 (2.3 mg, yield: 2.59%), LCMS (ESI) m/z=603.2 [M+H] ⁺ , purity: 98.44%. ¹ H NMR (400 MHz, Chloroform-d) δ9.72 (s, 1H), 9.30 (s, 1H), 8.81 (d, J = 8.4 Hz, 1H), 8.52-8.42 (m, 2H), 8.25 (s, 1H), 8.16 (s, 1H), 8.09 (d, J = 7.2 Hz, 1H), 7.86 (s, 1H), 7.74 (t, J = 8.0 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 5.05 (d, J = 5.6 Hz, 2H), 4.70 (s, 2H), 4.21 (d, J = 12.4 Hz, 2H), 3.83-3.75 (m, 2H), 3.22 (s, 3H), 2.69-2.59 (m, 2H), 1.33 (d, J = 6.0 Hz, 6H).

实施例34 EVO33313
Example 34 EVO33313

参照化合物EVO33168，经高效液相制备柱分离，再冷冻干燥得到黄色固体EVO33313(15mg，收率：40％)，LCMS(ESI)m/z＝575.4[M+H]⁺，纯度：99.14％。¹H NMR(400MHz,DMSO-d₆)δ9.44-9.40(m,2H),8.64(q,J＝8.4Hz,2H),8.53(d,J＝1.6Hz,1H),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)。The reference compound EVO33168 was separated by HPLC preparative column and freeze-dried to obtain yellow solid EVO33313 (15 mg, yield: 40%), LCMS (ESI) m/z=575.4 [M+H] ⁺ , purity: 99.14%. ¹ H NMR (400 MHz, DMSO-d ₆ )δ9.44-9.40(m,2H),8.64(q,J＝8.4Hz,2H),8.53(d,J＝1.6Hz,1H),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).

实施例35 EVO33323
Example 35 EVO33323

参照化合物EVO33168，经高效液相制备柱分离，再冷冻干燥得到黄色固体EVO33323(81mg，收率：95％)，LCMS(ESI)m/z＝586.4[M+H]⁺，纯度：95.6％。¹H 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)。The reference compound EVO33168 was separated by HPLC preparative column and then freeze-dried to obtain yellow solid EVO33323 (81 mg, yield: 95%), LCMS (ESI) m/z=586.4 [M+H] ⁺ , purity: 95.6%. ¹ H NMR (400 MHz, DMSO-d ₆ )δ13.80 (bs, 1H), 9.63 (t, J=6.0 Hz, 1H), 9.43 (s, 1H), 8.91 (d, J=1.6 Hz, 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).

实施例36 EVO33324
Example 36 EVO33324

参照化合物EVO33168，经高效液相制备柱分离，再冷冻干燥得到黄色固体EVO33324(30mg，收率：51％)，LCMS(ESI)m/z＝599.1[M+H]⁺，纯度：88.4％。¹H 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)。The reference compound EVO33168 was separated by HPLC preparative column and then freeze-dried to obtain yellow solid EVO33324 (30 mg, yield: 51%), LCMS (ESI) m/z=599.1 [M+H] ⁺ , purity: 88.4%. ¹ H NMR (400 MHz, 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).

实施例37 EVO33326
Example 37 EVO33326

参照化合物EVO33168，经高效液相制备柱分离，再冷冻干燥得到黄色固体EVO33326(17mg，收率：37％)，LCMS(ESI)m/z＝585.1[M+H]⁺，纯度：99.73％。¹H 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)。The reference compound EVO33168 was separated by HPLC preparative column and then freeze-dried to obtain yellow solid EVO33326 (17 mg, yield: 37%), LCMS (ESI) m/z=585.1 [M+H] ⁺ , purity: 99.73%. ¹ H NMR (400 MHz, 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=8.4 Hz, 1H), 7.63-7.61 (m, 1H), 7.38- 7.37 (m, 1H), 6.76 (d, J = 8.4 Hz, 1H). 6.73-6.71 (m, 1H), 5.01 (d, J = 5.2 Hz, 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 = 6.4 Hz, 6H), 1.26 (t, J = 7.6 Hz, 3H).

实施例38 EVO33327
Example 38 EVO33327

参照化合物EVO33168，经高效液相制备柱分离，再冷冻干燥得到黄色固体EVO33327(5mg，收率：22％)，LCMS(ESI)m/z＝599.1[M+H]⁺，纯度：99.03％。¹H 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)。The reference compound EVO33168 was separated by HPLC preparative column and freeze-dried to obtain yellow solid EVO33327 (5 mg, yield: 22%), LCMS (ESI) m/z=599.1 [M+H] ⁺ , purity: 99.03%. ¹ H NMR (400 MHz, 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 = 8.4 Hz, 1H), 7.54-7.53 (m, 1H), 7.17-7.16 (m, 1H), 6.78-6.73 (m, 2H), 5.02 (d, J = 5.6 Hz, 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 = 7.2 Hz, 3H), 1.32 (d, J = 6.4 Hz, 6H).

实施例39 EVO33330
Example 39 EVO33330

参照化合物EVO33168，经高效液相制备柱分离，再冷冻干燥得到黄色固体EVO33330(14.49mg，收率：25％)，LCMS(ESI)m/z＝586.4[M+H]⁺，纯度：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)。The reference compound EVO33168 was separated by HPLC preparative column and then freeze-dried to obtain yellow solid EVO33330 (14.49 mg, yield: 25%), LCMS (ESI) m/z=586.4 [M+H] ⁺ , purity: 98.6%. ¹ H NMR (400 MHz, DMSO-d ₆ )δ9.65 (t, J=6.0 Hz, 1H), 9.43 (s, 1H), 8.74-8.73 (m, 1H), 8.72-8.62 (m, 2H), 8.41 (d, J=1.6 Hz, 1H), 8.38 (d, J=2.4 Hz, 1H), 7.94-7.92 (m, 1H), 7.87 (s, 1H), 7.78-7.74 (m, 1H), 7.36 (d, J =2.0 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 4.87 (d, J = 6.0 Hz, 2H), 4.36-4.32 (m, 2H), 3.74-3.66 (m, 2H), 3.56 (q, J = 7.6 Hz, 2H), 2.56-2.48 (m, 2H), 1.24 (d, J = 6.4 Hz, 6H), 1.20 (t, J = 7.6 Hz, 3H).

实施例40 EVO33331
Example 40 EVO33331

参照化合物EVO33168，经高效液相制备柱分离，再冷冻干燥得到黄色固体EVO33331(9mg，收率：36％)，LCMS(ESI)m/z＝602.4[M+H]⁺，纯度：96.9％。¹H 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)。The reference compound EVO33168 was separated by HPLC preparative column and then freeze-dried to obtain yellow solid EVO33331 (9 mg, yield: 36%), LCMS (ESI) m/z=602.4 [M+H] ⁺ , purity: 96.9%. ¹ H NMR (400 MHz, DMSO-d ₆ )δ9.70 (t, J=6 Hz, 1H), 9.44 (s, 1H), 8.92 (d, J=1.6 Hz, 1H), 8.73-8.61 (m, 2H), 8.51 (d, J=1.6 Hz, 1H), 8.13 (d, J=5.6 Hz, 1H), 7.93 (d, J=7.2 Hz, 1H), 7.95-7.88 (m, 2H), 7.82-7.73 ( m, 2H), 7.05 (d, J = 8.4 Hz, 1H), 4.90 (d, J = 6.0 Hz, 2H), 4.37-4.30 (m, 2H), 3.76-3.64 (m, 2H), 3.48 (d, J = 7.4 Hz, 2H), 2.58-2.45 (m, 2H), 1.24 (d, J = 6.0 Hz, 6H), 1.17 (t, J = 7.2 Hz, 3H).

实施例41 EVO33356
Example 41 EVO33356

参照化合物EVO33168，经高效液相制备柱分离，再冷冻干燥得到黄色固体EVO33356(27.87mg，收率：30％)，LCMS(ESI)m/z＝586.4[M+H]⁺，纯度：98.4％。¹H NMR(400MHz,DMSO-d₆)δ9.64(t,J＝6.0Hz,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)。 The reference compound EVO33168 was separated by HPLC preparative column and then freeze-dried to obtain yellow solid EVO33356 (27.87 mg, yield: 30%), LCMS (ESI) m/z=586.4 [M+H] ⁺ , purity: 98.4%. ¹ H NMR (400 MHz, DMSO-d ₆ )δ9.64 (t, J=6.0 Hz, 1H), 9.41 (s, 1H), 8.72-8.58 (m, 3H), 8.46 (d, J=2.0 Hz, 1H), 8.42 (d, J=1.2 Hz, 1H), 7.90 (d, J=7.6 Hz, 1H), 7.86 (s, 1H), 7.75-7.71 (m, 1H), 7.35-7.34 (m, 1 H), 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).

实施例42 EVO33395
Example 42 EVO33395

参照化合物EVO33168，经高效液相制备柱分离，再冷冻干燥得到黄色固体EVO33395(9.8mg，收率：48.8％)，LCMS(ESI)m/z＝600.4[M+H]⁺，纯度：99.9％。¹H 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＝7.6Hz,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)。The reference compound EVO33168 was separated by HPLC preparative column and then freeze-dried to obtain yellow solid EVO33395 (9.8 mg, yield: 48.8%), LCMS (ESI) m/z=600.4 [M+H] ⁺ , purity: 99.9%. ¹ H NMR (400 MHz, DMSO-d ₆ )δ9.53 (t, J=5.8 Hz, 1H), 9.40 (s, 1H), 8.68-8.60 (m, 2H), 8.59 (d, J=1.6 Hz, 1H), 8.45 (d, J=1.6 Hz, 1H), 7.90 (d, J=7.2 Hz, 1H), 7.82 (s, 1H), 7.72 (t, J=7.6 Hz, 1H), 7.0 2(d, J＝8.4 Hz, 1H),4.84(d, J＝6.0 Hz, 2H),4.31(d, J＝12.4 Hz, 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＝6.4 Hz, 6H).

实施例43 EVO33362
Example 43 EVO33362

参照化合物EVO33173，经高效液相制备柱分离，再冷冻干燥得到黄色固体EVO33362(15mg，收率：53％)，LCMS(ESI)m/z＝520.9[M+H]⁺，纯度：99.89％。¹H 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)。The reference compound EVO33173 was separated by HPLC preparative column and freeze-dried to obtain yellow solid EVO33362 (15 mg, yield: 53%), LCMS (ESI) m/z=520.9 [M+H] ⁺ , purity: 99.89%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.44-9.41 (m, 2H), 8.72-8.61 (m, 2H), 8.20 (d, J=7.6 Hz, 1H), 7.92-7.88 (m, 2H), 7.81-7.80 (m, 2H), 6.98 (d, J=8.4 Hz, 1H), 6.35 (s, 2H), 4.78 (d, J=5.6 Hz, 2H), 4.51 (q, J=7.2 Hz, 2H), 3.38 (q, J=7.2 Hz, 2H), 1.41 (t, J=7.2 Hz, 3H), 1.18 (t, J=7.2 Hz, 3H).

实施例44 EVO33363
Example 44 EVO33363

参照化合物EVO33173，经高效液相制备柱分离，再冷冻干燥得到黄色固体EVO33363(9mg，收率：32％)，LCMS(ESI)m/z＝516.9[M+H]⁺，纯度：99.77％。¹H 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,1H),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)。The reference compound EVO33173 was separated by HPLC preparative column and freeze-dried to obtain yellow solid EVO33363 (9 mg, yield: 32%), LCMS (ESI) m/z=516.9 [M+H] ⁺ , purity: 99.77%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.44-9.41 (m, 2H), 8.70-8.60 (m, 2H), 8.34 (d, J=7.6 Hz, 1H), 7.90-7.80 (m, 4H), 7.47 (d, J=8.0 Hz, 1H), 6.35 (s, 2H), 4.78 (d, J=5.6 Hz, 2H), 3.38 (q, J=7.2 Hz, 2H), 2.26-2.20 (m, 1H), 1.18 (t, J=7.2 Hz, 3H), 1.12-1.03 (m, 4H).

实施例45 EVO33364
Example 45 EVO33364

参照化合物EVO33173，经高效液相制备柱分离，再冷冻干燥得到黄色固体EVO33364(10.8mg，收率：20.5％)，LCMS(ESI)m/z＝588.4[M+H]⁺，纯度：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),6.35(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)。The reference compound EVO33173 was separated by HPLC preparative column and freeze-dried to obtain yellow solid EVO33364 (10.8 mg, yield: 20.5%), LCMS (ESI) m/z=588.4 [M+H] ⁺ , purity: 92.7%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.42-9.39 (m, 2H), 8.63 (q, J=8.0 Hz, 2H), 7.93-7.87 (m, 2H), 7.82-7.77 (m, 2H), 7.73 (t, J=8.0 Hz, 1H), 6.91 (d, J=8.4 Hz, 1H), 6.35 (s, 2H), 4.78 (d, J=5.6 Hz, 2H), 4.49 (s, 2H), 4.00 (d, J=12.4 Hz, 2H), 3.38 (q, J=7.2 Hz, 2H), 3.07-3.03 (m, 2H), 1.93-1.74 (m, 4H), 1.18 (t, J=7.2 Hz, 3H).

实施例46 EVO33390
Example 46 EVO33390

参照化合物EVO33173，经高效液相制备柱分离，再冷冻干燥得到黄色固体EVO33390(18.8mg，收率：12.6％)，LCMS(ESI)m/z＝556.7[M+H]⁺，纯度：99.95％。¹H NMR(400MHz,Chloroform-d)δ9.31(s,1H),8.75(d,J＝8.7Hz,1H),8.45(d,J＝8.7Hz,1H),8.16(s,1H),8.09(d,J＝7.4Hz,1H),7.83-7.73(m,2H),7.71(d,J＝1.8Hz,1H),7.38(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)。The reference compound EVO33173 was separated by HPLC preparative column and then freeze-dried to obtain yellow solid EVO33390 (18.8 mg, yield: 12.6%), LCMS (ESI) m/z=556.7 [M+H] ⁺ , purity: 99.95%. ¹ H NMR (400 MHz, Chloroform-d) δ9.31 (s, 1H), 8.75 (d, J=8.7 Hz, 1H), 8.45 (d, J=8.7 Hz, 1H), 8.16 (s, 1H), 8.09 (d, J=7.4 Hz, 1H), 7.83-7.73 (m, 2H), 7.71 (d, J=1.8 Hz, 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).

实施例47 EVO33396
Example 47 EVO33396

参照化合物EVO33173，经高效液相制备柱分离，再冷冻干燥得到黄色固体EVO33396(17.4mg，收率：38％)，LCMS(ESI)m/z＝590.4[M+H]⁺，纯度：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)。The reference compound EVO33173 was separated by HPLC preparative column and freeze-dried to obtain yellow solid EVO33396 (17.4 mg, yield: 38%), LCMS (ESI) m/z=590.4 [M+H] ⁺ , purity: 99.49%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.45-9.34 (m, 2H), 8.70-8.58 (m, 2H), 7.92-7.87 (m, 2H), 7.81 (d, J=1.6 Hz, 1H), 7.79-7.78 (m, 1H), 7.75-7.71 (m, 1H), 7.01 (d, J=8.4 Hz, 1H), 6.35 (s, 2H), 4.78 (d, J=5.6 Hz, 2H), 4.12-4.05 (m, 2H), 3.76 (d, J=3.2 Hz, 1H), 3.72 (d, J=3.6 Hz, 1H), 3.42-3.33 (m, 4H), 1.25-1.14 (m, 9H).

实施例48 EVO33397
Example 48 EVO33397

参照化合物EVO33173，经高效液相制备柱分离，再冷冻干燥得到黄色固体EVO33397(13.09mg，收率：12％)，LCMS(ESI)m/z＝590.2[M+H]⁺，纯度：96.6％。¹H NMR(400MHz,Chloroform-d)δ9.27(s,1H),8.68-8.66(m,1H),8.40-8.37(m,1H),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)。The reference compound EVO33173 was separated by HPLC preparative column and freeze-dried to obtain yellow solid EVO33397 (13.09 mg, yield: 12%), LCMS (ESI) m/z=590.2 [M+H] ⁺ , purity: 96.6%. ¹ H NMR (400 MHz, Chloroform-d) δ 9.27 (s, 1H), 8.68-8.66 (m, 1H), 8.40-8.37 (m, 1H), 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 = 8.4 Hz, 1H), 6.24 (s, 2H), 4.98 (d, J = 5.2 Hz, 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).

实施例49 EVO33399
Example 49 EVO33399

参照化合物EVO33173，经高效液相制备柱分离，再冷冻干燥得到黄色固体EVO33399(24.5mg，收率：52％)，LCMS(ESI)m/z＝576.4[M+H]⁺，纯度：99.33％。¹H NMR(400MHz,Chloroform-d)δ9.27(s,1H),8.69(d,J＝8.8Hz,1H),8.38(d,J＝8.8Hz,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)。The reference compound EVO33173 was separated by HPLC preparative column and freeze-dried to obtain yellow solid EVO33399 (24.5 mg, yield: 52%), LCMS (ESI) m/z=576.4 [M+H] ⁺ , purity: 99.33%. ¹ H NMR (400 MHz, Chloroform-d) δ 9.27 (s, 1H), 8.69 (d, J = 8.8 Hz, 1H), 8.38 (d, J = 8.8 Hz, 1H), 8.06-8.01 (m, 2H), 7.83 (d, J = 1.6 Hz, 1H), 7.75-7.63 (m, 3H), 6.75 (d, J = 8.4 Hz, 1H), 6.24 (s, 2H), 4.98 (d, J = 5.2 Hz, 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).

实施例50 EVO33402
Example 50 EVO33402

参照化合物EVO33173，经高效液相制备柱分离，再冷冻干燥得到黄色固体EVO33402(4.18mg，收率：9.7％)，LCMS(ESI)m/z＝556.3[M+H]⁺，纯度：98.4％。¹H NMR(400MHz,Chloroform-d)δ9.27(s,1H),8.61-8.60(m,1H),8.39(d,J＝8.8Hz,1H),8.17-8.10(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,1H),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)。The reference compound EVO33173 was separated by HPLC preparative column and then freeze-dried to obtain 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),8.17-8.10(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).

实施例51 EVO33404
Example 51 EVO33404

参照化合物EVO33173，经高效液相制备柱分离，再冷冻干燥得到黄色固体EVO33404(18.2mg，收率：47％)，LCMS(ESI)m/z＝573.4[M+H]⁺，纯度：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)。The reference compound EVO33173 was separated by HPLC preparative column and freeze-dried to obtain yellow solid EVO33404 (18.2 mg, yield: 47%), LCMS (ESI) m/z=573.4 [M+H] ⁺ , purity: 98.10%. ¹ H NMR (400 MHz, 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 = 6.2 Hz, 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).

实施例52 EVO33502
Example 52 EVO33502

参照化合物EVO33173，经高效液相制备柱分离，再冷冻干燥得到黄色固体EVO33502(4.1mg，收率：12％)，LCMS(ESI)m/z＝562.1[M+H]⁺，纯度：99.43％。¹H 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)。The reference compound EVO33173 was separated by HPLC preparative column and freeze-dried to obtain yellow solid EVO33502 (4.1 mg, yield: 12%), LCMS (ESI) m/z=562.1 [M+H] ⁺ , purity: 99.43%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.39 (q, J = 2.8 Hz, 2H), 8.71-8.55 (m, 2H), 7.97-7.86 (m, 2H), 7.82-7.74 (m, 3H), 7.03 (d, J = 8.4 Hz, 1H), 6.35 (s, 2H), 4.78 (d, J = 5.7 Hz, 2H), 3.79-3.74 (m, 4H), 3.60 (t, J = 4.8 Hz, 4H), 3.38 (q, J = 7.2 Hz, 2H), 1.18 (t, J = 7.2 Hz, 3H).

实施例53 EVO33503
Example 53 EVO33503

参照化合物EVO33173，经高效液相制备柱分离，再冷冻干燥得到黄色固体EVO33503(2.1mg，收率：4.5％)，LCMS(ESI)m/z＝576.3[M+H]⁺，纯度：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)。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%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.44-9.34 (m, 2H), 8.64 (q, J=8.8 Hz, 2H), 7.94-7.87 (m, 2H), 7.83-7.72 (m, 3H), 7.03 (d, J=8.4 Hz, 1H), 6.35 (s, 2H), 4.78 (d, J=5.6 Hz, 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).

实施例54 EVO33506
Example 54 EVO33506

参照化合物EVO33173，经高效液相制备柱分离，再冷冻干燥得到黄色固体EVO33506(21.6mg，收率：22.5％)，LCMS(ESI)m/z＝576.2[M+H]⁺，纯度：98.69％。¹H 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),3.63(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).The reference compound EVO33173 was separated by HPLC preparative column and freeze-dried to obtain yellow solid EVO33506 (21.6 mg, yield: 22.5%), LCMS (ESI) m/z=576.2 [M+H] ⁺ , purity: 98.69%. ¹ H NMR (400 MHz, DMSO-d ₆ )δ9.44-9.33 (m, 2H), 8.65 (d, J = 8.6 Hz, 1H), 8.59 (d, J = 8.6 Hz, 1H), 7.90 (d, J = 1.7 Hz, 1H), 7.85-7.77 (m, 3H), 7.73-7.66 (m, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.35 (s, 2H), 4.78 (d, J = 5.8 Hz, 2H), 3.93-3.87 (m, 2H), 3.86-3.77 (m, 4H), 3.63 (t, J = 5.5 Hz, 2H), 3.38 (q, J = 7.3 Hz, 2H), 1.99-1.91 (m, 2H), 1.19 (t, J = 7.3 Hz, 3H).

实施例55 EVO33179
Example 55 EVO33179

参照化合物EVO33174，经高效液相制备柱分离，再冷冻干燥得到黄色固体EVO33179(10mg，收率：26％)，LCMS(ESI)m/z＝574.1[M+H]⁺，纯度：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),8.19(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,4H),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)。The reference compound EVO33174 was separated by HPLC preparative column and freeze-dried to obtain yellow solid EVO33179 (10 mg, yield: 26%), LCMS (ESI) m/z=574.1 [M+H] ⁺ , purity: 99.73%. ¹ H NMR (400 MHz, DMSO-d ₆ )δ9.35(t,J＝6.0Hz,1H),9.09(s,1H),8.29(d,J＝9.2Hz,1H),8.19(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,4H),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).

实施例56 EVO33361
Example 56 EVO33361

参照化合物EVO33174，经高效液相制备柱分离，再冷冻干燥得到黄色固体EVO33361(16mg，收率：47.5％)，LCMS(ESI)m/z＝577.9[M+H]+，纯度：99.3％。¹H 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),6.46(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)。The reference compound EVO33174 was separated by HPLC preparative column and freeze-dried to obtain yellow solid EVO33361 (16 mg, yield: 47.5%), LCMS (ESI) m/z=577.9 [M+H]+, purity: 99.3%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.36 (t, J = 5.9 Hz, 1H), 9.10 (s, 1H), 8.32 (s, 2H), 7.88 (d, J = 1.6 Hz, 1H), 7.79 (d, J = 1.7 Hz, 1H), 7.48 (s, 1H), 7.32 (d, J = 8.6 Hz, 1H), 6.46 (d, J = 8.5 Hz, 1H), 6.35 (s, 2H), 4.70 (d, J = 5.8 Hz, 2H), 4.28 (s, 4H), 4.17 (q, J = 7.0 Hz, 2H), 3.37 (q, J = 7.4 Hz, 2H), 1.28 (t, J = 7.0 Hz, 3H), 1.18 (t, J = 7.4 Hz, 3H).

实施例57 EVO33240
Example 57 EVO33240

第1步： step 1:

室温下，间溴苄胺(1.0g,5.37mmol)、Na₂CO₃(1.14g,10.75mmol)、Boc₂O(1.29g,5.91mmol)和THF(20mL)室温搅拌2小时，LC-MS监测反应结束，加入水(30mL)，EA(30mL*3)萃取，有机相用无水Na₂SO₄干燥，过滤，滤液浓缩后得到白色固体EVO33240-A1(1.15g,粗品)，LCMS(ESI)m/z＝286.1[M+H]⁺。At room temperature, m-bromobenzylamine (1.0 g, 5.37 mmol), Na ₂ CO ₃ (1.14 g, 10.75 mmol), Boc ₂ O (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 Na ₂ SO ₄ and filtered. The filtrate was concentrated to obtain a white solid EVO33240-A1 (1.15 g, crude product), LCMS (ESI) m/z=286.1[M+H] ⁺ .

第2步：Step 2:

N₂保护下，加入EVO33240-A1(130mg,454.28μmol)，(2S，6R)-2,6-二甲基-4-(6-乙烯基-2-吡啶基)吗啉(99.17mg,454.28μmol)，Pd(OAc)₂(10.20mg,45.43μmol)，三邻甲苯膦(27.65mg,90.86μmol)，三乙胺(137.91mg,1.36mmol)和DMF(2mL)，升温至120℃，5小时后检测反应有少量原料剩余，冷至室温后用硅藻土过滤，滤液中加入水(30mL)，EA(30mL*3)萃取，有机相用饱和氯化钠溶液(30mL*3)洗涤，无水Na₂SO₄干燥，过滤，滤液浓缩后，中压正相柱层析纯化(PE/EA＝0-50％)得淡黄色固体EVO33240-A2(50mg,收率：26％)，LCMS(ESI)m/z＝424.3[M+H]⁺。Under N ₂ 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 temperature was raised to 120°C. After 5 hours, a small amount of raw materials remained in the reaction. After cooling to room temperature, the mixture was filtered through diatomaceous earth. 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), anhydrous Na ₂ SO ₄ Drying, filtering, concentrating the filtrate, and purifying by medium pressure normal phase column chromatography (PE/EA=0-50%) to obtain light yellow solid EVO33240-A2 (50 mg, yield: 26%), LCMS (ESI) m/z=424.3 [M+H] ⁺ .

