WO2022127915A1

WO2022127915A1 - Pyridopyrimidinone compound

Info

Publication number: WO2022127915A1
Application number: PCT/CN2021/139271
Authority: WO
Inventors: 徐招兵; 胡利红; 丁照中; 陈曙辉
Original assignee: 正大天晴药业集团股份有限公司; 南京明德新药研发有限公司
Priority date: 2020-12-18
Filing date: 2021-12-17
Publication date: 2022-06-23
Also published as: TW202233617A; CN116529249A; TWI795129B

Abstract

Disclosed are a class of pyridopyrimidinone compounds, in particular related to are a compound of formula (I) and a pharmaceutically acceptable salt thereof, and the use of the compound of formula (I) and the pharmaceutically acceptable salt thereof in the preparation of a drug for treating related diseases.

Description

吡啶并嘧啶酮类化合物pyridopyrimidinones

本申请主张如下优先权：This application claims the following priority:

CN202011508100.7，申请日2020年12月18日；CN202011508100.7, application date December 18, 2020;

CN202110560291.X，申请日2021年5月21日；CN202110560291.X, application date May 21, 2021;

CN202111522022.0，申请日2021年12月13日。CN202111522022.0, application date December 13, 2021.

技术领域technical field

本申请涉及一类吡啶并嘧啶酮类化合物，具体涉及式(I)化合物及其药学上可接受的盐，以及式(I)化合物及其药学上可接受的盐在制备治疗相关疾病中的应用。The present application relates to a class of pyridopyrimidinone compounds, in particular to compounds of formula (I) and pharmaceutically acceptable salts thereof, and applications of compounds of formula (I) and pharmaceutically acceptable salts thereof in the preparation and treatment of related diseases .

背景技术Background technique

RAS基因是第一个在人类肿瘤中被鉴定出来的致癌基因，RAS蛋白可以与鸟嘌呤三核苷酸磷酸(GTP)或鸟嘌呤二核苷酸磷酸(GDP)结合，RAS蛋白的活性状态对细胞的生长、分化、细胞骨架、蛋白质运输和分泌等都具有影响，其活性是通过与GTP或GDP的结合进行调节：当RAS蛋白与GDP结合时，它处于休眠状态，也就是“失活”状态；当有上游特定的细胞生长因子刺激时，RAS蛋白被诱导交换GDP，与GTP结合，此时称为“活化”状态。与GTP结合的RAS蛋白能够活化下游的蛋白，进行信号传递。RAS蛋白自身具有弱的水解GTP水解活性，能够水解GTP到GDP。这样就可以实现从活化状态到失活状态的转化。在这个水解过程中，还需要GAP(GTPase activating proteins,GTP水解酶活化蛋白)参与。它能与RAS蛋白作用，大大促进其水解GTP到GDP的能力。RAS蛋白的突变将影响其与GAP的作用，也就影响了其水解GTP到GDP的能力，使其一直处于活化状态。活化的RAS蛋白持续的给予下游蛋白生长信号，最终导致细胞不停的生长和分化，最终产生肿瘤。RAS基因家族成员众多，其中与各种癌症密切相关的亚家族主要有克尔斯滕大鼠肉瘤病毒致癌基因同源物(KRAS)、哈维大鼠肉瘤病毒致癌同源物(HRAS)和神经母细胞瘤大鼠肉瘤病毒致癌基因同源物(NRAS)。人们发现大约30％的人类肿瘤中都携带某些突变的RAS基因，其中以KRAS突变最为显著，占到所有RAS突变中的86％。KRAS突变经常与靶向治疗的抵抗和癌症患者的预后不良有关。据统计，约13％的非小细胞肺癌(NSCLC)和1％-3％的结直肠癌和其他癌症会发生KRAS p.G12C突变。The RAS gene is the first oncogene identified in human tumors. The RAS protein can bind to either guanine trinucleotide phosphate (GTP) or guanine dinucleotide phosphate (GDP), and the active state of the RAS protein affects the Cell growth, differentiation, cytoskeleton, protein transport and secretion all have effects, and its activity is regulated by binding to GTP or GDP: when the RAS protein is bound to GDP, it is dormant, that is, "inactive" state; when stimulated by upstream specific cell growth factors, RAS protein is induced to exchange GDP and bind to GTP, which is called the "activated" state. The RAS protein bound to GTP can activate downstream proteins for signal transmission. The RAS protein itself has weak hydrolysis GTP hydrolysis activity and can hydrolyze GTP to GDP. In this way, the transition from the activated state to the deactivated state can be achieved. In this hydrolysis process, GAP (GTPase activating proteins, GTP hydrolase activating proteins) is also required. It can interact with RAS protein, greatly promoting its ability to hydrolyze GTP to GDP. Mutation of the RAS protein will affect its interaction with GAP, which also affects its ability to hydrolyze GTP to GDP, making it always active. Activated RAS proteins continue to give downstream proteins growth signals, which eventually lead to continuous cell growth and differentiation, and ultimately produce tumors. There are many members of the RAS gene family, among which subfamilies closely related to various cancers mainly include Kirsten rat sarcoma virus oncogene homolog (KRAS), Harvey rat sarcoma virus oncogene homolog (HRAS) and neuronal Blastoma rat sarcoma virus oncogene homolog (NRAS). It has been found that about 30% of human tumors carry some mutated RAS gene, among which KRAS mutation is the most significant, accounting for 86% of all RAS mutations. KRAS mutations are frequently associated with resistance to targeted therapy and poor prognosis in cancer patients. According to statistics, KRAS p.G12C mutation occurs in about 13% of non-small cell lung cancer (NSCLC) and 1%-3% of colorectal cancer and other cancers.

KRAS G12C突变蛋白作为一个前沿热门靶点，近几年有多款产品进入临床研究阶段，但是仍没有被批准的选择性KRAS G12C小分子抑制剂。近年来，Araxes Pharma公司申请了数篇针对KRAS G12C抑制剂的专利，例如WO2016164675和WO2016168540。Araxes Pharma公司开发的ARS-3248目前处在临床一期。Amgen公司自2018年以来有多篇关于KRAS G12C抑制剂的专利公开：WO2018119183，WO2018217651，WO2019051291，WO2019213516，WO2020050890等。MIRATI公司则开发的KRAS G12C抑制剂MRTX849已迈入二期临床。AMG 510是临床进展最快的选择性小分子KRAS G12C抑制剂，AMG 510有望成为治疗转移性非小细胞肺癌(NSCLC)新的选择，并与其他抗肿瘤药物联用以产生更好的疗效。美国食品和药物管理局(FDA)已授予靶向抗癌药AMG 510突破性药物资格(BTD)和实时肿瘤学审查资格(RTOR)，用于治疗经FDA批准的检测方法证实存在KRAS G12C突变的局部晚期或NSCLC患者。KRAS G12C mutant protein is a cutting-edge hot target. In recent years, many products have entered the clinical research stage, but there is still no approved selective KRAS G12C small molecule inhibitor. In recent years, Araxes Pharma has applied for several patents for KRAS G12C inhibitors, such as WO2016164675 and WO2016168540. ARS-3248, developed by Araxes Pharma, is currently in Phase I clinical trials. Amgen has published several patents on KRAS G12C inhibitors since 2018: WO2018119183, WO2018217651, WO2019051291, WO2019213516, WO2020050890, etc. The KRAS G12C inhibitor MRTX849 developed by MIRATI has entered Phase II clinical trials. AMG 510 is the fastest clinically advanced selective small molecule KRAS G12C inhibitor. AMG 510 is expected to become a new option for the treatment of metastatic non-small cell lung cancer (NSCLC), and it can be combined with other anti-tumor drugs to produce better efficacy. The U.S. Food and Drug Administration (FDA) has granted Breakthrough Drug Designation (BTD) and Real-Time Oncology Review Designation (RTOR) for the targeted cancer drug AMG 510 for the treatment of patients with KRAS G12C mutations confirmed by an FDA-approved test. Patients with locally advanced or NSCLC.

发明内容SUMMARY OF THE INVENTION

本申请提供式(I)化合物或其药学上可接受的盐，The application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,

其中，in,

X选自CR ₁₃和N； X is selected from CR ₁₃ and N;

Q和Y分别独立地选自CH和N；Q and Y are independently selected from CH and N, respectively;

R ₁选自H、F、Cl、Br、I、C _1-3烷基，所述C _1-3烷基任选被1、2或3个卤素取代； R ₁ is selected from H, F, Cl, Br, I, C _1-3 alkyl optionally substituted with ₁ , 2 or 3 halogens;

R ₂、R ₃、R ₄、R ₅和R ₆分别独立地选自H、F、Cl、Br、I、OH、C _1-3烷基、NH ₂和-NH-C _1-3烷基，所述C _1-3烷基任选被1、2或3个卤素取代； R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are each independently selected from H, F, Cl, Br, I, OH, C _1-3 alkyl, NH ₂ and -NH-C _1-3 alkyl , the C _1-3 alkyl is optionally substituted by 1, 2 or 3 halogens;

R ₇、R ₈、R ₉和R ₁₀分别独立地选自H和CH ₃； R ₇ , R ₈ , R ₉ and R ₁₀ are each independently selected from H and CH ₃ ;

R ₁₁选自H和F； R ₁₁ is selected from H and F;

R ₁₂和R ₁₃分别独立地选自H、C _1-6烷基、环丙基和C _1-3烷氧基。 R ₁₂ and R ₁₃ are each independently selected from H, C _1-6 alkyl, cyclopropyl and C _1-3 alkoxy.

在本申请的一些方案中，上述X选自CR ₁₃，其他变量如本申请所定义。 In some aspects of the present application, the above X is selected from CR ₁₃ , and other variables are as defined herein.

在本申请的一些方案中，上述Y选自N，其他变量如本申请所定义。In some aspects of the present application, the above Y is selected from N, and other variables are as defined herein.

在本申请的一些方案中，上述Q选自CH，其他变量如本申请所定义。In some aspects of the present application, the above Q is selected from CH, and other variables are as defined herein.

在本申请的一些方案中，上述R ₁选自H、F、Cl、Br、I、CH ₃，所述CH ₃任选被1、2或3个卤素取代，其他变量如本申请所定义。 In some aspects of the present application, the above R ₁ is selected from H, F, Cl, Br, I, CH ₃ optionally substituted with 1, 2 or ₃ halogens, and other variables are as defined herein.

在本申请的一些方案中，上述R ₁选自H、F和CF ₃，其他变量如本申请所定义。 In some aspects of the present application, the above R ₁ is selected from H, F and CF ₃ , and other variables are as defined herein.

在本申请的一些方案中，上述R ₁选自CF ₃，其他变量如本申请所定义。 In some aspects of this application, the above R ₁ is selected from CF ₃ , and other variables are as defined in this application.

在本申请的一些方案中，上述R ₂、R ₃、R ₄、R ₅和R ₆分别独立地选自H、F、Cl、Br、I、OH、CF ₃、CH ₃、NH ₂和-NHCH ₃，其他变量如本申请所定义。 In some aspects of the present application, the above R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are each independently selected from H, F, Cl, Br, I, OH, CF ₃ , CH ₃ , NH ₂ and - _NHCH3 , other variables are as defined herein.

在本申请的一些方案中，上述R ₂、R ₃、R ₄、R ₅和R ₆分别独立地选自H、F、Cl、Br、CF ₃、CH ₃、NH ₂和-NHCH ₃，其他变量如本申请所定义。 In some aspects of the present application, the above R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are independently selected from H, F, Cl, Br, CF ₃ , CH ₃ , NH ₂ and -NHCH ₃ , other Variables are as defined in this application.

在本申请的一些方案中，上述R ₂选自H、F、NH ₂和-NHCH ₃，其他变量如本申请所定义。 In some aspects of the present application, the above R ₂ is selected from H, F, NH ₂ and -NHCH ₃ , and other variables are as defined herein.

在本申请的一些方案中，上述R ₃选自H、F和Cl，其他变量如本申请所定义。 In some aspects of this application, the above _R3 is selected from H, F and Cl, and other variables are as defined in this application.

在本申请的一些方案中，上述R ₄选自H和F，其他变量如本申请所定义。 _In some aspects of this application, the above R4 is selected from H and F, and other variables are as defined in this application.

在本申请的一些方案中，上述R ₅选自H、F、Cl和CH ₃，其他变量如本申请所定义。 In some aspects of this application, the above R5 is selected from H, F, _Cl and _CH3 , and other variables are as defined in this application.

在本申请的一些方案中，上述R ₆选自H、F和CF ₃，其他变量如本申请所定义。 In some aspects of the present application, the above R ₆ is selected from H, F and CF ₃ , and other variables are as defined herein.

在本申请的一些方案中，上述R ₇选自H，其他变量如本申请所定义。 In some aspects of the present application, the above _R7 is selected from H, and other variables are as defined herein.

在本申请的一些方案中，上述R ₁₀选自H，其他变量如本申请所定义。 In some aspects of the present application, the above R ₁₀ is selected from H, and other variables are as defined herein.

在本申请的一些方案中，上述R ₁₁选自H，其他变量如本申请所定义。 In some aspects of this application, the above R ₁₁ is selected from H, and other variables are as defined in this application.

在本申请的一些方案中，上述R ₁₂选自

其他变量如本申请所定义。 In some aspects of the present application, the above R ₁₂ is selected from

Other variables are as defined in this application.

在本申请的一些方案中，上述R ₁₃选自CH ₃和OCH ₃，其他变量如本申请所定义。 In some aspects of the present application, the above R ₁₃ is selected from CH ₃ and OCH ₃ , and other variables are as defined herein.

在本申请的一些方案中，上述X选自CR ₁₃，Y选自N，Q选自CH，其他变量如本申请所定义。 In some aspects of the present application, the aforementioned X is selected from CR ₁₃ , Y is selected from N, Q is selected from CH, and other variables are as defined herein.

在本申请的一些方案中，上述X选自CR ₁₃，Y选自N，Q选自CH，R ₂选自F，R ₆选自F，其他变量如本申请所定义。 In some aspects of the present application, the above X is selected from CR ₁₃ , Y is selected from N, Q is selected from CH, R ₂ is selected from F, R ₆ is selected from F, and other variables are as defined herein.

在本申请的一些方案中，上述X选自CR ₁₃，Y选自N，Q选自CH，R ₁₂选自

R ₁₃选自CH ₃，其他变量如本申请所定义。 In some aspects of the present application, the above-mentioned X is selected from CR ₁₃ , Y is selected from N, Q is selected from CH, and R ₁₂ is selected from

R ₁₃ is selected from CH ₃ and other variables are as defined herein.

在本申请的一些方案中，上述结构单元

选自

其他变量如本申请所定义。 In some aspects of the present application, the above-mentioned structural unit

selected from

Other variables are as defined in this application.

在本申请的一些方案中，上述结构单元

选自

selected from

Other variables are as defined in this application.

在本申请的一些方案中，上述结构单元

选自

selected from

Other variables are as defined in this application.

在本申请的一些方案中，上述结构单元

选自

selected from

Other variables are as defined in this application.

在本申请的一些方案中，上述结构单元

选自

selected from

Other variables are as defined in this application.

在本申请的一些方案中，上述结构单元

选自

selected from

Other variables are as defined in this application.

在本申请的一些方案中，上述结构单元

选自

selected from

Other variables are as defined in this application.

在本申请的一些方案中，上述结构单元

选自

selected from

Other variables are as defined in this application.

在本申请的一些方案中，上述结构单元

选自

selected from

Other variables are as defined in this application.

在本申请的一些方案中，上述化合物选自In some aspects of the application, the above-mentioned compounds are selected from

其中，R ₁、R ₂、R ₃、R ₄、R ₅、R ₆、R ₇、R ₈、R ₉、R ₁₀、R ₁₁、R ₁₂和R ₁₃如本申请所定义。 wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ are as defined herein.

其中，R ₁、R ₃、R ₄、R ₅、R ₇、R ₈、R ₉、R ₁₀、R ₁₁、R ₁₂和R ₁₃如本申请所定义。 wherein R ₁ , R ₃ , R ₄ , R ₅ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ are as defined herein.

其中，R ₂、R ₃、R ₄、R ₅、R ₆、R ₈、和R ₉如本申请所定义。 wherein R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₈ , and R ₉ are as defined herein.

在本申请的一些方案中，上述化合物不选自下列化合物：In some aspects of the application, the above-mentioned compounds are not selected from the following compounds:

本申请还提供化合物或其药学上可接受的盐，其选自The application also provides compounds, or pharmaceutically acceptable salts thereof, selected from

在本申请的一些方案中，上述化合物或其药学上可接受的盐，其选自In some aspects of the application, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from

本申请还有一些方案是由上述各变量任意组合而来。There are also some solutions in the present application which are obtained by any combination of the above variables.

本申请还提供上述化合物或其药学上可接受的盐在制备KRAS G12C突变蛋白抑制剂的应用。The application also provides the application of the above-mentioned compound or a pharmaceutically acceptable salt thereof in the preparation of a KRAS G12C mutein inhibitor.

本申请还提供上述化合物或其药学上可接受的盐在制备治疗非小细胞肺癌药物中的应用。The present application also provides the use of the above compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating non-small cell lung cancer.

技术效果technical effect

本申请化合物是优效的KRAS G12C突变蛋白抑制剂。本申请化合物对于KRAS G12C突变型细胞NCI-H358显示了较高的细胞抗增殖活性，同时对于野生型的A375细胞抗增殖活性较弱，体现了高的选择性。The compounds of the present application are potent KRAS G12C mutein inhibitors. The compounds of the present application show high cell anti-proliferation activity on KRAS G12C mutant cells NCI-H358, and at the same time have weak anti-proliferative activity on wild-type A375 cells, showing high selectivity.

定义和说明Definition and Explanation

除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered indeterminate or unclear without specific definitions, but should be understood in its ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding commercial product or its active ingredient.

这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue , without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.

术语“药学上可接受的盐”是指本申请化合物的盐，由本申请发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本申请的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物接触的方式获得碱加成盐。当本申请的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物接触的方式获得酸加成盐。本申请的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。The term "pharmaceutically acceptable salts" refers to salts of the compounds of the present application, prepared from compounds with specific substituents discovered herein and relatively non-toxic acids or bases. When compounds of the present application contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent. When compounds of the present application contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. Certain specific compounds of the present application contain both basic and acidic functional groups and thus can be converted into either base or acid addition salts.

本申请的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。The pharmaceutically acceptable salts of the present application can be synthesized from the parent compound containing acid or base by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.

除非另有规定，术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。Unless otherwise specified, the term "effective amount" or "therapeutically effective amount" refers to an amount that is nontoxic but achieves the desired effect. The determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance, and the appropriate effective amount in individual cases can be determined by those skilled in the art based on routine experiments.

本申请的化合物可以存在特定的几何或立体异构体形式。本申请设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本申请的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本申请的范围之内。The compounds of the present application may exist in specific geometric or stereoisomeric forms. This application contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to this within the scope of the application. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of this application.

除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。Unless otherwise indicated, the terms "enantiomers" or "optical isomers" refer to stereoisomers that are mirror images of each other.

除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。Unless otherwise specified, the terms "cis-trans isomer" or "geometric isomer" result from the inability to rotate freely due to double bonds or single bonds to ring carbon atoms.

除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。Unless otherwise indicated, the term "diastereomer" refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are in a non-mirror-image relationship.

除非另有说明，“(+)”表示右旋，“(-)”表示左旋，“(±)”表示外消旋。Unless otherwise specified, "(+)" means dextrorotatory, "(-)" means levorotatory, and "(±)" means racemic.

除非另有说明，用楔形实线键

和楔形虚线键

表示一个立体中心的绝对构型，用直形实线键

和直形虚线键

表示立体中心的相对构型，用波浪线

表示楔形实线键

或楔形虚线键

或用波浪线

表示直形实线键

或直形虚线键

Use solid wedge keys unless otherwise specified

and wedge-dotted keys

Indicate the absolute configuration of a stereocenter, using a straight solid key

and straight dashed keys

Indicate the relative configuration of the stereocenter, with a wavy line

Represents a solid wedge key

or wedge-dotted key

or with wavy lines

Represents a straight solid key

or straight dashed key

除非另有说明，术语“互变异构体”或“互变异构体形式”是指在室温下，不同官能团异构体处于动态平衡，并能很快的相互转化。若互变异构体是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(proton tautomer)(也称质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键异构体(valence tautomer)包括一些成键电子的重组来进行的相互转化。其中酮-烯醇互变异构化的具体实例是戊烷-2,4-二酮与4-羟基戊-3-烯-2-酮两个互变异构体之间的互变。Unless otherwise specified, the term "tautomer" or "tautomeric form" refers to isomers of different functional groups that are in dynamic equilibrium and are rapidly interconverted at room temperature. A chemical equilibrium of tautomers can be achieved if tautomers are possible (eg, in solution). For example, proton tautomers (also called prototropic tautomers) include interconversions by migration of protons, such as keto-enol isomerization and imine-ene Amine isomerization. Valence tautomers include interconversions by recombination of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between two tautomers, pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

除非另有说明，术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100％，并且，该异构体或对映体的含量大于等于60％，或者大于等于70％，或者大于等于80％，或者大于等于90％，或者大于等于95％，或者大于等于96％，或者大于等于97％，或者大于等于98％，或者大于等于99％，或者大于等于99.5％，或者大于等于99.6％，或者大于等于99.7％，或者大于等于99.8％，或者大于等于99.9％。Unless otherwise indicated, the terms "enriched in one isomer", "enriched in isomers", "enriched in one enantiomer" or "enriched in one enantiomer" refer to one of the isomers or pairs The enantiomer content is less than 100%, and the isomer or enantiomer content is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or Greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.

除非另有说明，术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如，其中一种异构体或对映体的含量为90％，另一种异构体或对映体的含量为10％，则异构体或对映体过量(ee值)为80％。Unless otherwise indicated, the terms "isomeric excess" or "enantiomeric excess" refer to the difference between two isomers or relative percentages of two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80% .

可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本申请某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the present application is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, followed by conventional methods known in the art The diastereoisomers were resolved and the pure enantiomers recovered. In addition, separation of enantiomers and diastereomers is usually accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (eg, from amines to amino groups) formate).

本申请的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( ³H)，碘-125( ¹²⁵I)或C-14( ¹⁴C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本申请的化合物的所有同位素组成的变换，无论放射性与否，都包括在本申请的范围之内。 The compounds of the present application may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds. For example, compounds can be labeled with radioisotopes, such as tritium ( ³ H), iodine-125 ( ¹²⁵ I) or C-14 ( ¹⁴ C). For another example, deuterated drugs can be formed by replacing hydrogen with deuterium, and the bonds formed by deuterium and carbon are stronger than those formed by ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce toxic side effects and increase drug stability. , enhance the efficacy, prolong the biological half-life of drugs and other advantages. All alterations in the isotopic composition of the compounds of the present application, whether radioactive or not, are included within the scope of the present application.

术语“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。The terms "optional" or "optionally" mean that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. .

术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两个氢原子被取代。The term "substituted" means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable of. When the substituent is oxygen (ie =O), it means that two hydrogen atoms are substituted.

术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically achievable basis.

当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。When any variable (such as R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may optionally be substituted with up to two Rs, with independent options for R in each case. Furthermore, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.

除非另有规定，当某一基团具有一个或多个可连接位点时，该基团的任意一个或多个位点可以通过化学键与其他基团相连。当该化学键的连接方式是不定位的，且可连接位点存在H原子时，则连接化学键时，该位点的H原子的个数会随所连接化学键的个数而对应减少变成相应价数的基团。所述位点与其他基团连接的化学键可以用直形实线键

直形虚线键

或波浪线

表示。例如-OCH ₃中的直形实线键表示通过该基团中的氧原子与其他基团相连；

中的直形虚线键表示通过该基团中的氮原子的两端与其他基团相连；

中的波浪线表示通过该苯基基团中的1和2位碳原子与其他基团相连；

表示该哌啶基上的任意可连接位点可以通过1个化学键与其他基团相连，至少包括

这4种连接方式，即使-N-上画出了H原子，但是

仍包括

这种连接方式的基团，只是在连接1个化学键时，该位点的H会对应减少1个变成相应的一价哌啶基。 Unless otherwise specified, when a group has one or more attachable sites, any one or more sites in the group can be linked to other groups by chemical bonds. When the connection method of the chemical bond is not located, and there is an H atom at the linkable site, when the chemical bond is connected, the number of H atoms at the site will be correspondingly reduced with the number of chemical bonds connected to the corresponding valence. the group. The chemical bond connecting the site to other groups can be represented by straight solid line bonds

straight dotted key

or wavy lines

express. For example, a straight solid bond in -OCH ₃ indicates that it is connected to other groups through the oxygen atom in this group;

The straight dashed bond in the group indicates that it is connected to other groups through the two ends of the nitrogen atom in the group;

The wavy line in the phenyl group indicates that it is connected to other groups through the 1 and 2 carbon atoms in the phenyl group;

Indicates that any linkable site on the piperidinyl group can be connected to other groups through a chemical bond, including at least

These 4 connection methods, even if the H atom is drawn on -N-, but

still includes

The group in this connection method is only that when one chemical bond is connected, the H at the site will be correspondingly reduced by one to become the corresponding monovalent piperidinyl group.

除非另有规定，术语“C _1-6烷基”用于表示直链或支链的由1至6个碳原子组成的饱和碳氢基团。所述C _1-6烷基包括C _1-5、C _1-4、C _1-3、C _1-2、C _2-6、C _2-4、C ₆和C ₅烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C _1-6烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)、丁基(包括n-丁基，异丁基，s-丁基和t-丁基)、戊基(包括n-戊基，异戊基和新戊基)、己基等。 Unless otherwise specified, the term "C _1-6 alkyl" is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C _1-6 alkyl includes C _1-5 , C _1-4 , C _1-3 , C _1-2 , C _2-6 , C _2-4 , C ₆ and C ₅ alkyl and the like; it can be Is monovalent (eg methyl), divalent (eg methylene) or polyvalent (eg methine). Examples of C _1-6 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl , s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl and the like.

除非另有规定，术语“C _1-3烷基”用于表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述C _1-3烷基包括C _1-2和C _2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C _1-3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。 Unless otherwise specified, the term "C _1-3 alkyl" is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C _1-3 alkyl group includes C _1-2 and C _2-3 alkyl groups, etc.; it can be monovalent (eg methyl), divalent (eg methylene) or multivalent (eg methine) . Examples of _C1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.

除非另有规定，术语“C _1-3烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C _1-3烷氧基包括C _1-2、C _2-3、C ₃和C ₂烷氧基等。C _1-3烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)等。 Unless otherwise specified, the term " _C1-3alkoxy " refers to those alkyl groups containing 1 to 3 carbon atoms attached to the remainder of the molecule through an oxygen atom. The C _1-3 alkoxy group includes C _1-2 , C _2-3 , C ₃ and C ₂ alkoxy and the like. Examples of C _1-3 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.

除非另有规定，术语“卤代素”或“卤素”本身或作为另一取代基的一部分表示氟、氯、溴或碘原子。Unless otherwise specified, the term "halogen" or "halogen" by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.

本申请的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本申请的实施例。The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by their combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include but are not limited to the examples of the present application.

本申请的化合物可以通过本领域技术人员所熟知的常规方法来确认结构，如果本申请涉及化合物的绝对构型，则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD)，把培养出的单晶用Bruker D8 venture衍射仪收集衍射强度数据，光源为CuKα辐射，扫描方式：

扫描，收集相关数据后，进一步采用直接法(Shelxs97)解析晶体结构，便可以确证绝对构型。 The structures of the compounds of the present application can be confirmed by conventional methods well known to those skilled in the art. If the present application relates to the absolute configuration of the compounds, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction method (SXRD), the cultured single crystal is collected by Bruker D8 venture diffractometer, the light source is CuKα radiation, and the scanning mode is:

After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.

本申请所使用的溶剂可经市售获得。The solvent used in this application is commercially available.

本申请采用下述缩略词：aq代表水；eq代表当量、等量；CDI代表羰基二咪唑；DCM代表二氯甲烷；PE代表石油醚；DMF代表N，N-二甲基甲酰胺；DMAc代表N，N-二甲基乙酰胺；PyBrOP代表三吡咯烷基溴化鏻六氟磷酸盐；DMSO代表二甲亚砜；EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；CBz代表苄氧羰基，是一种胺保护基团；BOC代表叔丁氧羰基，是一种胺保护基团；Pd ₂dba ₃代表三(二亚苄基丙酮)二钯，NaH代表氢化钠，SiO ₂代表硅胶，HOAc代表乙酸；r.t.代表室温；O/N代表过夜；THF代表四氢呋喃；Boc ₂O代表二-叔丁基二碳酸酯；TFA代表三氟乙酸；DIPEA代表二异丙基乙基胺；TsOH代表对甲苯磺酸；NCS代表1-氯吡咯烷-2,5-二酮。 The following abbreviations are used in this application: aq stands for water; eq stands for equivalent, equivalent; CDI stands for carbonyldiimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DMF stands for N,N-dimethylformamide; DMAc stands for N,N-dimethylacetamide; PyBrOP stands for tripyrrolidinophosphonium bromide hexafluorophosphate; DMSO stands for dimethyl sulfoxide; EtOAc stands for ethyl acetate; EtOH stands for ethanol; MeOH stands for methanol; CBz stands for benzyloxy Carbonyl, is an amine protecting group; BOC stands for tert-butoxycarbonyl, is an amine protecting group; Pd ₂ dba ₃ stands for tris(dibenzylideneacetone)dipalladium, NaH stands for sodium hydride, SiO ₂ stands for silica gel , HOAc represents acetic acid; rt represents room temperature; O/N represents overnight; THF represents tetrahydrofuran; Boc ₂ O represents di-tert-butyl dicarbonate; TFA represents trifluoroacetic acid; DIPEA represents diisopropylethylamine; TsOH represents p-toluenesulfonic acid; NCS stands for 1-chloropyrrolidine-2,5-dione.

具体实施方式Detailed ways

下面通过实施例对本申请进行详细描述，但并不意味着对本申请任何不利限制。本申请的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本申请的实施例。对本领域的技术人员而言，在不脱离本申请精神和范围的情况下针对本申请具体实施方式进行各种变化和改进将是显而易见的。The present application will be described in detail below through the examples, but it does not mean any unfavorable limitation to the present application. The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by their combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include but are not limited to the examples of the present application. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present application without departing from the spirit and scope of the present application.

中间体A的合成Synthesis of Intermediate A

第一步：first step:

向化合物A-1(5克)的叔戊醇(50毫升)溶液中加入化合物A-2(5克)，碳酸铯(10.27克)和BrettPhos Pd G3(1.43克)，反应体系用氮气置换3次，在氮气保护下，反应液在105摄氏度反应36小时。反应液垫硅藻土过滤，滤饼用乙酸乙酯(50毫升*3)淋洗，滤液减压浓缩得到残留物，残留物经柱层析纯化(SiO ₂，洗脱剂：石油醚：乙酸乙酯＝10：1～2：1)得到化合物A-3。LCMS(ESI)m/z:451.1(m+1) ⁺。第二步： To a solution of compound A-1 (5 g) in tert-amyl alcohol (50 mL) were added compound A-2 (5 g), cesium carbonate (10.27 g) and BrettPhos Pd G3 (1.43 g), and the reaction system was replaced with nitrogen for 3 Second, under nitrogen protection, the reaction solution was reacted at 105 degrees Celsius for 36 hours. The reaction solution was filtered through a pad of celite, the filter cake was rinsed with ethyl acetate (50 mL*3), the filtrate was concentrated under reduced pressure to obtain a residue, and the residue was purified by column chromatography (SiO ₂ , eluent: petroleum ether: acetic acid) ethyl ester = 10:1 to 2:1) to obtain compound A-3. LCMS (ESI) m/z: 451.1 (m+1) ⁺ . Step 2:

在0-10摄氏度下，向化合物A-3(14.75克，92.2％纯度)的二氯甲烷(150毫升)溶液中加入N-溴代琥珀酰亚胺(5.37克)，反应液在0-10摄氏度下反应0.5小时。反应液在0-10摄氏度下用饱和亚硫酸钠溶液(40毫升)淬灭，然后静置分层，有机相用饱和食盐水(40毫升)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到化合物A-4。LCMS(ESI)m/z:531.0(m+1) ⁺。 To a solution of compound A-3 (14.75 g, 92.2% purity) in dichloromethane (150 mL) was added N-bromosuccinimide (5.37 g) at 0-10 degrees Celsius, and the reaction solution was heated at 0-10 The reaction was carried out at a temperature of 0.5 hours. The reaction solution was quenched with saturated sodium sulfite solution (40 mL) at 0-10 degrees Celsius, then left to stand for layers, the organic phase was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the compound A-4. LCMS (ESI) m/z: 531.0 (m+1) ⁺ .

第三步：third step:

向化合物A-4(16克)的乙醇(160毫升)和水(40毫升)的混合溶液中加入铁粉(8.44克)和氯化铵(8.09克)，反应液在80摄氏度下反应2小时。反应液冷却至25摄氏度，然后垫硅藻土过滤，滤饼用甲醇(50毫升*3)淋洗，滤液减压浓缩得到残留物，残留物用水(50毫升)和乙酸乙酯(150毫升)稀释，有机相用饱和食盐水(50毫升)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到化合物A-5。LCMS(ESI)m/z:501.0(m+1) ⁺。 To a mixed solution of compound A-4 (16 g) in ethanol (160 ml) and water (40 ml), iron powder (8.44 g) and ammonium chloride (8.09 g) were added, and the reaction solution was reacted at 80 degrees Celsius for 2 hours . The reaction solution was cooled to 25 degrees Celsius, then filtered through celite, the filter cake was rinsed with methanol (50 mL*3), the filtrate was concentrated under reduced pressure to obtain a residue, the residue was water (50 mL) and ethyl acetate (150 mL) After dilution, the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound A-5. LCMS (ESI) m/z: 501.0 (m+1) ⁺ .

第四步：the fourth step:

向化合物A-5(15克)的N，N-二甲基甲酰胺(150毫升)溶液中加入锌粉(0.96克)，氰化锌(2.76克)，DPPF(3.33克)，Pd ₂(dba) ₃(2.75克)和溴化锌(338.27毫克)，然后将反应体系置换氮气三次，在氮气保护下，反应液在120摄氏度反应14小时。将反应液垫硅藻土过滤，滤饼用乙酸乙酯(50毫升*4)洗涤，滤液用水(600毫升)稀释，然后静置分层，有机相用饱和食盐水(100毫升)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到残留物，残留物经柱层析纯化(SiO ₂，洗脱剂：石油醚：乙酸乙酯＝3：1)得到化合物A-6。LCMS(ESI)m/z:446.0(m+1) ⁺。 To a solution of compound A-5 (15 g) in N,N-dimethylformamide (150 mL) was added zinc powder (0.96 g), zinc cyanide (2.76 g), DPPF (3.33 g), Pd ₂ ( dba) ₃ (2.75 g) and zinc bromide (338.27 mg), then the reaction system was replaced with nitrogen three times, and under nitrogen protection, the reaction solution was reacted at 120 degrees Celsius for 14 hours. The reaction solution was filtered through a pad of celite, the filter cake was washed with ethyl acetate (50 mL*4), the filtrate was diluted with water (600 mL), and then the layers were left to stand, and the organic phase was washed with saturated brine (100 mL). Dry over sodium sulfate, filter, and concentrate under reduced pressure to obtain a residue, which is purified by column chromatography (SiO ₂ , eluent: petroleum ether: ethyl acetate = 3:1) to obtain compound A-6. LCMS (ESI) m/z: 446.0 (m+1) ⁺ .

第五步：the fifth step:

在0-10摄氏度下，向化合物A-6(10.8克)的二甲基亚砜(108毫升)和水(27毫升)混合溶液中加入氢氧化钠(969.82毫克)和过氧化氢(28.01克，质量百分比：30％)，反应液在0-10摄氏度反应0.5小时，升温至25摄氏度反应1小时。反应液用饱和亚硫酸钠溶液(500毫升)淬灭，用乙酸乙酯(100毫升*2)萃取，合并有机相用无水硫酸钠干燥，过滤，减压浓缩得到残留物，残留物用柱层析纯化(SiO ₂，洗脱剂：石油醚：乙酸乙酯＝1：1～1：2)得到化合物A-7。LCMS(ESI)m/z:464.1(m+1) ⁺。 To a mixed solution of compound A-6 (10.8 g) in dimethyl sulfoxide (108 ml) and water (27 ml) at 0-10 degrees Celsius was added sodium hydroxide (969.82 mg) and hydrogen peroxide (28.01 g) , mass percentage: 30%), the reaction solution was reacted at 0-10 degrees Celsius for 0.5 hours, and then heated to 25 degrees Celsius and reacted for 1 hour. The reaction solution was quenched with saturated sodium sulfite solution (500 mL), extracted with ethyl acetate (100 mL*2), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was subjected to column chromatography Purification (SiO ₂ , eluent: petroleum ether: ethyl acetate=1:1-1:2) gave compound A-7. LCMS (ESI) m/z: 464.1 (m+1) ⁺ .

第六步：Step 6:

在0-10摄氏度下，向化合物A-7(8克)的无水四氢呋喃(80毫升)溶液中加入羰基二咪唑(5.60克)和氢化钠(2.07克，质量百分比：60％)，反应液在25摄氏度反应2小时。将反应液加入到1摩尔/升的盐酸(80毫升)中，然后用饱和碳酸氢钠溶液调节水相pH值到8，静置分层，水相用乙酸乙酯(50毫升)萃取，有机相用饱和食盐水(50毫升)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到中间体A。LCMS(ESI)m/z:490.1(m+1) ⁺。 To a solution of compound A-7 (8 g) in anhydrous tetrahydrofuran (80 mL) at 0-10 degrees Celsius, carbonyldiimidazole (5.60 g) and sodium hydride (2.07 g, mass percentage: 60%) were added, and the reaction solution React at 25 degrees Celsius for 2 hours. The reaction solution was added to 1 mol/L hydrochloric acid (80 mL), then the pH value of the aqueous phase was adjusted to 8 with saturated sodium bicarbonate solution, the layers were left to stand, and the aqueous phase was extracted with ethyl acetate (50 mL). The phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Intermediate A. LCMS (ESI) m/z: 490.1 (m+1) ⁺ .

实施例1Example 1

第一步：first step:

向中间体A(400毫克)的N,N-二甲基甲酰胺(3毫升)溶液中加入DIEA(184.39毫克)，PyBrOP(997.63毫克)和化合物1-1(664.29毫克)，反应液在50摄氏度下反应10小时。将反应液减压浓缩得到残余物，残余物通过制备的HPLC(柱型号：Phenomenex luna C18 250*50mm*15μm；流动相：[0.225％的甲酸水溶液-乙腈]；乙腈：34％-64％，10分钟)纯化，得到化合物1-2。LCMS(ESI)m/z:658.2.(M+1) ⁺。第二步： To a solution of Intermediate A (400 mg) in N,N-dimethylformamide (3 mL) was added DIEA (184.39 mg), PyBrOP (997.63 mg) and compound 1-1 (664.29 mg), and the reaction solution was heated at 50 The reaction was carried out at degrees Celsius for 10 hours. The reaction solution was concentrated under reduced pressure to obtain a residue, which was passed through preparative HPLC (column type: Phenomenex luna C18 250*50mm*15μm; mobile phase: [0.225% aqueous formic acid-acetonitrile]; acetonitrile: 34%-64%, 10 minutes) to obtain compound 1-2. LCMS (ESI) m/z: 658.2.(M+1) ⁺ . Step 2:

向化合物1-2(300毫克)的乙腈(3毫升)溶液中加入对甲苯磺酸(60.43毫克)和N-氯代丁二酰亚胺(93.72毫克)，在氮气保护下，反应液在60摄氏度下反应1小时。向反应液中加入饱和的亚硫酸钠水溶液(15毫升)，在0摄氏度搅拌10分钟。再用饱和的碳酸氢钠水溶液将反应体系pH值调节为8，最后用乙酸乙酯(30毫升*3)萃取，合并有机相用饱和食盐水(20毫升)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到化合物1-3。LCMS(ESI)m/z:728.1(M+3) ⁺。 To a solution of compound 1-2 (300 mg) in acetonitrile (3 mL) was added p-toluenesulfonic acid (60.43 mg) and N-chlorosuccinimide (93.72 mg), and the reaction solution was heated at 60 under nitrogen protection. The reaction was carried out for 1 hour at degrees Celsius. A saturated aqueous sodium sulfite solution (15 ml) was added to the reaction solution, followed by stirring at 0°C for 10 minutes. The pH value of the reaction system was adjusted to 8 with saturated aqueous sodium bicarbonate solution, and finally extracted with ethyl acetate (30 mL*3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. , the filtrate was concentrated under reduced pressure to obtain compound 1-3. LCMS (ESI) m/z: 728.1 (M+3) ⁺ .

第三步：third step:

向化合物1-3(310毫克)的二氯甲烷(4.5毫升)溶液中加入三氟乙酸(2.31克)，反应液在25摄氏度下反应20分钟。将反应液直接减压浓缩得到化合物1-4的三氟乙酸盐，粗品直接用于下一步反应。LCMS(ESI)m/z:626.0(M+1) ⁺。 To a solution of compound 1-3 (310 mg) in dichloromethane (4.5 ml) was added trifluoroacetic acid (2.31 g), and the reaction solution was reacted at 25 degrees Celsius for 20 minutes. The reaction solution was directly concentrated under reduced pressure to obtain the trifluoroacetate salt of compound 1-4, and the crude product was directly used in the next reaction. LCMS (ESI) m/z: 626.0 (M+1) ⁺ .

第四步：the fourth step:

向化合物1-4(400毫克)的四氢呋喃(5毫升)和水(2毫升)混合溶液中，依次加入碳酸钾(194.09毫克)和化合物1-5(63.55毫克)，反应液在20摄氏度下反应10分钟。反应液用乙酸乙酯(10毫升*2)萃取，有机相用饱和食盐水(10毫升)洗涤，无水硫酸钠干燥，过滤，减压浓缩，得到的残余物通过制备的HPLC(柱型号：Phenomenex luna C18 150*25mm*10μm；流动相：[0.225％的甲酸水溶液-乙腈]；梯度：乙腈，32％-62％，10分钟)纯化，得到化合物1.To a mixed solution of compound 1-4 (400 mg) in tetrahydrofuran (5 mL) and water (2 mL), potassium carbonate (194.09 mg) and compound 1-5 (63.55 mg) were sequentially added, and the reaction solution was reacted at 20 degrees Celsius 10 minutes. The reaction solution was extracted with ethyl acetate (10 mL*2), the organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was passed through preparative HPLC (column type: Phenomenex luna C18 150*25mm*10μm; mobile phase: [0.225% formic acid in water-acetonitrile]; gradient: acetonitrile, 32%-62%, 10 minutes) purification to give compound 1.

化合物1用制备SFC(柱型号：DAICEL CHIRALPAK IC(250mm*30mm*10μm)；流动相：甲醇(0.1％氨水)；梯度:二氧化碳临界流体50％-50％，2.5分钟；40分钟)分离纯化得到化合物1A和化合物1B。Compound 1 was isolated and purified by preparative SFC (column type: DAICEL CHIRALPAK IC (250mm*30mm*10μm); mobile phase: methanol (0.1% ammonia water); gradient: carbon dioxide critical fluid 50%-50%, 2.5 minutes; 40 minutes) Compound 1A and Compound 1B.

化合物1A和化合物1B经SFC检测【柱型号：Chiralpak IC-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为甲醇(0.05％二乙胺)；梯度(B％)：40％-40％】得到：化合物1A的保留时间为0.867min，e.e.值为100％；化合物1B的保留时间为1.760min，e.e.值为100％。化合物1A(保留时间＝0.867min)： ¹H NMR(400MHz,CHLOROFORM-d)δ8.46(br d,J＝4.89Hz,1H),7.40(d,J＝7.15Hz,1H),6.97-7.19(m,2H),6.62(dd,J＝16.75,10.48Hz,1H),6.29-6.50(m,1H),5.83(dd,J＝10.48,1.44Hz,1H),4.06-4.32(m,2H),3.94(br s,8H),2.57-2.78(m,1H),2.12(s,3H),1.22(br d,J＝6.65Hz,3H),1.13(br d,J＝6.65Hz,3H)；LCMS(ESI)m/z:680.1(M+1) ⁺。 Compound 1A and compound 1B were detected by SFC [column model: Chiralpak IC-3 50×4.6mm ID, 3μm; mobile phase: supercritical carbon dioxide in phase A, methanol (0.05% diethylamine) in phase B; gradient (B% ): 40%-40%] obtained: the retention time of compound 1A is 0.867min, and the ee value is 100%; the retention time of compound 1B is 1.760min, and the ee value is 100%. Compound 1A (retention time=0.867min): ¹ H NMR (400MHz, CHLOROFORM-d) δ 8.46 (br d, J=4.89Hz, 1H), 7.40 (d, J=7.15Hz, 1H), 6.97-7.19 (m, 2H), 6.62 (dd, J=16.75, 10.48Hz, 1H), 6.29-6.50 (m, 1H), 5.83 (dd, J=10.48, 1.44Hz, 1H), 4.06-4.32 (m, 2H ),3.94(br s,8H),2.57-2.78(m,1H),2.12(s,3H),1.22(br d,J=6.65Hz,3H),1.13(br d,J=6.65Hz,3H ); LCMS (ESI) m/z: 680.1 (M+1) ⁺ .

化合物1B(保留时间＝1.760min)： ¹H NMR(400MHz,CHLOROFORM-d)δ8.49(d,J＝4.89Hz,1H),7.41(d,J＝7.15Hz,1H),7.11(br d,J＝4.39Hz,1H),7.05(s,1H),6.63(dd,J＝16.75,10.35Hz,1H),6.37-6.47(m,1H),5.84(d,J＝11.54Hz,1H),4.06-4.29(m,2H),3.74-4.05(m,8H),2.72-2.95(m,1H),2.12(s,3H),1.28(br d,J＝6.40Hz,3H),1.20(br d,J＝6.53Hz,3H)；LCMS(ESI)m/z:680.2(M+1) ⁺。 Compound 1B (retention time=1.760 min): ¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.49 (d, J=4.89 Hz, 1H), 7.41 (d, J=7.15 Hz, 1H), 7.11 (br d ,J=4.39Hz,1H),7.05(s,1H),6.63(dd,J=16.75,10.35Hz,1H),6.37-6.47(m,1H),5.84(d,J=11.54Hz,1H) ,4.06-4.29(m,2H),3.74-4.05(m,8H),2.72-2.95(m,1H),2.12(s,3H),1.28(br d,J=6.40Hz,3H),1.20( br d, J=6.53 Hz, 3H); LCMS (ESI) m/z: 680.2(M+1) ⁺ .

实施例2Example 2

第一步：first step:

向中间体A(150毫克)的四氢呋喃(3毫升)溶液中加入DIEA(79.22毫克)，PyBrOP(429毫克)和化合物2-1(307毫克)，反应液在70摄氏度下反应10小时。将反应混合物减压浓缩，得到的残余物通过制备的HPLC(柱型号：Phenomenex luna C18(250*50mm*15μm)；流动相：[0.225％的甲酸水溶液-乙腈]；乙腈：35％-65％，10分钟)分离纯化得到化合物2-2。LCMS(ESI)m/z:672.3.(M+1) ⁺。 To a solution of Intermediate A (150 mg) in tetrahydrofuran (3 mL) were added DIEA (79.22 mg), PyBrOP (429 mg) and compound 2-1 (307 mg), and the reaction solution was reacted at 70°C for 10 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was passed through preparative HPLC (column type: Phenomenex luna C18 (250*50mm*15 μm); mobile phase: [0.225% formic acid in water-acetonitrile]; acetonitrile: 35%-65% , 10 minutes) separation and purification to obtain compound 2-2. LCMS (ESI) m/z: 672.3.(M+1) ⁺ .

第二步：Step 2:

将化合物2-2(50毫克)的乙腈(3毫升)溶液冷却到0摄氏度，在0摄氏度下将对甲苯磺酸(12.82毫克)和NCS(19.88毫克)加入到反应液中，在氮气保护下，反应液在60摄氏度下反应1小时。向反应液中加入饱和的亚硫酸钠水溶液(2毫升)，在0摄氏度下搅拌10分钟。再用饱和的碳酸氢钠水溶液将反应体系pH值调节为8，最后用乙酸乙酯(10毫升*3)萃取三次，有机相用无水硫酸钠干燥后过滤，滤液得到化合物2-3。LCMS(ESI)m/z:740.2(M+1) ⁺。 A solution of compound 2-2 (50 mg) in acetonitrile (3 mL) was cooled to 0 °C, and p-toluenesulfonic acid (12.82 mg) and NCS (19.88 mg) were added to the reaction solution at 0 °C under nitrogen protection. , the reaction solution was reacted at 60 degrees Celsius for 1 hour. A saturated aqueous sodium sulfite solution (2 mL) was added to the reaction solution, followed by stirring at 0°C for 10 minutes. The pH value of the reaction system was adjusted to 8 with saturated aqueous sodium bicarbonate solution, and finally extracted with ethyl acetate (10 mL*3) three times. The organic phase was dried with anhydrous sodium sulfate and filtered. The filtrate obtained compound 2-3. LCMS (ESI) m/z: 740.2 (M+1) ⁺ .

第三步：third step:

向化合物2-3(50毫克)的二氯甲烷(0.9毫升)溶液中加入三氟乙酸(462毫克)，反应液在25摄氏度下反应0.5小时。将反应液直接减压浓缩得到化合物2-4的三氟乙酸盐，粗品直接用于下一步反应。 LCMS(ESI)m/z:640.4(M+1) ⁺。 To a solution of compound 2-3 (50 mg) in dichloromethane (0.9 mL) was added trifluoroacetic acid (462 mg), and the reaction solution was reacted at 25 degrees Celsius for 0.5 hour. The reaction solution was directly concentrated under reduced pressure to obtain the trifluoroacetate salt of compound 2-4, and the crude product was directly used in the next reaction. LCMS (ESI) m/z: 640.4 (M+1) ⁺ .

第四步：the fourth step:

将化合物2-4(130毫克，三氟乙酸盐)溶解在四氢呋喃(3毫升)和水(1毫升)混合溶液中，依次加入碳酸钾(62.06毫克)和化合物1-5(20.32毫克)，反应液在25摄氏度下反应10分钟。反应液用乙酸乙酯(10毫升*2)萃取，有机相用饱和食盐水(10毫升)洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，得到的残余物通过制备的HPLC(柱型号：Phenomenex luna C18 150*25mm*10μm；流动相：[0.225％的甲酸水溶液-乙腈]；梯度：29％-59％，10分钟)纯化，得到的化合物2。Compound 2-4 (130 mg, trifluoroacetate) was dissolved in a mixed solution of tetrahydrofuran (3 mL) and water (1 mL), potassium carbonate (62.06 mg) and compound 1-5 (20.32 mg) were added sequentially, The reaction solution was reacted at 25 degrees Celsius for 10 minutes. The reaction solution was extracted with ethyl acetate (10 mL*2), the organic phase was washed once with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was passed through preparative HPLC (column type : Phenomenex luna C18 150*25mm*10μm; mobile phase: [0.225% aqueous formic acid-acetonitrile]; gradient: 29%-59%, 10 minutes) purification to obtain compound 2.

化合物2用制备SFC(柱型号：DAICEL CHIRALPAK IC(250mm*30mm*10μm)；流动相：甲醇(0.1％氨水)；梯度:二氧化碳临界流体45％-45％，2.0分钟；40分钟)分离纯化得到化合物2A和化合物2B。Compound 2 was isolated and purified by preparative SFC (column type: DAICEL CHIRALPAK IC (250mm*30mm*10μm); mobile phase: methanol (0.1% ammonia water); gradient: carbon dioxide critical fluid 45%-45%, 2.0 minutes; 40 minutes) Compound 2A and Compound 2B.

化合物2A和化合物2B经SFC检测【柱型号：Chiralpak IC-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为甲醇(0.05％二乙胺)；梯度(B％)：40％-40％】得到：化合物2A的保留时间为0.702min，e.e.值为100％；化合物2B的保留时间为1.158min，e.e.值为100％。Compound 2A and compound 2B were detected by SFC [column model: Chiralpak IC-3 50×4.6mm I.D., 3μm; mobile phase: phase A was supercritical carbon dioxide, phase B was methanol (0.05% diethylamine); gradient (B% ): 40%-40%] obtained: the retention time of compound 2A is 0.702min, and the e.e. value is 100%; the retention time of compound 2B is 1.158min, and the e.e. value is 100%.

化合物2A(保留时间＝0.702min)：LCMS(ESI)m/z:694.2(M+1) ⁺。 Compound 2A (retention time = 0.702 min): LCMS (ESI) m/z: 694.2 (M+1) ⁺ .

化合物2B(保留时间＝1.158min)：LCMS(ESI)m/z:694.2(M+1) ⁺。 Compound 2B (retention time = 1.158 min): LCMS (ESI) m/z: 694.2 (M+1) ⁺ .

实施例3Example 3

第一步：first step:

向中间体A(150毫克)的四氢呋喃(5毫升)溶液中加入DIPEA(79.22毫克)，PyBrOP(429毫克)和化合物3-1(328毫克)，反应液在70摄氏度下反应10小时。反应混合物减压浓缩，得到的残余物通过制备的HPLC(柱型号：Phenomenexluna C18 250*50mm*15μm；流动相：[0.225％的甲酸水溶液-乙腈]；梯度：35％-65％，10分钟)纯化，得到化合物3-2。LCMS(ESI)m/z:686.3.(M+1) ⁺。 To a solution of Intermediate A (150 mg) in tetrahydrofuran (5 mL) were added DIPEA (79.22 mg), PyBrOP (429 mg) and compound 3-1 (328 mg), and the reaction solution was reacted at 70 degrees Celsius for 10 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was passed through preparative HPLC (column type: Phenomenexluna C18 250*50mm*15μm; mobile phase: [0.225% formic acid in water-acetonitrile]; gradient: 35%-65% in 10 minutes) Purification gave compound 3-2. LCMS (ESI) m/z: 686.3.(M+1) ⁺ .

第二步：Step 2:

将化合物3-2(70毫克)的乙腈(3毫升)溶液冷却到0摄氏度，在0摄氏度下将对甲苯磺酸(17.58毫克)和NCS(27.26毫克)加入到反应液中，在氮气保护下，反应液在60摄氏度下反应1小时。向反应液中加入饱和的亚硫酸钠水溶液(2毫升)，在0摄氏度下搅拌10分钟。再用饱和的碳酸氢钠水溶液将反应体系pH值调节为8，用乙酸乙酯(20毫升*3)萃取，有机相用无水硫酸钠干燥后过滤，滤液得到化合物3-3。LCMS(ESI)m/z:754.4(M+1) ⁺。 A solution of compound 3-2 (70 mg) in acetonitrile (3 mL) was cooled to 0 °C, and p-toluenesulfonic acid (17.58 mg) and NCS (27.26 mg) were added to the reaction solution at 0 °C under nitrogen protection. , the reaction solution was reacted at 60 degrees Celsius for 1 hour. A saturated aqueous sodium sulfite solution (2 mL) was added to the reaction solution, followed by stirring at 0°C for 10 minutes. The pH value of the reaction system was adjusted to 8 with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (20 mL*3), the organic phase was dried with anhydrous sodium sulfate and filtered, and the filtrate obtained compound 3-3. LCMS (ESI) m/z: 754.4 (M+1) ⁺ .