第3步：Step 3:

室温下，EVO33240-A2(50mg,118.05μmol)，DCM(5mL)和TFA(40.38mg,354.15μmol)，搅拌2小时，LC-MS监测反应结束，减压浓缩，除去大部分TFA，冻干处理得黄色油状物EVO33240-A3(50mg，粗品)直接进入下一步。LCMS(ESI)m/z＝324.1[M+H]⁺。At room temperature, EVO33240-A2 (50 mg, 118.05 μmol), DCM (5 mL) and TFA (40.38 mg, 354.15 μmol) were stirred for 2 hours. The reaction was completed after monitoring by LC-MS. The mixture was concentrated under reduced pressure to remove most of the TFA and freeze-dried to obtain a yellow oil EVO33240-A3 (50 mg, crude product) which was directly used in the next step. LCMS (ESI) m/z = 324.1 [M+H] ⁺ .

第4步：Step 4:

室温下，7-(乙基磺酰基)苯并[d][1,3]二氧戊烯-5-羧酸(22.47mg,92.76μmol)溶于DMF(7.94mL)中，加入DIPEA(59.94mg,463.78μmol)和HATU(52.90mg,139.13μmol)搅拌5分钟后加入EVO33240-A3(30mg,92.76μmol)，继续搅拌，3小时候反应结束，向体系中加入水(20mL)，乙酸乙酯(30mL*3)萃取，合并有机相盐水洗涤三次，无水Na₂SO₄干燥，过滤，浓缩，得到粗品，随后制备液相进行制备，浓缩，冻干得白色产物EVO33240(5mg,收率：9.6％)，LCMS(ESI)m/z＝564.1[M+H]⁺；纯度:96.14％。¹H 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),7.60-7.50(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＝7.2Hz,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)。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), and DIPEA (59.94 mg, 463.78 μmol) and HATU (52.90 mg, 139.13 μmol) were added. After stirring for 5 minutes, EVO33240-A3 (30 mg, 92.76 μmol) was added and stirred. After 3 hours, the reaction was completed. Water (20 mL) was added to the system, and ethyl acetate (30 mL*3) was used for extraction. The combined organic phases were washed with brine three times, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to obtain a crude product. Subsequently, the preparative liquid phase was prepared, concentrated, and freeze-dried to obtain a white product EVO33240 (5 mg, yield: 9.6%), LCMS (ESI) m/z=564.1[M+H] ⁺ ; purity: 96.14%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ9.17 (t, J=6.0 Hz, 1H), 7.82 (d, J=1.6 Hz, 1H), 7.73 (d, J=1.6 Hz, 1H), 7.60-7.50 (m, 4H), 7.35 (t, J=7.6 Hz, 1H), 7.25 (d, J=7.6 Hz, 1H), 7.17-7.09 (m, 1H), 6.82 (d, J=7.2 Hz, 1H), 6.7 5(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).

实施例58 EVO33343
Example 58 EVO33343

参照化合物EVO33240，经高效液相制备柱分离，再冷冻干燥得到黄色固体EVO33343(2.6mg，收率：6.2％)，LCMS(ESI)m/z＝665.6[M+H]⁺，纯度：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)。The reference compound EVO33240 was separated by HPLC preparative column and then freeze-dried to obtain yellow solid EVO33343 (2.6 mg, yield: 6.2%), LCMS (ESI) m/z=665.6 [M+H] ⁺ , purity: 97.71%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ9.22 (t, J=5.8 Hz, 1H), 8.49 (d, J=5.0 Hz, 1H), 7.84 (d, J=1.6 Hz, 1H), 7.76 (d, J=1.6 Hz, 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).

实施例59&实施例60 EVO33338&EVO33339
Example 59 & Example 60 EVO33338 & EVO33339

第1步：step 1:

室温下，5-溴-1,3-二氟-2-硝基苯(10g,42.02mmol)、K₂CO₃(29.04g,210.10mmol)、苄胺(4.50g,42.02mmol)和THF(500mL)搅拌3小时。TLC(PE/DCM＝5/1)显示原料苄胺消失，双氟化物有少量剩余。过滤，EA洗涤滤饼，滤液中加入粗硅胶旋干，中压正相柱层析纯化(PE/DCM＝0-20％)得黄色固体EVO33338-A1(10.3g,收率：75.39％)。LCMS(ESI)m/z＝324.8/326.8[M+H]⁺。At room temperature, 5-bromo-1,3-difluoro-2-nitrobenzene (10 g, 42.02 mmol), K ₂ CO ₃ (29.04 g, 210.10 mmol), benzylamine (4.50 g, 42.02 mmol) and THF (500 mL) were stirred for 3 hours. TLC (PE/DCM=5/1) showed that the raw material benzylamine disappeared and a small amount of difluoride remained. Filter, wash the filter cake with EA, add crude silica gel to the filtrate and spin dry, purify by medium pressure normal phase column chromatography (PE/DCM=0-20%) to obtain yellow solid EVO33338-A1 (10.3 g, yield: 75.39%). LCMS (ESI) m/z=324.8/326.8 [M+H] ⁺ .

第2步： Step 2:

氩气下，EVO33338-A1(9.9g,30.45mmol)、乙硫醇钠(3.84g,45.67mmol)和THF(200mL)油浴25℃搅拌过夜。TLC(PE/DCM＝4/1)显示少量原料未反应完全。加水(300mL)和饱和氯化钠溶液(100mL)，EA萃取3次，合并有机相，依次以水和饱和氯化钠溶液洗涤1次，无水Na₂SO₄干燥，过滤，滤液旋干，得橙红色固体EVO33338-A2(11.1g,粗品)。LCMS(ESI)m/z＝366.8/368.8[M+H]⁺。Under argon, EVO33338-A1 (9.9 g, 30.45 mmol), sodium ethanethiolate (3.84 g, 45.67 mmol) and THF (200 mL) were stirred overnight in an oil bath at 25°C. TLC (PE/DCM=4/1) showed that a small amount of raw materials were not completely reacted. Water (300 mL) and saturated sodium chloride solution (100 mL) were added, and EA was extracted three times. The organic phases were combined, washed with water and saturated sodium chloride solution once, dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was dried to obtain an orange-red solid EVO33338-A2 (11.1 g, crude product). LCMS (ESI) m/z=366.8/368.8 [M+H] ⁺ .

第3步：Step 3:

反应瓶中加入EVO33338-A2(11.1g,30.22mmol)，CH₃CN(200mL)，水(200mL)和Oxone(55.74g,90.67mmol)，油浴35℃搅拌过周末，LC-MS显示约25％为亚砜，75％为产物。补加Oxone(27.87g,45.34mmol)，CH₃CN(100mL)，水(100mL)，油浴35℃搅拌过夜。LC-MS显示约11％为亚砜。蒸去溶剂，加入水(200mL)，搅拌片刻后抽滤，水洗，收集滤饼，加入DCM溶解，中压正相柱层析纯化(PE/EA＝0-40％)得橙色固体EVO33338-A3(10.3g,粗品)。LCMS(ESI)m/z＝398.8/400.8[M+H]⁺。EVO33338-A2 (11.1 g, 30.22 mmol), CH ₃ CN (200 mL), water (200 mL) and Oxone (55.74 g, 90.67 mmol) were added to the reaction flask, and the mixture was stirred in an oil bath at 35°C over the weekend. LC-MS showed that about 25% was sulfoxide and 75% was product. Oxone (27.87 g, 45.34 mmol), CH ₃ CN (100 mL) and water (100 mL) were added, and the mixture was stirred in an oil bath at 35°C overnight. LC-MS showed that about 11% was sulfoxide. The solvent was evaporated, water (200 mL) was added, and the mixture was filtered after stirring for a while, washed with water, and the filter cake was collected, dissolved in DCM, and purified by medium pressure normal phase column chromatography (PE/EA=0-40%) to obtain orange solid EVO33338-A3 (10.3 g, crude product). LCMS (ESI) m/z = 398.8/400.8 [M+H] ⁺ .

第4步：Step 4:

室温下，向EVO33338-A3(3g,7.51mmol)中依次加入Pd(dppf)Cl₂-CH₂Cl₂(613.61mg,751.39μmol)，DMF(50mL)和MeOH(50mL)，TEA(2.28g,22.54mmol,3.14mL)，反应体系用CO置换3次后，油浴80℃搅拌过夜，TLC(PE/EA＝3/1)显示原料基本转化完全。蒸去MeOH，加入水，以EA萃取3次，合并有机相依次以水洗3次，饱和氯化钠溶液洗1次，有机相旋干，中压正相柱层析纯化(PE/EA＝0-25％)得橙黄色油状物EVO33338-A4(980mg,粗品)。At room temperature, Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (613.61 mg, 751.39 μmol), DMF (50 mL) and MeOH (50 mL), TEA (2.28 g, 22.54 mmol, 3.14 mL) were added to EVO33338-A3 (3 g, 7.51 mmol) in sequence. After the reaction system was replaced with CO 3 times, it was stirred overnight in an oil bath at 80°C. TLC (PE/EA=3/1) showed that the raw material was basically converted. MeOH was evaporated, water was added, and EA was extracted 3 times. The organic phases were combined and washed 3 times with water and 1 time with saturated sodium chloride solution. The organic phase was spin-dried and purified by medium pressure normal phase column chromatography (PE/EA=0-25%) to obtain an orange-yellow oil EVO33338-A4 (980 mg, crude product).

第5步：Step 5:

室温下，EVO33338-A4(980mg,2.59mmol)中加入MeOH(30mL)和Pd(OH)₂(20％)(200mg,1.42mmol)，H₂置换后，室温搅拌3小时。LC-MS显示反应结束。经Celite抽滤，MeOH洗涤，滤液旋干，中压正相柱层析纯化(DCM/MeOH＝0-5％)得到类白色固体EVO33338-A5(566mg,收率：84.61％)。LCMS(ESI)m/z＝258.9[M+H]⁺。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 H ₂ replacement, the mixture was stirred at room temperature for 3 hours. LC-MS showed that the reaction was complete. The mixture was filtered through Celite, washed with MeOH, and the filtrate was dried by spin drying. The mixture was purified by medium pressure normal phase column chromatography (DCM/MeOH=0-5%) to obtain an off-white solid EVO33338-A5 (566 mg, yield: 84.61%). LCMS (ESI) m/z=258.9 [M+H] ⁺ .

第6步：Step 6:

氩气保护下，EVO33338-A5(565mg,2.19mmol)，CH₃CN(18mL)和亚硝酸异戊酯(384.38mg,3.28mmol,439.29μL)油浴60℃搅拌1小时。LC-MS显示反应完全。旋干，加入MTBE(30mL)，超声后搅拌片刻，抽滤，少量MTBE洗涤，收集滤饼。滤液旋干，加入PE/EA＝1/2打浆，抽滤，少量PE/EA＝1/1洗涤，收集滤饼；两次滤饼合并，得浅灰色固体EVO33338-A6(490mg,收率：83％)。LCMS(ESI)m/z＝269.8[M+H]⁺。Under argon protection, EVO33338-A5 (565 mg, 2.19 mmol), CH ₃ CN (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 showed that the reaction was complete. The mixture was dried by spin-drying, MTBE (30 mL) was added, and the mixture was stirred for a while after ultrasonication. The mixture was filtered by suction, washed with a small amount of MTBE, and the filter cake was collected. The filtrate was dried by spin-drying, PE/EA=1/2 was added for pulping, filtered by suction, washed with a small amount of PE/EA=1/1, and the filter cake was collected; the two filter cakes were combined to obtain a light gray solid EVO33338-A6 (490 mg, yield: 83%). LCMS (ESI) m/z=269.8[M+H] ⁺ .

第7步：Step 7:

Ar保护，冰水浴下，三口瓶中加入EVO33338-A6(400mg,1.49mmol)和无水DMF(16mL)，加入NaH(60％)(76mg,1.9mmol)，搅拌1小时。滴入CH₃I(560mg,3.95mmol,245.6μL)，冰水浴下搅拌1小时，TLC(PE/EA＝1/1)显示原料反应完全。饱和NH₄Cl溶液淬灭，EA萃取3次，合并的有机相以水洗涤2次，饱和氯化钠溶液洗涤1次，有机相蒸干得粗品，中压正相柱层析纯化(PE/EA＝ 0-50％)出两个峰，依次收集组分，减压浓缩得到:A：白色固体EVO33338-A7(38mg)，LCMS(ESI)m/z＝283.9[M+H]⁺。B：类白色固体(109mg)，以PE/EA＝1/1(6mL)室温打浆10min，抽滤，洗涤，收集得到类白色固体EVO33339-A1(97mg)，LCMS(ESI)m/z＝283.9[M+H]⁺。Ar protection, in an ice-water bath, EVO33338-A6 (400 mg, 1.49 mmol) and anhydrous DMF (16 mL) were added to a three-necked flask, and NaH (60%) (76 mg, 1.9 mmol) was added, and stirred for 1 hour. CH ₃ I (560 mg, 3.95 mmol, 245.6 μL) was added dropwise, and stirred for 1 hour in an ice-water bath. TLC (PE/EA=1/1) showed that the raw material was completely reacted. The mixture was quenched with saturated NH ₄ Cl solution, extracted with EA 3 times, and the combined organic phase was washed with water 2 times and saturated sodium chloride solution 1 time. The organic phase was evaporated to dryness to obtain a crude product, which was purified by medium-pressure normal phase column chromatography (PE/EA= 0-50%), two peaks were obtained, and the components were collected in sequence and concentrated under reduced pressure to obtain: A: white solid EVO33338-A7 (38 mg), 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 off-white solid EVO33339-A1 (97 mg), LCMS (ESI) m/z = 283.9 [M+H] ⁺ .

第8步：Step 8:

室温下，加入EVO33338-A7(35mg,123.54μmol)，THF(2mL)，MeOH(1mL)和水(1mL)，油浴40℃搅拌溶清，加入NaOH(34.59mg,864.80μmol)，继续搅拌2小时。TLC(PE/EA＝1/2)显示原料反应完全。蒸去有机溶剂，加入水(6mL)，以2N稀HCl溶液调pH～1，析出固体，抽滤，水洗至中性，抽干，收集滤饼得到白色固体EVO33338-A8(26mg,收率：78.16％)。LCMS(ESI)m/z＝270.2[M+H]⁺,268.2[M+H]^-。At room temperature, EVO33338-A7 (35 mg, 123.54 μmol), THF (2 mL), MeOH (1 mL) and water (1 mL) were added, and the mixture was stirred in an oil bath at 40°C to dissolve. NaOH (34.59 mg, 864.80 μmol) was added and stirring was continued for 2 hours. TLC (PE/EA=1/2) showed that the raw material was completely reacted. The organic solvent was evaporated, water (6 mL) was added, and the pH was adjusted to 1 with 2N dilute HCl solution. The solid was precipitated, filtered, washed with water until neutral, dried, and the filter cake was collected to obtain a white solid EVO33338-A8 (26 mg, yield: 78.16%). LCMS (ESI) m/z=270.2[M+H] ⁺ ,268.2[M+H] ^- .

参照EVO33338-A8，得到白色固体EVO33339-A2(26mg,收率：68.39％)。LCMS(ESI)m/z＝270.2[M+H]⁺,268.2[M+H]^-。With reference 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] ⁻ .

第9步：Step 9:

室温下，加入中间体1-A1(25.95mg,67.26μmol)、EVO33338-A8(20mg,74.27μmol)、DMF(3mL)、DIPEA(95.99mg,742.73μmol,129.37μL)和HATU(33.89mg,89.13μmol)，油浴30℃搅拌40分钟。加入EA，依次以水、饱和氯化钠溶液洗涤，有机相旋干。剩余物经中压正相柱层析纯化(DCM/MeOH＝0-3％)得到黄色固体粗品(28mg)。加入CH₃CN(4mL)，室温打浆，抽滤，少量CH₃CN洗涤，抽干，收集滤饼得到黄绿色固体EVO33338(25mg,收率：56.03％)。LCMS(ESI)m/z＝601.1[M+H]⁺。HPLC纯度：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)。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 the mixture was stirred in an oil bath at 30°C for 40 minutes. EA was added, and the mixture was washed with water and saturated sodium chloride solution in turn, and the organic phase was spin-dried. The residue was purified by medium-pressure normal phase column chromatography (DCM/MeOH=0-3%) to obtain a yellow solid crude product (28 mg). CH ₃ CN (4 mL) was added, the mixture was slurried at room temperature, filtered, washed with a small amount of CH ₃ CN, dried, and the filter cake was collected to obtain a yellow-green solid EVO33338 (25 mg, yield: 56.03%). LCMS (ESI) m/z=601.1[M+H] ⁺ . HPLC purity: 98.0%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.75 (t, J = 6.0 Hz, 1H), 9.41 (s, 1H), 9.16 (d, J = 1.6 Hz, 1H), 8.70-8.61 (m, 3H), 7.94-7.86 (m, 2H), 7.73 (t, J = 8.0 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 4.87 (d, J = 5.8 Hz, 2H), 4.62 (s, 3H), 4.31 (d, J = 11.6 Hz, 2H), 3.72-3.58 (m, 4H), 2.54-2.46 (m, 2H), 1.25-1.17 (m, 9H).

参照EVO33338，经高效液相制备柱分离，再冷冻干燥得到黄色固体EVO33339(20mg,收率：44.83％)。LCMS(ESI)m/z＝601.1[M+H]⁺。纯度：97.6％。¹H 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),3.73-3.55(m,4H),2.54-2.46(m,2H),1.21(d,J＝6.2Hz,6H),1.15(t,J＝7.2Hz,3H)。Referring to EVO33338, the product was separated by HPLC preparative column and freeze-dried to obtain yellow solid EVO33339 (20 mg, yield: 44.83%). LCMS (ESI) m/z = 601.1 [M+H] ⁺ . Purity: 97.6%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.74 (t, J = 6.0 Hz, 1H), 9.41 (s, 1H), 9.03 (s, 1H), 8.65 (q, J = 8.4 Hz, 2H), 8.54 (s, 1H), 7.94-7.86 (m, 2H), 7.73 (t, J = 8.0 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 4.87 (d, J = 6.0 Hz, 2H), 4.67 (s, 3H), 4.31 (d, J = 10.4 Hz, 2H), 3.73-3.55 (m, 4H), 2.54-2.46 (m, 2H), 1.21 (d, J = 6.2 Hz, 6H), 1.15 (t, J = 7.2 Hz, 3H).

实施例61 EVO33341

Example 61 EVO33341

第1步：step 1:

将化合物EVO3337-A6(790mg,3.06mmol)及TEA(1.55g,15.29mmol)加入到无水DCM(5mL)中，缓慢滴加SOCl₂(1.09g,9.18mmol)。在50℃下反应2小时。反应完毕，将反应中加入DCM和水，分层萃取，合并有机相，无水Na₂SO₄干燥，过滤，减压浓缩得粗品，中压正相柱层析纯化(PE/EA＝5/1)，得到产物EVO33341-A1(650mg，收率：74％)。¹H NMR(400MHz,Chloroform-d)δ9.03(d,J＝1.6Hz,1H),8.95(d,J＝1.6Hz,1H),4.06(s,3H),3.67(q,J＝7.6Hz,2H),1.32(t,J＝7.6Hz,3H)。Compound EVO3337-A6 (790 mg, 3.06 mmol) and TEA (1.55 g, 15.29 mmol) were added to anhydrous DCM (5 mL), and SOCl ₂ (1.09 g, 9.18 mmol) was slowly added dropwise. The mixture was reacted at 50°C for 2 hours. After the reaction was completed, DCM and water were added to the reaction mixture, and the mixture was separated and extracted. The organic phases were combined, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by medium-pressure normal phase column chromatography (PE/EA=5/1) to obtain the product EVO33341-A1 (650 mg, yield: 74%). ¹ H NMR (400 MHz, Chloroform-d) δ 9.03 (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).

第2步：Step 2:

往25ml瓶中加入EVO33341-A1(650mg,2.27mmol)、THF(5mL)、Methanol(5mL)，水(2mL)和LiOH(476mg,11.35mmol)，25℃搅拌2小时。反应完毕，用稀HCl(1N)调pH＝3，用中压反相柱层析纯化(H₂O/CH₃CN＝0-50％)，冻干得白色固体EVO3341-A2(540mg，收率：87％)，LCMS(ESI)m/z＝271.2[M-H]^-。EVO33341-A1 (650 mg, 2.27 mmol), THF (5 mL), Methanol (5 mL), water (2 mL) and LiOH (476 mg, 11.35 mmol) were added to a 25 ml bottle and stirred at 25°C for 2 hours. After the reaction was completed, the pH was adjusted to 3 with dilute HCl (1N), purified by medium pressure reverse phase column chromatography (H ₂ O/CH ₃ CN=0-50%), and freeze-dried to obtain white solid EVO3341-A2 (540 mg, yield: 87%), LCMS (ESI) m/z=271.2 [MH] ^- .

第3步：Step 3:

室温下，将EVO33341-A2(30mg,0.109mmol)和中间体1-A1(38mg,0.109mmol)溶于DMF(3mL)中，依次加入DIPEA(42mg,0.326mmol)和HATU(62mg,0.163mmol)，反应体系在室温下搅拌1小时。反应完毕，反应体系加水淬灭，用EA萃取2次，合并有机相，水和饱和氯化钠溶液各洗涤1次，无水Na₂SO₄干燥，过滤，浓缩得粗品，Prep-HPLC制备后，冻干得淡黄色固体EVO33341(18mg，收率：27％)，LCMS(ESI)m/z＝604.4[M+H]⁺。纯度：99.16％。¹H NMR(400MHz,Chloroform-d)δ9.30(s,1H),8.91(d,J＝1.6Hz,1H),8.85(d,J＝1.6Hz,1H),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)。At room temperature, EVO33341-A2 (30 mg, 0.109 mmol) and intermediate 1-A1 (38 mg, 0.109 mmol) were dissolved in DMF (3 mL), and DIPEA (42 mg, 0.326 mmol) and HATU (62 mg, 0.163 mmol) were added in sequence. The reaction system was stirred at room temperature for 1 hour. After the reaction was completed, the reaction system was quenched with water, extracted twice with EA, the organic phases were combined, washed once with water and saturated sodium chloride solution, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to obtain a crude product. After Prep-HPLC preparation, the crude product was freeze-dried to obtain a light yellow solid EVO33341 (18 mg, yield: 27%), LCMS (ESI) m/z=604.4[M+H] ⁺ . Purity: 99.16%. ¹ H NMR (400 MHz, Chloroform-d) δ9.30 (s, 1H), 8.91 (d, J = 1.6 Hz, 1H), 8.85 (d, J = 1.6 Hz, 1H), 8.70 (d, J = 8.8 Hz, 1H), 8.42 (d, J = 8.8 Hz, 1H), 8.11-8.07 (m, 2H), 8.06 (d, J = 7.6 Hz , 1H), 7.76-7.69 (m, 1H), 6.80 (d, J = 8.4 Hz, 1H), 5.07 (d, J = 5.2 Hz, 2H), 4.25-4.17 (m, 2H), 3.84-3.75 (m, 2H), 3.67 (q, J = 7.6 Hz, 2H), 2.67-2.58 (m, 2H), 1.35-1.30 (m, 9H).

实施例62 EVO33349

Example 62 EVO33349

第1步：step 1:

Ar保护下，将化合物8-溴-[1,2,4]三唑并[1,5-a]吡啶-6-甲酸甲酯(800mg,3.12mmol)、乙基硫代S-甲基酯(1.41g,15.62mmol)、三(二亚苄基丙酮)二钯(286mg,312μmol)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(361mg,624μmol)和磷酸钾(1.99g,9.37mmol)加入到叔丁醇(0.5mL)及甲苯(5mL)混合溶液中，在110℃下反应24小时。反应完毕，反应液减压浓缩，中压正相快速柱层析得到白色固体EVO33349-A2(350mg，收率：50％)，LCMS(ESI)m/z＝224.1[M+H]⁺。Under Ar protection, compound 8-bromo-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylic acid methyl ester (800 mg, 3.12 mmol), ethyl thio S-methyl ester (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 mixed solution of tert-butyl alcohol (0.5 mL) and toluene (5 mL) and reacted at 110° C. for 24 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and medium-pressure normal phase flash column chromatography was used to obtain white solid EVO33349-A2 (350 mg, yield: 50%), LCMS (ESI) m/z=224.1[M+H] ⁺ .

第2步：Step 2:

室温下，将EVO33349-A2(350mg,1.57mmol)溶于乙腈(5mL)和水(5mL)溶液中，加入固体Oxone(2.89g,4.70mmol)，反应搅拌过夜。反应完毕，将反应液浓缩，加入EA和水，分层萃取，合并有机相，无水Na₂SO₄干燥，过滤，减压浓缩得粗品，中压正相柱层析纯化(PE/EA＝3/1)，得到白色固体EVO33349-A3(220mg，收率：54％)，LCMS(ESI)m/z＝256.1[M+H]⁺。At room temperature, EVO33349-A2 (350 mg, 1.57 mmol) was dissolved in acetonitrile (5 mL) and water (5 mL) solution, solid Oxone (2.89 g, 4.70 mmol) was added, and the reaction was stirred overnight. After the reaction was completed, the reaction solution was concentrated, EA and water were added, and the organic phases were combined, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by medium-pressure normal phase column chromatography (PE/EA=3/1) to obtain a white solid EVO33349-A3 (220 mg, yield: 54%), LCMS (ESI) m/z=256.1[M+H] ⁺ .