第三步：third step:

向化合物3-3(80毫克)的二氯甲烷(1.2毫升)溶液中加入三氟乙酸(690.90毫克)，反应液在25 摄氏度下反应0.5小时。将反应液直接减压浓缩得到化合物3-4的三氟乙酸盐，粗品直接用于下一步反应。LCMS(ESI)m/z:654.4(M+1) ⁺。 To a solution of compound 3-3 (80 mg) in dichloromethane (1.2 ml) was added trifluoroacetic acid (690.90 mg), and the reaction solution was reacted at 25 degrees Celsius for 0.5 hour. The reaction solution was directly concentrated under reduced pressure to obtain the trifluoroacetate salt of compound 3-4, and the crude product was directly used in the next reaction. LCMS (ESI) m/z: 654.4 (M+1) ⁺ .

第四步：the fourth step:

向化合物3-4(180毫克)的四氢呋喃(4毫升)和水(1毫升)混合溶液中依次加入碳酸钾(84.57毫克)和化合物1-5(27.69毫克)，反应液在20摄氏度下反应10分钟。反应液用乙酸乙酯(10毫升*2)萃取两次，有机相用饱和食盐水(10毫升)洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，得到的残余物通过制备的HPLC(柱型号：Phenomenex luna C18 150*25mm*10μm；流动相：[0.225％的甲酸水溶液-乙腈]；梯度：31％-64％，10分钟)纯化，得到化合物3。To a mixed solution of compound 3-4 (180 mg) in tetrahydrofuran (4 mL) and water (1 mL), potassium carbonate (84.57 mg) and compound 1-5 (27.69 mg) were sequentially added, and the reaction solution was reacted at 20 degrees Celsius for 10 minute. The reaction solution was extracted twice with ethyl acetate (10 mL*2), the organic phase was washed once with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was subjected to preparative HPLC ( Column type: Phenomenex luna C18 150*25mm*10μm; mobile phase: [0.225% aqueous formic acid-acetonitrile]; gradient: 31%-64%, 10 minutes) purification to obtain compound 3.

化合物3用制备SFC(柱型号：DAICEL CHIRALPAK IC(250mm*30mm*10μm)；流动相：甲醇(0.1％氨水)；梯度:二氧化碳临界流体45％-45％，2.3分钟；40分钟)分离纯化得到化合物3A和化合物3B。Compound 3 was isolated and purified by preparative SFC (column type: DAICEL CHIRALPAK IC (250mm*30mm*10μm); mobile phase: methanol (0.1% ammonia water); gradient: carbon dioxide critical fluid 45%-45%, 2.3 minutes; 40 minutes) Compound 3A and Compound 3B.

化合物3A和化合物3B经SFC检测【柱型号：Chiralpak IC-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为甲醇(0.05％二乙胺)；梯度(B％)：5％-40％】得到：化合物3A的保留时间为2.104min，e.e.值为100％；化合物3B的保留时间为2.654min，e.e.值为100％。Compound 3A and compound 3B were detected by SFC [column model: Chiralpak IC-3 50×4.6mm I.D., 3μm; mobile phase: supercritical carbon dioxide in phase A, methanol (0.05% diethylamine) in phase B; gradient (B% ): 5%-40%] obtained: the retention time of compound 3A was 2.104 min, and the e.e. value was 100%; the retention time of compound 3B was 2.654 min, and the e.e. value was 100%.

化合物3A(保留时间＝2.104min)： ¹H NMR(400MHz,DMSO-d ₆)δ8.32(d,J＝4.77Hz,1H),7.66(d,J＝7.46Hz,1H),7.04-7.18(m,2H),6.82(ddd,J＝16.60,12.68,10.58Hz,1H),6.11-6.28(m,3H),5.67-5.81(m,1H),4.48-4.81(m,2H),3.71-4.22(m,4H),2.62-2.75(m,1H),2.03(d,J＝3.42Hz,3H),1.28-1.37(m,3H),1.15-1.27(m,3H),1.03(br d,J＝6.60Hz,3H),0.93(d,J＝6.60Hz,3H)；LCMS(ESI)m/z:708.2(M+1) ⁺。 Compound 3A (retention time=2.104 min): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.32 (d, J=4.77 Hz, 1H), 7.66 (d, J=7.46 Hz, 1H), 7.04-7.18 (m,2H),6.82(ddd,J=16.60,12.68,10.58Hz,1H),6.11-6.28(m,3H),5.67-5.81(m,1H),4.48-4.81(m,2H),3.71 -4.22(m, 4H), 2.62-2.75(m, 1H), 2.03(d, J=3.42Hz, 3H), 1.28-1.37(m, 3H), 1.15-1.27(m, 3H), 1.03(br d, J=6.60 Hz, 3H), 0.93 (d, J=6.60 Hz, 3H); LCMS (ESI) m/z: 708.2 (M+1) ⁺ .

化合物3B(保留时间＝2.654min)： ¹H NMR(400MHz,DMSO-d ₆)δ8.31(d,J＝4.77Hz,1H),7.68(d,J＝7.58Hz,1H),7.04-7.14(m,2H),6.84(dt,J＝16.60,10.84Hz,1H),6.13-6.28(m,3H),5.68-5.81(m,1H),4.45-4.83(m,2H),3.44-4.16(m,4H),2.82(dq,J＝13.36,6.63Hz,1H),1.95(s,3H),1.31-1.37(m,3H),1.17-1.26(m,3H),1.03(br d,J＝6.60Hz,6H)；LCMS(ESI)m/z:708.3(M+1) ⁺。 Compound 3B (retention time=2.654 min): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.31 (d, J=4.77 Hz, 1H), 7.68 (d, J=7.58 Hz, 1H), 7.04-7.14 (m,2H),6.84(dt,J=16.60,10.84Hz,1H),6.13-6.28(m,3H),5.68-5.81(m,1H),4.45-4.83(m,2H),3.44-4.16 (m, 4H), 2.82(dq, J=13.36, 6.63Hz, 1H), 1.95(s, 3H), 1.31-1.37(m, 3H), 1.17-1.26(m, 3H), 1.03(br d, J=6.60 Hz, 6H); LCMS (ESI) m/z: 708.3 (M+1) ⁺ .

实施例4Example 4

第一步：first step:

向中间体A(200毫克)的乙腈(4毫升)溶液中加入N-氯代丁二酰亚胺(109.14毫克)和一水合甲苯磺酸(105.55毫克)。反应液在60摄氏度下反应2小时，反应液后处理加入饱和亚硫酸钠水(5毫升)溶液淬灭，乙酸乙酯(10毫升)萃取，有机相浓缩得到化合物4-1。LCMS(ESI)m/z:558.3(M+1) ⁺。 To a solution of Intermediate A (200 mg) in acetonitrile (4 mL) was added N-chlorosuccinimide (109.14 mg) and toluenesulfonic acid monohydrate (105.55 mg). The reaction solution was reacted at 60 degrees Celsius for 2 hours, the reaction solution was post-treated by adding saturated aqueous sodium sulfite (5 mL) solution to quench, extracted with ethyl acetate (10 mL), and the organic phase was concentrated to obtain compound 4-1. LCMS (ESI) m/z: 558.3 (M+1) ⁺ .

第二步：Step 2:

向化合物4-1(280毫克)的四氢呋喃(5毫升)溶液中加入化合物4-2(537.38毫克)及PyBROP(935.18毫克)，N,N-二异丙基乙胺(129.63毫克)。反应液在60摄氏度下反应12小时，反应浓缩液得到化合物4-3。LCMS(ESI)m/z:754.5(M+1) ⁺。 To a solution of compound 4-1 (280 mg) in tetrahydrofuran (5 mL) were added compound 4-2 (537.38 mg) and PyBROP (935.18 mg), N,N-diisopropylethylamine (129.63 mg). The reaction solution was reacted at 60 degrees Celsius for 12 hours, and the reaction concentrate obtained compound 4-3. LCMS (ESI) m/z: 754.5 (M+1) ⁺ .

第三步：third step:

向化合物4-3(80毫克)的二氯甲烷(3毫升)溶液中加入三氟乙酸(10.88毫克)。反应液在25摄氏度下反应1小时，反应浓缩液得到化合物4-4。LCMS(ESI)m/z:654.3(M+1) ⁺。 To a solution of compound 4-3 (80 mg) in dichloromethane (3 mL) was added trifluoroacetic acid (10.88 mg). The reaction solution was reacted at 25 degrees Celsius for 1 hour, and the reaction concentrate obtained compound 4-4. LCMS (ESI) m/z: 654.3 (M+1) ⁺ .

第四步：the fourth step:

向化合物4-4(375毫克)的四氢呋喃：水＝3:1(4毫升:1毫升)溶液中加入碳酸钾(395.95毫克)及化合物1-5(25.93毫克)。反应液在0摄氏度下反应半小时，反应液浓缩得到残余物。残余物通过制备HPLC[柱型号：Unisil 3-100 C18 Ultra(150*50mm*3μm)，流动相：水(0.225％甲酸)-乙腈，梯度：40％-60％，10分钟]纯化，得到化合物4。To a solution of compound 4-4 (375 mg) in tetrahydrofuran:water=3:1 (4 mL:1 mL) were added potassium carbonate (395.95 mg) and compound 1-5 (25.93 mg). The reaction solution was reacted at 0 degrees Celsius for half an hour, and the reaction solution was concentrated to obtain a residue. The residue was purified by preparative HPLC [column model: Unisil 3-100 C18 Ultra (150*50mm*3μm), mobile phase: water (0.225% formic acid)-acetonitrile, gradient: 40%-60%, 10 minutes] to give the compound 4.

化合物4通过制备SFC(柱型号：DAICEL CHIRALPAK IC(250mm*30mm,10μm)，流动相：甲醇(0.1％氨水)；梯度：二氧化碳临界流体35％-35％，2.2分钟；40分钟)分离纯化得到化合物4A和化合物4B。Compound 4 was isolated and purified by preparative SFC (column type: DAICEL CHIRALPAK IC (250mm*30mm, 10μm), mobile phase: methanol (0.1% ammonia water); gradient: carbon dioxide critical fluid 35%-35%, 2.2 minutes; 40 minutes) Compound 4A and Compound 4B.

化合物4A和化合物4B经SFC检测【柱型号：Chiralpak IC-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为甲醇+乙腈(0.05％二乙胺)；梯度(B％)：40％甲醇+乙腈(0.05％二乙胺)】得到：化合物4A的保留时间为0.552min，e.e.值为100％；化合物4B的保留时间为0.807min，e.e.值为100％。Compound 4A and compound 4B were detected by SFC [column model: Chiralpak IC-3 50×4.6mm I.D., 3μm; mobile phase: supercritical carbon dioxide in phase A, methanol + acetonitrile (0.05% diethylamine) in phase B; gradient ( B%): 40% methanol + acetonitrile (0.05% diethylamine)] yielded: compound 4A with a retention time of 0.552 min and an e.e. value of 100%; compound 4B with a retention time of 0.807 min and an e.e. value of 100%.

化合物4A(保留时间＝0.552分钟)： ¹H NMR(400MHz,DMSO-d ₆)δ8.24-8.40(m,1H),7.66(d,J＝7.58Hz,1H),7.29(s,1H),7.09(d,J＝4.77Hz,1H),6.82(dd,J＝16.57,10.45Hz,1H),6.14-6.23(m,3H),5.68-5.84(m,1H),4.52-4.74(m,2H),4.28(br d,J＝13.82Hz,1H),4.12(br d,J＝14.18Hz,1H),3.46-3.57(m,2H),3.44-3.59(m,1H),2.08(s,3H),1.37(br dd,J＝11.74,7.09Hz,6H),1.01(d,J＝6.60Hz,3H),0.91(d,J＝6.72Hz,3H)。LCMS(ESI)m/z:708.3(M+1) ⁺。 Compound 4A (retention time = 0.552 min): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.24-8.40 (m, 1H), 7.66 (d, J=7.58 Hz, 1H), 7.29 (s, 1H) ,7.09(d,J＝4.77Hz,1H),6.82(dd,J＝16.57,10.45Hz,1H),6.14-6.23(m,3H),5.68-5.84(m,1H),4.52-4.74(m ,2H),4.28(br d,J=13.82Hz,1H),4.12(br d,J=14.18Hz,1H),3.46-3.57(m,2H),3.44-3.59(m,1H),2.08( s, 3H), 1.37 (br dd, J=11.74, 7.09 Hz, 6H), 1.01 (d, J=6.60 Hz, 3H), 0.91 (d, J=6.72 Hz, 3H). LCMS (ESI) m/z: 708.3 (M+1) ⁺ .

化合物4B(保留时间＝0.807分钟)： ¹H NMR(400MHz,DMSO-d ₆)δ8.31(d,J＝5.01Hz,1H),7.60-7.74(m,1H),7.27(s,1H),7.07(d,J＝5.14Hz,1H),6.72-6.90(m,1H),6.11-6.27(m,3H),5.71-5.81(m,1H),4.51-4.74(m,2H),4.06-4.28(m,2H),3.48-3.58(m,2H),2.92(br d,J＝6.72Hz,1H),1.89(s,3H),1.33-1.44(m,6H),0.98-1.10(m,6H)。LCMS(ESI)m/z:708.3(M+1) ⁺。 Compound 4B (retention time = 0.807 min): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.31 (d, J=5.01 Hz, 1H), 7.60-7.74 (m, 1H), 7.27 (s, 1H) ,7.07(d,J＝5.14Hz,1H),6.72-6.90(m,1H),6.11-6.27(m,3H),5.71-5.81(m,1H),4.51-4.74(m,2H),4.06 -4.28(m, 2H), 3.48-3.58(m, 2H), 2.92(br d, J=6.72Hz, 1H), 1.89(s, 3H), 1.33-1.44(m, 6H), 0.98-1.10( m, 6H). LCMS (ESI) m/z: 708.3 (M+1) ⁺ .

实施例5Example 5

第一步：first step:

向中间体A(500毫克)的四氢呋喃(10毫升)溶液中加入DIPEA(263.65毫克)，PyBrOP(1.90克)和化合物5-1(1.63克)，该反应在70摄氏度反应15小时。将反应混合物减压浓缩，得到的残余物通过制备的HPLC(柱型号：Phenomenex Synergi Max-RP(250*50mm*10μm)；流动相：[0.225％的甲酸水溶液-乙腈]；梯度：36％-66％，18分钟)纯化，得到化合物5-2。LCMS(ESI)m/z:672.5(M+1) ⁺。 To a solution of Intermediate A (500 mg) in tetrahydrofuran (10 mL) was added DIPEA (263.65 mg), PyBrOP (1.90 g) and compound 5-1 (1.63 g), and the reaction was carried out at 70 degrees Celsius for 15 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was passed through preparative HPLC (column type: Phenomenex Synergi Max-RP (250*50mm*10 μm); mobile phase: [0.225% formic acid in water-acetonitrile]; gradient: 36%- 66%, 18 minutes) to give compound 5-2. LCMS (ESI) m/z: 672.5 (M+1) ⁺ .

第二步：Step 2:

向化合物5-2(200毫克)的乙腈(6毫升)溶液中依次加入对甲苯磺酸(76.91毫克)和N-氯代丁二酰亚胺(79.52毫克)，在氮气保护下，混合物在60摄氏度反应1小时。向反应液中加入饱和的亚硫酸钠水溶液(20毫升)，用乙酸乙酯(20毫升*2)萃取，有机相用无水硫酸钠干燥后过滤，滤液减压浓缩得到化合物5-3。LCMS(ESI)m/z:740.3(M+1) ⁺。 To a solution of compound 5-2 (200 mg) in acetonitrile (6 mL) were sequentially added p-toluenesulfonic acid (76.91 mg) and N-chlorosuccinimide (79.52 mg), and the mixture was heated at 60 under nitrogen protection. Celsius for 1 hour. Saturated aqueous sodium sulfite solution (20 mL) was added to the reaction solution, extracted with ethyl acetate (20 mL*2), the organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain compound 5-3. LCMS (ESI) m/z: 740.3 (M+1) ⁺ .

第三步：third step:

向化合物5-3(200毫克)的二氯甲烷(1毫升)溶液中加入三氟乙酸(924毫克)，在氮气保护下，反应体系在10摄氏度反应0.5小时。反应液直接减压浓缩得到化合物5-4，粗品直接用于下一步反应。LCMS(ESI)m/z:640.4(M+1) ⁺。 To a solution of compound 5-3 (200 mg) in dichloromethane (1 mL) was added trifluoroacetic acid (924 mg), and the reaction system was reacted at 10 degrees Celsius for 0.5 hour under nitrogen protection. The reaction solution was directly concentrated under reduced pressure to obtain compound 5-4, and the crude product was directly used in the next reaction. LCMS (ESI) m/z: 640.4 (M+1) ⁺ .

第四步：the fourth step:

将化合物5-4(250毫克)溶解在四氢呋喃(4毫升)和水(1毫升)混合溶液中，依次加入碳酸钾(119.35毫克)和化合物1-5(26.05毫克)，该反应在10摄氏度反应30分钟。向反应混合物中加入饱和的碳酸氢钠水溶液(15毫升)，用乙酸乙酯(10毫升*3)萃取，有机相用饱和食盐水(20毫升)洗涤，无水硫酸钠干燥，过滤，减压浓缩，得到的残余物通过制备的HPLC(柱型号：Phenomenex luna C18(150*25mm*10μm)；流动相：[0.225％的甲酸水溶液-乙腈]；梯度：28％-58％，2分钟)纯化，得到化合物5。Compound 5-4 (250 mg) was dissolved in a mixed solution of tetrahydrofuran (4 mL) and water (1 mL), potassium carbonate (119.35 mg) and compound 1-5 (26.05 mg) were added sequentially, and the reaction was carried out at 10 degrees Celsius 30 minutes. Saturated aqueous sodium bicarbonate solution (15 mL) was added to the reaction mixture, extracted with ethyl acetate (10 mL*3), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and reduced in pressure. Concentrated and the resulting residue was purified by preparative HPLC (column type: Phenomenex luna C18 (150*25mm*10μm); mobile phase: [0.225% formic acid in water-acetonitrile]; gradient: 28%-58% in 2 minutes) , to obtain compound 5.

化合物5用制备SFC(柱型号：DAICEL CHIRALPAK IC(250mm*30mm*10μm)；流动相：甲醇(0.1％氨水)；梯度:二氧化碳临界流体40％-40％，2.6分钟；40分钟)分离纯化得到化合物5A和化合物5B。Compound 5 was isolated and purified by preparative SFC (column type: DAICEL CHIRALPAK IC (250mm*30mm*10μm); mobile phase: methanol (0.1% ammonia water); gradient: carbon dioxide critical fluid 40%-40%, 2.6 minutes; 40 minutes) Compound 5A and Compound 5B.

化合物5A和化合物5B经SFC检测【柱型号：Chiralpak IC-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为甲醇(0.05％二乙胺)；梯度(B％)：40％-40％】得到：化合物5A的保留时间为0.785min，e.e.值为99.30％；化合物5B的保留时间为1.090min，e.e.值为98.98％。Compound 5A and compound 5B were detected by SFC [column model: Chiralpak IC-3 50×4.6mm I.D., 3μm; mobile phase: supercritical carbon dioxide in phase A, methanol (0.05% diethylamine) in phase B; gradient (B% ): 40%-40%] obtained: the retention time of compound 5A is 0.785min, the e.e. value is 99.30%; the retention time of compound 5B is 1.090min, and the e.e. value is 98.98%.

化合物5A(保留时间＝0.785min)：LCMS(ESI)m/z:694.1(M+1) ⁺。 Compound 5A (retention time = 0.785 min): LCMS (ESI) m/z: 694.1 (M+1) ⁺ .

化合物5B(保留时间＝1.090min)：LCMS(ESI)m/z:694.1(M+1) ⁺。 Compound 5B (retention time = 1.090 min): LCMS (ESI) m/z: 694.1 (M+1) ⁺ .

实施例6Example 6

第一步:first step:

向化合物6-1(18.45克)中加入180毫升N，N-二甲基甲酰胺和化合物6-2(18.56克)，然后在0-10摄氏度下分批加入氢化钠(6.36克，质量百分比：60％)，加毕，反应液在0-10摄氏度下反应1小时。反应液在0-10摄氏度用饱和氯化铵溶液(200毫升)淬灭，然后加水(600毫升)和乙酸乙酯(400毫升)稀释，水相用乙酸乙酯(400毫升)萃取一次，合并有机相用水(200毫升)和饱和食盐水(200毫升)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到残留物，残留物通过柱层析纯化(SiO ₂，洗脱液：石油醚：乙酸乙酯＝3:1～1:1)得到化合物6-3。LCMS(ESI)m/z:313.0(m+1) ⁺。 To compound 6-1 (18.45 g) was added 180 ml of N,N-dimethylformamide and compound 6-2 (18.56 g), and then sodium hydride (6.36 g, mass percent) was added in batches at 0-10 degrees Celsius : 60%), after the addition, the reaction solution was reacted at 0-10 degrees Celsius for 1 hour. The reaction solution was quenched with saturated ammonium chloride solution (200 mL) at 0-10 degrees Celsius, then diluted with water (600 mL) and ethyl acetate (400 mL), the aqueous phase was extracted once with ethyl acetate (400 mL), and the combined The organic phase was washed with water (200 mL) and saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO ₂ , eluent: petroleum ether: ethyl acetate=3:1～1:1) to obtain compound 6-3. LCMS (ESI) m/z: 313.0 (m+1) ⁺ .

第二步:Step 2:

向化合物6-3(4.25克)的1,4-二氧六环(42.5毫升)溶液中加入化合物6-4(2.45克)，碳酸铯(8.85克)，Pd ₂(dba) ₃(1.24克)和Xantphos(1.57克)，反应体系用氮气置换3次，氮气保护下，反应液在100摄氏度反应12个小时。将反应液垫硅藻土过滤，滤饼每次用乙酸乙酯(30毫升*3)淋洗，滤液减压浓缩得到残留物，残留物通过柱层析纯化(SiO ₂，洗脱液：石油醚：乙酸乙酯＝3：1～1：1)得到化合物6-5。LCMS(ESI)m/z:383.2(m+1) ⁺。 To a solution of compound 6-3 (4.25 g) in 1,4-dioxane (42.5 mL) was added compound 6-4 (2.45 g), cesium carbonate (8.85 g), Pd ₂ (dba) ₃ (1.24 g ) and Xantphos (1.57 g), the reaction system was replaced with nitrogen three times, and the reaction solution was reacted at 100 degrees Celsius for 12 hours under nitrogen protection. The reaction solution was filtered through a pad of celite, the filter cake was rinsed with ethyl acetate (30 mL*3) each time, the filtrate was concentrated under reduced pressure to obtain a residue, and the residue was purified by column chromatography (SiO ₂ , eluent: petroleum ether:ethyl acetate=3:1～1:1) to obtain compound 6-5. LCMS (ESI) m/z: 383.2(m+1) ⁺ .

第三步:third step:

在0-10摄氏度下，向化合物6-5(8.3克)的四氢呋喃(160毫升)溶液中，加入N-溴代琥珀酰亚胺(3.86克)，反应液在25摄氏度反应1个小时。将反应液用饱和亚硫酸钠溶液(40毫升)淬灭，然后静置分层，水相用乙酸乙酯(20毫升)萃取，合并有机相用饱和食盐水(40毫升)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到残留物，残留物经柱层析纯化(洗脱剂：石油醚：乙酸乙酯＝3：1)得到化合物6-6。LCMS(ESI)m/z:463.0(m+3) ⁺。 N-bromosuccinimide (3.86 g) was added to a solution of compound 6-5 (8.3 g) in tetrahydrofuran (160 ml) at 0-10 degrees Celsius, and the reaction solution was reacted at 25 degrees Celsius for 1 hour. The reaction solution was quenched with saturated sodium sulfite solution (40 mL), then left to stand for separation, the aqueous phase was extracted with ethyl acetate (20 mL), the combined organic phases were washed with saturated brine (40 mL), and dried over anhydrous sodium sulfate. , filtered and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (eluent: petroleum ether: ethyl acetate=3:1) to obtain compound 6-6. LCMS (ESI) m/z: 463.0 (m+3) ⁺ .

第四步:the fourth step:

向化合物6-6(6.7克)的乙醇(90毫升)和水(30毫升)溶液中加入铁粉(4.06克)和氯化铵(3.88克，反应液在80摄氏度下反应2个小时。将反应液垫硅藻土过滤，滤饼用乙酸乙酯(30毫升*3)洗涤，滤液减压浓缩得到残留物，残留物用水(20毫升)和乙酸乙酯(100毫升)稀释，有机相用饱和食盐水(20毫升)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到残留物，残留物经柱层析纯化(洗脱剂：石油醚：乙酸乙酯＝2：1到1：1)得到化合物6-7。LCMS(ESI)m/z:433.3(m+3) ⁺。 To a solution of compound 6-6 (6.7 g) in ethanol (90 mL) and water (30 mL), iron powder (4.06 g) and ammonium chloride (3.88 g) were added, and the reaction solution was reacted at 80 degrees Celsius for 2 hours. The reaction solution was filtered through a pad of celite, the filter cake was washed with ethyl acetate (30 mL*3), the filtrate was concentrated under reduced pressure to obtain a residue, the residue was diluted with water (20 mL) and ethyl acetate (100 mL), and the organic phase was Washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 2:1 to 1:1 ) to give compound 6-7. LCMS (ESI) m/z: 433.3 (m+3) ⁺ .

第五步:the fifth step:

向化合物6-7(5.3克)中加入N，N-二甲基甲酰胺(50毫升)，然后加入锌粉(0.4克)，氰化锌(1.16克)，DPPF(1.36克)，Pd ₂(dba) ₃(1.13克)和溴化锌(138.37毫克)，然后将反应体系置换氮气三次，在氮气保护下，反应液在120摄氏度下反应12个小时。将反应液垫硅藻土过滤，滤饼用乙酸乙酯(30毫升*3)淋洗，滤液用水(200毫升)稀释，然后静置分层，水相用乙酸乙酯(50毫升)洗涤2次，合并有机相用饱和食盐水(50毫升)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到残留物，残留物经柱层析纯化(洗脱剂：石油醚：乙酸乙酯＝2：1到1：2)得到化合物6-8。LCMS(ESI)m/z:378.4(m+1) ⁺。 To compound 6-7 (5.3 g) was added N,N-dimethylformamide (50 mL), followed by zinc powder (0.4 g), zinc cyanide (1.16 g), DPPF (1.36 g), Pd ₂ (dba) ₃ (1.13 g) and zinc bromide (138.37 mg), then the reaction system was replaced with nitrogen three times, and the reaction solution was reacted at 120 degrees Celsius for 12 hours under nitrogen protection. The reaction solution was filtered through a pad of celite, the filter cake was rinsed with ethyl acetate (30 mL*3), the filtrate was diluted with water (200 mL), and the layers were left to stand, and the aqueous phase was washed with ethyl acetate (50 mL) for 2 The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 2 : 1 to 1: 2) to obtain compound 6-8. LCMS (ESI) m/z: 378.4 (m+1) ⁺ .

第六步:Step 6:

向化合物6-8(4.3克)中加入浓硫酸(43毫升，w％＝98％)，反应液在60摄氏度下反应5个小时。将反应液缓慢加入到冰水(200毫升)中，然后将67克氢氧化钠固体溶于200毫升水中，在0-10摄氏度，加入到上述混合物中，再用饱和碳酸氢钠溶液调节混合液的pH值到8，将混合液垫硅藻土过滤，滤饼用乙酸乙酯(50毫升*3)淋洗，滤液静置分层，水相用乙酸乙酯(50毫升)萃取，合并有机相用饱和食盐水(50毫升)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到残留物。将上述硅藻土滤饼每次用甲醇(50毫升)淋洗3次，滤液减压浓缩得到化合物6-9。LCMS(ESI)m/z:396.2(m+1) ⁺。 To compound 6-8 (4.3 g) was added concentrated sulfuric acid (43 ml, w%=98%), and the reaction solution was reacted at 60 degrees Celsius for 5 hours. The reaction solution was slowly added to ice water (200 mL), then 67 g of solid sodium hydroxide was dissolved in 200 mL of water, added to the above mixture at 0-10 degrees Celsius, and the mixture was adjusted with saturated sodium bicarbonate solution. The pH value reached 8, the mixture was filtered through a pad of celite, the filter cake was rinsed with ethyl acetate (50 mL*3), the filtrate was allowed to stand for separation, the aqueous phase was extracted with ethyl acetate (50 mL), and the organic The phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The diatomaceous earth filter cake was rinsed three times with methanol (50 mL) each time, and the filtrate was concentrated under reduced pressure to obtain compound 6-9. LCMS (ESI) m/z: 396.2 (m+1) ⁺ .

第七步:Step 7:

向化合物6-9(2.07克)的N，N-二甲基甲酰胺(40毫升)溶液中加入羰基二咪唑(2.55克)和氢化钠(628.12毫克，质量百分比：60％)，反应液在25摄氏度下反应0.5个小时。将4毫升浓盐酸用200毫升水稀释，将反应液缓慢加入到上述酸性溶液中，然后用饱和碳酸氢钠溶液调节水相pH到8，静置分层，水相用乙酸乙酯(100毫升*2)萃取，合并有机相用饱和食盐水(50毫升)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到化合物6-10。LCMS(ESI)m/z:422.2(m+1) ⁺。 To a solution of compound 6-9 (2.07 g) in N,N-dimethylformamide (40 mL) were added carbonyldiimidazole (2.55 g) and sodium hydride (628.12 mg, mass percentage: 60%), and the reaction solution was The reaction was carried out at 25 degrees Celsius for 0.5 hours. 4 ml of concentrated hydrochloric acid was diluted with 200 ml of water, the reaction solution was slowly added to the above-mentioned acidic solution, then the pH of the aqueous phase was adjusted to 8 with saturated sodium bicarbonate solution, the layers were allowed to stand, and the aqueous phase was mixed with ethyl acetate (100 ml) *2) Extraction, the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 6-10. LCMS (ESI) m/z: 422.2(m+1) ⁺ .

第八步:Step 8:

向化合物6-10(1.62克，3.84毫摩尔，1当量)的乙腈(32毫升)溶液中加入N-氯代琥珀酰亚胺(1.03克，7.69毫摩尔，2当量)和对甲苯磺酸(1.32克，7.69毫摩尔，2当量)，反应液在60摄氏度下反应2小时。反应液冷却至25℃，然后加入饱和亚硫酸钠(10毫升)水溶液淬灭反应，然后将反应液减压浓缩得到残留物，残留物用饱和碳酸氢钠溶液(40毫升)和乙酸乙酯(40毫升)稀释，水相用乙酸乙酯(40毫升)萃取，合并有机相用饱和食盐水(50毫升)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到残留物，残留物经制备HPLC纯化[柱型号:Phenomenex luna C18 150*40mm*15μm；流动相：[水(0.225％甲酸)–乙腈]；梯度：20％-50％，10分钟]得到化合物6-11。LCMS(ESI)m/z:490.1(m+1) ⁺。 To a solution of compound 6-10 (1.62 g, 3.84 mmol, 1 equiv) in acetonitrile (32 mL) was added N-chlorosuccinimide (1.03 g, 7.69 mmol, 2 equiv) and p-toluenesulfonic acid ( 1.32 g, 7.69 mmol, 2 equiv), the reaction solution was reacted at 60 degrees Celsius for 2 hours. The reaction solution was cooled to 25°C, then a saturated aqueous solution of sodium sulfite (10 mL) was added to quench the reaction, and then the reaction solution was concentrated under reduced pressure to obtain a residue, which was treated with saturated sodium bicarbonate solution (40 mL) and ethyl acetate (40 mL). ), the aqueous phase was extracted with ethyl acetate (40 mL), the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by preparative HPLC [ Column model: Phenomenex luna C18 150*40mm*15μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; gradient: 20%-50%, 10 minutes] to obtain compound 6-11. LCMS (ESI) m/z: 490.1 (m+1) ⁺ .

第九步:Step 9:

向化合物6-11(490毫克)的N，N-二甲基乙酰胺(10毫升)溶液中加入化合物2-1(1.60克)和PyBrOP(1.86克)，反应液在75摄氏度反应12小时，将反应液加到水(40毫升)中，然后用乙酸乙酯(20毫升*2)萃取，合并有机相用饱和食盐水(20毫升)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到残留物，残留物经制备HPLC纯化[柱型号:Phenomenex luna C18(250*70mm，10μm)；流动相：[水(0.225％甲酸)–乙腈]；梯度：30％-60％，20分钟]得到化合物6-12。LCMS(ESI)m/z:672.4(m+1) ⁺。 To a solution of compound 6-11 (490 mg) in N,N-dimethylacetamide (10 mL) was added compound 2-1 (1.60 g) and PyBrOP (1.86 g), and the reaction solution was reacted at 75 degrees Celsius for 12 hours, The reaction solution was added to water (40 mL), then extracted with ethyl acetate (20 mL*2), the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain The residue, which was purified by preparative HPLC [column model: Phenomenex luna C18 (250*70 mm, 10 μm); mobile phase: [water (0.225% formic acid)-acetonitrile]; gradient: 30%-60%, 20 minutes] gave Compounds 6-12. LCMS (ESI) m/z: 672.4 (m+1) ⁺ .

第十步:Step 10:

向化合物6-12(450毫克)的二氯甲烷(4.5毫升)溶液中加入三氟乙酸(2.31克)，反应液在25摄氏度反应半个小时。将反应液减压浓缩得到残留物，然后将残留物用饱和碳酸氢钠溶液(10毫升)和乙酸乙酯(10毫升)稀释，水相用乙酸乙酯(5毫升)萃取，合并有机相用饱和食盐水(5毫升)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到化合物6-13的三氟乙酸盐。LCMS(ESI)m/z:572.2(m+1) ⁺。 To a solution of compound 6-12 (450 mg) in dichloromethane (4.5 ml) was added trifluoroacetic acid (2.31 g), and the reaction solution was reacted at 25 degrees Celsius for half an hour. The reaction solution was concentrated under reduced pressure to obtain a residue, which was then diluted with saturated sodium bicarbonate solution (10 mL) and ethyl acetate (10 mL), the aqueous phase was extracted with ethyl acetate (5 mL), and the organic phases were combined and used Washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the trifluoroacetic acid salt of compound 6-13. LCMS (ESI) m/z: 572.2 (m+1) ⁺ .

第十一步:Step 11:

向化合物6-13(179毫克)的四氢呋喃(6毫升)和水(2毫升)溶液中加入碳酸钾(86.43毫克)和化合物1-5(28.30毫克)，反应液在25摄氏度反应0.5小时。将反应液减压浓缩得到残留物，然后将残留物用饱和食盐水(10毫升)和乙酸乙酯(20毫升)稀释，有机相用无水硫酸钠干燥，过滤，减压浓缩得到残留物，残留物经制备HPLC[柱型号：Phenomenex Synergi C18(150*25mm*10μm)；流动相：[水(0.225％甲酸)–乙腈]；梯度：15％-45％，10分钟]纯化，得到的化合物6。To a solution of compound 6-13 (179 mg) in tetrahydrofuran (6 mL) and water (2 mL) were added potassium carbonate (86.43 mg) and compound 1-5 (28.30 mg), and the reaction solution was reacted at 25°C for 0.5 hour. The reaction solution was concentrated under reduced pressure to obtain a residue, then the residue was diluted with saturated brine (10 mL) and ethyl acetate (20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, The residue was purified by preparative HPLC [column type: Phenomenex Synergi C18 (150*25mm*10μm); mobile phase: [water (0.225% formic acid)-acetonitrile]; gradient: 15%-45%, 10 minutes] to give the compound 6.

将化合物6通过制备SFC(柱型号：DAICEL CHIRALCEL OD(250mm*30mm,10μm)，流动相：乙醇(0.1％氨水)，梯度：二氧化碳临界流体45％-45％，45分钟，50分钟]分离得到化合物6A和6AM。Compound 6 was separated by preparative SFC (column type: DAICEL CHIRALCEL OD (250mm*30mm, 10μm), mobile phase: ethanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 45%-45%, 45 minutes, 50 minutes] Compounds 6A and 6AM.

将6AM再通过制备SFC(柱型号：Daicel ChiralPak IG(250*30mm，10μm)，流动相：乙醇(0.1％氨水)，梯度：二氧化碳临界流体40％-40％，4.8分钟，45分钟)分离纯化得到化合物6B和6BM。6AM was then separated and purified by preparative SFC (column type: Daicel ChiralPak IG (250*30mm, 10μm), mobile phase: ethanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 40%-40%, 4.8 minutes, 45 minutes) Compounds 6B and 6BM were obtained.

将6BM再通过制备SFC(柱型号：Daicel ChiralPak IG(250*30mm，10μm)，流动相：乙醇(0.1％氨水)，梯度：二氧化碳临界流体40％-40％，4.8分钟，45分钟)分离纯化得到化合物6C和化合物6D。6BM was then separated and purified by preparative SFC (column type: Daicel ChiralPak IG (250*30mm, 10μm), mobile phase: ethanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 40%-40%, 4.8 minutes, 45 minutes) Compound 6C and compound 6D are obtained.

化合物6A经SFC检测【柱型号：Chiralpak IJ-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为乙醇(0.05％二乙胺)；梯度(B％)：5％-40％】得到：化合物6A的保留时间为2.494min，e.e.值为96.34％。Compound 6A was detected by SFC [column type: Chiralpak IJ-3 50×4.6mm I.D., 3μm; mobile phase: phase A was supercritical carbon dioxide, phase B was ethanol (0.05% diethylamine); gradient (B%): 5 %-40%] obtained: the retention time of compound 6A was 2.494 min, and the e.e. value was 96.34%.

化合物6B经SFC检测【柱型号：Cellucoat 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为乙醇(0.05％二乙胺)；梯度(B％)：5％-40％】得到：化合物6B的保留时间为1.066min。Compound 6B was detected by SFC [column type: Cellucoat 50×4.6mm I.D., 3μm; mobile phase: phase A was supercritical carbon dioxide, phase B was ethanol (0.05% diethylamine); gradient (B%): 5%-40 %] obtained: the retention time of compound 6B was 1.066 min.

化合物6C和化合物6D经SFC检测【柱型号：Chiralpak OJ-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为甲醇(0.05％二乙胺)；梯度(B％)：5％-40％】得到：化合物6C的保留时间为1.368min，e.e.值为100％；化合物6D的保留时间为1.492min，e.e.值为100％。Compound 6C and compound 6D were detected by SFC [column model: Chiralpak OJ-3 50×4.6mm I.D., 3μm; mobile phase: supercritical carbon dioxide in phase A, methanol (0.05% diethylamine) in phase B; gradient (B% ): 5%-40%] obtained: the retention time of compound 6C was 1.368 min, and the e.e. value was 100%; the retention time of compound 6D was 1.492 min, and the e.e. value was 100%.

化合物6A(保留时间＝2.494min)： ¹H NMR(400MHz，CHLOROFORM-d)δ8.47(d，J＝4.9Hz，1H)，7.39(d，J＝7.1Hz，1H)，7.04(d，J＝4.8Hz，1H)，6.89(br d，J＝7.0Hz，1H)，6.62(br s，1H)，6.52-6.32(m，2H)，5.82(br d，J＝10.9Hz，1H)，5.11-4.45(m，2H)，4.43-4.12(m，1H)，3.93-3.42(m，3H)，3.31-2.86(m，1H)，2.83-2.60(m，1H)，2.15(br s，3H)，1.44(br s，3H)，1.24-1.10(m，6H)；LCMS(ESI)m/z:626.2(M+1) ⁺。 Compound 6A (retention time=2.494 min): ¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.47 (d, J=4.9 Hz, 1H), 7.39 (d, J=7.1 Hz, 1H), 7.04 (d, J=4.8Hz, 1H), 6.89 (br d, J=7.0Hz, 1H), 6.62 (br s, 1H), 6.52-6.32 (m, 2H), 5.82 (br d, J=10.9Hz, 1H) , 5.11-4.45(m, 2H), 4.43-4.12(m, 1H), 3.93-3.42(m, 3H), 3.31-2.86(m, 1H), 2.83-2.60(m, 1H), 2.15(br s , 3H), 1.44 (br s, 3H), 1.24-1.10 (m, 6H); LCMS (ESI) m/z: 626.2 (M+1) ⁺ .

化合物6B(保留时间＝1.606min)：LCMS(ESI)m/z:626.2(M+1) ⁺。 Compound 6B (retention time = 1.606 min): LCMS (ESI) m/z: 626.2 (M+1) ⁺ .

化合物6C(保留时间＝1.368min)： ¹H NMR(400MHz,CHLOROFORM-d)δ8.47(d，J＝4.9Hz，1H)，7.39(d，J＝7.2Hz，1H)，7.04(d，J＝4.9Hz，1H)，6.90(d，J＝7.5Hz，1H)，6.75-6.53(m，1H)，6.52-6.34(m，2H)，5.82(dd，J＝1.7，10.4Hz，1H)，5.05-4.15(m，3H)，3.94-3.38(m，3H)，3.32-2.95(m，1H)，2.80-2.54(m，1H)，2.16(s，3H)，1.54-1.36(m，3H)，1.24-1.08(m，6H)；LCMS(ESI)m/z:626.3(M+1) ⁺。 Compound 6C (retention time=1.368 min): ¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.47 (d, J=4.9 Hz, 1H), 7.39 (d, J=7.2 Hz, 1H), 7.04 (d, J=4.9Hz, 1H), 6.90 (d, J=7.5Hz, 1H), 6.75-6.53 (m, 1H), 6.52-6.34 (m, 2H), 5.82 (dd, J=1.7, 10.4Hz, 1H) ), 5.05-4.15(m, 3H), 3.94-3.38(m, 3H), 3.32-2.95(m, 1H), 2.80-2.54(m, 1H), 2.16(s, 3H), 1.54-1.36(m , 3H), 1.24-1.08 (m, 6H); LCMS (ESI) m/z: 626.3 (M+1) ⁺ .

化合物6D(保留时间＝1.492min)： ¹H NMR(400MHz,CHLOROFORM-d)δ8.47(d，J＝4.9Hz，1H)，7.39(d，J＝7.1Hz，1H)，7.04(d，J＝4.9Hz，1H)，6.89(s，1H)，6.75-6.53(m，1H)，6.51-6.28(m，2H)，5.82(dd，J＝1.5，10.5Hz，1H)，5.17-4.47(m，2H)，4.43-4.12(m，1H)，3.97-3.37(m，3H)，3.34-2.92(m，1H)，2.89-2.60(m，1H)，2.11(s，3H)，1.44(br s，3H)，1.29-1.13(m，6H)；LCMS(ESI)m/z:626.2(M+1) ⁺。 Compound 6D (retention time=1.492 min): ¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.47 (d, J=4.9 Hz, 1H), 7.39 (d, J=7.1 Hz, 1H), 7.04 (d, J=4.9Hz, 1H), 6.89 (s, 1H), 6.75-6.53 (m, 1H), 6.51-6.28 (m, 2H), 5.82 (dd, J=1.5, 10.5Hz, 1H), 5.17-4.47 (m, 2H), 4.43-4.12 (m, 1H), 3.97-3.37 (m, 3H), 3.34-2.92 (m, 1H), 2.89-2.60 (m, 1H), 2.11 (s, 3H), 1.44 (br s, 3H), 1.29-1.13 (m, 6H); LCMS (ESI) m/z: 626.2 (M+1) ⁺ .

实施例7Example 7

第一步：first step:

在0-10摄氏度下，向化合物7-1(8克)的二氯甲烷(80毫升)溶液中滴加化合物7-2(8.01克)，加毕，反应液25摄氏度下反应12小时。LCMS检测原料剩余，然后补加化合物7-2(3.34克)到反应体系中，在25摄氏度下反应12小时。反应液减压浓缩得到残留物，残留物用二氯甲烷(50毫升)和饱和碳酸氢钠水溶液(100毫升)稀释，静置分层，水相用二氯甲烷(50毫升)萃取，合并有机相用饱和食盐水(40毫升)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到化合物7-3。LCMS(ESI)m/z:264.3(m+1) ⁺。 Compound 7-2 (8.01 g) was added dropwise to a solution of compound 7-1 (8 g) in dichloromethane (80 mL) at 0-10 degrees Celsius, and the reaction solution was reacted at 25 degrees Celsius for 12 hours. The remaining raw materials were detected by LCMS, and then compound 7-2 (3.34 g) was added to the reaction system, and the reaction was carried out at 25 degrees Celsius for 12 hours. The reaction solution was concentrated under reduced pressure to obtain a residue. The residue was diluted with dichloromethane (50 mL) and saturated aqueous sodium bicarbonate solution (100 mL), and the layers were allowed to stand. The aqueous phase was extracted with dichloromethane (50 mL), and the organic The phase was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 7-3. LCMS (ESI) m/z: 264.3 (m+1) ⁺ .

第二步：Step 2:

向化合物7-3(14克)的乙腈(140毫升)溶液中加入碳酸铯(17.30克)，然后在0-10摄氏度加入化合物7-4(9.11克)，反应液在25摄氏度反应1小时。将反应液垫硅藻土过滤，滤饼每次用乙酸乙酯(30毫升*3)淋洗，然后将滤液减压浓缩得到化合物7-5。LCMS(ESI)m/z:385.8(m+1) ⁺。 To a solution of compound 7-3 (14 g) in acetonitrile (140 ml) was added cesium carbonate (17.30 g), then compound 7-4 (9.11 g) was added at 0-10 degrees Celsius, and the reaction solution was reacted at 25 degrees Celsius for 1 hour. The reaction solution was filtered through a pad of celite, the filter cake was rinsed with ethyl acetate (30 mL*3) each time, and then the filtrate was concentrated under reduced pressure to obtain compound 7-5. LCMS (ESI) m/z: 385.8 (m+1) ⁺ .

第三步：third step:

向化合物7-5(28克)的三氟乙醇(140毫升)溶液中加入三乙胺(14.69克)，反应液在80摄氏度反应12小时。将反应液减压浓缩得到残留物，然后将残留物用乙酸乙酯(150毫升)和水(100毫升)稀释，用1摩尔/升的盐酸水溶液调节水相pH值到1，然后静置分层，水相用乙酸乙酯(50毫升)萃取，合并有机相用无水硫酸钠干燥，过滤，减压浓缩得到化合物7-6。LCMS(ESI)m/z:354.0(m+1) ⁺。 To a solution of compound 7-5 (28 g) in trifluoroethanol (140 ml) was added triethylamine (14.69 g), and the reaction solution was reacted at 80 degrees Celsius for 12 hours. The reaction solution was concentrated under reduced pressure to obtain a residue, which was then diluted with ethyl acetate (150 mL) and water (100 mL), and the pH of the aqueous phase was adjusted to 1 with 1 mol/L aqueous hydrochloric acid solution, and then allowed to stand for fractionation. layer, the aqueous phase was extracted with ethyl acetate (50 mL), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 7-6. LCMS (ESI) m/z: 354.0 (m+1) ⁺ .

第四步：the fourth step:

向化合物7-6(18.3克)的叔丁醇(183毫升)溶液中加入4A分子筛(18.3克)和三乙胺(10.47克)，然后在80摄氏度搅拌2小时。将DPPA(15.99克,98％纯度)加入到反应体系中，反应液在80摄氏度反应1小时。将反应液过滤滤饼每次用乙酸乙酯(50毫升*3)洗涤，滤液减压浓缩得到残留物，残留物用10％柠檬酸溶液(150毫升)和乙酸乙酯(150毫升)稀释，水相用乙酸乙酯(100毫升)萃取，合并有机相用饱和食盐水(50升)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到化合物7-7。LCMS(ESI)m/z:369.2(m+1-56) ⁺。 To a solution of compound 7-6 (18.3 g) in t-butanol (183 ml) were added 4A molecular sieves (18.3 g) and triethylamine (10.47 g), followed by stirring at 80 degrees Celsius for 2 hours. DPPA (15.99 g, 98% purity) was added to the reaction system, and the reaction solution was reacted at 80 degrees Celsius for 1 hour. The filter cake of the reaction solution was washed with ethyl acetate (50 mL*3) each time, the filtrate was concentrated under reduced pressure to obtain a residue, and the residue was diluted with 10% citric acid solution (150 mL) and ethyl acetate (150 mL), The aqueous phase was extracted with ethyl acetate (100 mL), and the combined organic phases were washed with saturated brine (50 L), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 7-7. LCMS (ESI) m/z: 369.2 (m+1-56) ⁺ .

第五步：the fifth step:

向化合物7-7(28克)的甲醇(140毫升)溶液中加入盐酸甲醇溶液(4摩尔/升，140.00毫升)，反应液在40摄氏度反应2小时。将反应液减压浓缩得到残留物，将残留物用饱和碳酸氢钠溶液(200毫升)和乙酸乙酯(200毫升)稀释，有机相用饱和食盐水(100毫升)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到残留物，残留物通过柱层析纯化(SiO ₂,石油醚：乙酸乙酯＝4:1)得到化合物7-8。LCMS(ESI)m/z:325.0(m+1) ⁺。 To a methanol (140 mL) solution of compound 7-7 (28 g) was added a methanolic hydrochloric acid solution (4 mol/L, 140.00 mL), and the reaction solution was reacted at 40 degrees Celsius for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a residue. The residue was diluted with saturated sodium bicarbonate solution (200 mL) and ethyl acetate (200 mL). The organic phase was washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. , filtered and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO ₂ , petroleum ether:ethyl acetate=4:1) to obtain compound 7-8. LCMS (ESI) m/z: 325.0 (m+1) ⁺ .

第六步：Step 6:

向化合物7-8(4.35克)的叔戊醇(45毫升)溶液中加入化合物A-2(4.30克),碳酸铯(8.73克)和BrettPhos Pd(1.21克)，反应体系用氮气置换3次，并在氮气保护下，在100摄氏度反应12小时。将反应液垫硅藻土过滤，滤饼每次用乙酸乙酯(50毫升*3)洗涤，滤液减压浓缩得到残留物，残留物经柱层析纯化(SiO ₂,石油醚/乙酸乙酯＝10:1～5:1)得到化合物7-9。LCMS(ESI)m/z:458.3(m+1) ⁺。 To a solution of compound 7-8 (4.35 g) in tert-amyl alcohol (45 mL) were added compound A-2 (4.30 g), cesium carbonate (8.73 g) and BrettPhos Pd (1.21 g), and the reaction system was replaced with nitrogen 3 times , and reacted at 100 degrees Celsius for 12 hours under nitrogen protection. The reaction solution was filtered through a pad of celite, the filter cake was washed with ethyl acetate (50 mL*3) each time, the filtrate was concentrated under reduced pressure to obtain a residue, and the residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate) =10:1～5:1) to obtain compound 7-9. LCMS (ESI) m/z: 458.3 (m+1) ⁺ .

第七步：Step 7:

在0-10摄氏度下，向化合物7-9(4.52克)的二氯甲烷(45毫升)溶液中，加入N-溴代丁二酰亚胺(1.76克)，反应液在0-10摄氏度反应1小时，将反应液用饱和亚硫酸钠溶液(20毫升)淬灭，然后静置分层，有机相用饱和食盐水(20毫升)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到化合物7-10。LCMS(ESI)m/z:538.2(m+3) ⁺。 To a solution of compound 7-9 (4.52 g) in dichloromethane (45 ml) at 0-10 degrees Celsius, N-bromosuccinimide (1.76 g) was added, and the reaction solution was reacted at 0-10 degrees Celsius For 1 hour, the reaction solution was quenched with saturated sodium sulfite solution (20 mL), then allowed to stand for layers, the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 7- 10. LCMS (ESI) m/z: 538.2 (m+3) ⁺ .

第八步：Step 8:

向化合物7-10(4.83克)的N,N-二甲基甲酰胺(50毫升)溶液中加入锌粉(0.33克)，氰化锌(0.86克)，DPPF(997.78毫克)，Pd ₂(dba) ₃(824.06毫克)和溴化锌(101.33毫克)，然后将反应体系置换氮气三次，在氮气保护下，反应液在120摄氏度反应12小时。将反应液垫硅藻土过滤，滤饼用乙酸乙酯(30 毫升*3)洗涤，滤液用水(250毫升)稀释，然后静置分层，水相用乙酸乙酯(50毫升*2)洗涤，合并有机相用饱和食盐水(50毫升)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到残留物，残留物经柱层析纯化(洗脱剂：石油醚：乙酸乙酯＝5:1到3:1)得到化合物7-11。LCMS(ESI)m/z:483.2(m+1) ⁺。 To a solution of compound 7-10 (4.83 g) in N,N-dimethylformamide (50 mL) was added zinc powder (0.33 g), zinc cyanide (0.86 g), DPPF (997.78 mg), Pd ₂ ( dba) ₃ (824.06 mg) and zinc bromide (101.33 mg), then the reaction system was replaced with nitrogen three times, and under nitrogen protection, the reaction solution was reacted at 120 degrees Celsius for 12 hours. The reaction solution was filtered through a pad of celite, the filter cake was washed with ethyl acetate (30 mL*3), the filtrate was diluted with water (250 mL), then left to stand for separation, and the aqueous phase was washed with ethyl acetate (50 mL*2). , the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 5: 1 to 3:1) yields compound 7-11. LCMS (ESI) m/z: 483.2 (m+1) ⁺ .

第九步：Step 9:

向化合物7-11(2.48克)中加入浓硫酸(25毫升)，反应液在60摄氏度下反应12小时，将反应液缓慢加入到冰水(80毫升)中，然后将氢氧化钠固体(32克)溶于(100毫升)水中，然后在0-10摄氏度加入到上述混合物中，再用碳酸氢钠固体调节混合液的pH到8，将混合液垫硅藻土过滤，滤饼用乙酸乙酯(50毫升*2)洗涤，滤液静置分层，水相用乙酸乙酯(50毫升)萃取，合并有机相用饱和食盐水(50毫升)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到化合物7-12。LCMS(ESI)m/z:501.2(m+1) ⁺。 To compound 7-11 (2.48 g) was added concentrated sulfuric acid (25 mL), the reaction solution was reacted at 60 degrees Celsius for 12 hours, the reaction solution was slowly added to ice water (80 mL), and then solid sodium hydroxide (32 g) is dissolved in (100 ml) water, then added to the above mixture at 0-10 degrees Celsius, then the pH of the mixed solution is adjusted to 8 with solid sodium bicarbonate, the mixed solution is filtered through celite, and the filter cake is washed with ethyl acetate Ester (50 mL*2) was washed, the filtrate was left to stand for layers, the aqueous phase was extracted with ethyl acetate (50 mL), the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and reduced in pressure. Concentration gave compound 7-12. LCMS (ESI) m/z: 501.2 (m+1) ⁺ .

第十步：Step 10:

向化合物7-12(1.9克)的无水四氢呋喃(40毫升)溶液中加入羰基二咪唑(1.85克)和氢化钠(455.23毫克，质量百分比：60％)，反应液在25摄氏度下反应1小时，将浓盐酸(2毫升)用水(40毫升)稀释，将反应液缓慢加入到上述酸性溶液中，然后用饱和碳酸氢钠溶液(40毫升)中和，静置分层，水相用乙酸乙酯(40毫升)萃取，合并有机相用饱和食盐水(40毫升)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到化合物7-13。LCMS(ESI)m/z:527.2(m+1) ⁺。 To a solution of compound 7-12 (1.9 g) in anhydrous tetrahydrofuran (40 ml), carbonyldiimidazole (1.85 g) and sodium hydride (455.23 mg, mass percentage: 60%) were added, and the reaction solution was reacted at 25 degrees Celsius for 1 hour , concentrated hydrochloric acid (2 mL) was diluted with water (40 mL), the reaction solution was slowly added to the above acidic solution, then neutralized with saturated sodium bicarbonate solution (40 mL), left to stand for layers, and the aqueous phase was washed with ethyl acetate Ester (40 mL) was extracted, the combined organic phases were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 7-13. LCMS (ESI) m/z: 527.2 (m+1) ⁺ .