第3步：Step 3:

反应瓶中加入EVO33349-A3(220mg,862μmol)、THF(2mL)、Methanol(2mL)、水(1mL)和LiOH(108mg,2.59mmol)，25℃搅拌2小时。反应完毕，用稀HCl(1N)调pH＝3，中压反相柱层析纯化(H₂O/CH₃CN＝0-50％)，冻干得白色固体EVO3349-A4(130mg，收率：62％)，LCMS(ESI)m/z＝240.2[M-H]^-。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 the reaction was completed, the pH was adjusted to 3 with dilute HCl (1N), purified by medium-pressure reverse phase column chromatography (H ₂ O/CH ₃ CN=0-50%), and freeze-dried to obtain white solid EVO3349-A4 (130 mg, yield: 62%), LCMS (ESI) m/z=240.2 [MH] ^- .

第4步：Step 4:

室温下，将EVO33349-A4(25mg,0.103mmol)和中间体1-A1(36mg,0.103mmol)溶于DMF(3mL)中，依次加入DIPEA(40mg,0.311mmol)和HATU(59mg,0.155mmol)，室温搅拌1小时。反应完毕，加水淬灭，用EA萃取2次，合并有机相，水和饱和氯化钠溶液各洗涤1次，无水Na₂SO₄干燥，过滤，浓缩得粗品，Prep-HPLC制备后，冻干得淡黄色固体EVO33349(6mg，收率：10％)，LCMS(ESI)m/z＝572.9[M+H]⁺。纯度：99.90％。¹H 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,1H),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)。 At room temperature, EVO33349-A4 (25 mg, 0.103 mmol) and intermediate 1-A1 (36 mg, 0.103 mmol) were dissolved in DMF (3 mL), and DIPEA (40 mg, 0.311 mmol) and HATU (59 mg, 0.155 mmol) were added in sequence, and stirred at room temperature for 1 hour. After the reaction was completed, water was added to quench, and EA was extracted twice. The organic phases were combined, washed once with water and saturated sodium chloride solution, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to obtain a crude product. After Prep-HPLC preparation, the crude product was freeze-dried to obtain a light yellow solid EVO33349 (6 mg, yield: 10%), LCMS (ESI) m/z = 572.9 [M+H] ⁺ . Purity: 99.90%. ¹ H NMR (400 MHz, Chloroform-d) δ9.54 (d, J = 1.6 Hz, 1H), 9.28 (s, 1H), 8.67 (d, J = 3.2 Hz, 1H), 8.66 (d, J = 3.6 Hz, 1H), 8.59 (s, 1H), 8.40 (d, J = 8.4 Hz, 1H), 8.03 (d, J = 7.2 Hz, 1H), 8.00 (s, 1 H), 7.88-7.84 (m, 1H), 7.74-7.69 (m, 1H), 6.79 (d, J = 8.4 Hz, 1H), 5.02 (d, J = 4.9 Hz, 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 = 6.4 Hz, 6H).

实施例63 EVO33350
Example 63 EVO33350

参照化合物EVO33349，经高效液相制备柱分离，再冷冻干燥得到黄色固体EVO33350(28mg，收率：36％)，LCMS(ESI)m/z＝572.4[M+H]⁺，纯度：99.97％，¹H 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＝8.0Hz,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)。The reference compound EVO33349 was separated by HPLC preparative column and freeze-dried to obtain yellow solid EVO33350 (28 mg, yield: 36%), LCMS (ESI) m/z=572.4 [M+H] ⁺ , purity: 99.97%, ¹ H NMR (400 MHz, DMSO-d ₆ )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＝8.0Hz,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).

实施例64 EVO33383
Example 64 EVO33383

第1步：step 1:

室温下，反应瓶中加入7-溴苯并[D][1,3]二氧戊环-5-羧酸(900mg,3.67mmol)、K₂CO₃(1.02g,7.35mmol)和DMF(10mL)，然后滴加CH₃I(1.04g,7.35mmol)，室温搅拌16小时。向体系缓慢滴加饱和氯化铵溶液，析出白色固体，过滤，滤饼用水淋洗(5mL*3)，滤饼烘干得白色固体EVO33383-A1(936mg，收率：98.4％)。At room temperature, 7-bromobenzo[D][1,3]dioxolane-5-carboxylic acid (900 mg, 3.67 mmol), K ₂ CO ₃ (1.02 g, 7.35 mmol) and DMF (10 mL) were added to the reaction flask, and then CH ₃ I (1.04 g, 7.35 mmol) was added dropwise, and stirred at room temperature for 16 hours. Saturated ammonium chloride solution was slowly added dropwise to the system to precipitate a white solid, which was filtered and the filter cake was rinsed with water (5 mL*3). The filter cake was dried to obtain a white solid EVO33383-A1 (936 mg, yield: 98.4%).

第2步：Step 2:

室温下，反应瓶中加入EVO33383-A1(400mg,1.54mmol)、苄硫醇(230.14mg,1.85mmol)、DIPEA(598.67mg,4.63mmol,806.84μL)和无水1,4-二氧六环(5mL)，Ar置换，加入Xantphos(178.69mg,308.82μmol)和Pd₂(dba)₃(141.39mg,154.41μmol)，再次Ar置换，油浴加热93℃，反应6小时。向体系加入水(30mL)，EA萃取(20mL*3)，有机相水洗和饱和氯化钠溶液洗，无水Na₂SO₄干燥，过滤，浓缩得粗品，中压正相柱层析纯化(PE/EA＝0–10％)得黄色油状物EVO33383-A2(570mg，粗品)。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 was replaced. Xantphos (178.69 mg, 308.82 μmol) and Pd ₂ (dba) ₃ (141.39 mg, 154.41 μmol) were added, and Ar was replaced again. The oil bath was heated at 93°C and the reaction was carried out 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, and dried over anhydrous Na ₂ SO ₄ . The residue was filtered and concentrated to obtain a crude product, which was purified by medium-pressure normal phase column chromatography (PE/EA=0-10%) to obtain a yellow oil EVO33383-A2 (570 mg, crude product).

第3步：Step 3:

室温下，EVO33383-A2(60mg,198.45μmol)溶于混合溶剂(2mL,ACN:H₂O:AcOH＝80:2:1)，加入1,3-二氯-5,5-二甲基咪唑啉-2,4-二酮(58.65mg,297.67μmol,39.10μL)，室温搅拌2.5小时。减压浓缩除去溶剂，得EVO33383-A3(60mg，粗品)直接下一步反应。At room temperature, EVO33383-A2 (60 mg, 198.45 μmol) was dissolved in a mixed solvent (2 mL, ACN:H ₂ O: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 used for the next step reaction.

第4步：Step 4:

室温下，反应瓶中加入EVO33383-A3(60mg,215.31μmol)，TEA(0.2mL)和DCM(2mL)，最后加入甲胺溶液(0.2mL,2M in THF)，室温搅拌1小时。减压浓缩拌料过柱，中压正相柱层析纯化(PE/EA＝0–50％)得淡黄色固体EVO33383-A4(36mg,收率：61.2％)，LCMS(ESI)m/z＝274.0[M+H]⁺。At room temperature, EVO33383-A3 (60 mg, 215.31 μmol), TEA (0.2 mL) and DCM (2 mL) were added to the reaction flask, and finally methylamine solution (0.2 mL, 2 M in THF) was added, and stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and passed through a column, and purified by medium-pressure normal phase column chromatography (PE/EA = 0-50%) to obtain a light yellow solid EVO33383-A4 (36 mg, yield: 61.2%), LCMS (ESI) m/z = 274.0 [M+H] ⁺ .

第5步：Step 5:

室温下，反应瓶中加入EVO33383-A4(36mg,131.74μmol)和MeOH(1.5mL)，再加入LiOH.H₂O(22.11mg,526.97μmol)和H₂O(1.5mL)，油浴加热33℃反应1.5小时。减压浓缩除去甲醇，加入水(0.5mL)，用1N稀盐酸调pH＝3，析出白色固体，过滤，滤饼水洗(1mL*3)，滤饼烘干，得到类白色固体EVO33383-A5(21mg,收率：61.5％)，LCMS(ESI)m/z＝260.0[M+H]⁺。At room temperature, EVO33383-A4 (36 mg, 131.74 μmol) and MeOH (1.5 mL) were added to the reaction flask, and then LiOH.H ₂ O (22.11 mg, 526.97 μmol) and H ₂ O (1.5 mL) were added, and the mixture was heated in an oil bath at 33°C for 1.5 hours. 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, which was filtered, and the filter cake was washed with water (1 mL*3). The filter cake was dried to obtain an off-white solid EVO33383-A5 (21 mg, yield: 61.5%), LCMS (ESI) m/z=260.0 [M+H] ⁺ .

第6步：Step 6:

室温下，反应瓶中加入EVO33383-A5(21mg,81.01μmol)、中间体1-A1(28.31mg,81.01μmol)、DIPEA(52.35mg,405.04μmol,70.55μL)、HATU(46.20mg,121.51μmol)和无水DMF(2mL)，25℃反应3小时。加水淬灭，EA萃取，有机相水洗，饱和氯化钠溶液洗，无水Na₂SO₄干燥，过滤，减压浓缩，高效液相制备柱分离，冷冻干燥得产物EVO33383(26mg,收率：54.3％)。LCMS(ESI)m/z＝591.0[M+H]⁺。纯度：99.7％。¹H 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)。At room temperature, 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 the reaction bottle and reacted at 25°C for 3 hours. Water was added to quench, EA was extracted, the organic phase was washed with water, washed with saturated sodium chloride solution, dried with anhydrous Na ₂ SO ₄ , filtered, concentrated under reduced pressure, separated with a high-performance liquid 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 (400 MHz, DMSO-d ₆ ) δ 9.39-9.35 (m, 2H), 8.68-8.61 (m, 2H), 7.91 (d, J=7.2 Hz, 1H), 7.86 (d, J=1.6 Hz, 1H), 7.78-7.72 (m, 3H), 7.66 (bs, 1H), 7.03 (d, J=8.4 Hz, 1H), 6.32 (s, 2H), 4.77 (d, J=6.0 Hz, 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=6.4 Hz, 6H).

实施例65 EVO33381
Example 65 EVO33381

参照化合物EVO33383，经高效液相制备柱分离，再冷冻干燥得到黄色固体EVO33381(20mg，收率：69.4％)，LCMS(ESI)m/z＝604.4[M+H]⁺，纯度：99.9％。¹H 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,2H),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)。The reference compound EVO33383 was separated by HPLC preparative column and then freeze-dried to obtain yellow solid EVO33381 (20 mg, yield: 69.4%), LCMS (ESI) m/z=604.4 [M+H] ⁺ , purity: 99.9%. ¹ H NMR (400 MHz, DMSO-d ₆ )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=8.8 Hz, 1H), 6.36 (s, 2H), 4.78 (d, J = 5.6 Hz, 2H), 4.31 (d, J = 11.6 Hz, 2H), 3.71-3.64 (m, 2H), 3.37-3.35 (m, 2H), 2.53-2.47 (m, 2H), 1.70-1.60 (m, 2H), 1.21 (d, J = 6.0 Hz, 6H), 0.96 (t, J = 7.4 Hz, 3H).

实施例66 EVO33382
Example 66 EVO33382

参照化合物EVO33383，经高效液相制备柱分离，再冷冻干燥得到黄色固体EVO33382(37mg，收率：63.9％)，LCMS(ESI)m/z＝602.4[M+H]⁺，纯度：99.9％。¹H 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)。The reference compound EVO33383 was separated by HPLC preparative column and freeze-dried to obtain yellow solid EVO33382 (37 mg, yield: 63.9%), LCMS (ESI) m/z=602.4 [M+H] ⁺ , purity: 99.9%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.43-9.39 (m, 2H), 8.64 (q, J=8.6 Hz, 2H), 7.92-7.90 (m, 2H), 7.80-7.79 (m, 2H), 7.74 (t, J=8.0 Hz, 1H), 7.03 (d, J=8.8 Hz, 1H), 6.36 (s, 2H), 4.78 (d, J=5.6 Hz, 2H), 4.31 (dd, J=13.2, 2.4 Hz, 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).

实施例67 EVO33384
Example 67 EVO33384

参照化合物EVO33383，经高效液相制备柱分离，再冷冻干燥得到黄色固体EVO33384(24mg，收率：57.6％)，LCMS(ESI)m/z＝605.0[M+H]⁺，纯度：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),6.30(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)。The reference compound EVO33383 was separated by HPLC preparative column and freeze-dried to obtain yellow solid EVO33384 (24 mg, yield: 57.6%), LCMS (ESI) m/z=605.0 [M+H] ⁺ , purity: 98.4%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.41-9.38 (m, 2H), 8.68-8.61 (m, 2H), 7.91 (d, J=7.6 Hz, 1H), 7.82-7.73 (m, 4H), 7.03 (d, J=8.4 Hz, 1H), 6.30 (s, 2H), 4.78 (d, J=6.0 Hz, 2H), 4.31 (d, J=11.6 Hz, 2H), 3.70-3.65 (m, 2H), 2.75 (s, 6H), 2.53-2.47 (m, 2H), 1.21 (d, J=6.0 Hz, 6H).

实施例68 EVO33500

Example 68 EVO33500

第1步：step 1:

室温下，4-氨基-5-溴-2-氯吡啶(1g,4.85mmol)、O-乙基二硫代碳酸钾(3.1g,19.41mmol)混于DMF(10mL)，油浴130℃搅拌。LC-MS监测反应结束。加水淬灭，EA(50mL*3)萃取，减压浓缩，中压正相柱层析纯化(PE/EA＝0-100％)得到类白色固体EVO33500-A1(850mg,收率：87％)，LCMS(ESI)m/z＝202.9[M+H]⁺。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. Water was added for quenching, EA (50 mL*3) was used for extraction, and the mixture was concentrated under reduced pressure. The mixture was purified by medium-pressure normal phase column chromatography (PE/EA=0-100%) to obtain an off-white solid EVO33500-A1 (850 mg, yield: 87%), LCMS (ESI) m/z=202.9 [M+H] ⁺ .

第2步：Step 2:

室温下，EVO33500-A1(850mg,4.21mmol)和SOCl₂(10mL)搅拌。LC-MS监测反应结束。加水(20mL)淬灭，产品析出，抽滤，得到类白色固体EVO33500-A2(800mg,收率：93％)，LCMS(ESI)m/z＝204.9[M+H]⁺。EVO33500-A1 (850 mg, 4.21 mmol) and SOCl ₂ (10 mL) were stirred at room temperature. The reaction was completed by LC-MS monitoring. Water (20 mL) was added to quench the reaction, and the product was precipitated and filtered to obtain an off-white solid EVO33500-A2 (800 mg, yield: 93%), LCMS (ESI) m/z = 204.9 [M+H] ⁺ .

第3步：Step 3:

N₂保护下，EVO33500-A2(700mg,3.46mmol)，(2S,6R)-2,6-二甲基-4-(6-(三甲基锡基)吡啶-2-基)吗啉(1.2g,3.46mmol),Pd(dppf)Cl₂(253mg,0.34mmol)和无水1,4-二氧六环(10mL)油浴100℃搅拌。LC-MS监测反应结束。加水淬灭，EA(50mL x 3)萃取，减压浓缩。中压正相柱层析纯化(DCM/EA＝0-30％)得到类白色固体EVO33500-A3(510mg,收率：41％)，LCMS(ESI)m/z＝361.1[M+H]⁺。Under N ₂ 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)Cl ₂ (253 mg, 0.34 mmol) and anhydrous 1,4-dioxane (10 mL) were stirred in an oil bath at 100°C. The reaction was monitored by LC-MS. Water was added to quench, 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] ⁺ .

第4步：Step 4:

N₂保护下，EVO33500-A3(480mg,1.33mmol)，N-叔丁基碳酰基甲基三氟硼酸钾(474mg,2mmol),cataCXium A-Pd-G2(87mg,0.13mmol),K₃PO₄(564mg,2.66mmol)，1,4-二氧六环(10mL)和水(1mL)油浴80℃搅拌。LC-MS监测反应结束，少量原料剩余。加水淬灭，EA(50mL x 3)萃取，减压浓缩，中压正相柱层析纯化(DCM/EA＝0-30％)得白色固体EVO33500-A4(212mg,收率：35％)，LCMS(ESI)m/z＝456.2[M+H]⁺。Under N ₂ protection, EVO33500-A3 (480 mg, 1.33 mmol), potassium N-tert-butylcarbonylmethyl trifluoroborate (474 mg, 2 mmol), cataCXium A-Pd-G2 (87 mg, 0.13 mmol), K ₃ PO ₄ (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 completion of the reaction, with a small amount of raw materials remaining. Water was added to quench, and EA (50 mL x 3) was used for extraction. The residue was concentrated under reduced pressure and purified by medium-pressure normal phase column chromatography (DCM/EA=0-30%) to obtain white solid EVO33500-A4 (212 mg, yield: 35%), LCMS (ESI) m/z=456.2 [M+H] ⁺ .

第5步：Step 5:

0℃下，氯化氢的1,4-二氧六环溶液(3mL)滴入EVO33500-A4(212mg,0.46mmol)的DCM(5mL)溶液中。LC-MS监测反应结束。直接浓缩得固体粗品EVO33500-A5(151mg，粗品)，LCMS(ESI)m/z＝356.1[M+H]⁺。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). The reaction was monitored by LC-MS. The solid crude product EVO33500-A5 (151 mg, crude product) was directly concentrated, LCMS (ESI) m/z = 356.1 [M+H] ⁺ .

第6步：Step 6:

N₂保护下，EVO33500-A5(60mg,0.17mmol)、EVO33138-A4(41mg,0.17mmol)、DMF(3mL)、EDCl(65mg,0.34mmol)、HOBt(46mg,0.34mmol)和DIEA(44mg,0.34mmol)室温搅拌过夜。LC-MS监测反应结束，生成产物。加水淬灭，EA(50mL)萃取，无水Na₂SO₄干燥后减压浓缩，经高效液相制备柱分离，冻干得产物EVO33500(22.6mg,收率：20％)，LCMS(ESI)m/z＝582.1[M+H]⁺；纯度:99.36％。¹H 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)。Under N ₂ 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 completion of the reaction and the product was generated. Water was added for quenching, EA (50 mL) was extracted, anhydrous Na ₂ SO ₄ was dried and concentrated under reduced pressure, separated by HPLC preparative column, and freeze-dried to obtain the product EVO33500 (22.6 mg, yield: 20%), LCMS (ESI) m/z = 582.1 [M+H] ⁺ ; purity: 99.36%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.38-9.27 (m, 2H), 7.90 (t, J=1.6 Hz, 2H), 7.82-7.75 (m, 2H), 7.62 (d, J=7.2 Hz, 1H), 7.13 (d, J=8.8 Hz, 1H), 6.36 (s, 2H), 4.71 (d, J=5.6 Hz, 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=6.0 Hz, 6H).

实施例69 EVO33408
Example 69 EVO33408

参照化合物EVO33168，经高效液相制备柱分离，再冷冻干燥得到黄色固体EVO33408(7mg，收率：27％)，LCMS(ESI)m/z＝604.0[M+H]⁺，纯度：98.1％。¹H 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,2H),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)。The reference compound EVO33168 was separated by HPLC preparative column and freeze-dried to obtain yellow solid EVO33408 (7 mg, yield: 27%), LCMS (ESI) m/z=604.0 [M+H] ⁺ , purity: 98.1%. ¹ H NMR (400 MHz, DMSO-d ₆ )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,2H),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).

实施例70 EVO33411
Example 70 EVO33411

参照化合物EVO33138，经高效液相制备柱分离，再冷冻干燥得到产物EVO33411(4.5mg，收率：5.07％)，LCMS(ESI)m/z＝602.27[M+H]⁺，纯度：96.99％。¹H 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＝7.2Hz,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)。The reference compound EVO33138 was separated by HPLC preparative column and 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 (400 MHz, DMSO-d ₆ ) δ 9.84 (t, J = 5.6 Hz, 1H), 9.41 (s, 1H), 8.71-8.59 (m, 2H), 8.57 (d, J = 8.4, 2H), 7.90 (d, J = 7.2 Hz, 1H), 7.86 (s, 1H), 7.75 (t, J = 8.4, 1H), 7.03 (d, J = 8.4 Hz, 1H), 5.58 (s, 2H), 4.85 (d, J = 6 Hz, 2H), 4.37-4.20 (m, 2H), 3.73 (q, J = 7.6 Hz, 2H), 3.69-3.65 (m, 2H), 2.54-2.45 (m, 2H), 1.22 (d, J = 6.4 Hz, 6H), 1.17 (t, J = 7.2 Hz, 3H).

实施例71 EVO33412
Example 71 EVO33412

参照化合物EVO33138，经高效液相制备柱分离，再冷冻干燥得到黄色固体EVO33412(5.5mg，收率：8.23％)，LCMS(ESI)m/z＝602.25[M+H]⁺，纯度：98.62％。¹H 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)。The reference compound EVO33138 was separated by HPLC preparative column and freeze-dried to obtain yellow solid EVO33412 (5.5 mg, yield: 8.23%), LCMS (ESI) m/z=602.25 [M+H] ⁺ , purity: 98.62%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.81 (t, J = 6 Hz, 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 = 8.0 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 5.75 (s, 2H), 4.86 (d, J = 5.6 Hz, 2H), 4.31 (d, J = 10.8 Hz, 2H), 3.72-3.62 (m, 2H), 3.48 (q, J = 7.6 Hz, 2H), 2.55-2.44 (m, 2H), 1.22 (d, J = 6 Hz, 6H), 1.18 (t, J = 7.6 Hz, 3H).

实施例72 EVO33376
Example 72 EVO33376

参照化合物EVO33173，经高效液相制备柱分离，再冷冻干燥得到白色固体EVO33376(17.1mg，收率：50.5％)，LCMS(ESI)m/z＝592.44[M+H]⁺，¹H 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)。The reference compound EVO33173 was separated by HPLC preparative column and freeze-dried to obtain white solid EVO33376 (17.1 mg, yield: 50.5%), LCMS (ESI) m/z=592.44 [M+H] ⁺ , ¹ H NMR (400 MHz, DMSO-d ₆ )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).

实施例73 EVO33398
Example 73 EVO33398

参照化合物EVO33173，经高效液相制备柱分离，再冷冻干燥得到黄色固体EVO33398(24.6mg，收率：50.2％)，LCMS(ESI)m/z＝576.18[M+H]⁺，¹H 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),6.75(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)。The reference compound EVO33173 was separated by HPLC preparative column and then freeze-dried to obtain a yellow solid EVO33398 (24.6 mg, yield: 50.2%), LCMS (ESI) m/z=576.18 [M+H] ⁺ , ¹ H NMR (400 MHz, Chloroform-d) δ9.27 (s, 1H), 8.67 (d, J=8.6 Hz, 1H), 8.44-8.31 (m, 1H), 8.08-7.98 (m, 2H), 7.82 (d, J=1.6 Hz, 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).

实施例74 EVO33403
Example 74 EVO33403

参照化合物EVO33138，经高效液相制备柱分离，再冷冻干燥得到产物EVO33403(18.2mg，收率：31％)，LCMS(ESI)m/z＝582.12[M+H]⁺，纯度：99.41％。¹H 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)。The reference compound EVO33138 was separated by HPLC preparative column and 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 (400 MHz, Chloroform-d) δ 9.32 (s, 1H), 8.90 (d, J = 8.4 Hz, 1H), 8.75 (d, J = 8.0 Hz, 1H), 8.47 (d, J = 8.4 Hz, 1H), 8.06-8.01 (m, 2H), 7.93 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 1.6 Hz, 1H), 7.77 (br, 2H), 7.69 (d, J = 1.6 Hz, 1H), 7.40 (t, J = 4.8 Hz, 1H), 6.25 (s, 2H), 4.98 (d, J = 5.2 Hz, 2H), 3.31 (q, J = 7.6 Hz, 2H), 2.73 (s, 6H), 1.35 (t, J = 7.6 Hz, 3H).

实施例75 EVO33416
Example 75 EVO33416

参照化合物EVO33138，经高效液相制备柱分离，再冷冻干燥得到产物EVO33416(32.8mg，收率：45％)，LCMS(ESI)m/z＝558.26[M+H]⁺，纯度：86.1％。¹H NMR(400MHz,Chloroform-d)δ9.46(s,1H),8.99(t,1H),8.92(d,J＝8.7Hz,1H),8.59-8.51(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)。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 (400 MHz, Chloroform-d) δ9.46 (s, 1H), 8.99 (t, 1H), 8.92 (d, J=8.7 Hz, 1H), 8.59-8.51 (m, 2H), 8.14 (d, J=7.4 Hz, 1H), 7.82-7.73 (m, 1H), 7.64-7.56 (m, 1H), 7.37 (d, J=1.7 Hz, 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).

实施例76 EVO33432
Example 76 EVO33432

参照化合物EVO33138，经高效液相制备柱分离，再冷冻干燥得到产物EVO33432(78.8mg，收率：54％)，LCMS(ESI)m/z＝542.23[M+H]⁺，纯度：99.55％。¹H 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)。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 (400 MHz, Chloroform-d) δ9.19 (s, 1H), 8.62 (d, J = 8.6 Hz, 1H), 8.35 (d, J = 8.7 Hz, 1H), 7.98 (d, J = 8.0 Hz, 2H), 7.73-7.63 (m, 2H), 7.60 (s, 1H), 7.29 (d, J = 1.5 Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H), 6.12-6.01 (m, 2H), 5.11-4.78 (m, 3H), 4.21 (d, J = 12.5 Hz, 2H), 3.80 (d, J = 4.0 Hz, 2H), 2.70-2.58 (m, 2H), 1.52 (d, J = 6.5 Hz, 3H), 1.34 (d, J = 6.2 Hz, 6H).

实施例77 EVO33458
Example 77 EVO33458

参照化合物EVO33138，经高效液相制备柱分离，再冷冻干燥得到产物EVO33458(3.88mg，收率：16％)，LCMS(ESI)m/z＝555.26[M+H]⁺，纯度：97.2％。¹H NMR(400MHz,Chloroform-d)δ9.26(s,1H),8.63(d,J＝8.5Hz,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)。The reference compound EVO33138 was separated by HPLC preparative column and 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 (400 MHz, Chloroform-d) δ 9.26 (s, 1H), 8.63 (d, J = 8.5 Hz, 1H), 8.37 (d, J = 8.7 Hz, 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 = 8.4 Hz, 1H), 6.07 (s, 2H), 4.96 (d, J = 4.8 Hz, 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 = 6.2 Hz, 6H).

实施例78 EVO33467
Example 78 EVO33467

参照化合物EVO33138，经高效液相制备柱分离，再冷冻干燥得到产物EVO33467(9.28mg，收率：24％)，LCMS(ESI)m/z＝570.19[M+H]⁺，纯度：98.4％。¹H 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＝8.4Hz,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)。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 (400 MHz, DMSO-d ₆ )δ9.39 (s, 1H), 9.20 (t, J=6.0 Hz, 1H), 8.69-8.59 (m, 2H), 7.90 (d, J=7.2 Hz, 1H), 7.77-7.69 (m, 2H), 7.65 (d, J=1.6 Hz, 1H), 7.49 (d, J=1.6 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 6.4 5(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).

实施例79 EVO33486
Example 79 EVO33486

参照化合物EVO33138，经高效液相制备柱分离，再冷冻干燥得到产物EVO33486(14.81mg，收率：42％)，LCMS(ESI)m/z＝588.20[M+H]⁺，纯度：99.06％。¹H 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)。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 (400 MHz, Chloroform-d) δ9.82 (d, J = 2.0 Hz, 1H), 9.56 (s, 1H), 8.78 (d, J = 2.0 Hz, 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 = 8.0 Hz, 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).

实施例80 EVO33490
Example 80 EVO33490

参照化合物EVO33138，经高效液相制备柱分离，再冷冻干燥得到产物EVO33490(16mg，收率：48％)，LCMS(ESI)m/z＝580.43[M+H]⁺，纯度：99.13％。¹H 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),4.85(d,J＝5.6Hz,2H),3.38(q,J＝7.2Hz,2H),2.57(s,6H),1.15(t,J＝7.2Hz,3H)。The reference compound EVO33138 was separated by HPLC preparative column and 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 (400 MHz, DMSO-d ₆ ) δ 9.61 (t, J = 6.0 Hz, 1H), 9.47 (s, 1H), 8.90 (d, J = 8.4 Hz, 1H), 8.78 (d, J = 8.4 Hz, 1H), 8.65 (d, J = 7.8 Hz, 1H), 8.33 (s, 1H), 8.29-8.23 (m, 2H), 8.16 (t, J = 7.8 Hz, 1H), 7.92-7.89 (m, 3H), 5.33 (s, 2H), 5.15 (s, 2H), 4.85 (d, J = 5.6 Hz, 2H), 3.38 (q, J = 7.2 Hz, 2H), 2.57 (s, 6H), 1.15 (t, J = 7.2 Hz, 3H).

实施例81 EVO33504
Example 81 EVO33504

参照化合物EVO33138，经高效液相制备柱分离，再冷冻干燥得到产物EVO33504(27.8mg，收率：36％)，LCMS(ESI)m/z＝576.2[M+H]⁺，纯度：99.31％。¹H NMR(400MHz,DMSO-d₆)δ9.44-9.36(m,2H),8.64(q,J＝8.4Hz,2H),7.94-7.87(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),3.40(q,J＝7.2Hz,2H),2.95-2.88(m,1H),2.62-2.52(m,1H),1.23-1.16(m,6H)。The reference compound EVO33138 was separated by HPLC preparative column and 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 (400 MHz, DMSO-d ₆ ) δ 9.44-9.36 (m, 2H), 8.64 (q, J=8.4 Hz, 2H), 7.94-7.87 (m, 2H), 7.82-7.73 (m, 3H), 7.03 (d, J=8.4 Hz, 1H), 6.35 (s, 2H), 4.78 (d, J=5.6 Hz, 2H), 4.32-4.20 (m, 2H), 3.97 (d, J=10 Hz, 1H), 3.70-3.52 (m, 2H), 3.40 (q, J=7.2 Hz, 2H), 2.95-2.88 (m, 1H), 2.62-2.52 (m, 1H), 1.23-1.16 (m, 6H).

实施例82 EVO33507
Example 82 EVO33507

参照化合物EVO33138，经高效液相制备柱分离，再冷冻干燥得到产物EVO33507(14.7mg，收率：19.1％)，LCMS(ESI)m/z＝576.22[M+H]⁺，纯度：98.65％。¹H 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)。The reference compound EVO33138 was separated by HPLC preparative column and 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 (400 MHz, DMSO-d ₆ ) δ 9.41-9.38 (m, 2H), 8.66 (s, 2H), 7.90 (d, J=1.6 Hz, 1H), 7.83-7.79 (m, 3H), 7.69 (t, J=8.4 Hz, 1H), 6.64 (d, J=8.4 Hz, 1H), 6.35 (s, 2H), 4.78 (d, J=5.6 Hz, 2H), 4.15-4.11 (m, 1H), 3.64-3.59 (m, 3H), 3.50 (q, J=8.6 Hz, 1H), 3.38 (q, J=7.4 Hz, 2H), 3.30 (s, 3H), 2.14-2.09 (m, 2H), 1.18 (t, J=7.2 Hz, 3H).

实施例83 EVO33508
Example 83 EVO33508

参照化合物EVO33138，经高效液相制备柱分离，再冷冻干燥得到产物EVO33508(17.8mg，收率：12.14％)，LCMS(ESI)m/z＝548.51[M+H]⁺，纯度：95.67％。¹H 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)。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 (400 MHz, DMSO-d ₆ )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).

实施例84 EVO33509
Example 84 EVO33509

参照化合物EVO33138，经高效液相制备柱分离，再冷冻干燥得到产物EVO33509(8.7mg，收率：12.6％)，LCMS(ESI)m/z＝574.57[M+H]⁺，纯度：85.2％。¹H 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)。The reference compound EVO33138 was separated by HPLC preparative column and 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 (400 MHz, DMSO) δ 9.42-9.36 (m, 2H), 8.67 (d, J = 8.8 Hz, 1H), 8.60 (d, J = 8.4 Hz, 1H), 7.92-7.87 (m, 2H), 7.83-7.77 (m, 2H), 7.72 (t, J = 8.0 Hz, 1H), 6.58 (d, J = 8.0 Hz, 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 = 7.2 Hz, 3H).

实施例85 EVO33511
Example 85 EVO33511

参照化合物EVO33138，经高效液相制备柱分离，再冷冻干燥得到产物EVO33511(15.7mg，收率：22.3％)，LCMS(ESI)m/z＝590.2[M+H]⁺，纯度：96.33％。¹H 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)。The reference compound EVO33138 was separated by HPLC preparative column and 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 (400 MHz, DMSO-d ₆ )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).

实施例86 EVO33512
Example 86 EVO33512

参照化合物EVO33138，经高效液相制备柱分离，再冷冻干燥得到产物EVO33512(20.7mg，收率：30.2％)，LCMS(ESI)m/z＝576.24[M+H]⁺，纯度：97.94％。¹H NMR(400MHz,DMSO-d₆)δ9.41-9.39(m,2H),8.68-8.63(m,2H),7.90(d,J＝1.6Hz,1H),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)。The reference compound EVO33138 was separated by HPLC preparative column and 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 (400 MHz, DMSO-d ₆ ) δ 9.41-9.39 (m, 2H), 8.68-8.63 (m, 2H), 7.90 (d, J = 1.6 Hz, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.81-7.80 (m, 2H), 7.72 (t, J = 8.4 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 6.35 (s, 2H), 5.51-5.44 (m, 1H), 4.78 (d, J = 6.0 Hz, 2H), 4.03-3.97 (m, 1H), 3.87-3.82 (m, 1H), 3.79-3.75 (m, 1H), 3.70 (q, J = 8.0 Hz, 1H), 3.38 (q, J = 7.2 Hz, 2H), 3.00(s, 3H), 2.33-2.25(m, 1H), 1.96-1.88(m, 1H), 1.19(t, J＝7.6Hz, 3H).

实施例87 EVO33513
Example 87 EVO33513

参照化合物EVO33138，经高效液相制备柱分离，再冷冻干燥得到产物EVO33513(2.1mg，收率：3.8％)，LCMS(ESI)m/z＝590.7[M+H]⁺，纯度：95.27％。¹H 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)。The reference compound EVO33138 was separated by HPLC preparative column and 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 (400 MHz, DMSO-d ₆ ) δ 9.40-9.38 (m, 2H), 8.68-8.59 (m, 2H), 7.90 (d, J=1.6 Hz, 1H), 7.83-7.79 (m, 3H), 7.69 (t, J=7.6 Hz, 1H), 6.81 (d, J=8.4 Hz, 1H), 6.35 (s, 2H), 4.78 (d, J=6.4 Hz, 2H), 3.81 (t, J=6.0 Hz, 2H), 3.70 (t, J=5.6 Hz, 2H), 3.41-3.34 (m, 3H), 3.13 (s, 3H), 1.18 (t, J=7.2 Hz, 3H), 0.45-0.40 (m, 4H).

实施例88 EVO33522
Example 88 EVO33522

参照化合物EVO33138，经高效液相制备柱分离，再冷冻干燥得到产物EVO33522(10.7mg，收率：23.48％)，LCMS(ESI)m/z＝591.24[M+H]⁺，纯度：91.3％。¹H 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)。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 (400 MHz, DMSO-d ₆ )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).

实施例89 EVO33525
Example 89 EVO33525

参照化合物EVO33138，经高效液相制备柱分离，再冷冻干燥得到产物EVO33525(13.5mg，收率：29.4％)，LCMS(ESI)m/z＝588.06[M+H]⁺，纯度：99.38％。¹H 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)。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 (400 MHz, DMSO-d ₆ )δ9.46 (t, J=5.6 Hz, 1H), 9.40 (s, 1H), 8.64 (q, J=8.4 Hz, 2H), 7.99 (s, 1H), 7.91 (d, J=7.2 Hz, 1H), 7.80 (s, 1H), 7.75 (t, J=8.0 Hz, 1H), 7.69 (s, 1H), 7.03 (d, J=8.8 Hz, 1H), 4.80 (d, J=5.6 Hz, 2H), 4.62 (t, J = 8.0 Hz, 1H), 4.41 (dd, J = 8.4, 2.0 Hz, 1H), 4.31 (d, J = 12.8 Hz, 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 = 7.2 Hz, 3H), 1.22 (d, J = 6.0 Hz, 6H).

实施例90 EVO33535
Example 90 EVO33535

参照化合物EVO33138，经高效液相制备柱分离，再冷冻干燥得到产物EVO33535(15.5mg，收率：22.12％)，LCMS(ESI)m/z＝560.24[M+H]⁺，纯度：98.57％。¹H 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)。The reference compound EVO33138 was separated by HPLC preparative column and 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 (400 MHz, Chloroform-d) δ 9.30 (s, 1H), 8.75 (d, J = 8.8 Hz, 1H), 8.40 (d, J = 8.8 Hz, 1H), 8.06 (s, 1H), 8.00 (d, J = 7.2 Hz, 1H), 7.82 (d, J = 1.6 Hz, 1H), 7.87-7.58 (m, 3H), 6.85 (d, J = 8.4 Hz, 1H), 6.27 (s, 2H), 5.01 (d, J = 5.2 Hz, 2H), 3.70-3.66 (m, 4H), 3.33 (q, J = 7.6 Hz, 2H), 1.75-1.68 (m, 6H), 1.37 (t, J = 7.6 Hz, 3H).

实施例91 EVO33536
Example 91 EVO33536

参照化合物EVO33138，经高效液相制备柱分离，再冷冻干燥得到产物EVO33536(23mg，收率：19％)，LCMS(ESI)m/z＝546.19[M+H]⁺，纯度：95.02％。¹H 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)。The reference compound EVO33138 was separated by HPLC preparative column and 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 (400 MHz, DMSO-d ₆ ) δ 9.43-9.35 (m, 2H), 8.65 (s, 2H), 7.90 (d, J=1.6 Hz, 1H), 7.82-7.78 (m, 3H), 7.68 (dd, J=8.4, 7.2 Hz, 1H), 6.62 (d, J=8.0 Hz, 1H), 6.35 (s, 2H), 4.78 (d, J=6.0 Hz, 2H), 3.57-3.47 (m, 4H), 3.38 (q, J=7.6 Hz, 2H), 2.04-1.96 (m, 4H), 1.18 (t, J=7.2 Hz, 3H).

实施例92 EVO33540
Example 92 EVO33540

参照化合物EVO33138，经高效液相制备柱分离，再冷冻干燥得到产物EVO33540(21.8mg，收率：31.19％)，LCMS(ESI)m/z＝562.21[M+H]⁺，纯度：98.33％。¹H 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＝3.6Hz,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)。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 (400 MHz, DMSO-d ₆ )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＝3.6Hz,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).

实施例93 EVO33546
Example 93 EVO33546

参照化合物EVO33138，经高效液相制备柱分离，再冷冻干燥得到产物EVO33546(7.1mg，收率：16.5％)，LCMS(ESI)m/z＝578.2[M+H]⁺，纯度：98.31％。¹H 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,4H),3.38(dd,J＝14.8,7.2Hz,2H),2.69-2.67(m,4H),1.18(t,J＝7.2Hz,3H)。The reference compound EVO33138 was separated by HPLC preparative column and 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 (400 MHz, DMSO-d ₆ ) δ 9.40-9.39 (m, 2H), 8.66 (d, J=8.4 Hz, 1H), 8.59 (d, J=8.4 Hz, 1H), 7.90-7.86 (m, 2H), 7.81-7.80 (m, 2H), 7.40 (t, J=8.0 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 6.35 (s, 2H), 4.78 (d, J=5.6 Hz, 2H), 4.06-4.03 (m, 4H), 3.38 (dd, J=14.8, 7.2 Hz, 2H), 2.69-2.67 (m, 4H), 1.18 (t, J=7.2 Hz, 3H).

实施例94 EVO33600
Example 94 EVO33600

参照化合物EVO33138，经高效液相制备柱分离，再冷冻干燥得到产物EVO33600(8.58mg，收率：20％)，LCMS(ESI)m/z＝556.2[M+H]⁺，纯度：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＝2.0Hz,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),4.30-4.26(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)。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%. ¹ H NMR (400MHz, Chloroform-d) δ9.77 (d, J=2.0 Hz, 1H), 9.55 (s, 1H), 8.73 (d, J=2.0 Hz, 1H), 8.00 (s, 1H), 7.74-7.72 (m, 1H), 7.72-7.70 (m, 1H), 7.67 (d, J=2.0 Hz, 1H), 7.36 (d, J=2.0 Hz, 1H). z, 1H), 7.35-7.33 (m, 1H), 6.79 (d, J = 8.8 Hz, 1H), 6.10 (d, 2H), 5.01 (d, J = 6.0 Hz, 2H), 4.30-4.26 (m, 2H), 3.85-3.80 (m, 2H), 2.72-2.64 (m, 2H), 1.67 (s, 6H), 1.38 (d, J = 6.4 Hz, 6H).

实施例95 EVO33415
Example 95 EVO33415

参照化合物EVO33174，经高效液相制备柱分离，再冷冻干燥得到棕色固体EVO33415(8.19mg,收率：17.25％,纯度：94％)，LCMS(ESI)m/z＝580.38[M+H]⁺。¹H 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,1H),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)。The 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 (400 MHz, Methanol-d ₄ ) δ 8.57 (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=6.8 Hz, 1H), 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=7.2 Hz, 3H), 1.25 (d, J=6.0 Hz, 6H).

实施例96 EVO33426
Example 96 EVO33426

参照化合物EVO33240，经高效液相制备柱分离，再冷冻干燥得到黄色固体EVO33426(14.14mg,收率：36.89％,纯度：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＝5.6Hz,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)。The reference compound EVO33240 was separated by HPLC preparative column and then 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] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ9.22 (t, J = 6.0 Hz, 1H), 8.54-8.45 (m, 1H), 7.88 (d, J = 1.6 Hz, 1H), 7.75 (d, J = 1.6 Hz, 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＝5.6Hz, 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).

实施例97 EVO33342
Example 97 EVO33342

参照化合物EVO33341，经高效液相制备柱分离，再冷冻干燥得到产物EVO33342(15.8mg，收率：28％)，LCMS(ESI)m/z＝588.39[M+H]⁺，纯度：98.8％。¹H 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＝8.4Hz,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)。The reference compound EVO33341 was separated by HPLC preparative column and 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 (400 MHz, Chloroform-d) δ 9.65-9.59 (m, 1H), 9.51 (s, 1H), 9.03 (d, J = 0.8 Hz, 1H), 8.91 (d, J = 8.8 Hz, 1H), 8.72 (d, J = 0.8 Hz, 1H), 8.62 (d, J = 8.8 Hz, 1H), 8.45 (s, 1H), 8.13 (d, J = 7.2 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 5.18 (d, J = 6.0 Hz, 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).

实施例98 EVO33430
Example 98 EVO33430

参照化合物EVO33341，经高效液相制备柱分离，再冷冻干燥得到产物EVO33430(10.3mg，收率：22％)，LCMS(ESI)m/z＝590.10[M+H]⁺，纯度：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)。The reference compound EVO33341 was separated by HPLC preparative column and freeze-dried to obtain the product EVO33430 (10.3 mg, yield: 22%), LCMS (ESI) m/z=590.10 [M+H] ⁺ , purity: 95.7%. ¹ H NMR (400 MHz, Chloroform-d) δ 9.28 (s, 1H), 8.89 (s, 1H), 8.86 (s, 1H), 8.68 (d, J = 8.4 Hz, 1H), 8.40 (d, J = 8.8 Hz, 1H), 8.06-8.00 (m, 3H), 7.72 (t, J = 8.0 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 5.06 (d, J = 4.8 Hz, 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 = 6.0 Hz, 6H).

实施例99 EVO33389

Example 99 EVO33389

第1步：step 1:

室温下，反应瓶中加入7-溴苯并[d][1,3]二氧代-5-羧酸甲酯(500mg,1.93mmol)，三丁基锡基甲醇(929.59mg,2.90mmol)，XPhosPd G2(151.86mg,193.01μmol)和无水1，4-二氧六环(20mL)，Ar置换三次，油浴加热至100℃反应16小时。反应液降至室温，减压浓缩后得粗品，中压正相柱层析纯化(EA/PE＝0-100％)得类白色固体EVO33389-A1(364mg,收率：89.7％)，LCMS(ESI)m/z＝211.0[M+H]⁺。At room temperature, 7-bromobenzo[d][1,3]dioxo-5-carboxylic acid methyl ester (500 mg, 1.93 mmol), tributyltinylmethanol (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, and Ar was replaced three times. The oil bath was heated to 100°C for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain a crude product, which was purified by medium pressure normal phase column chromatography (EA/PE=0-100%) to obtain an off-white solid EVO33389-A1 (364 mg, yield: 89.7%), LCMS (ESI) m/z=211.0[M+H] ⁺ .

第2步：Step 2:

室温，Ar保护下，反应瓶中加入EVO33389-A1(364mg,1.73mmol)和无水DCM(10mL)，冷浴降温至-10℃；控温±5℃加入PBr₃(937.57mg,3.46mmol,325.55μL)，加完后自然升至室温搅拌2小时。反应液直接减压浓缩得粗品，中压正相柱层析纯化(EA/PE＝0-20％)得类白色固体EVO33389-A2(322mg,收率：68.1％)，LCMS(ESI)m/z＝273.1/275.1[M+H]⁺。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 the temperature was cooled to -10°C in a cold bath; PBr ₃ (937.57 mg, 3.46 mmol, 325.55 μL) was added with a temperature control of ±5°C, and the temperature was naturally raised to room temperature and stirred for 2 hours after the addition. The reaction solution was directly concentrated under reduced pressure to obtain a crude product, which was purified by medium-pressure normal phase column chromatography (EA/PE=0-20%) to obtain an off-white solid EVO33389-A2 (322 mg, yield: 68.1%), LCMS (ESI) m/z=273.1/275.1 [M+H] ⁺ .

第3步：Step 3:

室温下，反应瓶中加入EVO33389-A2(322mg,1.18mmol)，无水ACN(10mL)和TMSCN(233.97mg,2.36mmol,295.04μL)，冰水浴降至0～5℃，缓慢滴加TBAF溶液(1.0M in THF，2.5mL)，自然升至室温反应2小时。减压浓缩得粗品，中压正相柱层析纯化(EA/PE＝0-30％)得类白色固体EVO33389-A3(229mg,收率：88.6％)，LCMS(ESI)m/z＝220.0[M+H]⁺。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 ice-water bath was cooled to 0-5°C, TBAF solution (1.0 M in THF, 2.5 mL) was slowly added dropwise, and the temperature was naturally raised to room temperature 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 obtain an off-white solid EVO33389-A3 (229 mg, yield: 88.6%), LCMS (ESI) m/z = 220.0 [M+H] ⁺ .

第4步：Step 4:

室温下，反应瓶中加入EVO33389-A3(50mg,228.11μmol)，LiOH.H₂O(19.14mg,456.22μmol)，MeOH(1mL)和H₂O(1mL)，室温搅拌16小时。减压浓缩旋除溶剂，1N稀盐酸溶液调pH＝3～4，析出白色固体，过滤，滤饼用冰水淋洗，烘干得类白色固体EVO33389-A4(44mg,收率：94.0％)，LCMS(ESI)m/z＝204.10[M-H]^-，含约15％氰基水解的副产物。At room temperature, EVO33389-A3 (50 mg, 228.11 μmol), LiOH.H ₂ O (19.14 mg, 456.22 μmol), MeOH (1 mL) and H ₂ O (1 mL) were added to the reaction flask 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 solution to precipitate a white solid, which was filtered, and 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% byproducts of cyano hydrolysis.

第5步：Step 5:

室温下，反应瓶中依次加入EVO33389-A4(21mg,102.36μmol)，EVO33070A7(35.77mg,102.36μmol)，无水DMF(2mL)和TEA(51.79mg,511.78μmol,71.33μL)，再加入HATU(58.38mg,153.53 μmol)，室温搅拌2小时，加水淬灭后处理。经高效液相制备柱分离，冷冻干燥得淡黄色固体EVO33389(36mg,收率：65.6％)，LCMS(ESI)m/z＝537.4[M+H]⁺，纯度：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)。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 bottle in sequence, and HATU (58.38 mg, 153.53 μmol), stirred at room temperature for 2 hours, quenched with water and then treated. Separated by HPLC preparative column, freeze-dried to obtain pale yellow solid EVO33389 (36 mg, yield: 65.6%), LCMS (ESI) m/z = 537.4 [M + H] ⁺ , purity: 99.5%. ¹ H NMR (400 MHz, DMSO-d ₆ )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).

实施例100 EVO33414
Example 100 EVO33414

参照化合物EVO33389，经高效液相制备柱分离，再冷冻干燥得黄色固体EVO33414(42mg,收率：43.4％)，LCMS(ESI)m/z＝565.4[M+H]⁺，纯度：97.6％。¹H 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＝1.6Hz,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)。The reference compound EVO33389 was separated by HPLC preparative column and freeze-dried to obtain yellow solid EVO33414 (42 mg, yield: 43.4%), LCMS (ESI) m/z=565.4 [M+H] ⁺ , purity: 97.6%. ¹ H NMR (400 MHz, DMSO-d ₆ )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＝1.6Hz,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).

实施例101 EVO33392
Example 101 EVO33392

第1步：step 1:

室温下，反应瓶中加入EVO33381-B1(124mg,415.67μmol)和THF(3mL)，再加入NaOMe的甲醇溶液(5.4M in methanol,623.51μmol)，室温搅拌2小时，原料消失，EVO33381-B2未出对应分子离子峰，母液直接用于下一步反应。 At room temperature, EVO33381-B1 (124 mg, 415.67 μmol) and THF (3 mL) were added to the reaction flask, and then a methanol solution of NaOMe (5.4 M in methanol, 623.51 μmol) was added. The mixture was stirred at room temperature for 2 hours. The raw material disappeared, and EVO33381-B2 did not produce the corresponding molecular ion peak. The mother liquor was directly used in the next reaction.

第2步：Step 2:

室温下，反应液中加入2-溴乙醇(155.83mg,1.25mmol)，室温搅拌1小时。反应液直接减压浓缩得粗品，中压正相柱层析纯化(EA/PE＝0-60％)得无色油状物EVO33392-A1(50mg,收率：46.9％)，LCMS(ESI)m/z＝257.0[M+H]⁺。At room temperature, 2-bromoethanol (155.83 mg, 1.25 mmol) was added to the reaction solution, and stirred at room temperature for 1 hour. The reaction solution was directly concentrated under reduced pressure to obtain a crude product, which was purified by medium-pressure normal phase column chromatography (EA/PE=0-60%) to obtain a colorless oil EVO33392-A1 (50 mg, yield: 46.9%), LCMS (ESI) m/z=257.0 [M+H] ⁺ .