第十一步：Step 11:

向化合物7-13(500毫克)的四氢呋喃(5毫升)溶液中加入化合物1-1(1.77克)和PyBrOP(2.21克)，反应液在60摄氏度下反应12小时，将反应液过滤，滤饼用乙酸乙酯(5毫升*3)洗涤，滤液减压浓缩得到残留物，残留物经制备HPLC[柱型号:Phenomenex luna c18 250mm*100mm*10μm；流动相:[水(0.225％甲酸)–乙腈]；梯度:40％-60％，20分钟]纯化得到化合物7-14。LCMS(ESI)m/z:695.3(m+1) ⁺。 To a solution of compound 7-13 (500 mg) in tetrahydrofuran (5 mL) was added compound 1-1 (1.77 g) and PyBrOP (2.21 g), the reaction solution was reacted at 60 degrees Celsius for 12 hours, the reaction solution was filtered, and the filter cake was Washed with ethyl acetate (5 mL*3), the filtrate was concentrated under reduced pressure to obtain a residue, which was subjected to preparative HPLC [column model: Phenomenex luna c18 250mm*100mm*10μm; mobile phase: [water (0.225% formic acid)-acetonitrile] ]; Gradient: 40%-60%, 20 min] Purification gave compounds 7-14. LCMS (ESI) m/z: 695.3 (m+1) ⁺ .

第十二步：Step 12:

向化合物7-14(1.65克)的二氯甲烷(15毫升)溶液中加入三氟乙酸(7.70克)，反应液在25摄氏度下反应半小时，将反应液减压浓缩得到残留物，然后将残留物用饱和碳酸氢钠溶液(20毫升)和乙酸乙酯(40毫升)稀释，有机相用饱和食盐水(20毫升)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到化合物7-15的三氟乙酸盐。LCMS(ESI)m/z:595.1(m+1) ⁺。 To a solution of compound 7-14 (1.65 g) in dichloromethane (15 ml) was added trifluoroacetic acid (7.70 g), the reaction solution was reacted at 25 degrees Celsius for half an hour, the reaction solution was concentrated under reduced pressure to obtain a residue, and then The residue was diluted with saturated sodium bicarbonate solution (20 mL) and ethyl acetate (40 mL), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 7-15 of trifluoroacetate. LCMS (ESI) m/z: 595.1 (m+1) ⁺ .

第十三步：Step Thirteen:

在0-10摄氏度下，向化合物7-15(1.47克)的四氢呋喃(14毫升)和水(4毫升)溶液中加入碳酸钾(341.47毫克)，然后将化合物1-5溶于无水四氢呋喃(2毫升)中再加入到上述反应液中，反应体系在25℃反应半个小时。将反应液减压浓缩得到残留物，然后将残留物用饱和食盐水(20毫升)和乙酸乙酯(40毫升)稀释，有机相用无水硫酸钠干燥，过滤，减压浓缩得到残留物，残留物通过制备HPLC[柱型号:Phenomenex luna C18(150*40mm*15μm)；流动相:[水(0.225％甲酸)–乙腈]；乙腈％:25％-55％,10分钟]纯化，得到化合物7。LCMS(ESI)m/z:649.4(m+1) ⁺。 To a solution of compound 7-15 (1.47 g) in tetrahydrofuran (14 mL) and water (4 mL) was added potassium carbonate (341.47 mg) at 0-10 degrees Celsius, then compound 1-5 was dissolved in anhydrous tetrahydrofuran ( 2 ml) was added to the above reaction solution, and the reaction system was reacted at 25° C. for half an hour. The reaction solution was concentrated under reduced pressure to obtain a residue, then the residue was diluted with saturated brine (20 mL) and ethyl acetate (40 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, The residue was purified by preparative HPLC [column model: Phenomenex luna C18 (150*40mm*15μm); mobile phase: [water (0.225% formic acid) - acetonitrile]; % acetonitrile: 25%-55%, 10 minutes] to give the compound 7. LCMS (ESI) m/z: 649.4 (m+1) ⁺ .

实施例8Example 8

第一步：first step:

零下78摄氏度下，向化合物8-1(7.0克)的四氢呋喃(70毫升)溶液中加入正丁基锂(2.5摩尔/升，15.3毫升)，反应液在零下78摄氏度下搅拌1小时，然后将反应液倒入干冰中，反应液用1摩尔/升的盐酸酸化，然后用乙酸乙酯(150毫升*2)萃取，所得有机相经饱和食盐水(150毫升)洗涤后用无水硫酸钠干燥，减压浓缩得化合物8-2。粗品直接用于下一步。To a solution of compound 8-1 (7.0 g) in tetrahydrofuran (70 mL) was added n-butyllithium (2.5 mol/L, 15.3 mL) at minus 78 degrees Celsius, the reaction solution was stirred at minus 78 degrees Celsius for 1 hour, and then the The reaction solution was poured into dry ice, the reaction solution was acidified with 1 mol/L hydrochloric acid, and then extracted with ethyl acetate (150 mL*2). The obtained organic phase was washed with saturated brine (150 mL) and dried over anhydrous sodium sulfate. , and concentrated under reduced pressure to obtain compound 8-2. The crude product was used directly in the next step.

第二步：Step 2:

室温下向化合物8-2(8.5克)的叔丁醇(90毫升)溶液中加入4A分子筛(10.0克)和三乙胺(7.58克)，反应液在80摄氏度条件下搅拌1小时，然后加入叠氮磷酸二苯酯(10.82克)，反应液在80摄氏度条件下搅拌11小时，反应液过滤，滤饼用乙酸乙酯(200毫升*3)洗涤，滤液浓缩得残余物。残余物用乙酸乙酯(250毫升)稀释，经10％柠檬酸(200毫升*2)、饱和食盐水(250毫升)洗涤后用无水硫酸钠干燥，减压浓缩得化合物8-3。粗品直接用于下一步。4A molecular sieve (10.0 g) and triethylamine (7.58 g) were added to a solution of compound 8-2 (8.5 g) in tert-butanol (90 ml) at room temperature, the reaction solution was stirred at 80 degrees Celsius for 1 hour, and then added Diphenylphosphoryl azide (10.82 g), the reaction solution was stirred at 80°C for 11 hours, the reaction solution was filtered, the filter cake was washed with ethyl acetate (200 mL*3), and the filtrate was concentrated to obtain a residue. The residue was diluted with ethyl acetate (250 mL), washed with 10% citric acid (200 mL*2), saturated brine (250 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 8-3. The crude product was used directly in the next step.

第三步：third step:

室温下将化合物8-3(11.0克)溶于盐酸乙酸乙酯(4.0摩尔/升，110.0毫升)中，反应液在室温条件下搅拌0.5小时，反应液浓缩得中间体8-4。粗品直接用于下一步。Compound 8-3 (11.0 g) was dissolved in ethyl acetate hydrochloride (4.0 mol/L, 110.0 mL) at room temperature, the reaction solution was stirred at room temperature for 0.5 hours, and the reaction solution was concentrated to obtain intermediate 8-4. The crude product was used directly in the next step.

第四步：the fourth step:

室温下将化合物8-4(9.0克，盐酸盐)和化合物8-5(6.29克)溶于二氯甲烷(90毫升)中，反应液在室温条件下搅拌12小时，反应液浓缩得化合物8-6。粗品直接用于下一步。LCMS(ESI)m/z:298.0(M+1) ⁺。 Compound 8-4 (9.0 g, hydrochloride) and compound 8-5 (6.29 g) were dissolved in dichloromethane (90 mL) at room temperature, the reaction solution was stirred at room temperature for 12 hours, and the reaction solution was concentrated to obtain compound 8-6. The crude product was used directly in the next step. LCMS (ESI) m/z: 298.0 (M+1) ⁺ .

第五步：the fifth step:

室温下将化合物8-6(10.0克)，化合物8-7(5.92克)和碳酸铯(10.93.克)溶于乙腈(120毫升)中，反应液在室温条件下搅拌1小时，反应液倒入水(250毫升)中，然后用乙酸乙酯(250毫升*3)萃取，所得有机相经饱和食盐水(250毫升)洗涤后用无水硫酸钠干燥，减压浓缩得化合物8-8。粗品直接用于下一步。LCMS(ESI)m/z:420.0(M+1) ⁺。 Compound 8-6 (10.0 g), compound 8-7 (5.92 g) and cesium carbonate (10.93 g) were dissolved in acetonitrile (120 mL) at room temperature, the reaction solution was stirred at room temperature for 1 hour, and the reaction solution was poured It was poured into water (250 mL) and extracted with ethyl acetate (250 mL*3). The obtained organic phase was washed with saturated brine (250 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 8-8. The crude product was used directly in the next step. LCMS (ESI) m/z: 420.0 (M+1) ⁺ .

第六步：Step 6:

室温下将化合物8-8(14.0克)和三乙胺(6.74克)溶于三氟乙醇(140毫升)中，反应液在80摄氏度下搅拌12小时，反应液用1摩尔/升的盐酸(250毫升)酸化，然后用乙酸乙酯(250毫升*2)萃取，所得有机相经饱和食盐水(250毫升)洗涤后用无水硫酸钠干燥，减压浓缩得化合物8-9。粗品直接用于下一步。LCMS(ESI)m/z:388.0(M+1) ⁺。 Compound 8-8 (14.0 g) and triethylamine (6.74 g) were dissolved in trifluoroethanol (140 mL) at room temperature, the reaction solution was stirred at 80 degrees Celsius for 12 hours, and the reaction solution was added with 1 mol/L hydrochloric acid ( 250 mL) for acidification, then extracted with ethyl acetate (250 mL*2), the obtained organic phase was washed with saturated brine (250 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 8-9. The crude product was used directly in the next step. LCMS (ESI) m/z: 388.0 (M+1) ⁺ .

第七步：Step 7:

室温下向化合物8-9(13.0克)的叔丁醇(130毫升)溶液中加入

分子筛(13.0克)和三乙胺(6.78克)，反应液在80摄氏度搅拌1小时，然后加入叠氮磷酸二苯酯(9.68克)，反应液在80摄氏度搅拌11小时，反应液过滤，滤饼用乙酸乙酯(250毫升*3)洗涤，滤液浓缩得残余物。残余物用乙酸乙酯(250毫升)稀释，经10％柠檬酸(250毫升*2)、饱和食盐水(250毫升)洗涤后用无水硫酸钠干燥，减压浓缩得化合物8-10。产物无需纯化直接用于下一步。LCMS(ESI)m/z:403.1(M+1-56) ⁺。 To a solution of compound 8-9 (13.0 g) in t-butanol (130 mL) was added at room temperature

Molecular sieves (13.0 g) and triethylamine (6.78 g), the reaction solution was stirred at 80 degrees Celsius for 1 hour, then diphenylphosphoryl azide (9.68 g) was added, the reaction solution was stirred at 80 degrees Celsius for 11 hours, the reaction solution was filtered, filtered The cake was washed with ethyl acetate (250 mL*3), and the filtrate was concentrated to a residue. The residue was diluted with ethyl acetate (250 mL), washed with 10% citric acid (250 mL*2), saturated brine (250 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 8-10. The product was used in the next step without purification. LCMS (ESI) m/z: 403.1 (M+1-56) ⁺ .

第八步：Step 8:

室温下将化合物8-10(15.0克)溶于盐酸乙酸乙酯(4.0摩尔/升，100.0毫升)中，反应液在室温条件下搅拌0.5小时，反应液浓缩得残余物，残余物经反相色谱柱分离(柱型号:Welch Ultimate XB_C18(20-40μm；120A)，流动相:[水(0.05％甲酸)-乙腈]；梯度:15-70％，30分钟；70％，30分钟)得化合物8-11。 ¹H NMR(400MHz,DMSO-d ₆)δ8.47-8.37(m,1H),7.05-6.97(m,1H),6.59-6.50(m,1H),6.46-6.25 (m,2H)。LCMS(ESI)m/z:359.0(M+1) ⁺。 Compound 8-10 (15.0 g) was dissolved in ethyl acetate hydrochloride (4.0 mol/L, 100.0 mL) at room temperature, the reaction solution was stirred at room temperature for 0.5 hours, the reaction solution was concentrated to obtain a residue, and the residue was reversed Column separation (column model: Welch Ultimate XB_C18 (20-40μm; 120A), mobile phase: [water (0.05% formic acid)-acetonitrile]; gradient: 15-70%, 30 minutes; 70%, 30 minutes) to obtain the compound 8-11. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.47-8.37 (m, 1H), 7.05-6.97 (m, 1H), 6.59-6.50 (m, 1H), 6.46-6.25 (m, 2H). LCMS (ESI) m/z: 359.0 (M+1) ⁺ .

第九步：Step 9:

室温下向化合物8-11(2.5克)的叔戊醇(30毫升)溶液中加入化合物A-2(2.24克)，BrettPhos Pd G3(631.13毫克)和碳酸铯(4.54克)，反应液在105摄氏度，氮气保护条件下反应3小时，反应液过滤，滤饼用乙酸乙酯(150毫升*3)洗涤，滤液浓缩得残余物，残余物经反相色谱柱分离(柱型号:Welch Ultimate XB_C18 20-40μm；120A；流动相:[水(0.0 5％甲酸)-乙腈]；梯度:60％，10分钟)得化合物8-12。LCMS(ESI)m/z:492.1(M+1) ⁺。 To a solution of compound 8-11 (2.5 g) in tert-amyl alcohol (30 mL) was added compound A-2 (2.24 g), BrettPhos Pd G3 (631.13 mg) and cesium carbonate (4.54 g) at room temperature, and the reaction solution was heated at 105 Degree Celsius, reacted under nitrogen protection for 3 hours, the reaction solution was filtered, the filter cake was washed with ethyl acetate (150 ml * 3), the filtrate was concentrated to obtain a residue, and the residue was separated by a reversed-phase chromatographic column (column model: Welch Ultimate XB_C18 20 -40 μm; 120A; mobile phase: [water (0.05% formic acid)-acetonitrile]; gradient: 60%, 10 minutes) to give compound 8-12. LCMS (ESI) m/z: 492.1 (M+1) ⁺ .

第十步：Step 10:

在0摄氏度下，向化合物8-12(1.9克)的二氯甲烷(20毫升)溶液中加入N-溴代丁二酰亚胺(686.96毫克)，反应液在0摄氏度条件下搅拌0.5小时，反应液在0摄氏度下用饱和亚硫酸钠(20毫升)淬灭，经饱和食盐水(20毫升)洗涤后用无水硫酸钠干燥，减压浓缩得残余物，向残余物中加入甲醇(10毫升)，室温搅拌0.5小时，混合物过滤，滤饼干燥得到化合物8-13。LCMS(ESI)m/z:572.0(M+3) ⁺。 To a solution of compound 8-12 (1.9 g) in dichloromethane (20 mL) was added N-bromosuccinimide (686.96 mg) at 0 degrees Celsius, and the reaction solution was stirred at 0 degrees Celsius for 0.5 hours, The reaction solution was quenched with saturated sodium sulfite (20 mL) at 0°C, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue, to which was added methanol (10 mL) , stirred at room temperature for 0.5 hours, the mixture was filtered, and the filter cake was dried to obtain compound 8-13. LCMS (ESI) m/z: 572.0 (M+3) ⁺ .

第十一步：Step 11:

室温下向化合物8-13(0.8克)的N,N-二甲基甲酰胺(5毫升)溶液中加入锌粉(54.95毫克)，氰化锌(131.58毫克)，溴化锌(15.77毫克)，1,1’-双(二苯基膦)二茂铁(155.30毫克)和三(二亚苄基丙酮)二钯(128.26毫克)，反应液在120摄氏度，氮气保护条件下搅拌2小时，反应液过滤，滤饼用乙酸乙酯(150毫升*3)洗涤，滤液浓缩得残余物，向残余物中加入甲醇(10毫升)，室温搅拌0.5小时，混合物过滤，滤饼干燥得到化合物8-14。LCMS(ESI)m/z:517.3(M+1) ⁺。 To a solution of compound 8-13 (0.8 g) in N,N-dimethylformamide (5 mL) at room temperature were added zinc powder (54.95 mg), zinc cyanide (131.58 mg), zinc bromide (15.77 mg) , 1,1'-bis(diphenylphosphino)ferrocene (155.30 mg) and tris(dibenzylideneacetone)dipalladium (128.26 mg), the reaction solution was stirred at 120 degrees Celsius under nitrogen protection for 2 hours, The reaction solution was filtered, the filter cake was washed with ethyl acetate (150 mL*3), the filtrate was concentrated to obtain a residue, methanol (10 mL) was added to the residue, and the mixture was stirred at room temperature for 0.5 hours. The mixture was filtered, and the filter cake was dried to obtain compound 8- 14. LCMS (ESI) m/z: 517.3 (M+1) ⁺ .

第十二步：Step 12:

室温下将化合物8-14(0.6克)溶于浓硫酸(12.0毫升)中，反应液在60摄氏度下搅拌4小时，反应液缓慢滴加到2摩尔/升的氢氧化钠(250毫升)水溶液中，然后用乙酸乙酯(250毫升*2)萃取，所得有机相经饱和食盐水(250毫升)洗涤后用无水硫酸钠干燥，减压浓缩得化合物8-15。产物无需纯化直接用于下一步。LCMS(ESI)m/z:535.3(M+1) ⁺。 Compound 8-14 (0.6 g) was dissolved in concentrated sulfuric acid (12.0 mL) at room temperature, the reaction solution was stirred at 60 degrees Celsius for 4 hours, and the reaction solution was slowly added dropwise to a 2 mol/L aqueous solution of sodium hydroxide (250 mL). , and then extracted with ethyl acetate (250 mL*2), the obtained organic phase was washed with saturated brine (250 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 8-15. The product was used in the next step without purification. LCMS (ESI) m/z: 535.3 (M+1) ⁺ .

第十三步：Step Thirteen:

室温下向化合物8-15(0.5克)的四氢呋喃(25毫升)溶液中加入氢化钠(186.80毫克，质量百分比：60％)和1,1-羰基二咪唑(454.37毫克)，反应液在室温条件下搅拌0.5小时反应液倒入饱和氯化铵(150毫升)水溶液中淬灭，然后用乙酸乙酯(150毫升*3)萃取，所得有机相经饱和食盐水(150毫升)洗涤后用无水硫酸钠干燥，减压浓缩得残余物，向残余物中加入甲醇(5毫升)，室温搅拌0.5小时，混合物过滤，滤饼干燥得到化合物8-16。LCMS(ESI)m/z:561.3(M+1) ⁺。 To a solution of compound 8-15 (0.5 g) in tetrahydrofuran (25 mL) was added sodium hydride (186.80 mg, mass percentage: 60%) and 1,1-carbonyldiimidazole (454.37 mg) at room temperature, and the reaction solution was kept at room temperature. The reaction solution was stirred for 0.5 hours and poured into saturated aqueous ammonium chloride (150 mL) to quench, and then extracted with ethyl acetate (150 mL*3). The obtained organic phase was washed with saturated brine (150 mL) and then washed with anhydrous It was dried over sodium sulfate and concentrated under reduced pressure to obtain a residue. Methanol (5 mL) was added to the residue, and the mixture was stirred at room temperature for 0.5 hours. The mixture was filtered, and the filter cake was dried to obtain compound 8-16. LCMS (ESI) m/z: 561.3 (M+1) ⁺ .

第十四步：Step 14:

室温下向化合物8-16(0.3克)和化合物1-1(497.74毫克)的四氢呋喃(10毫升)溶液中加入N,N-二异丙基乙胺(345.39毫克)和三吡咯烷基溴化鏻六氟磷酸盐(1.25克)，反应液在80摄氏度下搅拌24小时，反应液倒入水(150毫升)中，然后用乙酸乙酯(150毫升*3)萃取，所得有机相经饱和食盐水(150毫升)洗涤后用无水硫酸钠干燥，减压浓缩得化合物8-17。产物无需纯化直接用于下一步。LCMS(ESI)m/z:729.4(M+1) ⁺。 To a solution of compound 8-16 (0.3 g) and compound 1-1 (497.74 mg) in tetrahydrofuran (10 mL) were added N,N-diisopropylethylamine (345.39 mg) and tripyrrolidinyl bromide at room temperature Phosphonium hexafluorophosphate (1.25 g), the reaction solution was stirred at 80 degrees Celsius for 24 hours, the reaction solution was poured into water (150 mL), and then extracted with ethyl acetate (150 mL*3), and the obtained organic phase was saturated with common salt Washed with water (150 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 8-17. The product was used in the next step without purification. LCMS (ESI) m/z: 729.4 (M+1) ⁺ .

第十五步：Step 15:

室温下向化合物8-17(0.3克)的二氯甲烷(9毫升)溶液中加入三氟乙酸(13.86克)，反应液在室温条件下搅拌0.5小时，反应液浓缩得化合物8-18的三氟乙酸盐。产物无需纯化直接用于下一步。LCMS(ESI)m/z:629.4(M+1) ⁺。 To a solution of compound 8-17 (0.3 g) in dichloromethane (9 mL) was added trifluoroacetic acid (13.86 g) at room temperature, the reaction solution was stirred at room temperature for 0.5 hours, and the reaction solution was concentrated to obtain trifluoroacetic acid of compound 8-18. Fluoroacetate. The product was used in the next step without purification. LCMS (ESI) m/z: 629.4 (M+1) ⁺ .

第十六步：Step 16:

在0摄氏度下，向化合物8-18(0.2克)的四氢呋喃(10毫升)和水(2毫升)溶液中加入碳酸钾(219.58毫克)，然后加入化合物1-5(28.76毫克)，反应液在0摄氏度下搅拌0.5小时，反应液倒入水(50毫升)中，然后用乙酸乙酯(50毫升*3)萃取，所得有机相经饱和食盐水(50毫升)洗涤后用无水硫酸钠干燥，减压浓缩得残余物，残余物经制备色谱柱分离(柱型号:Phenomenex Gemini-NX C18(75*30mm*3μm)，流动相:[水(0.225％甲酸)-乙腈]；乙腈％:32％-62％，7分钟)纯化，得到的化合物8。To a solution of compound 8-18 (0.2 g) in tetrahydrofuran (10 mL) and water (2 mL) at 0 degrees Celsius was added potassium carbonate (219.58 mg), followed by compound 1-5 (28.76 mg), and the reaction solution was Stir at 0 degrees Celsius for 0.5 hours, pour the reaction solution into water (50 mL), and then extract with ethyl acetate (50 mL*3). The resulting organic phase is washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. , concentrated under reduced pressure to obtain the residue, the residue was separated by preparative chromatography column (column model: Phenomenex Gemini-NX C18 (75*30mm*3μm), mobile phase: [water (0.225% formic acid)-acetonitrile]; acetonitrile%: 32 %-62%, 7 min) to give compound 8.

化合物8再通过制备SFC(柱型号:DAICEL CHIRALCEL OD(250mm*30mm,10um；流动相:[甲醇(0.1％氨水)]；梯度：二氧化碳临界流体:30％-30％，3.3分钟,50分钟)后都经制备色谱柱分离(柱型:Phenomenex Gemini-NX C18 75*30mm*3μm；流动相:[水(0.225％甲酸)-乙腈]；乙腈％:32％-62％，7分钟)得化合物8A和化合物8B。Compound 8 was then passed through preparative SFC (column model: DAICEL CHIRALCEL OD (250mm*30mm, 10um; mobile phase: [methanol (0.1% ammonia water)]; gradient: carbon dioxide critical fluid: 30%-30%, 3.3 minutes, 50 minutes) All were separated by preparative chromatographic column (column type: Phenomenex Gemini-NX C18 75*30mm*3μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; acetonitrile%: 32%-62%, 7 minutes) to obtain the compound 8A and Compound 8B.

化合物8A(保留时间＝1.688min)： ¹H NMR(400MHz,DMSO-d ₆)δ8.51-8.37(m,1H),8.37-8.30(m,1H),7.41-7.28(m,1H),7.16-7.05(m,1H),6.92-6.77(m,1H),6.28-6.12(m,1H),5.83-5.69(m,1H),4.02-3.66(m,9H),2.02-1.96(m,3H),1.07-1.04(m,3H),1.01-0.95(m,3H)。LCMS(ESI)m/z:683.4(M+1) ⁺。 Compound 8A (retention time=1.688 min): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.51-8.37 (m, 1H), 8.37-8.30 (m, 1H), 7.41-7.28 (m, 1H), 7.16-7.05(m, 1H), 6.92-6.77(m, 1H), 6.28-6.12(m, 1H), 5.83-5.69(m, 1H), 4.02-3.66(m, 9H), 2.02-1.96(m , 3H), 1.07-1.04 (m, 3H), 1.01-0.95 (m, 3H). LCMS (ESI) m/z: 683.4 (M+1) ⁺ .

化合物8B(保留时间＝1.808min)： ¹H NMR(400MHz,DMSO-d ₆)δ8.49-8.38(m,1H),8.36-8.31(m,1H),7.42-7.28(m,1H),7.17-7.04(m,1H),6.92-6.76(m,1H),6.28-6.08(m,1H),5.84-5.63(m,1H),4.03-3.68(m,9H),2.04-1.94(m,3H),1.12-1.03(m,3H),1.01-0.93(m,3H)。LCMS(ESI)m/z:683.4(M+1) ⁺。 Compound 8B (retention time = 1.808 min): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.49-8.38 (m, 1H), 8.36-8.31 (m, 1H), 7.42-7.28 (m, 1H), 7.17-7.04(m, 1H), 6.92-6.76(m, 1H), 6.28-6.08(m, 1H), 5.84-5.63(m, 1H), 4.03-3.68(m, 9H), 2.04-1.94(m , 3H), 1.12-1.03 (m, 3H), 1.01-0.93 (m, 3H). LCMS (ESI) m/z: 683.4 (M+1) ⁺ .

实施例9Example 9

第一步：first step:

将中间体A(2.5克)的甲酸(12.5毫升)溶液中加热到100摄氏度，在100摄氏度反应2小时。在15摄氏度将反应混合物倒入饱和的碳酸氢钠水溶液(100毫升)中，然后用乙酸乙酯(10毫升*3)萃取，合并有机相用饱和的食盐水(10毫升)洗涤，无水硫酸钠干燥，过滤。滤液减压浓缩，得到化合物9-1。LCMS(ESI)m/z:518.2(M+1) ⁺。 A solution of Intermediate A (2.5 g) in formic acid (12.5 mL) was heated to 100 degrees Celsius and reacted at 100 degrees Celsius for 2 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution (100 mL) at 15 degrees Celsius, then extracted with ethyl acetate (10 mL*3), the combined organic phases were washed with saturated brine (10 mL), and anhydrous sulfuric acid Dry over sodium and filter. The filtrate was concentrated under reduced pressure to obtain compound 9-1. LCMS (ESI) m/z: 518.2 (M+1) ⁺ .

第二步：Step 2:

在0摄氏度下向化合物9-1(2.0克)的四氢呋喃(50毫升)溶液中滴加三氟化硼***溶液(1摩尔/升,30.92毫升)，加毕，在0摄氏度反应1小时。将水(30毫升)滴加到反应混合物中。然后用乙酸乙酯(100毫升)萃取，有机相用饱和的食盐水(30毫升)洗涤，无水硫酸钠干燥，过滤。滤液减压浓缩，得到化合物9-2。LCMS(ESI)m/z:504.0(M+1) ⁺。 To a solution of compound 9-1 (2.0 g) in tetrahydrofuran (50 mL) was added dropwise boron trifluoride ether solution (1 mol/L, 30.92 mL) at 0 degrees Celsius, the addition was completed, and the reaction was carried out at 0 degrees Celsius for 1 hour. Water (30 mL) was added dropwise to the reaction mixture. Then extracted with ethyl acetate (100 mL), the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain compound 9-2. LCMS (ESI) m/z: 504.0 (M+1) ⁺ .