第3步：Step 3:

室温下，反应瓶中加入Oxone(431.79mg,702.37μmol)和H₂O(2mL)，用饱和碳酸氢钠溶液调pH＝7～8，再加入EVO33392-A1(60mg,234.12μmol)和ACN(3.5mL)，室温搅拌3小时。反应液减压浓缩得粗品，中压正相柱层析纯化(MeOH/DCM＝0-10％)得无色油状物EVO33392-A2(60mg,收率：88.9％)，LCMS(ESI)m/z＝289.0[M+H]⁺。At room temperature, Oxone (431.79 mg, 702.37 μmol) and H ₂ O (2 mL) were added to the reaction flask, and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution, and EVO33392-A1 (60 mg, 234.12 μmol) and ACN (3.5 mL) were added, and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by medium pressure normal phase column chromatography (MeOH/DCM=0-10%) to obtain a colorless oil EVO33392-A2 (60 mg, yield: 88.9%), LCMS (ESI) m/z=289.0 [M+H] ⁺ .

第4步：Step 4:

室温下，反应瓶中加入EVO33392-A2(60mg,208.14μmol)和MeOH(1mL)，氢氧化锂(17.47mg,416.27μmol)用水(1mL)溶解后加入，油浴加热33℃反应1小时。反应液减压浓缩后，DMF(2mL)溶解浓缩产品，过反相柱(乙腈：0.1％甲酸水)，再冷冻干燥得类白色固体EVO33392-A3(29mg,收率：50.8％)，LCMS(ESI)m/z＝273.0[M-H]^-。At room temperature, EVO33392-A2 (60 mg, 208.14 μmol) and MeOH (1 mL) were added to the reaction flask, and lithium hydroxide (17.47 mg, 416.27 μmol) was dissolved in water (1 mL) and then added, and the mixture was heated in an oil bath at 33°C for 1 hour. After the reaction solution was concentrated under reduced pressure, the concentrated product was dissolved in DMF (2 mL), passed through a reverse phase column (acetonitrile: 0.1% formic acid water), and then freeze-dried to obtain an off-white solid EVO33392-A3 (29 mg, yield: 50.8%), LCMS (ESI) m/z = 273.0 [MH] ^- .

第5步：Step 5:

室温下，反应瓶中依次加入EVO33392-A3(29mg,105.74μmol)，中间体1-A1(36.95mg,105.74μmol)，无水DMF(2mL)，DIPEA(68.33mg,528.72μmol,92.09μL)，最后加入HATU(60.31mg,158.62μmol)室温搅拌1小时。加水淬灭后处理，经高效液相制备柱分离，冷冻干燥得淡黄色固体EVO33392(36mg,收率：56.2％)，LCMS(ESI)m/z＝606.4[M+H]⁺，纯度：99.9％。¹H NMR(400MHz,DMSO-d₆)δ9.41-9.38(m,2H),8.68-8.61(m,2H),7.92-7.89(m,2H),7.79-7.73(m,3H),7.03(d,J＝8.4Hz,1H),6.35(s,2H),4.90(t,J＝5.4Hz,1H),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)。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) were added to the reaction bottle in sequence, and finally HATU (60.31 mg, 158.62 μmol) was added and stirred at room temperature for 1 hour. After quenching with water, the mixture was separated by HPLC preparative column and freeze-dried to obtain light yellow solid EVO33392 (36 mg, yield: 56.2%), LCMS (ESI) m/z = 606.4 [M+H] ⁺ , purity: 99.9%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.41-9.38 (m, 2H), 8.68-8.61 (m, 2H), 7.92-7.89 (m, 2H), 7.79-7.73 (m, 3H), 7.03 (d, J=8.4 Hz, 1H), 6.35 (s, 2H), 4.90 (t, J=5.4 Hz, 1H), 4.78 (d, J=5.6 Hz, 2H), 4.32 (d, J=12.8 Hz, 2H), 3.76 (q, J=5.6 Hz, 2H), 3.70-3.65 (m, 2H), 3.54 (t, J=6.2 Hz, 2H), 2.53-2.47 (m, 2H), 1.21 (d, J=6.4 Hz, 6H).

实施例102 EVO33523

Example 102 EVO33523

第1步：step 1:

室温下，微波管中加入EVO33522-A2(30mg,84.55μmol)，DMSO(1.0mL)，甲基肼硫酸盐(243mg,1.69mmol)，K₂CO₃(350mg,2.54mmol)，水(1.0mL)，封管，投料8批次。先搅拌0.5h，然后加热到110℃搅拌48小时。冷至室温后，分别向各个微波管中加入甲基肼硫酸盐(243mg,1.69mmol)和K₂CO₃(350mg,2.54mmol)，封管，先室温搅拌0.5小时，然后加热到110℃搅拌48小时。LC-MS检测反应结果均为60％产物和30％原料。加入EA(10mL)和H₂O(10mL)稀释，收集有机相，水相用EA反萃3次。合并有机相，用饱和氯化钠溶液(50mL x 1)洗涤，无水硫酸钠干燥，过滤浓缩至干，剩余物经柱层析纯化(DCM/MeOH：10/1)得到黄色油状物EVO33523-A1(150mg,纯度：70％)，经制备板纯化(DCM/MeOH：10/1)得EVO33523-A1(100mg，收率：36.51％，纯度：90％)。LCMS(ESI)m/z＝365.46[M+H]⁺。At room temperature, EVO33522-A2 (30 mg, 84.55 μmol), DMSO (1.0 mL), methylhydrazine sulfate (243 mg, 1.69 mmol), K ₂ CO ₃ (350 mg, 2.54 mmol), and water (1.0 mL) were added to the microwave tube, and the tube was sealed. Eight batches of materials were added. Stir for 0.5 h, and then heated to 110 ° C and stirred for 48 hours. After cooling to room temperature, methylhydrazine sulfate (243 mg, 1.69 mmol) and K ₂ CO ₃ (350 mg, 2.54 mmol) were added to each microwave tube, and the tube was sealed. Stir for 0.5 h at room temperature, and then heated to 110 ° C and stirred for 48 hours. The reaction results of LC-MS detection were 60% product and 30% starting material. EA (10 mL) and H ₂ O (10 mL) were added to dilute, the organic phase was collected, and the aqueous phase was back-extracted with EA 3 times. 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, and the residue was purified by column chromatography (DCM/MeOH: 10/1) to obtain yellow oil EVO33523-A1 (150 mg, purity: 70%), which was purified by preparative plate (DCM/MeOH: 10/1) to obtain EVO33523-A1 (100 mg, yield: 36.51%, purity: 90%). LCMS (ESI) m/z = 365.46 [M+H] ⁺ .

第2步：Step 2:

冰水浴下，EVO33522-A1(56mg,137.40μmol)，DMF(1mL)和DIPEA(88mg,687.00μmol)搅拌10分钟，加入7-乙基砜苯并[d][1,3]二氧代-5-羧酸(28mg,109.92μmol)，继续搅拌10分钟，然后加入EDCI(53mg,275.00μmol)及HOBt(19mg,140.74μmol)，室温搅拌1小时。加入EA(30mL)，用水(50mL x 2)洗涤，水相反萃取，合并有机相，用饱和氯化钠溶液(50mL)洗涤，无水硫酸钠干燥，过滤浓缩至干，经高效液相制备柱分离，冷冻干燥得淡黄色固体EVO33523(28mg,收率：32.71％)，LCMS(ESI)m/z＝605.24[M+H]⁺，纯度：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)。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, stirring was continued for 10 minutes, and then EDCI (53 mg, 275.00 μmol) and HOBt (19 mg, 140.74 μmol) were added, and stirring was continued at room temperature for 1 hour. EA (30 mL) was added, washed with water (50 mL x 2), aqueous phase was reversed, the organic phase was combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness, separated by HPLC preparative column, and freeze-dried to obtain light yellow solid EVO33523 (28 mg, yield: 32.71%), LCMS (ESI) m/z = 605.24 [M+H] ⁺ , purity: 97.02%. ¹ H NMR (400 MHz, DMSO-d ₆ )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).

实施例103 EVO33031
Example 103 EVO33031

参照化合物EVO33138，经高效液相制备柱分离，再冷冻干燥得到EVO33031(26mg，收率：43％)，LCMS(ESI)m/z＝556.51[M+H]⁺，纯度：98.8％。¹H 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＝8.4Hz,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)。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 (400 MHz, Chloroform-d) δ9.28 (s, 1H), 8.74 (d, J=8.6 Hz, 1H), 8.43 (d, J=8.6 Hz, 1H), 8.17 (s, 1H), 8.06 (d, J=7.2 Hz, 1H), 7.98-7.91 (m, 1H), 7.76-7.68 (m, 3H), 6.82 (d, J=8.4 Hz, 1H). z, 1H), 5.29-5.24 (m, 2H), 5.11 (s, 2H), 5.04 (d, J = 5.6 Hz, 2H), 4.21 (d, J = 11.2 Hz, 2H), 3.82-3.76 (m, 2H), 2.64 (t, J = 11.6 Hz, 2H), 1.75 (s, 3H), 1.70 (s, 3H), 1.33 (d, J = 6.0 Hz, 6H).

实施例104 EVO33036
Example 104 EVO33036

参照化合物EVO33138，经高效液相制备柱分离，再冷冻干燥得到EVO33036(3mg，收率：3％)，LCMS(ESI)m/z＝546.21[M+H]⁺，纯度：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),5.36(s,2H),5.10(s,2H),5.01(d,J＝5.4Hz,2H),2.77(s,6H),1.62(s,6H)。The reference compound EVO33138 was separated by HPLC preparative column and freeze-dried to obtain EVO33036 (3 mg, yield: 3%), LCMS (ESI) m/z=546.21 [M+H] ⁺ , purity: 98.1%. ¹ H NMR (400 MHz, Chloroform-d) δ 9.31 (s, 1H), 8.87 (d, J = 8.4 Hz, 1H), 8.76 (d, J = 7.6 Hz, 1H), 8.46 (d, J = 8.4 Hz, 1H), 8.08-8.01 (m, 2H), 7.94 (d, J = 7.6 Hz, 1H), 7.83-7.76 (m, 3H), 7.62 (s, 1H), 7.42 (t, J = 5.4 Hz, 1H), 5.36 (s, 2H), 5.10 (s, 2H), 5.01 (d, J = 5.4 Hz, 2H), 2.77 (s, 6H), 1.62 (s, 6H).

实施例105 EVO33038
Example 105 EVO33038

参照化合物EVO33138，经高效液相制备柱分离，再冷冻干燥得到EVO33038(23mg，收率：30％)，LCMS(ESI)m/z＝548.42[M+H]⁺，纯度：99.23％。¹H 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)。The reference compound EVO33138 was separated by HPLC preparative column and freeze-dried to obtain EVO33038 (23 mg, yield: 30%), LCMS (ESI) m/z=548.42 [M+H] ⁺ , purity: 99.23%. ¹ H NMR (400 MHz, Chloroform-d) δ 9.32 (s, 1H), 8.88 (d, J = 8.4 Hz, 1H), 8.77 (d, J = 7.6 Hz, 1H), 8.47 (d, J = 8.4 Hz, 1H), 8.08-8.03 (m, 2H), 7.95 (d, J = 7.6 Hz, 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 = 4.8 Hz, 2H), 2.78 (s, 6H), 1.75 (s, 3H), 1.70 (s, 3H).

实施例106 EVO33041
Example 106 EVO33041

参照化合物EVO33138，经高效液相制备柱分离，再冷冻干燥得到棕色固体EVO33041(5.22mg，收率：14.04％)，LCMS(ESI)m/z＝562.22[M+H]⁺，纯度：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)。The reference compound EVO33138 was separated by HPLC preparative column and freeze-dried to obtain brown solid EVO33041 (5.22 mg, yield: 14.04%), LCMS (ESI) m/z=562.22 [M+H] ⁺ , purity: 99.47%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.38 (s, 1H), 9.10 (t, J = 6.0 Hz, 1H), 8.70-8.57 (m, 2H), 7.91 (d, J = 7.6 Hz, 1H), 7.82 (d, J = 1.6 Hz, 1H), 7.78-7.69 (m, 2H), 7.43 (d, J = 1.6 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 6.10 (s, 2H), 5.24 (s, 1H), 4.76 (d, J = 5.6 Hz, 2H), 4.31 (dd, J＝13.2, 2.4 Hz, 2H), 3.71-3.63 (m, 2H), 2.45-2.39 (m, 2H), 1.21 (d, J＝6.4 Hz, 6H).

实施例107 EVO33140
Example 107 EVO33140

参照化合物EVO33138，经高效液相制备柱分离，再冷冻干燥得到EVO33140(24.1mg，收率：36.3％)，LCMS(ESI)m/z＝573.68[M+H]⁺，纯度：92.5％。¹H NMR(400MHz,Chloroform-d)δ9.29(s,1H),8.72(d,J＝8.7Hz,1H),8.43(d,J＝8.7Hz,1H),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)。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 (400 MHz, Chloroform-d) δ9.29 (s, 1H), 8.72 (d, J = 8.7 Hz, 1H), 8.43 (d, J = 8.7 Hz, 1H), 8.13 (s, 1H), 8.06 (d, J = 7.4 Hz, 1H), 7.98 (s, 1H), 7.86 (s, 1H), 7.76-7.70 (m, 2H), 6.82 (d, J = 8.5 Hz, 1H), 5.87 (s, 1H), 5.01 (d, J = 5.5 Hz, 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 = 6.2 Hz, 6H).

实施例108 EVO33412-B
Example 108 EVO33412-B

参照化合物EVO33138，经高效液相制备柱分离，再冷冻干燥得到EVO33412-B(34mg，收率：14.83％)，LCMS(ESI)m/z＝588.31[M+H]⁺，纯度：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＝7.2Hz,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)。The reference compound EVO33138 was separated by HPLC preparative column and freeze-dried to obtain EVO33412-B (34 mg, yield: 14.83%), LCMS (ESI) m/z=588.31 [M+H] ⁺ , purity: 98.83%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.80 (t, J = 5.6 Hz, 1H), 9.42 (s, 1H), 8.77 (dd, J = 13.2, 1.2 Hz, 2H), 8.71-8.61 (q, J = 8.8 Hz, 2H), 7.91 (d, J = 7.2 Hz, 2H), 7.75 (t, J = 7.2 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 5.78 (s, 2H), 4.87 (d, J = 5.6 Hz, 2H), 4.31 (d, J = 11.2 Hz, 2H), 3.67 (m, 2H), 3.39 (s, 3H), 2.53-2.47 (m, 2H), 1.22 (d, J = 6.0 Hz, 6H).

实施例109 EVO33435
Example 109 EVO33435

参照化合物EVO33138，经高效液相制备柱分离，再冷冻干燥得到EVO33435(23mg，收率：22％)，LCMS(ESI)m/z＝554.49[M+H]⁺，纯度：97.5％。¹H 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),7.66(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)。The reference compound EVO33138 was separated by HPLC preparative column and then freeze-dried to obtain EVO33435 (23 mg, yield: 22%), LCMS (ESI) m/z=554.49 [M+H] ⁺ , purity: 97.5%. ¹ H NMR (400 MHz, Chloroform-d) δ9.28 (s, 1H), 8.74 (d, J=8.6 Hz, 1H), 8.42 (d, J=8.6 Hz, 1H), 8.17 (s, 1H), 8.06 (d, J=7.2 Hz, 1H), 7.99-7.92 (m, 1H), 7.85 (s, 1H), 7.72 (t, J=8.0 Hz, 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).

实施例110 EVO33453
Example 110 EVO33453

参照化合物EVO33138，经高效液相制备柱分离，再冷冻干燥得到EVO33453(5mg，收率：8.3％)，LCMS(ESI)m/z＝575.16[M+H]⁺，纯度：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)。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%. ¹ H NMR (400 MHz, Chloroform-d) δ9.24 (s, 1H), 8.63 (d, J = 8.4 Hz, 1H), 8.35 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 7.2 Hz, 1H), 7.97 (s, 1H), 7.86 (d, J = 1.6 Hz, 1H), 7.70 (t, J = 8.0 Hz, 1H), 7.64 (d, J = 1.6 Hz, 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).

实施例111 EVO33461
Example 111 EVO33461

参照化合物EVO33138，经高效液相制备柱分离，再冷冻干燥得到EVO33461(3.32mg，收率：23％)，LCMS(ESI)m/z＝562.47[M+H]⁺，纯度：96.7％。¹H 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)。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 (400 MHz, DMSO-d ₆ )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).

实施例112 EVO33485
Example 112 EVO33485

参照化合物EVO33138，经高效液相制备柱分离，再冷冻干燥得到EVO33485(20mg，收率：27％)，LCMS(ESI)m/z＝570.47[M+H]⁺，纯度：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,1H),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)。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%. ¹ H NMR (400 MHz, DMSO-d ₆ )δ9.41 (s, 1H), 9.12 (t, J=6.0 Hz, 1H), 8.73-8.60 (m, 2H), 7.93 (d, J=7.2 Hz, 1H), 7.83 (d, J=2.0 Hz, 1H), 7.80-7.73 (m, 2H), 7.46 (d, J=2.0 Hz, 1H), 7.05 (d, J=8.4 Hz, 1H), 6.10 (s, 2H), 5.09 (s, 1H), 4.78 (d, J = 6.0 Hz, 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 = 6.0 Hz, 6H), 0.76 (t, J = 7.2 Hz, 3H).

实施例113 EVO33488
Example 113 EVO33488

参照化合物EVO33138，经高效液相制备柱分离，再冷冻干燥得到淡黄色固体EVO33488(33mg,收率：46.5％)，LCMS(ESI)m/z＝587.5[M+H]⁺，纯度：98.4％。¹H 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)。The reference compound EVO33138 was separated by HPLC preparative column and then 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 (400 MHz, DMSO-d ₆ )δ9.55 (t, J=6.0 Hz, 1H), 9.38 (s, 1H), 8.63 (d, J=8.4 Hz, 1H), 8.32-8.26 (m, 3H), 7.85 (s, 1H), 7.79 (t, J=2.2 Hz, 1H), 7.69 (d, J=7.6 Hz, 1H), 7.40 (t, J=8.0 Hz, 1H), 7.13 (dd, J=8.4, 2.4 Hz, 3H). z, 1H), 5.32 (t, J = 2.0 Hz, 2H), 5.14 (s, 2H), 4.82 (d, J = 6.0 Hz, 2H), 3.76-3.70 (m, 4H), 3.37 (q, J = 7.2 Hz, 2H), 2.33 (dd, J = 12.2, 10.6 Hz, 2H), 1.18 (d, J = 6.0 Hz, 6H), 1.15 (t, J = 7.2 Hz, 3H).

实施例114 EVO33526
Example 114 EVO33526

参照化合物EVO33138，经高效液相制备柱分离，再冷冻干燥得到EVO33526(10.3mg，收率：18.4％)，LCMS(ESI)m/z＝600.15[M+H]⁺，纯度：98.6％。¹H 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)。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 (400 MHz, DMSO-d ₆ )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).

实施例115 EVO33530
Example 115 EVO33530

参照化合物EVO33138，经高效液相制备柱分离，再冷冻干燥得到EVO33530(26mg，收率：22％)，LCMS(ESI)m/z＝588.5[M+H]⁺，纯度：98.56％。¹H 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)。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 (400 MHz, DMSO-d ₆ ) δ9.55 (t, J=6.0 Hz, 1H), 9.40 (s, 1H), 8.69-8.59 (m, 2H), 8.39 (s, 1H), 8.23 (s, 1H), 7.90 (d, J=7.2 Hz, 1H), 7.83 (s, 1H), 7.75 (t, J=8.4 Hz, 1H), 7.03 (d, J=8.8 Hz, 1H), 5.80-5.75 (m, 1H), 5.15 ( d, J = 12.4 Hz, 1H), 5.05 (d, J = 13.6 Hz, 1H), 4.82 (d, J = 4.8 Hz, 2H), 4.31 (dd, J = 12.8, 2.4 Hz, 2H), 3.70-3.65 (m, 2H), 3.32 (s, 3H), 2.52-2.48 (m, 2H), 1.50 (d, J = 6.4 Hz, 3H), 1.21 (d, J = 6.4 Hz, 6H).

实施例116 EVO33605
Example 116 EVO33605

参照化合物EVO33138，经高效液相制备柱分离，再冷冻干燥得到黄色固体EVO33605(8mg，收率：33％)，LCMS(ESI)m/z＝548.15[M+H]⁺，纯度：99.07％。¹H NMR(400MHz,DMSO-d₆)δ9.45(s,1H),9.14(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),8.24(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)。The reference compound EVO33138 was separated by HPLC preparative column and freeze-dried to obtain a yellow solid EVO33605 (8 mg, yield: 33%), LCMS (ESI) m/z=548.15 [M+H] ⁺ , purity: 99.07%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.45 (s, 1H), 9.14 (t, J=6.0 Hz, 1H), 8.89 (d, J=8.4 Hz, 1H), 8.77 (d, J=8.4 Hz, 1H), 8.66 (d, J=7.6 Hz, 1H), 8.24 (d, J=8.0 Hz, 1H), 8.14 (t, J=7.6 Hz, 1H), 7.91 (s, 2H), 7.86-7.80 (m, 2H), 7.45 (d, J=1.6 Hz, 1H), 6.10 (s, 2H), 5.29 (s, 1H), 4.78 (d, J=5.6 Hz, 2H), 2.57 (s, 6H), 1.49 (s, 6H).

实施例117 EVO33607
Example 117 EVO33607

参照化合物EVO33138，经高效液相制备柱分离，再冷冻干燥得到EVO33607(11mg，收率：36％)，LCMS(ESI)m/z＝550.14[M+H]⁺，纯度：97.40％。¹H 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)。The reference compound EVO33138 was separated by HPLC preparative column and freeze-dried to obtain EVO33607 (11 mg, yield: 36%), LCMS (ESI) m/z=550.14 [M+H] ⁺ , purity: 97.40%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.46 (s, 1H), 9.24 (t, J=6.0 Hz, 1H), 8.89 (d, J=8.4 Hz, 1H), 8.77 (d, J=8.4 Hz, 1H), 8.66 (d, J=7.6 Hz, 1H), 8.25 (d, J=7.6 Hz, 1H), 8.15 (t, J=7.6 Hz, 1H), 7.91 (s, 2H), 7.83 (s, 1H), 7.65 (d, J=1.6 Hz, 1H), 7.52 (d, J=1.6 Hz, 1H), 6.16 (s, 2H), 4.79 (d, J=5.6 Hz, 2H), 2.57 (s, 6H), 1.75 (s, 3H), 1.70 (s, 3H).

实施例118 EVO33537
Example 118 EVO33537

参照化合物EVO33173，经高效液相制备柱分离，再冷冻干燥得到EVO33537(5.4mg，收率：11.8％)，LCMS(ESI)m/z＝532.2[M+H]⁺，纯度：99.48％。¹H 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,1H),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)。The reference compound EVO33173 was separated by HPLC preparative column and 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 (400 MHz, DMSO-d ₆ ) δ 9.41-9.38 (m, 2H), 8.66 (d, J=8.6 Hz, 1H), 8.59 (d, J=8.6 Hz, 1H), 7.90-7.81 (m, 2H), 7.80 (d, J=6.0 Hz, 2H), 7.70 (t, J=8.0 Hz, 1H), 6.53 (d, J=8.0 Hz, 1H), 6.35 (s, 2H), 4.78 (d, J=5.6 Hz, 2H), 4.07 (t, J=7.2 Hz, 4H), 3.37 (q, J=7.2 Hz, 2H), 2.42-2.34 (m, 2H), 1.18 (t, J=7.2 Hz, 3H).

实施例119 EVO33541
Example 119 EVO33541

参照化合物EVO33173，经高效液相制备柱分离，再冷冻干燥得到EVO33541(7.6mg，收率： 17.2％)，LCMS(ESI)m/z＝589.2[M+H]⁺，纯度：97.08％。¹H NMR(400MHz,DMSO-d₆)δ9.41-9.38(m,2H),8.66(d,J＝8.8Hz,1H),8.59(d,J＝8.8Hz,1H),7.89(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)。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 (400 MHz, DMSO-d ₆ ) δ 9.41-9.38 (m, 2H), 8.66 (d, J = 8.8 Hz, 1H), 8.59 (d, J = 8.8 Hz, 1H), 7.89 (d, J = 1.6 Hz, 1H), 7.85 (d, J = 7.2 Hz, 1H), 7.81-7.79 (m, 2H), 7.70 (t, J = 8.4 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H). H), 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).

实施例120 EVO33544
Example 120 EVO33544

参照化合物EVO33173，经高效液相制备柱分离，再冷冻干燥得到EVO33544(11.1mg，收率：9.18％)，LCMS(ESI)m/z＝592.66[M+H]⁺，纯度：98.31％。¹H NMR(400MHz,DMSO-d₆)δ9.42-9.39(m,2H),8.68-8.60(m,2H),7.94-7.90(m,2H),7.81-7.75(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),4.34(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)。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 (400 MHz, DMSO-d ₆ ) δ 9.42-9.39 (m, 2H), 8.68-8.60 (m, 2H), 7.94-7.90 (m, 2H), 7.81-7.75 (m, 3H), 7.01 (d, J = 8.4 Hz, 1H), 6.35 (s, 2H), 4.86-4.81 (m, 1H), 4.78 (d, J = 5.6 Hz, 2H), 4.34 (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).