第三步：third step:

向化合物9-2(1.6克)的四氢呋喃(100毫升)溶液中加入PyBrOP(5.93克)和化合物1-1(4.74克)，该反应在70摄氏度反应12小时。将反应液过滤，滤液减压浓缩，得到的残余物通过制备的HPLC(柱型号：Phenomenex luna C18(250*70mm*10μm)；流动相：[0.225％的甲酸水溶液-乙腈]；乙腈：30％-60％，22分钟)纯化，得到的产品用制备SFC(柱型号：DAICEL CHIRALPAK IC(250mm*30mm*10μm)；流动相：甲醇(0.1％氨水)；梯度：二氧化碳临界流体45％-45％，2.5分钟；50分钟)分离纯化得到化合物9-3A(保留时间＝1.851min)和化合物9-3B(保留时间＝2.297min)。To a solution of compound 9-2 (1.6 g) in tetrahydrofuran (100 mL) were added PyBrOP (5.93 g) and compound 1-1 (4.74 g), and the reaction was carried out at 70 degrees Celsius for 12 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was passed through preparative HPLC (column type: Phenomenex luna C18 (250*70mm*10μm); mobile phase: [0.225% aqueous formic acid-acetonitrile]; acetonitrile: 30% -60%, 22 minutes) purification, the obtained product was purified by preparative SFC (column model: DAICEL CHIRALPAK IC (250mm*30mm*10μm); mobile phase: methanol (0.1% ammonia water); gradient: carbon dioxide critical fluid 45%-45% , 2.5 minutes; 50 minutes) separation and purification to obtain compound 9-3A (retention time = 1.851 min) and compound 9-3B (retention time = 2.297 min).

LCMS(ESI)m/z:672.5(M+1) ⁺。 LCMS (ESI) m/z: 672.5 (M+1) ⁺ .

第四步：the fourth step:

将化合物9-3A(200毫克)的乙腈(10毫升)溶液冷却到0摄氏度，在0摄氏度下将对甲苯磺酸(51.27毫克)和NCS(39.76毫克)加入到反应液中，在氮气保护下，混合物在60摄氏度反应2小时。向反应液中加入饱和的亚硫酸钠水溶液(20毫升)和饱和的碳酸氢钠水溶液(20毫升)，用乙酸乙酯(30毫升*2)萃取两次，有机相用饱和的食盐水(20毫升)洗涤一次，无水硫酸钠干燥后过滤，滤液减压浓缩，得到的残余物通过制备TLC(二氧化硅：石油醚：乙酸乙酯：甲醇＝8:3:1)纯化，分别得到化合物9-4A(Rf＝0.26)和10-1A(Rf＝0.18)。A solution of compound 9-3A (200 mg) in acetonitrile (10 mL) was cooled to 0 °C, and p-toluenesulfonic acid (51.27 mg) and NCS (39.76 mg) were added to the reaction solution at 0 °C under nitrogen protection. , the mixture was reacted at 60 degrees Celsius for 2 hours. Saturated aqueous sodium sulfite solution (20 mL) and saturated aqueous sodium bicarbonate solution (20 mL) were added to the reaction solution, extracted twice with ethyl acetate (30 mL*2), and the organic phase was washed with saturated brine (20 mL). Washed once, dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by preparative TLC (silica: petroleum ether: ethyl acetate: methanol = 8:3:1) to obtain compound 9- 4A (Rf=0.26) and 10-1A (Rf=0.18).

化合物9-4A： ¹H NMR(400MHz,CHLOROFORM-d)δ8.25-8.43(m,1H),7.17-7.27(m,2H),6.94(s, 1H),6.91(br d,J＝4.75Hz,1H),6.26-6.43(m,1H),3.80(br d,J＝4.13Hz,4H),3.53-3.69(m,4H),2.66-2.73(m,3H),2.55-2.65(m,1H)1.97-2.08(m,3H),1.44(s,9H),1.02-1.18(m,6H)。LCMS(ESI)m/z:706.2(M+1) ⁺。 Compound 9-4A: ¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.25-8.43 (m, 1H), 7.17-7.27 (m, 2H), 6.94 (s, 1H), 6.91 (br d, J=4.75 Hz,1H),6.26-6.43(m,1H),3.80(br d,J=4.13Hz,4H),3.53-3.69(m,4H),2.66-2.73(m,3H),2.55-2.65(m , 1H) 1.97-2.08 (m, 3H), 1.44 (s, 9H), 1.02-1.18 (m, 6H). LCMS (ESI) m/z: 706.2 (M+1) ⁺ .

化合物10-1A：LCMS(ESI)m/z:706.3(M+1) ⁺。将化合物9-3B(200毫克)的乙腈(10毫升)溶液冷却到0摄氏度，在0摄氏度下将对甲苯磺酸(51.27毫克)和NCS(39.76毫克)加入到反应液中，在氮气保护下，混合物在60摄氏度反应2小时。向反应液中加入饱和的亚硫酸钠水溶液(20毫升)和饱和的碳酸氢钠水溶液(20毫升)，用乙酸乙酯(30毫升*2)萃取两次，有机相用饱和的食盐水(20毫升)洗涤一次，无水硫酸钠干燥后过滤，滤液减压浓缩，得到的残余物通过制备TLC(二氧化硅：石油醚：乙酸乙酯：甲醇＝8:3:1)纯化，分别得到化合物9-4B(Rf＝0.30)和10-1B(Rf＝0.35)。 Compound 10-1A: LCMS (ESI) m/z: 706.3 (M+1) ⁺ . A solution of compound 9-3B (200 mg) in acetonitrile (10 mL) was cooled to 0 °C, and p-toluenesulfonic acid (51.27 mg) and NCS (39.76 mg) were added to the reaction solution at 0 °C under nitrogen protection. , the mixture was reacted at 60 degrees Celsius for 2 hours. Saturated aqueous sodium sulfite solution (20 mL) and saturated aqueous sodium bicarbonate solution (20 mL) were added to the reaction solution, extracted twice with ethyl acetate (30 mL*2), and the organic phase was washed with saturated brine (20 mL). Washed once, dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by preparative TLC (silica: petroleum ether: ethyl acetate: methanol = 8:3:1) to obtain compound 9- 4B (Rf=0.30) and 10-1B (Rf=0.35).

化合物9-4B：LCMS(ESI)m/z:706.3(M+1) ⁺。 Compound 9-4B: LCMS (ESI) m/z: 706.3 (M+1) ⁺ .

化合物10-1B：LCMS(ESI)m/z:706.2(M+1) ⁺。 Compound 10-1B: LCMS (ESI) m/z: 706.2 (M+1) ⁺ .

第五步：the fifth step:

分别向化合物9-4A和9-4B(70毫克)的二氯甲烷(0.9毫升)溶液中加入三氟乙酸(462毫克)，该反应在10摄氏度反应0.5小时。将反应液直接减压浓缩得到化合物9-5A和9-5B的三氟乙酸盐粗品直接用于下一步反应。LCMS(ESI)m/z:606.3(M+1) ⁺。 To a solution of compounds 9-4A and 9-4B (70 mg) in dichloromethane (0.9 mL), respectively, was added trifluoroacetic acid (462 mg), and the reaction was carried out at 10 degrees Celsius for 0.5 hr. The reaction solution was directly concentrated under reduced pressure to obtain crude trifluoroacetate salts of compounds 9-5A and 9-5B, which were directly used in the next reaction. LCMS (ESI) m/z: 606.3 (M+1) ⁺ .

第六步：Step 6:

分别将化合物9-5A和9-5B(100毫克)溶解在THF(4毫升)和水(1毫升)混合溶液中，依次加入碳酸钾(49.71毫克)和化合物1-5(10.85毫克)，该反应在15摄氏度反应30分钟。反应液用饱和的碳酸氢钠水溶液(20毫升)将混合物体系pH调节到8，乙酸乙酯(20毫升*2)萃取两次，有机相用饱和食盐水(10毫升)洗涤一次，无水硫酸钠干燥后过滤，滤液减压浓缩，得到的残余物通过制备的HPLC (柱型号：Phenomenex luna C18(150*25mm*10μm)；流动相：[0.225％的甲酸水溶液-乙腈]；乙腈：25％-55％，10分钟)纯化，分别得到化合物9A和9B。化合物9A： ¹H NMR(400MHz,METHANOL-d ₄)δ8.36(d,J＝5.14Hz,1H),7.32-7.39(m,1H),7.29(s,1H),7.24(br d,J＝5.01Hz,1H),6.83(dd,J＝16.75,10.64Hz,1H),6.51(dd,J＝9.29,1.34Hz,1H),6.30(dd,J＝16.75,1.96Hz,1H),5.80-5.87(m,1H),3.86-4.12(m,8H),2.82(dt,J＝13.54,6.86Hz,1H),2.75(s,3H),2.17(s,3H),1.18-1.21(m,3H),1.11(d,J＝6.85Hz,3H)。LCMS(ESI)m/z:660.2(M+1) ⁺。 Compounds 9-5A and 9-5B (100 mg) were dissolved in a mixed solution of THF (4 mL) and water (1 mL), respectively, and potassium carbonate (49.71 mg) and compound 1-5 (10.85 mg) were added successively. The reaction was carried out at 15 degrees Celsius for 30 minutes. The reaction solution was adjusted to pH 8 with saturated aqueous sodium bicarbonate solution (20 mL), extracted twice with ethyl acetate (20 mL*2), the organic phase was washed once with saturated brine (10 mL), and anhydrous sulfuric acid The filtrate was concentrated under reduced pressure, and the obtained residue was passed through preparative HPLC (column type: Phenomenex luna C18 (150*25mm*10μm); mobile phase: [0.225% aqueous formic acid-acetonitrile]; acetonitrile: 25% -55%, 10 min) purification to give compounds 9A and 9B, respectively. Compound 9A: ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ 8.36 (d, J=5.14 Hz, 1H), 7.32-7.39 (m, 1H), 7.29 (s, 1H), 7.24 (br d, J ＝5.01Hz,1H),6.83(dd,J＝16.75,10.64Hz,1H),6.51(dd,J＝9.29,1.34Hz,1H),6.30(dd,J＝16.75,1.96Hz,1H),5.80 -5.87(m,1H),3.86-4.12(m,8H),2.82(dt,J=13.54,6.86Hz,1H),2.75(s,3H),2.17(s,3H),1.18-1.21(m , 3H), 1.11 (d, J=6.85Hz, 3H). LCMS (ESI) m/z: 660.2 (M+1) ⁺ .

化合物9B： ¹H NMR(400MHz,METHANOL-d ₄)δ8.36(d,J＝5.01Hz,1H),7.37(dd,J＝8.93,5.87Hz,1H),7.33(s,1H),7.19(d,J＝5.01Hz,1H),6.84(dd,J＝16.81,10.58Hz,1H),6.49(t,J＝8.93Hz,1H),6.31(dd,J＝16.81,1.90Hz,1H),5.78-5.89(m,1H),3.90-4.11(m,8H),2.74-2.86(m,1H),2.67(s,3H),2.12(s,3H),1.19(d,J＝6.72Hz,3H),1.10(d,J＝6.72Hz,3H)；LCMS(ESI)m/z:660.2(M+1) ⁺。 Compound 9B: ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ 8.36 (d, J=5.01 Hz, 1H), 7.37 (dd, J=8.93, 5.87 Hz, 1H), 7.33 (s, 1H), 7.19 (d, J=5.01Hz, 1H), 6.84 (dd, J=16.81, 10.58Hz, 1H), 6.49 (t, J=8.93Hz, 1H), 6.31 (dd, J=16.81, 1.90Hz, 1H) ,5.78-5.89(m,1H),3.90-4.11(m,8H),2.74-2.86(m,1H),2.67(s,3H),2.12(s,3H),1.19(d,J=6.72Hz , 3H), 1.10 (d, J=6.72 Hz, 3H); LCMS (ESI) m/z: 660.2 (M+1) ⁺ .

实施例10Example 10

第一步：first step:

分别向化合物10-1A和10-1B(90毫克)的二氯甲烷(0.9毫升)溶液中加入三氟乙酸(471.33毫克)，该反应在10摄氏度反应1小时。分别将反应液直接减压浓缩得到化合物10-2A和10-2B的三氟乙酸盐，粗品直接用于下一步反应。LCMS(ESI)m/z:606.4(M+1) ⁺。 To a solution of compounds 10-1A and 10-1B (90 mg) in dichloromethane (0.9 mL), respectively, was added trifluoroacetic acid (471.33 mg), and the reaction was carried out at 10 degrees Celsius for 1 hour. The reaction solution was directly concentrated under reduced pressure to obtain the trifluoroacetate salts of compounds 10-2A and 10-2B, and the crude products were directly used in the next reaction. LCMS (ESI) m/z: 606.4 (M+1) ⁺ .

第二步：Step 2:

分别将化合物10-2A和10-2B(150毫克)溶解在四氢呋喃(4毫升)和水(1毫升)混合溶液中，依次加入碳酸钾(102.63毫克)和化合物1-5(22.40毫克)，该反应在15摄氏度反应30分钟。反应液用饱和的碳酸氢钠水溶液(20毫升)将混合物体系pH调节到8，乙酸乙酯(20毫升*2)萃取，合并有机相用饱和食盐水(10毫升)洗涤，无水硫酸钠干燥后过滤，滤液减压浓缩，得到的残余物通过制备的HPLC(柱型号：Phenomenex luna C18(150*25mm*10μm)，流动相：[0.225％的甲酸水溶液-乙腈]；梯度：乙腈％：20％-50％，10分钟)纯化，分别得到化合物10A的甲酸盐和10B的甲酸盐。LCMS(ESI)m/z:660.4(M+1) ⁺。 Compounds 10-2A and 10-2B (150 mg) were dissolved in a mixed solution of tetrahydrofuran (4 mL) and water (1 mL), respectively, potassium carbonate (102.63 mg) and compound 1-5 (22.40 mg) were added successively, the The reaction was carried out at 15 degrees Celsius for 30 minutes. The reaction solution was adjusted to pH 8 with saturated aqueous sodium bicarbonate solution (20 mL), extracted with ethyl acetate (20 mL*2), the combined organic phases were washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. After post-filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was passed through preparative HPLC (column type: Phenomenex luna C18 (150*25mm*10μm), mobile phase: [0.225% aqueous formic acid-acetonitrile]; gradient: acetonitrile %: 20 %-50%, 10 minutes) to obtain the formate salt of compound 10A and the formate salt of 10B, respectively. LCMS (ESI) m/z: 660.4 (M+1) ⁺ .

化合物10A的甲酸盐： ¹H NMR(400MHz,METHANOL-d ₄)δ8.36(d,J＝5.01Hz,1H),7.37(dd,J＝8.93,5.87Hz,1H),7.33(s,1H),7.19(d,J＝5.01Hz,1H),6.84(dd,J＝16.81,10.58Hz,1H),6.49(t,J＝8.93Hz,1H),6.31(dd,J＝16.81,1.90Hz,1H),5.78-5.89(m,1H),3.90-4.11(m,8H),2.74-2.86(m,1H),2.67(s,3H),2.12(s,3H),1.19(d,J＝6.72Hz,3H),1.10(d,J＝6.72Hz,3H)。LCMS(ESI)m/z:660.2(M+1) ⁺。 Formate salt of compound 10A: ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ 8.36 (d, J=5.01 Hz, 1H), 7.37 (dd, J=8.93, 5.87 Hz, 1H), 7.33 (s, 1H), 7.19(d, J＝5.01Hz, 1H), 6.84(dd, J＝16.81, 10.58Hz, 1H), 6.49(t, J＝8.93Hz, 1H), 6.31(dd, J＝16.81, 1.90 Hz, 1H), 5.78-5.89(m, 1H), 3.90-4.11(m, 8H), 2.74-2.86(m, 1H), 2.67(s, 3H), 2.12(s, 3H), 1.19(d, J=6.72Hz, 3H), 1.10 (d, J=6.72Hz, 3H). LCMS (ESI) m/z: 660.2 (M+1) ⁺ .

化合物10B的甲酸盐： ¹H NMR(400MHz,METHANOL-d ₄)δ8.36(d,J＝5.01Hz,1H),7.36(dd,J＝8.86,5.93Hz,1H),7.32(s,1H),7.15-7.20(m,1H),6.84(dd,J＝16.75,10.64Hz,1H),6.48(t,J＝8.99Hz,1H),6.31(dd,J＝16.75,1.83Hz,1H),5.84(dd,J＝10.58,1.90Hz,1H),3.85-4.20(m,8H),2.96(dt,J＝13.51,6.69Hz,1H),2.67(s,3H),2.04(s,3H),1.14-1.25(m,6H)；LCMS(ESI)m/z:660.2(M+1) ⁺。 Formate salt of compound 10B: ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ 8.36 (d, J=5.01 Hz, 1H), 7.36 (dd, J=8.86, 5.93 Hz, 1H), 7.32 (s, 1H),7.15-7.20(m,1H),6.84(dd,J=16.75,10.64Hz,1H),6.48(t,J=8.99Hz,1H),6.31(dd,J=16.75,1.83Hz,1H) ),5.84(dd,J＝10.58,1.90Hz,1H),3.85-4.20(m,8H),2.96(dt,J＝13.51,6.69Hz,1H),2.67(s,3H),2.04(s, 3H), 1.14-1.25 (m, 6H); LCMS (ESI) m/z: 660.2 (M+1) ⁺ .

实施例11Example 11

第一步：first step:

在20-30摄氏度下，向化合物11-1(20克)的乙醇(200毫升)溶液中一次性加入氨水(182克，质量百分比：34％)。反应液在75摄氏度下反应16个小时。反应液浓缩得到残余物，用乙酸乙酯(80mL*3)萃取，有机相用无水硫酸钠干燥，过滤，浓缩滤液得到化合物11-2。To a solution of compound 11-1 (20 g) in ethanol (200 mL) at 20-30 degrees Celsius, ammonia water (182 g, mass percentage: 34%) was added at one time. The reaction solution was reacted at 75 degrees Celsius for 16 hours. The reaction solution was concentrated to obtain a residue, which was extracted with ethyl acetate (80 mL*3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 11-2.

第二步：Step 2:

在20-30摄氏度下，向化合物11-2(2克)的二氯甲烷(20毫升)溶液中依次加入三乙胺(1.56克)和丙二酸甲酯酰氯(1.57克)，反应液在20-30摄氏度下反应4小时。向反应液中加入柠檬酸至pH＝6-7，反应液分层，水相用二氯甲烷(50毫升)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液浓缩得到残余物。残余物经硅胶柱纯化(石油醚：乙酸乙酯＝20:1到3:1)得到化合物11-3。 ¹H NMR(400MHz,CDCl ₃)δ10.32(br s,1H),8.25-8.15(m,1H),7.59-7.48(m,1H),7.11-6.98(m,1H),3.85(s,3H),3.56(s,2H)。 LCMS(ESI)m/z:257.1(M+1) ⁺。 To a solution of compound 11-2 (2 g) in dichloromethane (20 mL) at 20-30 degrees Celsius, triethylamine (1.56 g) and methyl malonate acid chloride (1.57 g) were sequentially added, and the reaction solution was React at 20-30 degrees Celsius for 4 hours. Citric acid was added to the reaction solution to pH=6-7, the reaction solution was separated, the aqueous phase was extracted with dichloromethane (50 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column (petroleum ether:ethyl acetate=20:1 to 3:1) to obtain compound 11-3. ¹ H NMR (400MHz, CDCl ₃ ) δ 10.32(br s, 1H), 8.25-8.15(m, 1H), 7.59-7.48(m, 1H), 7.11-6.98(m, 1H), 3.85(s, 3H), 3.56(s, 2H). LCMS (ESI) m/z: 257.1 (M+1) ⁺ .

第三步：third step:

在20-30摄氏度下，向化合物11-3(15克)的乙腈(150毫升)溶液中依次加入碳酸铯(19.08克)和4-乙氧基-1,1,1-三氟-3-丁烯-2-酮(7.87克)，反应液在氮气保护下于20-30摄氏度下反应3小时。反应液过滤，滤液浓缩得到残余物。残余物经硅胶柱纯化(石油醚：乙酸乙酯＝10:1到0:1)得到化合物11-4。LCMS(ESI)m/z:379.0(M+1) ⁺。 To a solution of compound 11-3 (15 g) in acetonitrile (150 mL) at 20-30 degrees Celsius was added cesium carbonate (19.08 g) followed by 4-ethoxy-1,1,1-trifluoro-3- Buten-2-one (7.87 g), the reaction solution was reacted under nitrogen protection at 20-30 degrees Celsius for 3 hours. The reaction solution was filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column (petroleum ether:ethyl acetate=10:1 to 0:1) to obtain compound 11-4. LCMS (ESI) m/z: 379.0 (M+1) ⁺ .

第四步：the fourth step:

在20-30摄氏度下，向化合物11-4(5克)的乙醇(50毫升)和水(50毫升)混合溶液中依次加入氯化铵(3.54克)和还原铁粉(3.69克)，反应液在80摄氏度下反应16小时。反应液过滤，滤液浓缩得到残余物。残余物经硅胶柱纯化(石油醚：乙酸乙酯＝10:1到0:1)得到化合物11-5。LCMS(ESI)m/z:317.0(M+1) ⁺。 Ammonium chloride (3.54 g) and reduced iron powder (3.69 g) were sequentially added to a mixed solution of compound 11-4 (5 g) in ethanol (50 ml) and water (50 ml) at 20-30 degrees Celsius to react The solution was reacted at 80 degrees Celsius for 16 hours. The reaction solution was filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column (petroleum ether:ethyl acetate=10:1 to 0:1) to obtain compound 11-5. LCMS (ESI) m/z: 317.0 (M+1) ⁺ .

第五步：the fifth step:

在20-30摄氏度下，向化合物11-5(0.2克)的醋酸(2毫升)溶液中一次性加入NCS(84.46毫克)，反应液在20-30摄氏度下反应16小时。向反应液中加入水(20毫升),然后用乙酸乙酯(20毫升*3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液浓缩得到残余物。残余物经制备板纯化(石油醚：乙酸乙酯＝0:1)得到化合物11-6。 ¹H NMR(400MHz,DMSO-d ₆)δ8.19-8.03(m,1H),7.43-7.26(m,1H),7.18-7.00(m,2H),5.65(br s,2H)。LCMS(ESI)m/z:351.0(M+1) ⁺。 To a solution of compound 11-5 (0.2 g) in acetic acid (2 mL) was added NCS (84.46 mg) in one portion at 20-30 degrees Celsius, and the reaction solution was reacted at 20-30 degrees Celsius for 16 hours. Water (20 mL) was added to the reaction solution, followed by extraction with ethyl acetate (20 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by preparative plate (petroleum ether:ethyl acetate=0:1) to give compound 11-6. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.19-8.03 (m, 1H), 7.43-7.26 (m, 1H), 7.18-7.00 (m, 2H), 5.65 (br s, 2H). LCMS (ESI) m/z: 351.0 (M+1) ⁺ .

第六步：Step 6:

在20-30摄氏度下，向化合物11-6(1.1克)的吡啶(15毫升)溶液中一次性加入液溴(1.55克)。反应液在氮气保护下于50摄氏度下反应12小时。向反应液中加入水(100毫升),然后用乙酸乙酯(50毫升*3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液浓缩得到残余物。残余物经硅胶柱纯化(洗脱剂：石油醚：乙酸乙酯＝10:1到1:1)得到化合物11-7。LCMS(ESI)m/z:386.9(M+3) ⁺。 To a solution of compound 11-6 (1.1 g) in pyridine (15 mL) was added liquid bromine (1.55 g) in one portion at 20-30 degrees Celsius. The reaction solution was reacted at 50 degrees Celsius for 12 hours under nitrogen protection. Water (100 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column (eluent: petroleum ether: ethyl acetate = 10:1 to 1:1) to obtain compound 11-7. LCMS (ESI) m/z: 386.9 (M+3) ⁺ .

第七步：Step 7:

在20-30摄氏度下，向化合物11-7(1.6克)的1,4-二氧六环(20毫升)溶液中依次加入2-异丙基-4-甲基吡啶-3-胺(498.74毫克)，三(二亚苄基丙酮)二钯(380.03毫克)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(480.26毫克)，碳酸铯(2.7克)。反应液在氮气保护下于100摄氏度反应6小时。反应液过滤，滤液浓缩得到残余物。残余物经硅胶柱纯化(洗脱剂：石油醚：乙酸乙酯＝10:1到1:2)得到化合物11-8。LCMS(ESI)m/z:455.1(M+1) ⁺。 To a solution of compound 11-7 (1.6 g) in 1,4-dioxane (20 mL) at 20-30 degrees Celsius, 2-isopropyl-4-methylpyridin-3-amine (498.74 mg), tris(dibenzylideneacetone)dipalladium (380.03 mg), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (480.26 mg), cesium carbonate (2.7 g). The reaction solution was reacted at 100 degrees Celsius for 6 hours under nitrogen protection. The reaction solution was filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column (eluent: petroleum ether: ethyl acetate=10:1 to 1:2) to obtain compound 11-8. LCMS (ESI) m/z: 455.1 (M+1) ⁺ .

第八步：Step 8:

在20-30摄氏度下，向化合物11-8(0.3克)的DMF(3毫升)溶液中一次性加入N-溴代丁二酰亚胺(176.09毫克)。反应液在20-30摄氏度下反应一个小时。向反应液中加入水(40毫升)，然后用乙酸乙酯(30毫升*3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液浓缩得到残余物。残余物经制备板纯化(石油醚：乙酸乙酯＝1:1)得到化合物11-9。LCMS(ESI)m/z:534.9(M+3) ⁺。 To a solution of compound 11-8 (0.3 g) in DMF (3 mL) was added N-bromosuccinimide (176.09 mg) in one portion at 20-30 degrees Celsius. The reaction solution was reacted at 20-30 degrees Celsius for one hour. Water (40 mL) was added to the reaction solution, followed by extraction with ethyl acetate (30 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by preparative plate (petroleum ether:ethyl acetate=1:1) to give compound 11-9. LCMS (ESI) m/z: 534.9 (M+3) ⁺ .

第九步：Step 9:

在20-30摄氏度下，向化合物11-9(0.17克)的DMF(5毫升)和水(0.05毫升)混合溶液中依次一次性加入锌粉(210毫克)，氰化锌(300毫克)，溴化锌(71.73毫克)，1,1-双(二苯基膦基)二茂铁(96.33毫克)和三(二亚苄基丙酮)二钯(85.00毫克)。反应液在100摄氏度下反应3个小时。反应液过滤，滤液浓缩得到残余物。残余物经制备板纯化(石油醚：乙酸乙酯＝1:1)得到化合物11-10。LCMS(ESI)m/z:480.0(M+1) ⁺。 To a mixed solution of compound 11-9 (0.17 g) in DMF (5 mL) and water (0.05 mL) at 20-30 degrees Celsius, zinc powder (210 mg), zinc cyanide (300 mg) were added in sequence at one time, Zinc bromide (71.73 mg), 1,1-bis(diphenylphosphino)ferrocene (96.33 mg) and tris(dibenzylideneacetone)dipalladium (85.00 mg). The reaction solution was reacted at 100 degrees Celsius for 3 hours. The reaction solution was filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by preparative plate (petroleum ether:ethyl acetate=1:1) to give compound 11-10. LCMS (ESI) m/z: 480.0 (M+1) ⁺ .

第十步：Step 10:

化合物11-10(46毫克)的浓硫酸(1.41g)于60摄氏度下反应16小时。反应液加入到饱和碳酸氢钠水溶液(50毫升)中，用乙酸乙酯(20毫升*3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液浓缩得到化合物11-11。LCMS(ESI)m/z:498.1(M+1) ⁺。 Compound 11-10 (46 mg) in concentrated sulfuric acid (1.41 g) was reacted at 60 degrees Celsius for 16 hours. The reaction solution was added to saturated aqueous sodium bicarbonate solution (50 mL), extracted with ethyl acetate (20 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 11-11. LCMS (ESI) m/z: 498.1 (M+1) ⁺ .