实施例121 EVO33547
Example 121 EVO33547

参照化合物EVO33173，经高效液相制备柱分离，再冷冻干燥得到EVO33547(13.3mg，收率：15.1％)，LCMS(ESI)m/z＝554.55[M+H]⁺，纯度：98.26％。¹H 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＝6.4Hz,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)。The reference compound EVO33173 was separated by HPLC preparative column and 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 (400 MHz, DMSO-d ₆ ) δ 9.46 (s, 1H), 9.43 (t, J=6.0 Hz, 1H), 8.91 (d, J=8.8 Hz, 1H), 8.79-8.77 (m, 3H), 8.69 (d, J=8.0 Hz, 1H), 8.32 (d, J=8.0 Hz, 1H), 8.27 (d, J=6.4 Hz, 2H), 8.20 (t, J=8.0 Hz, 1H), 7.91 (s, 1H), 7.87 (s, 1H), 7.82 (d, J=1.6 Hz, 1H), 6.36 (s, 2H), 4.81 (d, J=5.6 Hz, 2H), 3.39 (q, J=7.2 Hz, 2H), 1.19 (t, J=7.2 Hz, 3H).

实施例122 EVO33561
Example 122 EVO33561

参照化合物EVO33173，经高效液相制备柱分离，再冷冻干燥得到黄色固体EVO33561(7mg，收率：22.22％)，LCMS(ESI)m/z＝589.55[M+H]⁺，纯度：96.44％。¹H 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)。The reference compound EVO33173 was separated by HPLC preparative column and freeze-dried to obtain yellow solid EVO33561 (7 mg, yield: 22.22%), LCMS (ESI) m/z=589.55 [M+H] ⁺ , purity: 96.44%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.46-9.33 (m, 2H), 8.73-8.62 (m, 2H), 7.95-7.86 (m, 2H), 7.82-7.72 (m, 3H), 6.74 (d, J＝8.0 Hz, 1H), 6.36 (s, 2H), 4.78 (d, J＝5.6 Hz, 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, 4.4 Hz, 6H), 2.47-2.44 (m, 1H), 2.27 (m, 1H), 1.18 (t, J = 7.2 Hz, 3H).

实施例123 EVO33077
Example 123 EVO33077

参照化合物EVO33240，经高效液相制备柱分离，再冷冻干燥得到黄色固体EVO33077(3.45mg，收率：13.26％)，LCMS(ESI)m/z＝563.18[M+H]⁺，纯度：95.8％。¹H 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),3.66-3.58(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)。The reference compound EVO33240 was separated by HPLC preparative column and then freeze-dried to obtain 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-d ₆ )δ9.39 (t, J=5.6 Hz, 1H), 8.51 (d, J=5.2 Hz, 1H), 8.27 (d, J=1.6 Hz, 1H), 8.21 (d, J=1.6 Hz, 1H), 7.61-7.49 (m, 4H), 7.39 (d, J=16.0 Hz, 1H), 6.87 (d, J=7.2 Hz, 1H), 6.81 (d, J=8.8 Hz, 1H), 5.30 (d, J = 2.0 Hz, 2H), 5.12 (s, 2H), 4.62 (d, J = 6.0 Hz, 2H), 4.24 (dd, J = 13.2, 2.4 Hz, 2H), 3.66-3.58 (m, 2H), 3.38-3.32 (m, 2H), 2.43-2.37 (m, 2H), 1.18 (d, J = 6.0 Hz, 6H), 1.13 (t, J = 7.2 Hz, 3H).

实施例124 EVO33466
Example 124 EVO33466

参照化合物EVO33392，经高效液相制备柱分离，再冷冻干燥得到黄色固体EVO33466(6mg,收率：11.0％)，LCMS(ESI)m/z＝618.2[M+H]⁺，纯度：98.6％。¹H 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),7.03(d,J＝8.4Hz,1H),5.75(s,2H),4.90-4.85(m,3H),4.31(d,J＝12.4Hz,2H),3.78(q,J＝5.6Hz,2H),3.70-3.63(m,4H),2.53-2.47(m,2H),1.21(d,J＝6.0Hz,6H)。The reference compound EVO33392 was separated by HPLC preparative column and freeze-dried to obtain yellow solid EVO33466 (6 mg, yield: 11.0%), LCMS (ESI) m/z=618.2 [M+H] ⁺ , purity: 98.6%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.78 (t, J = 6.0 Hz, 1H), 9.41 (s, 1H), 8.75 (dd, J = 16.8, 1.4 Hz, 2H), 8.65 (q, J = 8.8 Hz, 2H), 7.92-7.89 (m, 2H), 7.75 (t, J = 8.0 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 5.75 (s, 2H), 4.90-4.85 (m, 3H), 4.31 (d, J = 12.4 Hz, 2H), 3.78 (q, J = 5.6 Hz, 2H), 3.70-3.63 (m, 4H), 2.53-2.47 (m, 2H), 1.21 (d, J = 6.0 Hz, 6H).

实施例125 EVO33493
Example 125 EVO33493

参照化合物EVO33392，经高效液相制备柱分离，再冷冻干燥得到黄色固体EVO33493(85.35mg,收率：69.7％)，LCMS(ESI)m/z＝620.2[M+H]⁺，纯度：99.8％。¹H 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)。The reference compound EVO33392 was separated by HPLC preparative column and freeze-dried to obtain yellow solid EVO33493 (85.35 mg, yield: 69.7%), LCMS (ESI) m/z=620.2 [M+H] ⁺ , purity: 99.8%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.41-9.38 (m, 2H), 8.64 (q, J=8.8 Hz, 2H), 7.91-7.89 (m, 2H), 7.79-7.73 (m, 3H), 7.03 (d, J=8.4 Hz, 1H), 6.35 (s, 2H), 4.78 (d, J=5.6 Hz, 2H), 4.31 (dd, J=13.0, 2.4 Hz, 2H), 3.71-3.63 (m, 6H), 3.14 (s, 3H), 2.53-2.47 (m, 2H), 1.21 (d, J=6.4 Hz, 6H).

实施例126 EVO33602
Example 126 EVO33602

参照化合物EVO33392，经高效液相制备柱分离，再冷冻干燥得到EVO33602(8.54mg，收率：25％)，LCMS(ESI)m/z＝598.43[M+H]⁺，纯度：99.78％。¹H NMR(400MHz,DMSO-d₆)δ9.50(s,1H),9.44(t,J＝5.6Hz,1H),8.93(d,J＝8.4Hz,1H),8.80(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)。The reference compound EVO33392 was separated by HPLC preparative column and freeze-dried to obtain EVO33602 (8.54 mg, yield: 25%), LCMS (ESI) m/z=598.43 [M+H] ⁺ , purity: 99.78%. ¹ H NMR (400 MHz, DMSO-d ₆ )δ9.50(s,1H),9.44(t,J＝5.6Hz,1H),8.93(d,J＝8.4Hz,1H),8.80(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).

实施例127 EVO33037
Example 127 EVO33037

参照化合物EVO33138，经高效液相制备柱分离，再冷冻干燥得到EVO33037(4.72mg，收率：32.7％)，LCMS(ESI)m/z＝568.49[M+H]⁺，纯度：90.9％。¹H 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),6.13(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)。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 (400 MHz, DMSO-d ₆ )δ9.38 (s, 1H), 9.15 (t, J=5.9 Hz, 1H), 8.69-8.58 (m, 2H), 7.90 (d, J=7.4 Hz, 1H), 7.78-7.70 (m, 2H), 7.66 (d, J=1.7 Hz, 1H), 7.44 (d, J=1.7 Hz, 1H), 7.03 (d, J=8.5 Hz, 1H), 6.13 (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).

实施例128 EVO33185
Example 128 EVO33185

参照化合物EVO33138，经高效液相制备柱分离，再冷冻干燥得到产物EVO33185(27mg,收率：58％)，LCMS(ESI)m/z＝587.2[M+H]⁺，纯度：94.8％。¹H NMR(400MHz,DMSO-d₆)δ9.79-9.71(m,1H),9.40(s,1H),9.06(s,1H),8.70-8.57(m,4H),7.93-7.87(m,1H),7.86(s,1H),7.74(t,J＝7.9Hz,1H),7.02(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)。The reference compound EVO33138 was separated by HPLC preparative column and 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 (400 MHz, DMSO-d ₆ ) δ 9.79-9.71 (m, 1H), 9.40 (s, 1H), 9.06 (s, 1H), 8.70-8.57 (m, 4H), 7.93-7.87 (m, 1H), 7.86 (s, 1H), 7.74 (t, J=7.9 Hz, 1H), 7.02 (d, J=8.5 Hz, 1H), 4.85 (d, J=5.7 Hz, 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=6.2 Hz, 6H).

实施例129 EVO33438
Example 129 EVO33438

参照化合物EVO33138，经高效液相制备柱分离，再冷冻干燥得到产物EVO33438(60mg,收率：86％)，LCMS(ESI)m/z＝615.23[M+H]⁺，纯度：98.1％。¹H 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)。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 (400 MHz, Chloroform-d) δ9.42 (s, 1H), 9.17-9.03 (m, 1H), 8.88 (d, J=8.8 Hz, 1H), 8.61-8.52 (m, 2H), 8.48-8.38 (m, 2H), 8.12 (d, J=7.4 Hz, 1H), 7.79-7.71 (m, 1H), 7.30 (d, J=3.2 Hz, 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).

实施例130 EVO33080
Example 130 EVO33080

参照化合物EVO33173，经高效液相制备柱分离，再冷冻干燥得到黄色固体EVO33080(16.86mg，收率：26.15％),LCMS(ESI)m/z＝628.30[M+H]⁺，纯度：98.54％。¹H 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),5.32(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)。The reference compound EVO33173 was separated by HPLC preparative column and freeze-dried to obtain yellow solid EVO33080 (16.86 mg, yield: 26.15%), LCMS (ESI) m/z=628.30 [M+H] ⁺ , purity: 98.54%. ¹ H NMR (400 MHz, DMSO-d ₆ )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),5.32(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).

实施例131 EVO33081
Example 131 EVO33081

参照化合物EVO33173，经高效液相制备柱分离，再冷冻干燥得到黄色固体EVO33081(23.13mg，收率：37.94％)，LCMS(ESI)m/z＝630.30[M+H]⁺，纯度：99.89％。¹H 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)。The reference compound EVO33173 was separated by HPLC preparative column and freeze-dried to obtain yellow solid EVO33081 (23.13 mg, yield: 37.94%), LCMS (ESI) m/z=630.30 [M+H] ⁺ , purity: 99.89%. ¹ H NMR (400 MHz, DMSO-d ₆ )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).

实施例132 EVO33229
Example 132 EVO33229

参照化合物EVO33173，经高效液相制备柱分离，再冷冻干燥得到白色固体EVO33229(12.97mg,收率：16.3％)，LCMS(ESI)m/z＝559.26[M+H]⁺，纯度：99.89％。¹H NMR(400MHz,DMSO-d₆)δ9.47(s,1H),9.13(t,J＝5.9Hz,1H),8.97(d,J＝8.6Hz,1H),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,1H),6.10(s,2H),5.27(s,1H),4.78(d,J＝5.7Hz,2H),2.69(s,3H),1.50(s,6H)。The reference compound EVO33173 was separated by HPLC preparative column and freeze-dried to obtain white solid EVO33229 (12.97 mg, yield: 16.3%), LCMS (ESI) m/z=559.26 [M+H] ⁺ , purity: 99.89%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.47 (s, 1H), 9.13 (t, J=5.9 Hz, 1H), 8.97 (d, J=8.6 Hz, 1H), 8.78 (d, J=8.6 Hz, 1H), 8.75-8.70 (m, 2H), 8.50 (d, J=1.6 Hz, 1H), 8.40 (dd, J=7.9, 1.0 Hz, 1H), 8.21 (t, J=7.9 Hz, 1H), 7.85-7.79 (m, 2H), 7.45 (d, J=1.8 Hz, 1H), 6.10 (s, 2H), 5.27 (s, 1H), 4.78 (d, J=5.7 Hz, 2H), 2.69 (s, 3H), 1.50 (s, 6H).

实施例133 EVO33566
Example 133 EVO33566

参照化合物EVO33173，经高效液相制备柱分离，再冷冻干燥得到黄色固体EVO33566(9.8mg，收率：19.85％)，LCMS(ESI)m/z＝608.4[M+H]⁺，纯度：99.66％。¹H NMR(400MHz,DMSO-d₆)δ9.40(d,J＝4.0Hz,2H),8.73-8.65(m,1H),8.55(d,J＝8.6Hz,1H),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)。The reference compound EVO33173 was separated by HPLC preparative column and freeze-dried to obtain yellow solid EVO33566 (9.8 mg, yield: 19.85%), LCMS (ESI) m/z=608.4 [M+H] ⁺ , purity: 99.66%. ¹ H NMR (400 MHz, DMSO-d ₆ )δ9.40(d,J＝4.0Hz,2H),8.73-8.65(m,1H),8.55(d,J＝8.6Hz,1H),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).

实施例134 EVO33571
Example 134 EVO33571

参照化合物EVO33173，经高效液相制备柱分离，再冷冻干燥得到白色固体EVO33571(16.87mg,收率:20.1％)，LCMS(ESI)m/z＝591.3[M+H]⁺，纯度：99.65％。¹H 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)。The reference compound EVO33173 was separated by HPLC preparative column and freeze-dried to obtain white solid EVO33571 (16.87 mg, yield: 20.1%), LCMS (ESI) m/z=591.3 [M+H] ⁺ , purity: 99.65%. ¹ H NMR (400 MHz, DMSO-d ₆ )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).

实施例135 EVO33012
Example 135 EVO33012

参照化合物EVO33240，经高效液相制备柱分离，再冷冻干燥得到黄色固体EVO33012(23mg，收率：28.8％)，LCMS(ESI)m/z＝529.53[M+H]⁺，纯度：97.40％。¹H NMR(400MHz,Chloroform-d)δ8.51(d,J＝5.2Hz,1H),7.79(s,2H),7.61(s,1H),7.56-7.49(m,3H),7.42(d,J＝4.4Hz,1H),7.28-7.24(m,1H),6.76(d,J＝7.2Hz,1H),6.62(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)。The reference compound EVO33240 was separated by HPLC preparative column and freeze-dried to obtain yellow solid EVO33012 (23 mg, yield: 28.8%), LCMS (ESI) m/z=529.53 [M+H] ⁺ , purity: 97.40%. ¹ H NMR (400 MHz, Chloroform-d) δ 8.51 (d, J = 5.2 Hz, 1H), 7.79 (s, 2H), 7.61 (s, 1H), 7.56-7.49 (m, 3H), 7.42 (d, J = 4.4 Hz, 1H), 7.28-7.24 (m, 1H), 6.76 (d, J = 7.2 Hz, 1H), 6.62 (d, J = 8.4 Hz, 1H), 5.34 (s, 2H), 5.09 (s, 2H), 4.80 (d, J = 5.2 Hz, 2H), 4.17 (d, J = 11.2 Hz, 2H), 3.80-3.70 (m, 2H), 2.60-2.54 (m, 2H), 1.61 (s, 6H), 1.31 (d, J = 6.0 Hz, 6H).

实施例136 EVO33024
Example 136 EVO33024

参照化合物EVO33240，经高效液相制备柱分离，再冷冻干燥得到黄色固体EVO33012(9.3mg，收率：58.8％)，LCMS(ESI)m/z＝531.50[M+H]⁺，纯度：98.50％。¹H 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)。The reference compound EVO33240 was separated by HPLC preparative column and then freeze-dried to obtain yellow solid EVO33012 (9.3 mg, yield: 58.8%), LCMS (ESI) m/z=531.50 [M+H] ⁺ , purity: 98.50%. ¹ H NMR (400 MHz, Chloroform-d) δ8.53 (d, J=5.2 Hz, 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=4.8 Hz, 1H), 7.30-7.25 (m, 1H), 6.77 (d, J=7.2 Hz , 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).

实施例137 EVO33608
Example 137 EVO33608

参照化合物EVO33240，经高效液相制备柱分离，再冷冻干燥得到EVO33608(21.26mg，收率：30.7％)，LCMS(ESI)m/z＝549.49[M+H]⁺，纯度：97.2％。¹H 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)。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 (400 MHz, DMSO-d ₆ )δ9.26 (t, J=5.9 Hz, 1H), 8.50 (d, J=5.1 Hz, 1H), 7.90 (d, J=1.4 Hz, 1H), 7.62 (d, J=1.4 Hz, 1H), 7.61-7.48 (m, 4H), 7.38 (d, J=16.0 Hz, 1H), 6.87 (d, J=7.2 Hz, 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).

实施例138 EVO33039
Example 138 EVO33039

参照化合物EVO33138，经高效液相制备柱分离，再冷冻干燥得到EVO33039(13.26mg，收率：13％)，LCMS(ESI)m/z＝594.2[M+H]⁺，纯度：98.67％。¹H 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＝7.4Hz,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)。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 (400 MHz, DMSO-d ₆ )δ9.39 (s, 1H), 9.25 (t, J=5.9 Hz, 1H), 8.64 (q, J=8.6 Hz, 2H), 7.91 (d, J=7.4 Hz, 1H), 7.78 (s, 1H), 7.74 (t, J=7.9 Hz, 1H), 7.67 (d, J=1.7 Hz, 1H), 7.61 (d, J=1.6 Hz, 1H), 7.03 (d, J=8.5 Hz, 1 H), 6.43 (td, J = 54.0, 8.0 Hz, 1H), 6.18 (s, 2H), 4.77 (d, J = 5.8 Hz, 2H), 4.31 (dd, J = 12.9, 2.4 Hz, 2H), 3.70-3.65 (m, 2H), 2.53-2.47 (m, 2H), 1.84 (d, J = 23.8 Hz, 3H), 1.22 (d, J = 6.2 Hz, 6H).

实施例139 EVO33484
Example 139 EVO33484

参照化合物EVO33138，经高效液相制备柱分离，再冷冻干燥得到EVO33484(22.93mg，收率：41.8％)，LCMS(ESI)m/z＝610.4[M+H]⁺，纯度：98.88％。¹H 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)。The reference compound EVO33138 was separated by HPLC preparative column and 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 (400 MHz, DMSO-d ₆ ) δ 9.38 (s, 1H), 9.18 (t, J=5.9 Hz, 1H), 8.67-8.60 (m, 2H), 7.92-7.90 (m, 2H), 7.76-7.72 (m, 2H), 7.58 (d, J=1.8 Hz, 1H), 7.03 (d, J=8.5 Hz, 1H), 6.80 (s, 1H), 6.13 (s, 2H), 4.76 (d, J=5.8 Hz, 2H), 4.31 (dd, J=13.0, 2.4 Hz, 2H), 3.70-3.65 (m, 2H), 2.53-2.47 (m, 2H), 1.80 (s, 3H), 1.21 (d, J=6.2 Hz, 6H).

实施例140 EVO33492
Example 140 EVO33492

参照化合物EVO33138，经高效液相制备柱分离，再冷冻干燥得到EVO33492(14.92mg，收率：14.5％)，LCMS(ESI)m/z＝592.3[M+H]⁺，纯度：99.97％。¹H 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)。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 (400 MHz, DMSO-d ₆ )δ9.39 (s, 1H), 9.15 (t, J=5.9 Hz, 1H), 8.69-8.59 (m, 2H), 7.91 (d, J=7.4 Hz, 1H), 7.83 (d, J=1.7 Hz, 1H), 7.78-7.70 (m, 2H), 7.52 (d, J=1.7 Hz, 1H), 7.03 (d, J=8.5 Hz, 1H), 6 .15-6.09 (m, 3H), 6.06 (t, J = 55.7 Hz, 1H), 4.76 (d, J = 5.8 Hz, 2H), 4.31 (dd, J = 13.0, 2.4 Hz, 2H), 3.74-3.60 (m, 2H), 2.53-2.47 (m, 2H), 1.60 (s, 3H), 1.22 (d, J = 6.2 Hz, 6H).

实施例141 EVO33604
Example 141 EVO33604

参照化合物EVO33138，经高效液相制备柱分离，再冷冻干燥得到EVO33604(20.54mg，收率：23.5％)，LCMS(ESI)m/z＝612.2[M+H]⁺，纯度：99.95％。¹H 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)。The reference compound EVO33138 was separated by HPLC preparative column and 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 (400 MHz, DMSO-d ₆ ) δ 9.39 (s, 1H), 9.29 (t, J=5.9 Hz, 1H), 8.64 (q, J=8.6 Hz, 2H), 7.91 (d, J=7.4 Hz, 1H), 7.78-7.71 (m, 3H), 7.67 (d, J=1.6 Hz, 1H), 7.03 (d, J=8.5 Hz, 1H), 6.20 (d, J=4.9 Hz, 2H), 4.77 (d, J=5.8 Hz, 2H), 4.31 (dd, J=12.9, 2.3 Hz, 2H), 3.71-3.64 (m, 2H), 2.53-2.47 (m, 2H), 2.03 (d, J=24.4 Hz, 3H), 1.21 (d, J=6.2 Hz, 6H).

实施例142 EVO33082
Example 142 EVO33082

参照化合物EVO33173，经高效液相制备柱分离，再冷冻干燥得到EVO33082(8.71mg，收率：14.24％)，LCMS(ESI)m/z＝596.37[M+H]⁺，纯度：99.68％。¹H 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)。The reference compound EVO33173 was separated by HPLC preparative column and 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 (400 MHz, DMSO-d ₆ ) δ 9.28 (s, 1H), 9.08 (t, J=6.0 Hz, 1H), 8.59-8.53 (m, 2H), 8.28 (d, J=8.6 Hz, 1H), 7.96 (s, 1H), 7.82 (d, J=1.8 Hz, 1H), 7.73 (d, J=1.6 Hz, 1H), 7.70 (s, 1H), 7.43 (d, J=1.7 Hz, 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=10.2 Hz, 2H), 1.49 (s, 6H), 1.22 (d, J=6.1 Hz, 6H).

实施例143 EVO33083
Example 143 EVO33083

参照化合物EVO33173，经高效液相制备柱分离，再冷冻干燥得到EVO33083(9.16mg，收率：36.52％)，LCMS(ESI)m/z＝598.36[M+H]⁺，纯度：95.82％。¹H 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),3.76-3.63(m,2H),2.93(t,J＝11.0Hz,2H),1.72(d,J＝22.3Hz,6H),1.22(d,J＝6.1Hz,6H)。The reference compound EVO33173 was separated by HPLC preparative column and 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 (400 MHz, DMSO-d ₆ ) δ 9.28 (s, 1H), 9.19 (t, J=6.0 Hz, 1H), 8.60-8.53 (m, 2H), 8.28 (d, J=8.7 Hz, 1H), 7.96 (s, 1H), 7.74 (d, J=1.7 Hz, 1H), 7.71 (s, 1H), 7.64 (d, J=1.7 Hz, 1H), 7.50 (d, J=1.7 Hz, 1H), 6.16 (s, 2H), 4.82-4.64 (m, 4H), 3.76-3.63 (m, 2H), 2.93 (t, J=11.0 Hz, 2H), 1.72 (d, J=22.3 Hz, 6H), 1.22 (d, J=6.1 Hz, 6H).

实施例144 EVO33253
Example 144 EVO33253

参照化合物EVO33173，经高效液相制备柱分离，再冷冻干燥得到EVO33253(11.27mg，收率：16.67％)，LCMS(ESI)m/z＝584.24[M+H]⁺，纯度：99.56％。¹H 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)。The reference compound EVO33173 was separated by HPLC preparative column and 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 (400 MHz, DMSO-d ₆ ) δ 9.60 (t, J = 5.9 Hz, 1H), 9.47 (s, 1H), 8.92 (d, J = 8.6 Hz, 1H), 8.77 (d, J = 8.6 Hz, 1H), 8.69 (d, J = 7.8 Hz, 1H), 8.35–8.30 (m, 2H), 8.27 (s, 1H), 8.20 (t, J = 7.9 Hz, 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 = 5.7 Hz, 2H), 3.37 (q, J = 7.3 Hz, 2H), 2.58 (s, 3H), 1.16 (t, J = 7.3 Hz, 3H).

实施例145 EVO33254
Example 145 EVO33254

参照化合物EVO33173，经高效液相制备柱分离，再冷冻干燥得到EVO33254(6.95mg，收率：10.96％)，LCMS(ESI)m/z＝552.20[M+H]⁺，纯度：94.91％。¹H NMR(400MHz,DMSO-d₆)δ9.46(s,1H),9.13(t,J＝5.9Hz,1H),8.91(d,J＝8.6Hz,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)。The reference compound EVO33173 was separated by HPLC preparative column and 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 (400 MHz, DMSO-d ₆ ) δ 9.46 (s, 1H), 9.13 (t, J=5.9 Hz, 1H), 8.91 (d, J=8.6 Hz, 1H), 8.77 (d, J=8.6 Hz, 1H), 8.71 (d, J=7.9 Hz, 1H), 8.33 (d, J=7.8 Hz, 1H), 8.19 (t, J=7.9 Hz, 1H), 8.12 (s, 1H), 7.86-7.79 (m, 3H), 7.45 (d, J=1.8 Hz, 1H), 6.10 (s, 2H), 5.27 (s, 1H), 4.78 (d, J=5.8 Hz, 2H), 2.58 (s, 3H), 1.50 (s, 6H).

实施例146 EVO33573
Example 146 EVO33573

参照化合物EVO33173，经高效液相制备柱分离，再冷冻干燥得到EVO33573(8.03mg，收率：10.4％)，LCMS(ESI)m/z＝567.24[M+H]⁺，纯度：99.15％。¹H 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)。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 (400 MHz, DMSO-d ₆ )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).

实施例147 EVO33610Example 147 EVO33610

参照化合物EVO33240，经高效液相制备柱分离，再冷冻干燥得到EVO33610(25mg，收率：32.7％)，LCMS(ESI)m/z＝531.53[M+H]⁺，纯度：99.0％。¹H 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)。 The reference compound EVO33240 was separated by HPLC preparative column and freeze-dried to obtain EVO33610 (25 mg, yield: 32.7%), LCMS (ESI) m/z=531.53 [M+H] ⁺ , purity: 99.0%. ¹ H NMR (400 MHz, Chloroform-d) δ8.50 (d, J = 5.4 Hz, 1H), 7.82-7.73 (m, 1H), 7.62 (d, J = 1.7 Hz, 1H), 7.58-7.48 (m, 3H), 7.44 (dd, J = 5.4, 1.6 Hz, 1H), 7.32-7.27 (m, 1H), 6.76 (d, J = 7.2 Hz, 1H), 6.62 (d, J = 8.5 Hz, 1H), 6.04 (s, 2H), 4.80 (d, J = 5.3 Hz, 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).

效果实施例1化合物对BRM和BRG1ATPase的抑制活性检测实验Effect Example 1 Inhibitory Activity Detection Experiment of Compounds on BRM and BRG1 ATPase

为了表征化合物对BRM和BRG1的ATPase抑制活性，使用ADP-Glo^TM Kinase Assay(Promega，#V9101)检测ATPase反应终点体系中的ADP量来评价ATPase活性，分两步进行：首先，ATPase反应后，加入ADP-Glo Reagent终止反应并耗尽剩余的ATP；然后，加入Kinase Detection Reagent，将ADP转化为ATP，并通过荧光素酶/荧光素反应消耗ATP产生化学发光信号，信号与ATP(ATPase反应生成的ADP转化而来)浓度成正比。与无化合物处理的对照孔相比，通过发光信号的减少，来评价化合物的ATPase抑制活性。通过化合物浓度与ATPase活性百分比之间的数据关系，计算IC₅₀值。In order to characterize the ATPase inhibitory activity of the compounds against BRM and BRG1, the ADP-Glo ^TM Kinase Assay (Promega, #V9101) was used to detect the amount of ADP in the ATPase reaction endpoint system to evaluate the ATPase activity. The process was carried out in two steps: first, after the ATPase reaction, ADP-Glo Reagent was added to terminate the reaction and deplete the remaining ATP; then, Kinase Detection Reagent was added to convert ADP into ATP, and ATP was consumed by the luciferase/luciferin reaction to generate a chemiluminescent signal, which was 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 was evaluated by the reduction of the luminescent signal. The IC ₅₀ value was calculated based on the data relationship between the compound concentration and the percentage of ATPase activity.

具体操作如下：将待测化合物(溶解在DMSO中，浓度10uM-1nM，50nL/孔)添加到384孔板中(Greiner#781280)中。每孔加入2.5μL BRM截断体(表达纯化的BRM ATPase-SnAC Domain，参照文献描述DOI:10.1021/acs.jmedchem.8b01318)或BRG1截断体(表达纯化的BRG1 ATPase-SnAC Domain，参照文献描述DOI:10.1021/acs.jmedchem.8b01318)和DNA(Invitrogen#15632011)的混合溶液(蛋白终浓度30nM，DNA终浓度80nM)。每孔加入2.5μL ATP(Promega#V9101，终浓度400uM)开始酶反应。体系缓冲液为20mM Tris，pH 8.0，50mM NaCl，20mM MgCl₂，0.1％Tween-20，1mM DTT，总体积为5μL，在25℃下反应60分钟。之后加入ADP Glo试剂(5μL)，25℃下孵育90分钟。然后加入Kinase Detection Reagent(10μL)，25℃下孵育60分钟。最后检测化学发光。The specific operation is as follows: the test compound (dissolved in DMSO, concentration 10uM-1nM, 50nL/well) is added to a 384-well plate (Greiner#781280). 2.5μL of a mixed solution of BRM truncations (expressed and purified BRM ATPase-SnAC Domain, refer to the literature description DOI:10.1021/acs.jmedchem.8b01318) or BRG1 truncations (expressed and purified BRG1 ATPase-SnAC Domain, refer to the literature description DOI:10.1021/acs.jmedchem.8b01318) and DNA (Invitrogen#15632011) is added to each well (protein final concentration 30nM, DNA final concentration 80nM). 2.5μL of ATP (Promega#V9101, final concentration 400uM) is added to each well to start the enzyme reaction. The system buffer is 20mM Tris, pH 8.0, 50mM NaCl, 20mM MgCl ₂ , 0.1% Tween-20, 1mM DTT, the total volume is 5μL, and the reaction is carried out at 25°C for 60 minutes. Then, ADP Glo reagent (5μL) is added and incubated at 25°C for 90 minutes. Then, Kinase Detection Reagent (10μL) is added and incubated at 25°C for 60 minutes. Finally, chemiluminescence is detected.

酶活的测定结果列于下表中：

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

其中，A表示IC₅₀≤100nM；B表示100nM＜IC₅₀≤500nM；C表示500nM＜IC₅₀≤1000nM；D表示1000nM＜IC₅₀≤5000nM；E表示5000nM＜IC₅₀≤10000nM；F表示IC₅₀＞10000nM；N.A.表示未检测。Among them, A represents IC ₅₀ ≤100nM; B represents 100nM＜IC ₅₀ ≤500nM; C represents 500nM＜IC ₅₀ ≤1000nM; D represents 1000nM＜IC ₅₀ ≤5000nM; E represents 5000nM＜IC ₅₀ ≤10000nM; F represents IC ₅₀ ＞10000nM; NA represents not detected.

虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。 Although the specific embodiments of the present invention are described above, it should be understood by those skilled in the art that these are only examples, and various changes or modifications may be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the protection scope of the present invention is limited by the appended claims.

Claims

A compound as shown in formula I or a pharmaceutically acceptable salt thereof, characterized in that:

in,

Y is C or N;

^R1 is Hydroxyl, cyano, halogen, amino, deuterium, C ₁ -C ₆ alkyl which is unsubstituted or substituted by one or more R ^1-3 , C ₃ -C ₆ cycloalkyl which is unsubstituted or substituted by one or more R ^1-4 , or 3-6 membered heterocycloalkyl which is unsubstituted or substituted by one or more R ^1-5 ; 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 C ₁ -C ₆ alkyl which is unsubstituted or substituted by one or more R ^1-1-1 , C ₃ -C ₆ cycloalkyl which is unsubstituted or substituted by one or more deuterium, or -NR ^1-1-2 R ^1-1-3 ;

R ^1-2 is O or NR ^1-2-1 ; R ^1-2-1 is hydrogen or a C ₁ -C ₆ alkyl group which is unsubstituted or substituted with one or more deuteriums;

Each R ^1-1-1 is independently OR ^1-1-1-1 , C ₁ -C ₆ alkyl which is unsubstituted or substituted with one or more deuteriums, or deuterium;

R ^1-1-1-1 is hydrogen or C ₁ -C ₆ alkyl which is unsubstituted or substituted with one or more deuteriums;

R ^1-1-2 and R ^1-1-3 are independently hydrogen or C ₁ -C ₆ alkyl which is unsubstituted or substituted with one or more deuteriums;

Each R ^1-3 is independently hydroxy, cyano, halogen, amino, C ₁ -C ₆ alkyl which is unsubstituted or substituted with one or more deuteriums, or deuterium;

Each of R ^1-4 and R ^1-5 is independently hydroxy, deuterium, or C ₁ -C ₆ alkyl which is unsubstituted or substituted with one or more deuteriums;

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 C ₁ -C ₆ alkyl which is unsubstituted or substituted with one or more deuteriums;

R ^1-8 is hydrogen or C ₁ -C ₆ alkyl which is unsubstituted or substituted with one or more deuteriums;

^R2 and ^R3 and the atoms connected thereto form a 5-6 membered heteroaryl group which is unsubstituted or substituted by one or more ^R2-1 , a 4-6 membered heterocycloalkyl group which is unsubstituted or substituted by one or more ^R2-2 , a _C4 -C6 cycloalkyl group which is unsubstituted or substituted by one or more ^R2-3 , or a _C6 - _C10 aryl group which is unsubstituted or substituted by _one or more ^R2-4 ; 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 the 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 the heteroatoms is 1, 2 or 3;

Each R ^2-1 is independently deuterium, halogen, C ₁ -C ₆ alkyl which is unsubstituted or substituted by one or more R ^2-1-1 , oxo (═O), or two R ^2-1 and the carbon atom to which they are attached form a C ₃ -C ₆ cycloalkyl which is unsubstituted or substituted by one or more deuterium;

Each R ^2-2 is independently deuterium, halogen, C ₁ -C ₆ alkyl which is unsubstituted or substituted by one or more R ^2-2-1 , or oxo (═O), Alternatively, two R ^2-2 and the carbon atom to which they are attached form a C ₃ -C ₆ cycloalkyl group which is unsubstituted or substituted with one or more deuterium groups;

Each R ^2-3 is independently deuterium, halogen, C ₁ -C ₆ alkyl which is unsubstituted or substituted by one or more R ^2-3-1 , oxo (═O), or two R ^2-3 and the carbon atom to which they are attached form a C ₃ -C ₆ cycloalkyl which is unsubstituted or substituted by one or more deuterium;

Each R ^2-4 is independently deuterium, halogen, C ₁ -C ₆ alkyl which is unsubstituted or substituted by one or more R ^2-4-1 , oxo (═O), or two R ^2-4 and the carbon atom to which they are attached form a C ₃ -C ₆ cycloalkyl which is unsubstituted or substituted by one or more deuterium;

R ^2-1-1 , R ^2-2-1 , R ^2-3-1 and R ^2-4-1 are independently deuterium or hydroxyl;

A is a C ₆ -C ₁₀ arylene group which is unsubstituted or substituted by one or more deuteriums, a 5-12-membered heteroarylene group which is unsubstituted or substituted by one or more deuteriums, or a 5-12-membered heterocycloalkylene group which is unsubstituted or substituted by one or more deuteriums; 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;

L is a linking bond, a C ₂ -C ₆ alkenylene group which is unsubstituted or substituted by one or more deuterium groups, or a C ₁ -C ₆ alkylene group which is unsubstituted or substituted by one or more deuterium groups;

Q is a C ₆ -C ₁₀ arylene group which is unsubstituted or substituted by one or more R ^3-1 , a 5-12-membered heteroarylene group which is unsubstituted or substituted by one or more R ^3-1 , or a 5-12-membered heterocycloalkylene group which is unsubstituted or substituted by one or more R ^3-1 ; 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 is independently halogen or deuterium;

R ⁴ is C ₁ -C ₆ alkyl which is unsubstituted or substituted by one or more R ^4-1 , C 2 -C 6 alkenyl which is unsubstituted or substituted by one or more R ^4-2 , C ₂ -C ₆ alkynyl which _is unsubstituted or substituted by one or more R ^4-3 , C ₃ _-C ₆ cycloalkyl which is unsubstituted or substituted by one or more R ^4-4 , 4-12 membered heterocycloalkyl which is unsubstituted or substituted by one or more R ^4-5 , 5-12 membered heteroaryl which is unsubstituted or substituted by one or more R ^4-6 , C ₁ -C ₆ alkoxy which is unsubstituted or substituted by one or more R ^4-7 , or -NR ^4-9 R ^4-8 ; 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;

Each R ^4-1 is independently deuterium, halogen, hydroxyl, C ₁ -C ₆ alkyl which is unsubstituted or substituted by 1 or more deuterium, or C ₁ -C ₆ alkoxy which is unsubstituted or substituted by 1 or more deuterium;

Each R ^4-2 is independently deuterium, halogen, hydroxyl, or C ₁ -C ₆ alkyl which is unsubstituted or substituted with one or more deuteriums;

Each R ^4-3 is independently deuterium, halogen, hydroxyl, or C ₁ -C ₆ alkyl which is unsubstituted or substituted with one or more deuteriums;

Each R ^4-4 is independently deuterium, halogen, hydroxyl, or C ₁ -C ₆ alkyl which is unsubstituted or substituted with one or more deuteriums;

Each R ^4-5 is independently deuterium, halogen, hydroxyl, C ₁ -C ₆ alkyl which is unsubstituted or substituted with one or more R ^4-5-1 , -NR ^4-5- ² R ^4-5-3 , or C ₁ -C ₆ alkoxy which is unsubstituted or substituted with one or more deuterium;

Each R ^4-5-1 is independently deuterium, hydroxyl or halogen;

R ^4-5-2 and R ^4-5-3 are independently hydrogen or C ₁ -C ₆ alkyl which is unsubstituted or substituted with one or more deuteriums;

Each R ^4-6 is independently deuterium, halogen, cyano, hydroxyl, C ₁ -C ₆ alkyl which is unsubstituted or substituted by 1 or more deuterium, or C ₁ -C ₆ alkoxy which is unsubstituted or substituted by 1 or more deuterium;

Each R ^4-7 is independently deuterium, halogen, C ₁ -C ₆ alkyl which is unsubstituted or substituted by 1 or more deuterium, or C ₁ -C ₆ alkoxy which is unsubstituted or substituted by 1 or more deuterium;

R ^4-9 and R ^4-8 are independently hydrogen, C ₁ -C ₆ alkyl which is unsubstituted or substituted by one or more R ^4-8-1, or 4-6 membered heterocycloalkyl which is unsubstituted or substituted by one or more deuteriums; 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 is independently deuterium, hydroxy, C ₁ -C ₆ alkoxy which is unsubstituted or substituted by one or more R ^4-8-1-1 , or OR ^4-8-1-2 ;

Each R ^4-8-1-1 is independently deuterium or a C ₃ -C ₆ cycloalkyl group which is unsubstituted or substituted with one or more deuteriums;

Each R ^4-8-1-2 is independently a C ₃ -C ₆ cycloalkyl group which is unsubstituted or substituted with one or more deuterium groups.

The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula I satisfies one or more of the following conditions:

(1) In R ¹ , the plurality is 2, 3, 4, 5, 6 or 7;

(2) In R ¹ , the C ₁ -C ₆ alkyl group is methyl, ethyl, propyl, isopropyl or isobutyl;

(3) In R ¹ , in the "C ₃ -C ₆ cycloalkyl group which is unsubstituted or substituted by one or more R ^1-4 ", the C ₃ -C ₆ cycloalkyl group is cyclobutyl, for example,

(4) In R ¹ , 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) In R ¹ , in the “3-6 membered heterocycloalkyl group which is unsubstituted or substituted by one or more R ^1-5 ”, the 3-6 membered heterocycloalkyl group is a 4 membered heterocycloalkyl group, for example,

(6) In R ^1-1 , the "C ₁ -C ₆ alkyl group which is unsubstituted or substituted by one or more R ^1-1-1 "; the "plurality" is 2;

(7) In R ^1-1 , the C ₁ -C ₆ alkyl group is methyl, ethyl or propyl;

(8) In R ^1-1 , the C ₃ -C ₆ cycloalkyl group is a cyclopropyl group;

(9) In R ^1-1-1 , the C ₁ -C ₆ alkyl group is a methyl group;

(10) In R ^1-1-1-1 , the C ₁ -C ₆ alkyl group is a methyl group;

(11) In R ^1-1-2 and R ^1-1-3 , the C ₁ -C ₆ alkyl group is a methyl group;

(12) In R ^1-3 , the halogen is F, Cl or Br, preferably F;

(13) In R ^1-3 , the "C ₁ -C ₆ alkyl group which is unsubstituted or substituted with one or more deuterium groups"; the "plurality" is 2 or 3;

(14) In R ^1-3 , the C ₁ -C ₆ alkyl group is a methyl group or an ethyl group;

(15) In R ^1-6 and R ^1-7 , the C ₁ -C ₆ alkyl group is a methyl group;

(16) In R ^1-8 , the C ₁ -C ₆ alkyl group is a methyl group;

(17) In ^R2 and ^R3 , 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) In ^R2 and ^R3 , in the “ ^R2 and ^R3 and the atoms to which they are attached form a 5-6 membered heteroaryl group which is unsubstituted or substituted by one or more ^R2-1 ”, the 5-6 membered heteroaryl group is a 5 membered heteroaryl group, for example,

(19) In ^R2 and ^R3 , 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 preferably 1 or 2;

(20) In ^R2 and ^R3 , in the “ ^R2 and ^R3 and the atoms to which they are attached form a 4-6 membered heterocycloalkyl group which is unsubstituted or substituted by one or more ^R2-2 ”, the 4-6 membered heterocycloalkyl group is a 5-6 membered heterocycloalkyl group, for example,

(21) In R ² and R ³ , in the "R ² and R ³ and the atoms to which they are attached form a C ₄ -C ₆ cycloalkyl group which is unsubstituted or substituted by one or more R ^2-3 ", the C ₄ -C ₆ cycloalkyl group is cyclopentane;

(22) In R ² and R ³ , the C ₆ -C ₁₀ aryl group is phenyl;

(23) In R ^2-1 , the halogen is F, Cl or Br, preferably F;

(24) In R ^2-1 , the C ₁ -C ₆ alkyl group is a methyl group or an ethyl group;

(25) In R ^2-2 , the halogen is F, Cl or Br, preferably F;

(26) In R ^2-2 , the C ₃ -C ₆ 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 group and a 5-membered heteroarylene group, or a 6-membered heteroarylene group and 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 C ₂ -C ₆ alkenylene group is vinyl, for example,

(33) In Q, the C ₆ -C ₁₀ arylene group is a phenylene group;

(34) 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;

(35) In Q, the “5-12-membered heteroarylene group which is unsubstituted or substituted by one or more R ^3-1 ”; the 5-12-membered heteroarylene group is a 6-membered heteroarylene group, a 5-membered heteroarylene group and a 6-membered heteroarylene group, or a 6-membered heteroarylene group and a 5-membered heteroarylene group, 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 5-12 membered heterocycloalkylene group is a 6-membered heteroarylene group and a 6-membered heterocycloalkylene group, for example,

(38) In R ^3-1 , the halogen is F, Cl or Br, preferably F;

(39) In R ⁴ , the "C ₁ -C ₆ alkyl group which is unsubstituted or substituted by one or more R ^4-1 "; the C ₁ -C ₆ alkyl group is ethyl, for example,

(40) In R ⁴ , the C ₂ -C ₆ alkynyl group is ethynyl;

(41) In R ⁴ , the "C ₃ -C ₆ cycloalkyl group which is unsubstituted or substituted by one or more R ^4-4 "; the plurality is two;

(42) In R ⁴ , the "C ₃ -C ₆ cycloalkyl group which is unsubstituted or substituted by one or more R ^4-4 "; the C ₃ -C ₆ cycloalkyl group is cyclopropyl or cyclobutyl, for example,

(43) In R ⁴ , the heteroatoms in the 4-12 membered heterocycloalkyl group 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 the 4-12 membered heterocycloalkyl group is unsubstituted or substituted by one or more R ^4-5 ; the plurality is two;

(45) In R ⁴ , in the “4-12-membered heterocycloalkyl group which is unsubstituted or substituted by one or more R ^4-5 ”, the 4-12-membered heterocycloalkyl group is a 4-7-membered heterocycloalkyl group or a 7-9-membered double-bridged ring, for example,

(46) In R ⁴ , the heteroatom in the 5-12 membered heteroaryl group is N, and the number of heteroatoms is preferably 1 or 2;

(47) In R ⁴ , the “5-12 membered heteroaryl group which is unsubstituted or substituted by one or more R ^4-6 ”; the plurality is two;

(48) In R ⁴ , the “5-12 membered heteroaryl group which is unsubstituted or substituted by one or more R ^4-6 ”; the 5-12 membered heteroaryl group is a 5-membered or 6-membered heteroaryl group, for example,

(49) In R ⁴ , the C ₁ -C ₆ alkoxy group is an ethoxy group, for example,

(50) In R ^4-1 , the C ₁ -C ₆ alkoxy group is a methoxy group;

(51) In R ^4-4 , the halogen is F, Cl or Br, preferably F;

(52) In R ^4-5 , the C ₁ -C ₆ alkyl group is a methyl group;

(53) In R ^4-5 , the C ₁ -C ₆ alkoxy group is a methoxy group;

(54) In R ^4-5-2 and R ^4-5-3 , the C ₁ -C ₆ alkyl group is a methyl group;

(55) In R ^4-6 , the halogen is F, Cl or Br, preferably F;

(56) In R ^4-6 , the C ₁ -C ₆ alkyl group is a methyl group;

(57) The C ₁ -C ₆ alkyl group in R ^4-9 and R ^4-8 is methyl or ethyl;

(58) In R ^4-9 and R ^4-8 , the heteroatom in the 4-6-membered heterocycloalkyl is O, and the number of heteroatoms is preferably 1;

(59) In R ^4-9 and R ^4-8 , the 4-6-membered heterocycloalkyl group is a 5-membered or 6-membered heterocycloalkyl group;

(60) In R ^4-8-1-2 , the C ₃ -C ₆ cycloalkyl group is a cyclopropyl group.

(1) Y is C or N; preferably C;

(2) ^R1 is C ₁ -C ₆ alkyl substituted by one or more R ^1-3 , C ₃ -C 6 cycloalkyl unsubstituted or substituted by one or more R ^1-4 , or _3-6 membered heterocycloalkyl unsubstituted or substituted by one or more R ^1-5 ; 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 C ₁ -C ₆ alkyl substituted by one or more R ^1-3 or C ₃ -C ₆ cycloalkyl unsubstituted or substituted by one or more R ^1-4 ; further preferably or a C ₁ -C ₆ alkyl group substituted by one or more R ^1-3 ; more preferably

(3) R ^1-1 is C ₁ -C ₆ alkyl, unsubstituted or substituted by one or more R ^1-1-1 , unsubstituted C ₃ -C ₆ cycloalkyl, or -NR ^1- ^1-2 R ^1-1-3 ; preferably C 1 -C 6 alkyl, unsubstituted or substituted by one or more R ^1-1-1 _, or -NR ^1-1-2 R ^1-1-3 ; more preferably C ₁ -C ₆ alkyl, unsubstituted or substituted by one or more R ^1-1-1 ; even more preferably unsubstituted C ₁ _-C ₆ alkyl;

(4) R ^1-2 is O or NR ^1-2-1 ; preferably O;

(5) R ^1-2-1 is hydrogen;

(6) Each R ^1-1-1 is independently OR ^1-1-1-1 , unsubstituted C ₁ -C ₆ alkyl or unsubstituted C ₁ -C ₆ alkoxy; preferably OR ^1-1-1-1 or unsubstituted C ₁ -C ₆ alkyl; more preferably unsubstituted C ₁ -C ₆ alkyl;

(7) R ^1-1-1-1 is hydrogen or unsubstituted C ₁ -C ₆ alkyl; preferably unsubstituted C ₁ -C ₆ alkyl;

(8) R ^1-1-2 and R ^1-1-3 are independently hydrogen or unsubstituted C ₁ -C ₆ alkyl;

(9) Each R ^1-3 is independently hydroxyl, cyano, halogen, amino, unsubstituted C ₁ -C ₆ alkyl or deuterium; preferably hydroxyl, cyano, halogen, unsubstituted C ₁ -C ₆ alkyl or deuterium; more preferably hydroxyl, cyano, halogen or unsubstituted C ₁ -C ₆ alkyl; further preferably hydroxyl or halogen;

(10) Each R ^1-3 is independently hydroxyl, halogen, unsubstituted C ₁ -C ₆ alkyl or deuterium; preferably hydroxyl, halogen or unsubstituted C ₁ -C ₆ alkyl;

(11) each of R ^1-4 and R ^1-5 is independently hydroxyl;

(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 C ₁ -C ₆ alkyl; preferably hydrogen;

(14) R ^1-8 is an unsubstituted C ₁ -C ₆ alkyl group;

(15) ^R2 and ^R3 and the atoms to which they are connected form a 5-6 membered heteroaryl group which is unsubstituted or substituted by one or more ^R2-1 , a 4-6 membered heterocycloalkyl group which is unsubstituted or substituted by one or more ^R2-2 , a _C4 - _C6 cycloalkyl group which is unsubstituted or substituted by one or more ^R2-3 _, or an unsubstituted C6- _C10 aryl group; preferably a 5-6 membered heteroaryl group which is unsubstituted or substituted by one or more ^R2-1 , a 4-6 membered heterocycloalkyl group which is unsubstituted or substituted by one or more R2-2. substituted by one or more R ^2-2, or a C ₄ -C ₆ cycloalkyl group which is unsubstituted or substituted by one or more R ^2-3 ; preferably, a 5-6-membered heteroaryl group which is unsubstituted or substituted by one or more R ^2-1 , a 4-6-membered heterocycloalkyl group which is unsubstituted or substituted by one or more R ^2-2 , or an unsubstituted C 4 -C 6 cycloalkyl group; preferably, a 5-6-membered heteroaryl group which is unsubstituted or substituted by one or more R 2-1, an unsubstituted 4-6-membered heterocycloalkyl group, or an unsubstituted C ₄ -C ₆ cycloalkyl group; preferably, a 4-6-membered heterocycloalkyl group which is unsubstituted or substituted by one or more R ^2-1 , an unsubstituted 4-6-membered heterocycloalkyl group, or an unsubstituted C ₄ -C ₆ cycloalkyl group; preferably, a 4-6-membered heterocycloalkyl group which is unsubstituted or substituted by one or more R _2-1 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 is independently halogen, unsubstituted or substituted C ₁ -C ₆ alkyl or oxo (═O) with one or more R ^2-1-1 ; preferably halogen or unsubstituted C ₁ -C ₆ alkyl; more preferably unsubstituted C ₁ -C ₆ alkyl;