第十一步：Step 11:

在0摄氏度下，向化合物11-11(30毫克)的四氢呋喃(1毫升)溶液中一次性加入氢化钠(12.05毫克，质量百分比：60％)，反应液在0摄氏度下反应0.3小时，然后一次性加入1,1-羰基二咪唑(29.31毫克)。反应液在0-25摄氏度下反应0.7小时。将反应液加入到饱和氯化铵(20毫升)溶液中，用乙酸乙酯(10毫升*3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液浓缩得到残余物。残余物经制备板纯化(石油醚：乙酸乙酯＝1:1)得到化合物11-12。LCMS(ESI)m/z:524.0(M+1) ⁺。 At 0 degrees Celsius, sodium hydride (12.05 mg, mass percentage: 60%) was added to a solution of compound 11-11 (30 mg) in tetrahydrofuran (1 ml) at one time, and the reaction solution was reacted at 0 degrees Celsius for 0.3 hours, and then once 1,1-Carbonyldiimidazole (29.31 mg) was added immediately. The reaction solution was reacted at 0-25 degrees Celsius for 0.7 hours. The reaction solution was added to saturated ammonium chloride (20 mL) solution, extracted with ethyl acetate (10 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by preparative plate (petroleum ether:ethyl acetate=1:1) to give compound 11-12. LCMS (ESI) m/z: 524.0 (M+1) ⁺ .

第十二步：Step 12:

在20-30摄氏度下，向化合物11-12(30毫克)的THF(2毫升)溶液中一次性加入N,N-二异丙基乙胺(29.60毫克)，三吡咯烷基溴化鏻六氟磷酸盐(106.79毫克)，反应液在20-30℃下反应1个小时，然后一次性加入化合物1-1(42.66毫克)，反应液在80摄氏度下反应3小时。反应液过滤，滤液浓缩得到残余物。残余物经制备板纯化(石油醚：乙酸乙酯＝0:1)得到化合物11-13。LCMS(ESI)m/z:692.1(M+1) ⁺。 To a solution of compounds 11-12 (30 mg) in THF (2 mL) at 20-30 °C was added N,N-diisopropylethylamine (29.60 mg), tripyrrolidinophosphonium hexamide in one portion Fluorophosphate (106.79 mg), the reaction solution was reacted at 20-30 °C for 1 hour, then compound 1-1 (42.66 mg) was added at one time, and the reaction solution was reacted at 80 °C for 3 hours. The reaction solution was filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by preparative plate (petroleum ether:ethyl acetate=0:1) to give compound 11-13. LCMS (ESI) m/z: 692.1 (M+1) ⁺ .

第十三步：Step Thirteen:

在10-25摄氏度下，向化合物11-13(22毫克)的二氯甲烷(0.6毫升)溶液中一次性加入三氟乙酸(308.00毫克)。反应液在10-25摄氏度下反应0.5小时。将反应液浓缩得到化合物11-14的三氟乙酸盐，粗品直接用于下一步。To a solution of compounds 11-13 (22 mg) in dichloromethane (0.6 mL) was added trifluoroacetic acid (308.00 mg) in one portion at 10-25 degrees Celsius. The reaction solution was reacted at 10-25 degrees Celsius for 0.5 hours. The reaction solution was concentrated to obtain the trifluoroacetate salt of compound 11-14, and the crude product was directly used in the next step.

第十四步：Step 14:

在0摄氏度下，向化合物11-14(22毫克，TFA盐)的四氢呋喃(1.0毫升)和水(0.2毫升)的混合溶液中依次一次性加入无水碳酸钾(21.53毫克)，丙烯酰氯(2.82毫克)。反应液在0摄氏度下反应0.5小时。向反应液中加入水(10毫升)，用乙酸乙酯(10毫升*3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液浓缩得到残余物。残余物先经制备板纯化(二氯甲烷：甲醇＝7:1)，得到的化合物11。To a mixed solution of compound 11-14 (22 mg, TFA salt) in tetrahydrofuran (1.0 mL) and water (0.2 mL) at 0 degrees Celsius, anhydrous potassium carbonate (21.53 mg), acryloyl chloride (2.82 mL) were sequentially added in one portion. mg). The reaction solution was reacted at 0 degrees Celsius for 0.5 hours. Water (10 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was first purified by preparative plate (dichloromethane:methanol=7:1) to give compound 11.

化合物11过制备SFC(柱型号：DAICEL CHIRALPAK IC(250mm*30mm，10μm)，流动相：甲醇(0.1％氨水)，梯度：二氧化碳临界流体50％-50％，5分钟，50分钟)分离纯化得到实施例11AM(保留时间＝3.325min和保留时间＝4.538min的混合物)及实施例11CM(保留时间＝1.622min和保留时间＝1.789min的混合物)。Compound 11 was isolated and purified by preparative SFC (column type: DAICEL CHIRALPAK IC (250mm*30mm, 10μm), mobile phase: methanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 50%-50%, 5 minutes, 50 minutes) Example 11AM (mixture of retention time = 3.325 min and retention time = 4.538 min) and Example 11CM (mixture of retention time = 1.622 min and retention time = 1.789 min).

11AM再通过制备SFC(柱型号：DAICEL CHIRALPAK AD(250mm*30mm，10μm)，流动相：异丙醇(0.1％氨水)，梯度：二氧化碳临界流体25％-25％，5.7分钟，40分钟)分离纯化得到化合物11A，和化合物11B。11AM and then separated by preparative SFC (column type: DAICEL CHIRALPAK AD (250mm*30mm, 10μm), mobile phase: isopropanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 25%-25%, 5.7 minutes, 40 minutes) Purification gave compound 11A, and compound 11B.

11CM再通过制备SFC(柱型号：DAICEL CHIRALPAK IG(250mm*30mm，10μm)，流动相：异丙醇(0.1％氨水)，梯度：二氧化碳临界流体40％-40％，5.8分钟，40分钟)分离纯化得到化合物11C和化合物11D。11CM was separated by preparative SFC (column type: DAICEL CHIRALPAK IG (250mm*30mm, 10μm), mobile phase: isopropanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 40%-40%, 5.8 minutes, 40 minutes) Purification gave compound 11C and compound 11D.

化合物11A和化合物11B经SFC检测【柱型号：Chiralpak IC-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为乙醇(0.05％二乙胺)；梯度(B％)：5％-40％】得到：化合物11A的保留时间为4.538min，e.e.值为100％；化合物11B的保留时间为3.318min，e.e.值为100％。Compound 11A and compound 11B were detected by SFC [column type: Chiralpak IC-3 50×4.6mm I.D., 3μm; mobile phase: phase A was supercritical carbon dioxide, phase B was ethanol (0.05% diethylamine); gradient (B% ): 5%-40%] obtained: the retention time of compound 11A is 4.538min, and the e.e. value is 100%; the retention time of compound 11B is 3.318min, and the e.e. value is 100%.

化合物11C和化合物11D经SFC检测【柱型号：Chiralcel OJ-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为异丙醇(0.05％二乙胺)；梯度(B％)：5％-40％】得到：化合物11C的保留时间为1.314min，e.e.值为100％；化合物11D的保留时间为1.471min，e.e.值为100％。Compound 11C and compound 11D were detected by SFC [column model: Chiralcel OJ-3 50×4.6mm I.D., 3μm; mobile phase: supercritical carbon dioxide in phase A, isopropanol (0.05% diethylamine) in phase B; gradient ( B%): 5%-40%] Obtained: Compound 11C has a retention time of 1.314 min and an e.e. value of 100%; Compound 11D has a retention time of 1.471 min and an e.e. value of 100%.

化合物11A(保留时间＝4.538min)：LCMS(ESI)m/z:646.1(M+1) ⁺。 Compound 11A (retention time = 4.538 min): LCMS (ESI) m/z: 646.1 (M+1) ⁺ .

化合物11B(保留时间＝3.318min)：LCMS(ESI)m/z:646.1(M+1) ⁺。 Compound 11B (retention time = 3.318 min): LCMS (ESI) m/z: 646.1 (M+1) ⁺ .

化合物11C(保留时间＝1.314min)： ¹H NMR(400MHz,METHANOL-d ₄)δ8.36-8.30(m,1H),7.25-7.22(m,1H),7.19-7.13(m,2H),6.94-6.84(m,1H),6.83-6.80(m,1H),6.35-6.26(m,1H),5.88-5.81(m,1H),4.10-4.00(m,4H),3.98-3.87(m,4H),2.97-2.76(m,1H),2.17-2.06(m,3H),1.22-1.08(m,6H)。LCMS(ESI)m/z:646.1(M+1) ⁺。 Compound 11C (retention time = 1.314 min): ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ 8.36-8.30 (m, 1H), 7.25-7.22 (m, 1H), 7.19-7.13 (m, 2H), 6.94-6.84(m, 1H), 6.83-6.80(m, 1H), 6.35-6.26(m, 1H), 5.88-5.81(m, 1H), 4.10-4.00(m, 4H), 3.98-3.87(m , 4H), 2.97-2.76 (m, 1H), 2.17-2.06 (m, 3H), 1.22-1.08 (m, 6H). LCMS (ESI) m/z: 646.1 (M+1) ⁺ .

化合物11D(保留时间＝1.471min)： ¹H NMR(400MHz,METHANOL-d ₄)δ8.25-8.17(m,1H),7.14-7.08(m,1H),7.08-6.99(m,2H),6.83-6.66(m,2H),6.25-6.15(m,1H),5.77-5.69(m,1H),4.00-3.90(m,4H),3.87-3.74(m,4H),2.86-2.63(m,1H),2.06-1.94(m,3H),1.12-0.95(m,6H)。LCMS(ESI)m/z:646.1(M+1) ⁺。 Compound 11D (retention time = 1.471 min): ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ 8.25-8.17 (m, 1H), 7.14-7.08 (m, 1H), 7.08-6.99 (m, 2H), 6.83-6.66(m, 2H), 6.25-6.15(m, 1H), 5.77-5.69(m, 1H), 4.00-3.90(m, 4H), 3.87-3.74(m, 4H), 2.86-2.63(m , 1H), 2.06-1.94 (m, 3H), 1.12-0.95 (m, 6H). LCMS (ESI) m/z: 646.1 (M+1) ⁺ .

实施例12Example 12

第一步：first step:

向化合物A(600毫克)的四氢呋喃(20毫升)溶液中加入PYBROP(2.29克)，DIEA(633.77毫克)以及化合物3-1(2.10克)。反应液在70摄氏度下反应16小时，反应液浓缩得到残余物。残余物通过制备HPLC[柱型号：Phenomenex luna C18(250*50mm*10μm)，流动相：水(0.225％甲酸)-乙腈：35％-65％，20分钟]纯化得到化合物12-1。LCMS(ESI)m/z:686.3.(M+1) ⁺。 To a solution of compound A (600 mg) in tetrahydrofuran (20 mL) were added PYBROP (2.29 g), DIEA (633.77 mg) and compound 3-1 (2.10 g). The reaction solution was reacted at 70 degrees Celsius for 16 hours, and the reaction solution was concentrated to obtain a residue. The residue was purified by preparative HPLC [column model: Phenomenex luna C18 (250*50mm*10μm), mobile phase: water (0.225% formic acid)-acetonitrile: 35%-65%, 20 minutes] to give compound 12-1. LCMS (ESI) m/z: 686.3.(M+1) ⁺ .

第二步：Step 2:

将12-1(300毫克)溶解在二氯甲烷(3毫升)和三氟甲酸(1毫升)的混合溶液中。反应液在25摄氏度下反应1小时，反应液浓缩得到粗品化合物12-2的三氟乙酸盐，粗品直接用于下一步。LCMS(ESI)m/z:586.2.(M+1) ⁺。 12-1 (300 mg) was dissolved in a mixed solution of dichloromethane (3 mL) and trifluoroformic acid (1 mL). The reaction solution was reacted at 25 degrees Celsius for 1 hour, and the reaction solution was concentrated to obtain the trifluoroacetate salt of the crude compound 12-2, and the crude product was directly used in the next step. LCMS (ESI) m/z: 586.2.(M+1) ⁺ .

第三步：third step:

向化合物12-2(400毫克)的四氢呋喃(4毫升)和水(1毫升)的混合溶液中加入碳酸钾(203.83毫克)，调节pH至8后，向反应液中加入化合物1-5(44.50毫克)。反应液在0摄氏度反应15分钟，向反应液中加入饱和碳酸氢钠水溶液，调节pH到8，用乙酸乙酯(10毫升*2)萃取，有机相用饱和食盐水(5毫升*2)洗后经无水硫酸钠干燥后浓缩得到残余物。残余物通过制备HPLC[柱型号：Phenomenex Synergi C18(150*25mm*10μm)，流动相：水(0.1％甲酸)-乙腈：25％-55％，10分钟]纯化，得到化合物12。To a mixed solution of compound 12-2 (400 mg) in tetrahydrofuran (4 mL) and water (1 mL), potassium carbonate (203.83 mg) was added to adjust the pH to 8, and compound 1-5 (44.50 mg) was added to the reaction solution. mg). The reaction solution was reacted at 0 degrees Celsius for 15 minutes, a saturated aqueous sodium bicarbonate solution was added to the reaction solution, the pH was adjusted to 8, extracted with ethyl acetate (10 mL*2), and the organic phase was washed with saturated brine (5 mL*2). It was then dried over anhydrous sodium sulfate and concentrated to obtain a residue. The residue was purified by preparative HPLC [column model: Phenomenex Synergi C18 (150*25mm*10μm), mobile phase: water (0.1% formic acid)-acetonitrile: 25%-55%, 10 minutes] to give compound 12.

化合物12经过制备SFC(柱型号：DAICEL CHIRALPAK AS-H(250mm*30mm,5μm)，流动相：甲醇(0.1％氨水)，梯度：二氧化碳临界流体15％-15％，4.7分钟，145分钟)分离得到化合物12A和化合物12B。Compound 12 was separated by preparative SFC (column type: DAICEL CHIRALPAK AS-H (250mm*30mm, 5μm), mobile phase: methanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 15%-15%, 4.7 minutes, 145 minutes) Compound 12A and compound 12B were obtained.

化合物12A和化合物12B经SFC检测【柱型号：Chiralpak AS-3 50×4.6mm I.D,3μm；流动相：A相为超临界二氧化碳，B相为异丙醇(0.05％二乙胺)；梯度(B％)：5％-40％】得到：化合物12A的保留时间为1.014min，e.e.值为98.16％；化合物12B的保留时间为1.104min，e.e.值为99.28％。Compound 12A and compound 12B were detected by SFC [column type: Chiralpak AS-3 50×4.6mm I.D, 3μm; mobile phase: supercritical carbon dioxide in phase A, isopropanol (0.05% diethylamine) in phase B; gradient ( B%): 5%-40%] Obtained: the retention time of compound 12A is 1.014min, the e.e. value is 98.16%; the retention time of compound 12B is 1.104min, and the e.e. value is 99.28%.

化合物12A(保留时间＝1.014min)： ¹H NMR(400MHz,CHLOROFORM-d)δ8.50-8.35(m,1H),7.20-7.12(m,1H),7.05-6.96(m,2H),6.68-6.49(m,3H),6.46-6.34(m,1H),5.86-5.77(m,1H),5.16-4.78(m,2H),4.52-4.32(m,1H),4.29-4.13(m,1H),3.98-3.85(m,2H),3.81-3.64(m,2H),2.85-2.68(m,1H),2.17-2.10(m,3H),1.49-1.40(m,6H),1.26(br s,3H),1.18(br d,J＝2.0Hz,3H)。LCMS(ESI)m/z:640.3.(M+1) ⁺。 Compound 12A (retention time = 1.014 min): ¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.50-8.35 (m, 1H), 7.20-7.12 (m, 1H), 7.05-6.96 (m, 2H), 6.68 -6.49(m,3H),6.46-6.34(m,1H),5.86-5.77(m,1H),5.16-4.78(m,2H),4.52-4.32(m,1H),4.29-4.13(m, 1H), 3.98-3.85(m, 2H), 3.81-3.64(m, 2H), 2.85-2.68(m, 1H), 2.17-2.10(m, 3H), 1.49-1.40(m, 6H), 1.26( br s, 3H), 1.18 (br d, J=2.0Hz, 3H). LCMS (ESI) m/z: 640.3.(M+1) ⁺ .

化合物12B(保留时间＝1.104min)：1H NMR(400MHz,CHLOROFORM-d)δ1.11(br s,3H),1.20-1.24(m,3H),1.29-1.37(m,3H),1.43-1.46(m,3H),2.02-2.18(m,3H),2.65-2.73(m,1H),3.46-3.54(m,1H),3.60-3.65(m,2H),3.69-3.78(m,1H),3.82-3.95(m,2H),4.37-4.58(m,1H),4.98-5.13(m,1H),5.77-5.87(m,1H),6.36-6.46(m,1H),6.54-6.59(m,2H),6.91-7.09(m,2H),7.14-7.22(m,1H),7.34-7.56(m,1H),8.34-8.54(m,1H)。LCMS(ESI)m/z:640.3.(M+1) ⁺。 Compound 12B (retention time = 1.104 min): 1H NMR (400 MHz, CHLOROFORM-d) δ 1.11 (br s, 3H), 1.20-1.24 (m, 3H), 1.29-1.37 (m, 3H), 1.43-1.46 (m,3H), 2.02-2.18(m,3H), 2.65-2.73(m,1H), 3.46-3.54(m,1H), 3.60-3.65(m,2H), 3.69-3.78(m,1H) ,3.82-3.95(m,2H),4.37-4.58(m,1H),4.98-5.13(m,1H),5.77-5.87(m,1H),6.36-6.46(m,1H),6.54-6.59( m, 2H), 6.91-7.09 (m, 2H), 7.14-7.22 (m, 1H), 7.34-7.56 (m, 1H), 8.34-8.54 (m, 1H). LCMS (ESI) m/z: 640.3.(M+1) ⁺ .

实施例13Example 13

第一步：first step:

向中间体A(1克)的乙腈(15毫升)溶液中依次加入对甲苯磺酸(526.94毫克)和N-氯代丁二酰亚胺(544.81毫克)，在氮气保护下，反应液在60摄氏度下反应1小时。向反应液中加入饱和的亚硫酸钠水溶液(10毫升)，用乙酸乙酯(20毫升*3)萃取，有机相用饱和的食盐水(20毫升)洗涤，无水硫酸钠干燥后过滤，滤液浓缩得到化合物13-1。LCMS(ESI)m/z:558.0(M+1) ⁺。 To a solution of Intermediate A (1 g) in acetonitrile (15 mL) was added p-toluenesulfonic acid (526.94 mg) and N-chlorosuccinimide (544.81 mg) successively, and the reaction solution was heated at 60 under nitrogen protection. The reaction was carried out for 1 hour at degrees Celsius. Saturated aqueous sodium sulfite solution (10 mL) was added to the reaction solution, extracted with ethyl acetate (20 mL*3), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain Compound 13-1. LCMS (ESI) m/z: 558.0 (M+1) ⁺ .

第二步：Step 2:

将化合物13-1(1.11克)的四氢呋喃(20毫升)溶液中加入DIEA(770.86毫克)，PyBrOP(3.71克)和化合物1-1(2.96克)，反应液在70摄氏度下反应12小时。反应混合物过滤，滤液减压浓缩，得到化合物13-2。LCMS(ESI)m/z:726.1(M+1) ⁺。 To a solution of compound 13-1 (1.11 g) in tetrahydrofuran (20 mL) were added DIEA (770.86 mg), PyBrOP (3.71 g) and compound 1-1 (2.96 g), and the reaction solution was reacted at 70 degrees Celsius for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 13-2. LCMS (ESI) m/z: 726.1 (M+1) ⁺ .

第三步：third step:

向化合物13-2(2.3克)的乙酸乙酯(10毫升)溶液中加入盐酸乙酸乙酯(4摩尔/升，10毫升)溶液，反应液在15摄氏度反应1小时。将反应液过滤，滤饼溶解在乙酸乙酯(50毫升)和饱和的碳酸氢钠水溶液(50毫升)中，分层，水相用乙酸乙酯(20毫升)萃取。有机相用饱和的食盐水(20毫升)洗涤，无水硫酸钠干燥后过滤，滤液减压浓缩得到化合物13-3。LCMS(ESI)m/z:626.2(M+1) ⁺。 To a solution of compound 13-2 (2.3 g) in ethyl acetate (10 mL) was added a solution of ethyl acetate hydrochloride (4 mol/L, 10 mL), and the reaction solution was reacted at 15 degrees Celsius for 1 hour. The reaction solution was filtered, the filter cake was dissolved in ethyl acetate (50 mL) and saturated aqueous sodium bicarbonate solution (50 mL), the layers were separated, and the aqueous phase was extracted with ethyl acetate (20 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 13-3. LCMS (ESI) m/z: 626.2 (M+1) ⁺ .

第四步：the fourth step:

向化合物13-4(28.75毫克)的N,N-二甲基甲酰胺(5毫升)溶液中依次加入DIEA(165.05毫克)和HATU(242.79毫克)，反应液在15摄氏度下反应30分钟。然后加入化合物13-3，在15摄氏度下继续反应1小时。将反应液倒入水中(20毫升)，用乙酸乙酯(20毫升*3)萃取，有机相用饱和食盐水(20毫升)洗涤，无水硫酸钠干燥，过滤，减压浓缩，得到的残余物通过制备的HPLC(柱型号：Phenomenex luna C18 150*25mm*10μm；流动相：[0.225％的甲酸水溶液-乙腈]；乙腈：34％-64％，2分钟)纯化，得到的化合物13。DIEA (165.05 mg) and HATU (242.79 mg) were sequentially added to a solution of compound 13-4 (28.75 mg) in N,N-dimethylformamide (5 mL), and the reaction solution was reacted at 15 degrees Celsius for 30 minutes. Then compound 13-3 was added, and the reaction was continued at 15 degrees Celsius for 1 hour. The reaction solution was poured into water (20 mL), extracted with ethyl acetate (20 mL*3), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The compound was purified by preparative HPLC (column type: Phenomenex luna C18 150*25mm*10μm; mobile phase: [0.225% aqueous formic acid-acetonitrile]; acetonitrile: 34%-64%, 2 minutes) to obtain compound 13.

化合物13用制备SFC(柱型号：DAICEL CHIRALPAK IC(250mm*30mm*10μm)；流动相：甲醇(0.1％氨水)；梯度:二氧化碳临界流体50％-50％，2.5分钟；430分钟)分离纯化得到化合物13A(保留时间＝0.649min)和化合物13B(保留时间＝1.218min)。Compound 13 was isolated and purified by preparative SFC (column type: DAICEL CHIRALPAK IC (250mm*30mm*10μm); mobile phase: methanol (0.1% ammonia water); gradient: carbon dioxide critical fluid 50%-50%, 2.5 minutes; 430 minutes) Compound 13A (retention time = 0.649 min) and compound 13B (retention time = 1.218 min).

化合物13A和化合物13B经SFC检测【柱型号：Chiralpak IC-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为甲醇(0.05％二乙胺)；梯度(B％)：40％-40％】得到：化合物13A的保留时间为0.649min，e.e.值为100％；化合物13B的保留时间为1.218min，e.e.值为100％。化合物13A(保留时间＝0.649min)：LCMS(ESI)m/z:698.1(M+1) ⁺。 Compound 13A and compound 13B were detected by SFC [column model: Chiralpak IC-3 50×4.6mm ID, 3μm; mobile phase: supercritical carbon dioxide in phase A, methanol (0.05% diethylamine) in phase B; gradient (B% ): 40%-40%] obtained: the retention time of compound 13A is 0.649min, and the ee value is 100%; the retention time of compound 13B is 1.218min, and the ee value is 100%. Compound 13A (retention time = 0.649 min): LCMS (ESI) m/z: 698.1 (M+1) ⁺ .

化合物13B(保留时间＝1.218min)：LCMS(ESI)m/z:698.1(M+1) ⁺。 Compound 13B (retention time = 1.218 min): LCMS (ESI) m/z: 698.1 (M+1) ⁺ .

实施例14Example 14

第一步：first step:

在10-20摄氏度下，向化合物14-1(50克)的二氯甲烷(500毫升)溶液中依次加入三乙胺(30.79克)和化合物7-2(43.73克)，反应液在10-20摄氏度下反应12小时。向反应液中加入水(500毫升)，反应液分层，有机相用无水硫酸钠干燥，过滤，滤液浓缩得到残余物。残余物经硅胶柱纯化(石油醚：乙酸乙酯＝5:1到1:1)得到化合物14-2。LCMS m/z(ESI):257.0(M+1) ⁺。 Triethylamine (30.79 g) and compound 7-2 (43.73 g) were sequentially added to a solution of compound 14-1 (50 g) in dichloromethane (500 ml) at 10-20 degrees Celsius. The reaction was carried out at 20 degrees Celsius for 12 hours. Water (500 mL) was added to the reaction solution, the layers of the reaction solution were separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column (petroleum ether:ethyl acetate=5:1 to 1:1) to obtain compound 14-2. LCMS m/z (ESI): 257.0 (M+1) ⁺ .

第二步：Step 2:

在氮气保护下化合物14-2(50克)的甲醇(500毫升)溶液中加入湿钯碳(5克，纯度：10％)，再用氮气和氢气分别置换三次。反应混合物在氢气氛围(1个大气压)，50摄氏度下反应20小时。将反应混合物硅藻土过滤，滤液浓缩得到残余物。残余物经硅胶柱纯化(石油醚：乙酸乙酯＝5:1到1:1)得到化合物14-3。LCMS m/z(ESI):209.0(M+1-18) ⁺。 To a solution of compound 14-2 (50 g) in methanol (500 mL) under nitrogen protection was added wet palladium carbon (5 g, purity: 10%), and then replaced with nitrogen and hydrogen three times respectively. The reaction mixture was reacted under a hydrogen atmosphere (1 atm) at 50 degrees Celsius for 20 hours. The reaction mixture was filtered through celite and the filtrate was concentrated to give a residue. The residue was purified by silica gel column (petroleum ether:ethyl acetate=5:1 to 1:1) to obtain compound 14-3. LCMS m/z (ESI): 209.0 (M+1-18) ⁺ .

第三步：third step:

向化合物14-3(20克)的乙腈(200毫升)溶液中加入三乙胺(8.95克)，在15-20摄氏度下将乙酰氯(10.41克)滴加到反应液中，该反应在20摄氏度反应2小时。向反应混合物中加入饱和食盐水(200毫升)，再用乙酸乙酯(200毫升*3)萃取三次。合并有机相，干燥，过滤，浓缩得到化合物14-4的粗品，粗品直接用于下一步反应。LCMS m/z(ESI):269.0(M+1) ⁺。 To a solution of compound 14-3 (20 g) in acetonitrile (200 ml) was added triethylamine (8.95 g), and acetyl chloride (10.41 g) was added dropwise to the reaction solution at 15-20 degrees Celsius, and the reaction was carried out at 20 Celsius for 2 hours. Saturated brine (200 mL) was added to the reaction mixture, followed by extraction three times with ethyl acetate (200 mL*3). The organic phases were combined, dried, filtered, and concentrated to obtain the crude product of compound 14-4, which was directly used in the next reaction. LCMS m/z (ESI): 269.0 (M+1) ⁺ .

第四步：the fourth step:

向化合物14-4(22克)的乙腈(220毫升)溶液中依次加入碳酸铯(26.72克)和化合物7-4(16.55克)，该反应在20摄氏度反应4小时。向反应混合物中加入饱和食盐水(200毫升)，再用乙酸乙酯(200毫升*2)萃取两次，有机相用无水硫酸钠干燥，过滤，滤液浓缩得到化合物14-5的粗品，粗品直接用于下一步反应。LCMS m/z(ESI):390.9(M+1) ⁺。 To a solution of compound 14-4 (22 g) in acetonitrile (220 ml) were sequentially added cesium carbonate (26.72 g) and compound 7-4 (16.55 g), and the reaction was carried out at 20 degrees Celsius for 4 hours. Saturated brine (200 mL) was added to the reaction mixture, extracted twice with ethyl acetate (200 mL*2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product of compound 14-5, the crude product used directly in the next reaction. LCMS m/z (ESI): 390.9 (M+1) ⁺ .