(17) Each R ^2-2 is independently halogen, unsubstituted C ₁ -C ₆ alkyl, oxo (=O), or two R ^2-2 and the carbon atom to which they are attached form a C ₃ -C ₆ cycloalkyl; preferably oxo (=O), or two R ^2-2 and the carbon atom to which they are attached form a C ₃ -C ₆ cycloalkyl; more preferably oxo (=O);

(18) Each R ^2-2 is independently halogen, unsubstituted C ₁ -C ₆ alkyl or oxo (=O); preferably halogen;

(19) Each R ^2-3 is independently oxo (=O);

(20) R ^2-1-1 is hydroxyl;

(21) A is an unsubstituted C ₆ -C ₁₀ arylene group, an unsubstituted 5-12 membered heterocycloalkylene group or an unsubstituted 5-12 membered heteroarylene group; preferably an unsubstituted 5-12 membered heteroarylene group; 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; 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;

(22) L is a linker or an unsubstituted C ₂ -C ₆ alkenylene group; preferably, it is a linker;

(23) Q is an unsubstituted _C6 - _C10 arylene group, an unsubstituted or substituted ^5-12 -membered heteroarylene group or an unsubstituted 5-12-membered heterocycloalkylene group; preferably an unsubstituted or substituted ^5-12 -membered heteroarylene group or an unsubstituted 5-12-membered heterocycloalkylene group; more 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 is independently halogen;

(25) R ⁴ is C ₁ -C ₆ alkyl which is unsubstituted or substituted by one or more R ^4-1 , unsubstituted C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl which is unsubstituted or substituted by one or more R ^4-4 , 4-12-membered heterocycloalkyl which is unsubstituted or substituted by one or more R ^4-5 , 5-12-membered heteroaryl which is unsubstituted or substituted by one or more R ^4-6 , unsubstituted C ₁ -C ₆ alkoxy or -NR ^4-9 R ^4-8 ; preferably C ₁ -C ₆ alkyl which is substituted by one or more R ^4-1 , unsubstituted C ₂ -C ₆ alkynyl, unsubstituted C ₃ -C ₆ cycloalkyl, 4-12-membered heterocycloalkyl which is unsubstituted or substituted by one or more R ^4-5 , 5-12-membered heteroaryl which is unsubstituted or substituted by one or more R ^4-6, or unsubstituted C ₁ -C ₆ -membered alkoxy; further preferably unsubstituted C ₂ -C ₆ alkynyl, unsubstituted C ₃ -C ₆ cycloalkyl, 4-12-membered heterocycloalkyl substituted by one or more R ^4-5 , 5-12-membered heteroaryl substituted by one or more R ^4-6 , or unsubstituted C ₁ - C ₆ alkoxy; further preferably unsubstituted C ₂ -C ₆ alkynyl, unsubstituted C ₃ -C ₆ cycloalkyl or 5-12 membered heteroaryl substituted by one or ^more R ^4-6 ; 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 is independently an unsubstituted C ₁ -C ₆ alkoxy group;

(27) each R ^4-4 is independently halogen;

(28) Each R ^4-5 is independently hydroxyl, C ₁ -C ₆ alkyl which is unsubstituted or substituted by one or more R ^4-5-1 , -NR ^4-5-2 R ^4-5-3 , or unsubstituted C ₁ -C ₆ alkoxy; preferably C ₁ -C ₆ alkyl which is unsubstituted or substituted by one or more R ^4-5-1 , or unsubstituted C ₁ -C ₆ alkoxy; further preferably unsubstituted C ₁ -C ₆ alkoxy;

(29) each R ^4-5-1 is independently hydroxyl;

(30) R ^4-5-2 and R ^4-5-3 are independently unsubstituted C ₁ -C ₆ alkyl;

(31) Each R ^4-6 is independently cyano, halogen or unsubstituted C ₁ -C ₆ alkyl; preferably cyano or unsubstituted C ₁ -C ₆ alkyl;

(32) R ^4-9 and R ^4-8 are independently C ₁ -C ₆ alkyl or unsubstituted 4-6 membered heterocycloalkyl which is unsubstituted or substituted by one or more R ^4-8-1 ; 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 is independently OR ^4-8-1-2 ;

and (34) each R ^4-8-1-2 is independently an unsubstituted C ₃ -C ₆ cycloalkyl group.

The compound as shown in formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that the compound as shown in formula I satisfies any of the following schemes:

plan 1:

Y is C or N;

^R1 is C ₁ -C ₆ alkyl substituted by one or more R ^1-3 , C ₃ -C 6 cycloalkyl unsubstituted or substituted by one or more R ^1-4 , or _3-6 membered heterocycloalkyl unsubstituted or substituted by one or more R ^1-5 ; 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 C ₁ -C ₆ alkyl, unsubstituted C ₃ -C ₆ cycloalkyl or -NR ^1-1-2 R ^1-1- ³ which is unsubstituted or substituted by one or more R ^1-1-1 ;

R ^1-2 is O or NR ^1-2-1 ; R ^1-2-1 is hydrogen;

Each R ^1-1-1 is independently OR ^1-1-1-1 , an unsubstituted C ₁ -C ₆ alkyl group or an unsubstituted C ₁ -C ₆ alkoxy group;

R ^1-1-1-1 is hydrogen or unsubstituted C ₁ -C ₆ alkyl;

R ^1-1-2 and R ^1-1-3 are independently hydrogen or unsubstituted C ₁ -C ₆ alkyl;

Each R ^1-3 is independently hydroxy, cyano, halogen, amino, unsubstituted C ₁ -C ₆ alkyl or deuterium;

Each of R ^1-4 and R ^1-5 is independently hydroxyl;

X is -CR ^1-6 R ^1-7 - or -NR ^1-8 -;

R ^1-6 and R ^1-7 are independently hydrogen or unsubstituted C ₁ -C ₆ alkyl;

R ^1-8 is an unsubstituted C ₁ -C ₆ alkyl group;

^R2 and ^R3 and the atoms connected thereto form a 5-6 membered heteroaryl group which is unsubstituted or substituted by one or more ^R2-1 , a 4-6 membered heterocycloalkyl group which is unsubstituted or substituted by one or more ^R2-2 , a _C4 - _C6 cycloalkyl group which is unsubstituted or substituted by one or more ^R2-3 , or an unsubstituted _C6 - _C10 aryl group; 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 the 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 the heteroatoms is 1, 2 or 3;

Each R ^2-1 is independently halogen, C ₁ -C ₆ alkyl which is unsubstituted or substituted by one or more R ^2-1-1 , or oxo (═O);

Each R ^2-2 is independently halogen, unsubstituted C ₁ -C ₆ alkyl, oxo (=O), or two R ^2-2 and the carbon atom to which they are attached form a C ₃ -C ₆ cycloalkyl;

Each R ^2-3 is independently oxo (=O);

R ^2-1-1 is a hydroxyl group;

A is an unsubstituted C ₆ -C ₁₀ arylene group, an unsubstituted 5-12-membered heterocycloalkylene group or an unsubstituted 5-12-membered heteroarylene group; 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; 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;

L is a linker or an unsubstituted C ₂ -C ₆ alkenylene group;

Q is an unsubstituted C ₆ -C ₁₀ arylene group, an unsubstituted or one or more R ^3-1 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 is independently halogen;

R ⁴ is C ₁ -C ₆ alkyl which is unsubstituted or substituted by one or more R ^4-1 , unsubstituted C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl which is unsubstituted or substituted by one or more R ^4-4 , 4-12-membered heterocycloalkyl which is unsubstituted or substituted by one or more R ^4-5 , 5-12-membered heteroaryl which is unsubstituted or substituted by one or more R ^4-6 , unsubstituted C ₁ -C ₆ alkoxy or -NR ^4-9 R ^4-8 ; 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;

Each R ^4-1 is independently an unsubstituted C ₁ -C ₆ alkoxy group;

Each R ^4-4 is independently halogen;

Each R ^4-5 is independently hydroxy, C ₁ -C ₆ alkyl which is unsubstituted or substituted by one or more R ^4-5-1 , -NR ^4-5-2 R ^4-5-3 or unsubstituted C ₁ -C ₆ alkoxy;

Each R ^4-5-1 is independently hydroxyl;

R ^4-5-2 and R ^4-5-3 are independently unsubstituted C ₁ -C ₆ alkyl groups;

Each R ^4-6 is independently cyano, halogen or unsubstituted C ₁ -C ₆ alkyl; preferably cyano or unsubstituted C ₁ -C ₆ alkyl;

R ^4-9 and R ^4-8 are independently C ₁ -C ₆ alkyl or unsubstituted 4-6-membered heterocycloalkyl which is unsubstituted or substituted by one or more R ^4-8-1 ; 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 is independently OR ^4-8-1-2 ;

Each R ^4-8-1-2 is independently an unsubstituted C ₃ -C ₆ cycloalkyl group;

Scenario 2:

Y is C or N;

^R1 is C ₁ -C ₆ alkyl substituted by 1 or more R ^1-3 or C ₃ -C ₆ cycloalkyl unsubstituted or substituted by 1 or more R ^1-4 ;

R ^1-1 is a C ₁ -C ₆ alkyl group which is unsubstituted or substituted by one or more R ^1-1-1 or -NR ^1-1-2 R ^1-1-3 ;

R ^1-2 is O or NR ^1-2-1 ; R ^1-2-1 is hydrogen;

Each R ^1-1-1 is independently OR ^1-1-1-1 or an unsubstituted C ₁ -C ₆ alkyl group;

R ^1-1-1-1 is hydrogen or unsubstituted C ₁ -C ₆ alkyl;

Each R ^1-3 is independently hydroxy, cyano, halogen, unsubstituted C ₁ -C ₆ alkyl or deuterium;

Each R ^1-4 is hydroxyl;

X is -CR ^1-6 R ^1-7 - or -NR ^1-8 -;

R ^1-8 is an unsubstituted C ₁ -C ₆ alkyl group;

^R2 and ^R3 and the atoms connected thereto form a 5-6 membered heteroaryl group which is unsubstituted or substituted by one or more ^R2-1 , a 4-6 membered heterocycloalkyl group which is unsubstituted or substituted by one or more ^R2-2 , or a _C4 - _C6 cycloalkyl group which is unsubstituted or substituted by one or more ^R2-3 ; 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; preferably, the heteroatoms in the 4-6 membered heterocycloalkyl group are N or O, and the number of heteroatoms is 1 or 2;

Each R ^2-1 is independently halogen or unsubstituted C ₁ -C ₆ alkyl;

Each R ^2-3 is 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 both of N and S, with 1, 2 or 3 heteroatoms;

L is a linker or an unsubstituted C ₂ -C ₆ alkenylene group;

Q is a 5-12-membered heteroarylene group or an unsubstituted 5-12-membered heterocycloalkylene group which is unsubstituted or substituted by one or more R ^3-1 ; 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 is independently halogen;

R ⁴ is a C ₁ -C ₆ alkyl group substituted by one or more R ^4-1 , an unsubstituted C ₂ -C ₆ alkynyl group, an unsubstituted C ₃ -C ₆ cycloalkyl group, a 4-12-membered heterocycloalkyl group unsubstituted or substituted by one or more R ^4-5 , a 5-12-membered heteroaryl group unsubstituted or substituted by one or more R ^4-6 , or an unsubstituted C ₁ -C ₆ alkoxy group; 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; preferably, R ⁴ is a C ₁ -C ₆ alkyl group substituted by one or more R ^4-1 , an unsubstituted C ₂ -C ₆ alkynyl group, an unsubstituted C ₃ -C ₆ cycloalkyl group, an unsubstituted or substituted by one or more R ^4-5 substituted 4-6 membered heterocycloalkyl, unsubstituted or substituted by one or more R ^4-6 membered heteroaryl, or unsubstituted C ₁ -C ₆ alkoxy; the heteroatom in the 4-6 membered heterocycloalkyl is 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 or 2;

R ^4-1 is independently an unsubstituted C ₁ -C ₆ alkoxy group;

Each R ^4-5 is independently a C ₁ -C ₆ alkyl group or an unsubstituted C ₁ -C ₆ alkoxy group which is unsubstituted or substituted by one or more R ^4-5-1 ;

Each R ^4-5-1 is independently hydroxyl;

Each R ^4-6 is independently cyano, halogen or unsubstituted C ₁ -C ₆ alkyl;

Scenario 3:

Y is C or N;

R ^1-2 is O or NR ^1-2-1 ; R ^1-2-1 is hydrogen;

R ^1-1-1-1 is an unsubstituted C ₁ -C ₆ alkyl group;

Each R ^1-3 is independently hydroxy, cyano, halogen or unsubstituted C ₁ -C ₆ alkyl;

Each R ^1-4 is hydroxyl;

X is -CR ^1-6 R ^1-7 - or -NR ^1-8 -;

R ^1-8 is an unsubstituted C ₁ -C ₆ alkyl group;

Each R ^2-1 is independently an unsubstituted C ₁ -C ₆ alkyl group;

Each R ^2-2 is independently halogen, unsubstituted C ₁ -C ₆ alkyl, oxo (═O), or two R ^2-2 and the carbon atom to which they are attached form a C ₃ -C ₆ cycloalkyl;

Each R ^2-3 is 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 an unsubstituted C ₂ -C ₆ alkenylene group;

Each R ^3-1 is independently halogen;

R ^4-1 is independently an unsubstituted C ₁ -C ₆ alkoxy group;

Each R ^4-5-1 is independently hydroxyl;

Solution 4:

Y is C or N;

R ^1-2 is O or NR ^1-2-1 ; R ^1-2-1 is hydrogen;

R ^1-1-1-1 is an unsubstituted C ₁ -C ₆ alkyl group;

Each R ^1-4 is hydroxyl;

X is -CR ^1-6 R ^1-7 - or -NR ^1-8 -;

R ^1-8 is an unsubstituted C ₁ -C ₆ alkyl group;

Each R ^2-1 is independently an unsubstituted C ₁ -C ₆ alkyl group;

Each R ^2-3 is independently oxo (=O);

L is a linker or an unsubstituted C ₂ -C ₆ alkenylene group;

Q is a 5-12 membered heteroarylene group or an unsubstituted 5-12 membered heterocycloalkylene group which is unsubstituted or substituted by one or more R ^3-1 ; 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 is independently halogen;

R ^4-1 is independently an unsubstituted C ₁ -C ₆ alkoxy group;

Each R ^4-5-1 is independently hydroxyl;

Each R ^4-6 is independently cyano or unsubstituted C ₁ -C ₆ alkyl;

Solution 5:

Y is C;

R ^1-2 is O or NR ^1-2-1 ; R ^1-2-1 is hydrogen;

Each R ^1-1-1 is independently an unsubstituted C ₁ -C ₆ alkyl group;

Each R ^1-3 is independently hydroxy or halogen;

Each R ^1-4 is hydroxyl;

X is -CR ^1-6 R ^1-7 - or -NR ^1-8 -;

R ^1-8 is an unsubstituted C ₁ -C ₆ alkyl group;

^R2 and ^R3 and the atoms connected thereto form a 5-6 membered heteroaryl group which is unsubstituted or substituted by one or more ^R2-1 , a 4-6 membered heterocycloalkyl group which is unsubstituted or substituted by one or more ^R2-2 , or an unsubstituted _C4 - _C6 cycloalkyl group; 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; 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 is independently an unsubstituted C ₁ -C ₆ alkyl group;

Each R ^2-2 is independently an oxo group (=O), or two R ^2-2 and the carbon atom to which they are attached form a C ₃ -C ₆ 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 an unsubstituted C ₂ -C ₆ alkenylene group;

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;

^R4 is an unsubstituted _C2 - _C6 alkynyl, an unsubstituted _C3 - _C6 cycloalkyl, a 4-12-membered heterocycloalkyl substituted by one or more ^R4-5 , a 5-12-membered heteroaryl substituted by one or more ^R4-6 , or an unsubstituted _C1 - _C6 alkoxyl group; 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, ^R4 is an unsubstituted _C2 - _C6 alkynyl, an unsubstituted C3- _C6 cycloalkyl, a _4-6 -membered heterocycloalkyl substituted by one or more ^R4-5 , a 5-6-membered heteroaryl substituted by one or more ^R4-6 , or an unsubstituted _C1 -C6 alkoxyl group; The heteroatom in _the 4-6 membered heterocycloalkyl is 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 is independently an unsubstituted C ₁ -C ₆ alkyl group;

Each R ^4-6 is independently cyano or unsubstituted C ₁ -C ₆ alkyl;

Solution 6:

Y is C;

R ^1-1 is a C ₁ -C ₆ alkyl group which is unsubstituted or substituted by one or more R ^1-1-1 ;

R ^1-2 is O;

Each R ^1-1-1 is independently an unsubstituted C ₁ -C ₆ alkyl group;

Each R ^1-3 is independently halogen;

Each R ^1-4 is hydroxyl;

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 C ₁ -C ₆ alkyl group;

^R2 and ^R3 and the atoms connected thereto form a 5-6 membered heteroaryl group which is unsubstituted or substituted by one or more ^R2-1 , a 4-6 membered heterocycloalkyl group which is unsubstituted or substituted by one or more ^R2-2 , or an unsubstituted _C4 - _C6 cycloalkyl group; 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; preferably, the heteroatom in the 5-6 membered heteroaryl group is N, and the number of heteroatoms is 1 or 2; the heteroatom in the 4-6 membered heterocycloalkyl group is N or O, and the number of heteroatoms is 1 or 2;

Each R ^2-1 is independently an unsubstituted C ₁ -C ₆ alkyl group;

Each R ^2-2 is independently oxo (=O);

L is a linker or an unsubstituted C ₂ -C ₆ alkenylene group;

Each R ^4-5 is independently an unsubstituted C ₁ -C ₆ alkyl group;

Each R ^4-6 is independently cyano or unsubstituted C ₁ -C ₆ alkyl;

Solution 7:

Y is C;

^R1 is or C ₁ -C ₆ alkyl which is unsubstituted or substituted by one or more R ^1-3 ;

R ^1-2 is O;

Each R ^1-1-1 is independently OR ^1-1-1-1 ;

R ^1-1-1-1 is hydrogen or unsubstituted C ₁ -C ₆ alkyl;

Each R ^1-3 is independently hydroxy, halogen, unsubstituted C ₁ -C ₆ alkyl or deuterium;

X is -CR ^1-6 R ^1-7 -;

R ^1-6 and R ^1-7 are independently hydrogen;

^R2 and ^R3 and the atoms connected thereto form a 5-6 membered heteroaryl group which is unsubstituted or substituted by one or more ^R2-1 , a 4-6 membered heterocycloalkyl group which is unsubstituted or substituted by one or more ^R2-2 , or an unsubstituted _C4 - _C6 cycloalkyl group; 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; preferably, the heteroatom in the 4-6 membered heterocycloalkyl group is O, and the number of heteroatoms is 1 or 2;

Each R ^2-1 is independently halogen or unsubstituted C ₁ -C ₆ alkyl;

Each R ^2-2 is independently halogen, unsubstituted C ₁ -C ₆ 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 an unsubstituted C ₂ -C ₆ alkenylene group;

Each R ^3-1 is independently halogen;

^R4 is an unsubstituted _C2 - _C6 alkynyl, an unsubstituted _C3 - _C6 cycloalkyl, a 4-12-membered heterocycloalkyl substituted by one or more ^R4-5 , a 5-12-membered heteroaryl substituted by one or more ^R4-6 , or an unsubstituted _C1 - _C6 alkoxyl group; 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, ^R4 is an unsubstituted _C2 - _C6 alkynyl, an unsubstituted C3- _C6 cycloalkyl, a _4-6 -membered heterocycloalkyl substituted by one or more ^R4-5 , a 5-6-membered heteroaryl substituted by one or more ^R4-6 , or an unsubstituted _C1 -C6 alkoxyl group; ₆ -membered alkoxy; the heterocyclic alkyl group of the 4-6-membered 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 is independently an unsubstituted C ₁ -C ₆ alkyl group;

Solution 8:

Y is C;

^R1 is or a C ₁ -C ₆ alkyl group substituted by one or more R ^1-3 ;

R ^1-2 is O;

Each R ^1-1-1 is independently OR ^1-1-1-1 ;

R ^1-1-1-1 is hydrogen or unsubstituted C ₁ -C ₆ alkyl;

X is -CR ^1-6 R ^1-7 -;

R ^1-6 and R ^1-7 are independently hydrogen;

^R2 and ^R3 and the atoms connected thereto form a 5-6-membered heteroaryl group which is unsubstituted or substituted by one or more ^R2-1 , a 4-6-membered heterocycloalkyl group which is unsubstituted or substituted by one or more ^R2-2 , or an unsubstituted _C4 - _C6 cycloalkyl group; the heteroatoms in the 5-6-membered heteroaryl group 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 group are independently selected from one or more of N, O and S, 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 or 2;

Each R ^2-1 is independently a halogen or an unsubstituted C ₁ -C ₆ alkyl group;

Each R ^2-2 is independently halogen, unsubstituted C ₁ -C ₆ 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 an unsubstituted C ₂ -C ₆ alkenylene group;

Each R ^3-1 is independently halogen;

Each R ^4-5 is independently an unsubstituted C ₁ -C ₆ alkyl group;

Solution 9:

Y is C;

^R1 is or a C ₁ -C ₆ alkyl group substituted by one or more R ^1-3 ;

R ^1-2 is O;

Each R ^1-1-1 is independently OR ^1-1-1-1 ;

R ^1-1-1-1 is an unsubstituted C ₁ -C ₆ alkyl group;

Each R ^1-3 is independently hydroxy, halogen or unsubstituted C ₁ -C ₆ alkyl;

X is -CR ^1-6 R ^1-7 -;

R ^1-6 and R ^1-7 are independently hydrogen;

Each R ^2-1 is independently an unsubstituted C ₁ -C ₆ alkyl group;

Each R ^2-2 is independently halogen;

L is a linker or an unsubstituted C ₂ -C ₆ alkenylene group;

Each R ^3-1 is independently halogen;

Each R ^4-5 is independently an unsubstituted C ₁ -C ₆ alkyl group;

Solution 10:

Y is C;

^R1 is or a C ₁ -C ₆ alkyl group substituted by one or more R ^1-3 ;

R ^1-2 is O;

Each R ^1-1-1 is independently OR ^1-1-1-1 ;

R ^1-1-1-1 is an unsubstituted C ₁ -C ₆ alkyl group;

X is -CR ^1-6 R ^1-7 -;

R ^1-6 and R ^1-7 are independently hydrogen;

^R2 and ^R3 and the atoms connected thereto form a 5-6-membered heteroaryl group, an unsubstituted 4-6-membered heterocycloalkyl group or an unsubstituted _C4 - _C6 cycloalkyl group, which is unsubstituted or substituted by one or more ^R2-1 ; 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; preferably, the heteroatoms in the 5-6-membered heteroaryl group are N or O, and the number of heteroatoms is 1 or 2; the heteroatoms in the 4-6-membered heterocycloalkyl group are O, and the number of heteroatoms is 1 or 2;

Each R ^2-1 is independently an unsubstituted C ₁ -C ₆ alkyl group;

L is a linker or an unsubstituted C ₂ -C ₆ alkenylene group;

Each R ^4-5 is independently an unsubstituted C ₁ -C ₆ alkyl group;

Each R ^4-6 is independently cyano or unsubstituted C ₁ -C ₆ alkyl;

Solution 11:

Y is C;

^R1 is

R ^1-1 is an unsubstituted C ₁ -C ₆ 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;

^R2 and ^R3 and the atoms to which they are connected form an unsubstituted 4-6 membered heterocycloalkyl or an unsubstituted _C4 - _C6 cycloalkyl; the heteroatom in the 4-6 membered heterocycloalkyl is independently selected from one or more of N, O and S, and the number of the heteroatom is 1, 2 or 3; preferably, the heteroatom in the 4-6 membered heterocycloalkyl is O, and the number of the heteroatom is 1;

L is the connection key;

^R4 is an unsubstituted _C2 - _C6 alkynyl, an unsubstituted _C3 - _C6 cycloalkyl, or a 5-12-membered heteroaryl substituted by one or more ^R4-6 ; the heteroatom in the 5-12-membered heteroaryl is independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, ^R4 is an unsubstituted _C2 - _C6 alkynyl, an unsubstituted C3- _C6 cycloalkyl, or a _5-6 -membered heteroaryl substituted by one or more ^R4-6 ; the heteroatom in the 5-6-membered heteroaryl is N, and the number of heteroatoms is 1;

Each R ^4-6 is independently cyano or unsubstituted C ₁ -C ₆ alkyl.

(1) R ¹ is

(2) X is a methylene group,

(3) for

(4) A is

(5) L is

(6) Q is

(7) R ⁴ is

The compound as shown in formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that the compound as shown in formula I is any of the following structures,

A use of a compound as shown in formula I or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 6 in the preparation of a BRM ATPase inhibitor.

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.

A use of a compound as shown in formula I or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 6 in the preparation of a medicament, characterized in that the medicament is used to treat BRM ATPase-related diseases or the medicament is used to treat melanoma, endometrial cancer, non-small cell lung cancer, esophageal gastric adenocarcinoma, urothelial bladder cancer or colorectal cancer.

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