第五步：the fifth step:

向化合物14-5(38克)的三氟乙醇(300毫升)溶液中加入三乙胺(19.70克)，该反应在100摄氏度反应12小时。将反应液浓缩得到残余物，残余物用饱和食盐水(100毫升)溶解，再向反应混合物中加入饱和食盐水(200毫升)，用1摩尔每升的盐酸溶液将体系pH值调节到2，再用乙酸乙酯(200毫升*3)萃取三次，有机相用无水硫酸钠干燥，过滤，滤液浓缩得到化合物14-6的粗品，粗品直接用于下一步反应。LCMS m/z(ESI):359.0(M+1) ⁺。 To a solution of compound 14-5 (38 g) in trifluoroethanol (300 mL) was added triethylamine (19.70 g), and the reaction was carried out at 100 degrees Celsius for 12 hours. The reaction solution was concentrated to obtain a residue, the residue was dissolved in saturated brine (100 ml), saturated brine (200 ml) was added to the reaction mixture, and the pH of the system was adjusted to 2 with 1 mol per liter of hydrochloric acid solution, It was then extracted three times with ethyl acetate (200 mL*3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product of compound 14-6, which was directly used in the next reaction. LCMS m/z (ESI): 359.0 (M+1) ⁺ .

第六步：Step 6:

向化合物14-6(24克)的乙腈(250毫升)溶液中依次加入磷酸钾(26.02克)和三溴吡啶嗡盐(58.81克)，该反应在50摄氏度反应2小时。向反应混合物中加入饱和亚硫酸钠水溶液(200毫升)，用1摩尔每升的盐酸溶液将体系pH值调节到2，再用乙酸乙酯(200毫升*2)萃取两次，有机相用饱和食盐水(100毫升)洗涤一次，无水硫酸钠干燥，过滤，滤液浓缩得残余物，残余物经硅胶柱纯化(洗脱剂：石油醚：乙酸乙酯＝5:1到1:1)得到化合物14-7。LCMS m/z(ESI):393.0(M+1) ⁺。 To a solution of compound 14-6 (24 g) in acetonitrile (250 ml) were sequentially added potassium phosphate (26.02 g) and pyridinium tribromide (58.81 g), and the reaction was carried out at 50 degrees Celsius for 2 hours. Saturated aqueous sodium sulfite solution (200 mL) was added to the reaction mixture, the pH of the system was adjusted to 2 with 1 mol/liter hydrochloric acid solution, and extracted twice with ethyl acetate (200 mL*2), and the organic phase was washed with saturated brine. (100 mL) washed once, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue, which was purified by silica gel column (eluent: petroleum ether: ethyl acetate = 5:1 to 1:1) to obtain compound 14 -7. LCMS m/z (ESI): 393.0 (M+1) ⁺ .

第七步：Step 7:

向化合物14-7(10克)的二氧六环(100毫升)溶液中依次加入化合物6-4(4.20克)、碳酸钾(7.03克)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(2.94克)和三(二亚苄基丙酮)二钯(2.33克)，该反应在氮气保护下，100摄氏度反应6小时。将反应混合物硅藻土过滤，滤液浓缩得到残余物。残余物经硅胶柱纯化(石油醚：乙酸乙酯＝3:1到1:1)得到化合物14-8。LCMS m/z(ESI):463.2(M+1) ⁺。 To a solution of compound 14-7 (10 g) in dioxane (100 mL) were sequentially added compound 6-4 (4.20 g), potassium carbonate (7.03 g), 4,5-bisdiphenylphosphine-9, 9-dimethylxanthene (2.94 g) and tris(dibenzylideneacetone)dipalladium (2.33 g), the reaction was carried out under nitrogen protection at 100 degrees Celsius for 6 hours. The reaction mixture was filtered through celite and the filtrate was concentrated to give a residue. The residue was purified by silica gel column (petroleum ether:ethyl acetate=3:1 to 1:1) to obtain compound 14-8. LCMS m/z (ESI): 463.2 (M+1) ⁺ .

第八步：Step 8:

向化合物14-8(5.90克)的二氯甲烷(60毫升)溶液中加入N-溴代丁二酰亚胺(2.77克)，该反应在氮气保护下，10摄氏度反应1小时。向反应液中加入饱和的亚硫酸钠水溶液(10毫升)，二氯甲烷(5毫升*2)萃取两次。有机相用饱和食盐水(50毫升)洗涤一次，无水硫酸钠干燥，过滤，滤液浓缩得化合物14-9。LCMS m/z(ESI):541.0(M+1) ⁺。 To a solution of compound 14-8 (5.90 g) in dichloromethane (60 mL) was added N-bromosuccinimide (2.77 g), and the reaction was carried out at 10 degrees Celsius for 1 hour under nitrogen protection. Saturated aqueous sodium sulfite solution (10 mL) was added to the reaction solution, and the mixture was extracted twice with dichloromethane (5 mL*2). The organic phase was washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 14-9. LCMS m/z (ESI): 541.0 (M+1) ⁺ .

第九步：Step 9:

向化合物14-9(8.00克)的N,N-二甲基甲酰胺(80毫升)溶液中依次加入锌粉(773.08毫克)、氰化锌(1.74克)、溴化锌(332.80毫克)、1,1-双(二苯基膦基)二茂铁(1.64克)和三(二亚苄基丙酮)二钯(1.35克)，该反应在氮气保护下，120摄氏度反应2小时。将反应混合物硅藻土过滤，滤液滴加到水中(300毫升)，乙酸乙酯(100毫升*2)萃取两次。有机相浓缩得到残余物。残余物用水(100毫升)和乙酸乙酯(100毫升)的混合溶剂溶剂，再用1摩尔每升的盐酸溶液将体系pH调节到2，然后分层，水相用饱和碳酸氢钠水溶液调剂pH值到8，乙酸乙酯萃取(50毫升*3)萃取三次。有机相用饱和食盐水(100毫升)洗涤，无水硫酸钠干燥，过滤，滤液浓缩得到残余物14-10。LCMS m/z(ESI):487.9(M+1) ⁺。 To a solution of compound 14-9 (8.00 g) in N,N-dimethylformamide (80 mL) were added zinc powder (773.08 mg), zinc cyanide (1.74 g), zinc bromide (332.80 mg), 1,1-bis(diphenylphosphino)ferrocene (1.64 g) and tris(dibenzylideneacetone)dipalladium (1.35 g), the reaction was carried out under nitrogen protection at 120 degrees Celsius for 2 hours. The reaction mixture was filtered through celite, the filtrate was added dropwise to water (300 mL), and extracted twice with ethyl acetate (100 mL*2). The organic phase was concentrated to give a residue. The residue was dissolved in a mixed solvent of water (100 mL) and ethyl acetate (100 mL), and the pH of the system was adjusted to 2 with 1 mole per liter of hydrochloric acid solution, then the layers were separated, and the aqueous phase was adjusted to pH with saturated aqueous sodium bicarbonate solution When the value reached 8, ethyl acetate extraction (50 mL*3) was performed three times. The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain residue 14-10. LCMS m/z (ESI): 487.9 (M+1) ⁺ .

第十步：Step 10:

将化合物14-10(2.5克)加入到装有浓硫酸(13毫升)的反应瓶中，该反应在氮气保护下，60摄氏度反应10小时。将反应液滴加到水(130毫升)中，用饱和的碳酸氢钠水溶液将体系pH调节至8，乙酸乙酯(30毫升*3)萃取三次。有机相用饱和食盐水(50毫升)洗涤一次，无水硫酸钠干燥，过滤，滤液浓缩得到化合物14-11。LCMS m/z(ESI):464.2(M+1) ⁺。 Compound 14-10 (2.5 g) was added to a reaction flask containing concentrated sulfuric acid (13 mL), and the reaction was carried out under nitrogen protection at 60 degrees Celsius for 10 hours. The reaction was added dropwise to water (130 mL), the pH of the system was adjusted to 8 with saturated aqueous sodium bicarbonate solution, and extracted three times with ethyl acetate (30 mL*3). The organic phase was washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 14-11. LCMS m/z (ESI): 464.2 (M+1) ⁺ .

第十一步：Step 11:

向化合物14-11(1.6克)的四氢呋喃(20毫升)溶液中依次加入羰基二咪唑(1.68克)和氢化钠(552.35毫克，质量百分比：60％)，该反应在氮气保护下，20摄氏度反应1小时。将反应液滴加到水(100毫升)中，用1摩尔每升的盐酸水溶液将体系pH调节至2，再用饱和的碳酸氢钠水溶液将体系pH调节至8，乙酸乙酯(50毫升*2)萃取两次。有机相用饱和食盐水(50毫升)洗涤，无水硫酸钠干燥，过滤，滤液浓缩得到化合物14-12。LCMS m/z(ESI):490.0(M+1) ⁺。 To a solution of compound 14-11 (1.6 g) in tetrahydrofuran (20 mL), carbonyldiimidazole (1.68 g) and sodium hydride (552.35 mg, mass percentage: 60%) were added successively, and the reaction was carried out under nitrogen protection at 20 degrees Celsius. 1 hour. The reaction was added dropwise to water (100 mL), the pH of the system was adjusted to 2 with 1 mol/liter aqueous hydrochloric acid solution, and the pH of the system was adjusted to 8 with saturated aqueous sodium bicarbonate solution, ethyl acetate (50 mL* 2) Extract twice. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 14-12. LCMS m/z (ESI): 490.0 (M+1) ⁺ .

化合物14-12(消旋体)经过制备的HPLC(柱型号：Phenomenex luna C18(250*70mm,15μm)；流动相：[0.225％的甲酸水溶液-乙腈]；梯度：40％-70％，35分钟)纯化后再通过制备SFC(柱型号：REGIS(s,s)WHELK-O1(250mm*50mm,10μm)，流动相：异丙醇(0.1％氨水)，梯度：二氧化碳临界流体50％-50％，4.4分钟，90分钟)分离纯化得到化合物14-12A(保留时间＝1.348min)和14-12M(14-12B、14-12C和14-12D的混合物)。Compounds 14-12 (racemate) were subjected to preparative HPLC (column type: Phenomenex luna C18 (250*70mm, 15μm); mobile phase: [0.225% aqueous formic acid-acetonitrile]; gradient: 40%-70%, 35 minutes) and then purified by preparative SFC (column type: REGIS(s,s) WHELK-O1 (250mm*50mm, 10μm), mobile phase: isopropanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 50%-50 %, 4.4 min, 90 min) was isolated and purified to give compound 14-12A (retention time=1.348 min) and 14-12M (mixture of 14-12B, 14-12C and 14-12D).

第十二步：Step 12:

向14-12M(1.70克)的四氢呋喃(30毫升)溶液中依次加入三吡咯烷基溴化鏻六氟磷酸盐(2.94克)、化合物1-1(2.03克)和DIEA(0.81克)，该反应在氮气保护下，70摄氏度反应10小时。LC-MS检测到目标产物已生成。将反应混合物过滤，滤液浓缩得到残余物。得到的残余物通过制备的HPLC(色谱柱：Phenomenex luna C18(250*70mm,15μm)；流动相：[0.225％的甲酸水溶液-乙腈]；乙腈：40％-70％，35分钟)纯化得到14-13M(14-13B、14-13C和14-13D的混合物)。LCMS m/z(ESI):686.3(M+1) ⁺。 To a solution of 14-12M (1.70 g) in tetrahydrofuran (30 mL) were added tripyrrolidinophosphonium bromide hexafluorophosphate (2.94 g), compound 1-1 (2.03 g) and DIEA (0.81 g) in sequence, the The reaction was carried out at 70 degrees Celsius for 10 hours under nitrogen protection. LC-MS detected the formation of the target product. The reaction mixture was filtered and the filtrate was concentrated to give a residue. The resulting residue was purified by preparative HPLC (column: Phenomenex luna C18 (250*70 mm, 15 μm); mobile phase: [0.225% formic acid in water-acetonitrile]; acetonitrile: 40%-70%, 35 minutes) to give 14 -13M (mixture of 14-13B, 14-13C and 14-13D). LCMS m/z (ESI): 686.3 (M+1) ⁺ .

14-13A由14-12A按照14-13M的制备方法合成得到。14-13A was synthesized from 14-12A according to the preparation method of 14-13M.

第十三步：Step Thirteen:

向14-13M(920毫克)的二氯甲烷(6毫升)溶液中加入三氟乙酸(3.08克)，该反应在氮气保护下，15摄氏度反应1小时。将反应液减压浓缩得到14-14M(14-14B、14-14C和14-14D的混合物)的三氟乙酸盐粗品，14-14M的三氟乙酸盐，粗品直接用于下一步反应。LCMS m/z(ESI):586.1(M+1) ⁺。 To a solution of 14-13M (920 mg) in dichloromethane (6 mL) was added trifluoroacetic acid (3.08 g) and the reaction was carried out at 15 degrees Celsius for 1 hour under nitrogen. The reaction solution was concentrated under reduced pressure to obtain 14-14M (mixture of 14-14B, 14-14C and 14-14D) crude trifluoroacetate, 14-14M trifluoroacetate, the crude product was directly used in the next reaction . LCMS m/z (ESI): 586.1 (M+1) ⁺ .

14-14A由14-13A按照14-14M的制备方法合成得到。14-14A was synthesized from 14-13A according to the preparation method of 14-14M.

第十四步：Step 14:

向化合物14-14M(1.3克，三氟乙酸盐)的四氢呋喃(20毫升)和水(4毫升)的混合溶液中依次加入碳酸钾(0.66克)和化合物1-5(130.33毫克)，该反应在15摄氏度下反应10分钟。向反应混合物中加入饱和食盐水(20毫升)，乙酸乙酯(30毫升*2)萃取两次，有机相用无水硫酸钠干燥，过滤，浓缩得到残余物。得到的残余物通过制备的HPLC(色谱柱：Phenomenex Synergi Max-RP 250*50mm*10)；流动相：[0.225％的甲酸水溶液-乙腈]；乙腈：15％-45％，20分钟)纯化得到14M(14B、14C和14D的混合物)。To a mixed solution of compound 14-14M (1.3 g, trifluoroacetate) in tetrahydrofuran (20 mL) and water (4 mL) were sequentially added potassium carbonate (0.66 g) and compound 1-5 (130.33 mg), the The reaction was carried out at 15 degrees Celsius for 10 minutes. To the reaction mixture was added saturated brine (20 mL), extracted twice with ethyl acetate (30 mL*2), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The obtained residue was purified by preparative HPLC (column: Phenomenex Synergi Max-RP 250*50mm*10); mobile phase: [0.225% aqueous formic acid-acetonitrile]; acetonitrile: 15%-45%, 20 minutes) to give 14M (mixture of 14B, 14C and 14D).

14A由14-14A按照14M的制备方法合成得到。14A was synthesized from 14-14A according to the preparation method of 14M.

将14M通过制备SFC(柱型号：DAICEL CHIRALPAK IC(250mm*30mm，10μm)，流动相：乙醇(0.1％氨水)，梯度：二氧化碳临界流体60％-60％，4分钟，75分钟)分离纯化得到化合物14B(保留时间＝2.084min)及14-P(保留时间＝1.937min和保留时间＝2.093min的混合物)。14M was separated and purified by preparative SFC (column type: DAICEL CHIRALPAK IC (250mm*30mm, 10μm), mobile phase: ethanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 60%-60%, 4 minutes, 75 minutes) Compounds 14B (retention time = 2.084 min) and 14-P (mixture of retention time = 1.937 min and retention time = 2.093 min).

14-P再通过制备SFC(柱型号：DAICEL CHIRALPAK IG(250mm*30mm，10μm)，流动相：乙醇(0.1％氨水)，梯度：二氧化碳临界流体35％-35％，3分钟，90分钟)分离纯化得到化合物14C(保留时间＝1.387min)和化合物14D(保留时间＝1.910min)。14-P was then separated by preparative SFC (column type: DAICEL CHIRALPAK IG (250mm*30mm, 10μm), mobile phase: ethanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 35%-35%, 3 minutes, 90 minutes) Purification gave compound 14C (retention time = 1.387 min) and compound 14D (retention time = 1.910 min).

化合物14B经SFC检测【柱型号：Chiralpak IG-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为乙醇(0.05％二乙胺)；梯度(B％)：5％-40％】得到：化合物14B的保留时间为2.084min，e.e.值为100％。Compound 14B was detected by SFC [column model: Chiralpak IG-3 50×4.6mm I.D., 3μm; mobile phase: phase A was supercritical carbon dioxide, phase B was ethanol (0.05% diethylamine); gradient (B%): 5 %-40%] obtained: the retention time of compound 14B was 2.084 min, and the e.e. value was 100%.

化合物14C和化合物14D经SFC检测【柱型号：Chiralpak IC-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为甲醇(0.05％二乙胺)；梯度(B％)：40％-40％】得到：化合物14C的保留时间为1.387min，e.e.值为100％；化合物14D的保留时间为1.910min，e.e.值为100％。Compound 14C and compound 14D were detected by SFC [column model: Chiralpak IC-3 50×4.6mm I.D., 3μm; mobile phase: supercritical carbon dioxide in phase A, methanol (0.05% diethylamine) in phase B; gradient (B% ): 40%-40%] obtained: the retention time of compound 14C was 1.387 min, and the e.e. value was 100%; the retention time of compound 14D was 1.910 min, and the e.e. value was 100%.

化合物14A： ¹H NMR(400MHz,DMSO-d ₆)δ8.34(d,J＝4.8Hz,1H),7.23-7.02(m,3H),6.98-6.81(m,2H),6.55(dt,J＝5.6,8.0Hz,1H),6.33-6.19(m,1H),5.82(ddd,J＝2.1,7.3,9.9Hz,1H),5.42(s,2H),4.85-4.48(m,2H),4.13-3.54(m,4H),2.95-2.79(m,1H),2.05(s,3H),1.46-1.34(m,3H),1.31-1.21(m,3H),1.14-1.02(m,6H)。LCMS(ESI)m/z:640.3(M+1) ⁺。 Compound 14A: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.34 (d, J=4.8 Hz, 1H), 7.23-7.02 (m, 3H), 6.98-6.81 (m, 2H), 6.55 (dt, J=5.6,8.0Hz,1H),6.33-6.19(m,1H),5.82(ddd,J=2.1,7.3,9.9Hz,1H),5.42(s,2H),4.85-4.48(m,2H) ,4.13-3.54(m,4H),2.95-2.79(m,1H),2.05(s,3H),1.46-1.34(m,3H),1.31-1.21(m,3H),1.14-1.02(m, 6H). LCMS (ESI) m/z: 640.3 (M+1) ⁺ .

化合物14B(保留时间＝2.084min)： ¹H NMR(400MHz,DMSO-d ₆)δ8.29(d,J＝4.9Hz,1H),7.13-7.05(m,2H),7.00(s,1H),6.84(td,J＝10.7,16.6Hz,1H),6.67(br d,J＝7.9Hz,1H),6.50(dt,J＝5.5,8.1Hz,1H),6.27-6.15(m,1H),5.82-5.71(m,1H),5.43(s,2H),4.84-4.47(m,2H),4.20-3.71(m,4H),2.72(td,J＝6.9,13.4Hz,1H),2.03(d,J＝3.8Hz,3H),1.33(br t,J＝6.8Hz,3H),1.27-1.14(m,3H),1.05(br d,J＝6.6Hz,3H),0.96(d,J＝6.5Hz,3H)。LCMS(ESI)m/z:640.3(M+1) ⁺。 Compound 14B (retention time=2.084 min): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.29 (d, J=4.9 Hz, 1H), 7.13-7.05 (m, 2H), 7.00 (s, 1H) ,6.84(td,J＝10.7,16.6Hz,1H),6.67(br d,J＝7.9Hz,1H),6.50(dt,J＝5.5,8.1Hz,1H),6.27-6.15(m,1H) ,5.82-5.71(m,1H),5.43(s,2H),4.84-4.47(m,2H),4.20-3.71(m,4H),2.72(td,J＝6.9,13.4Hz,1H),2.03 (d, J=3.8Hz, 3H), 1.33 (br t, J=6.8Hz, 3H), 1.27-1.14 (m, 3H), 1.05 (br d, J=6.6Hz, 3H), 0.96 (d, J=6.5Hz, 3H). LCMS (ESI) m/z: 640.3 (M+1) ⁺ .

化合物14C(保留时间＝1.387min)： ¹H NMR(400MHz,DMSO-d ₆)δ8.29(d,J＝4.8Hz,1H),7.19-6.96(m,3H),6.93-6.77(m,1H),6.70(br d,J＝8.1Hz,1H),6.49(dt,J＝5.5,8.1Hz,1H),6.27-6.13(m,1H),5.81-5.70(m,1H),5.38(s,2H),4.81-4.43(m,2H),4.16-3.45(m,4H),2.59(quin,J＝6.7Hz,1H),2.12(s,3H),1.33(br t,J＝6.1Hz,3H),1.26-1.11(m,3H),0.98(dd,J＝6.8,10.1Hz,6H)。LCMS(ESI)m/z:640.3(M+1) ⁺。 Compound 14C (retention time=1.387 min): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.29 (d, J=4.8 Hz, 1H), 7.19-6.96 (m, 3H), 6.93-6.77 (m, 1H),6.70(br d,J=8.1Hz,1H),6.49(dt,J=5.5,8.1Hz,1H),6.27-6.13(m,1H),5.81-5.70(m,1H),5.38( s, 2H), 4.81-4.43 (m, 2H), 4.16-3.45 (m, 4H), 2.59 (quin, J=6.7Hz, 1H), 2.12 (s, 3H), 1.33 (br t, J=6.1 Hz, 3H), 1.26-1.11 (m, 3H), 0.98 (dd, J=6.8, 10.1 Hz, 6H). LCMS (ESI) m/z: 640.3 (M+1) ⁺ .

化合物14D(保留时间＝1.910min)： ¹H NMR(400MHz,DMSO-d ₆)δ8.28(d,J＝4.9Hz,1H),7.13-6.95(m,3H),6.88-6.77(m,2H),6.48(dt,J＝5.6,8.0Hz,1H),6.19(dd,J＝2.4,16.4Hz,1H),5.81-5.70(m,1H),5.36(s,2H),4.82-4.44(m,2H),4.16-3.42(m,4H),3.09-2.92(m,1H),1.90(d,J＝2.4Hz,3H),1.32(br t,J＝6.3Hz,3H),1.25-1.14(m,3H),1.07(br dd,J＝6.5,15.7Hz,6H)。LCMS(ESI)m/z:640.3(M+1) ⁺。 Compound 14D (retention time=1.910 min): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.28 (d, J=4.9 Hz, 1H), 7.13-6.95 (m, 3H), 6.88-6.77 (m, 2H), 6.48(dt, J＝5.6, 8.0Hz, 1H), 6.19(dd, J＝2.4, 16.4Hz, 1H), 5.81-5.70(m, 1H), 5.36(s, 2H), 4.82-4.44 (m, 2H), 4.16-3.42 (m, 4H), 3.09-2.92 (m, 1H), 1.90 (d, J=2.4Hz, 3H), 1.32 (br t, J=6.3Hz, 3H), 1.25 -1.14 (m, 3H), 1.07 (br dd, J=6.5, 15.7Hz, 6H). LCMS (ESI) m/z: 640.3 (M+1) ⁺ .

实施例15Example 15

第一步：first step:

向化合物11-12(400毫克)的四氢呋喃(10毫升)溶液中依次加入三吡咯烷基溴化鏻六氟磷酸盐 (1.01克)、化合物3-2(930.74毫克)和DIEA(280.66毫克)，该反应在氮气保护下，70摄氏度反应10小时。LC-MS检测到目标产物已生成。将反应混合物过滤，滤液浓缩得到化合物15-1。得到的粗品直接用于下一步反应。LCMS m/z(ESI):720.3(M+1) ⁺。 To a solution of compound 11-12 (400 mg) in tetrahydrofuran (10 mL) were added in this order tripyrrolidinophosphonium bromide hexafluorophosphate (1.01 g), compound 3-2 (930.74 mg) and DIEA (280.66 mg), The reaction was carried out under nitrogen protection at 70 degrees Celsius for 10 hours. LC-MS detected the formation of the target product. The reaction mixture was filtered, and the filtrate was concentrated to obtain compound 15-1. The obtained crude product was directly used in the next reaction. LCMS m/z (ESI): 720.3 (M+1) ⁺ .

第二步：Step 2:

向化合物15-1(500毫克)的二氯甲烷(3毫升)溶液中加入三氟乙酸(1.54克)，该反应在氮气保护下，10摄氏度反应20分钟。将反应液浓缩得到化合物15-2的三氟乙酸盐，粗品直接用于下一步反应。LCMS m/z(ESI):620.2(M+1) ⁺。 To a solution of compound 15-1 (500 mg) in dichloromethane (3 mL) was added trifluoroacetic acid (1.54 g), and the reaction was carried out at 10 degrees Celsius for 20 minutes under nitrogen protection. The reaction solution was concentrated to obtain the trifluoroacetate salt of compound 15-2, and the crude product was directly used in the next reaction. LCMS m/z (ESI): 620.2 (M+1) ⁺ .

第三步：third step:

向化合物15-2(600.00毫克，三氟乙酸盐)的四氢呋喃(6毫升)和水(2毫升)混合溶液中依次加入碳酸钾(293.34毫克)和化合物1-5(64.03毫克)，该反应在10摄氏度下反应10分钟。向反应混合物中加入饱和碳酸氢钠水溶液(20毫升)，乙酸乙酯(30毫升*3)萃取三次。有机相用饱和食盐水(20毫升)洗涤一次，无水硫酸钠干燥，过滤，浓缩得到残余物。残余物通过制备板纯化(二氯甲烷呢：甲醇＝20:1)。得到的化合物15。To a mixed solution of compound 15-2 (600.00 mg, trifluoroacetate) in tetrahydrofuran (6 mL) and water (2 mL) were sequentially added potassium carbonate (293.34 mg) and compound 1-5 (64.03 mg), the reaction React at 10 degrees Celsius for 10 minutes. Saturated aqueous sodium bicarbonate solution (20 mL) was added to the reaction mixture, which was extracted three times with ethyl acetate (30 mL*3). The organic phase was washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by preparative plate (dichloromethane:methanol=20:1). Compound 15 was obtained.

化合物15通过制备SFC(柱型号：DAICEL CHIRALPAK IC 250mm*30mm，10μm)，流动相：乙醇(0.1％氨水)，梯度：二氧化碳临界流体55％-55％，38分钟，40分钟)分离纯化得到化合物15A及15-P1。Compound 15 was isolated and purified by preparative SFC (column type: DAICEL CHIRALPAK IC 250mm*30mm, 10μm), mobile phase: ethanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 55%-55%, 38 minutes, 40 minutes) to obtain the compound 15A and 15-P1.

15-P1再通过制备SFC(REGIS(S,S)WHELK-O1 250mm*25mm,10μm)，流动相：乙醇(0.1％氨水)，梯度：二氧化碳临界流体40％-40％，4.3分钟，570分钟)分离纯化得到化合物15B(和15-P2。15-P1 was then prepared by SFC (REGIS(S,S) WHELK-O1 250mm*25mm, 10μm), mobile phase: ethanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 40%-40%, 4.3 minutes, 570 minutes ) was isolated and purified to obtain compound 15B (and 15-P2.

15-P2再通过制备SFC(柱型号：DAICEL CHIRALPAK AD(250mm*30mm，10μm)，流动相：异丙醇(0.1％氨水)，梯度：二氧化碳临界流体35％-35％，4.1分钟，50分钟)分离纯化得到化合物15C，和化合物15D。15-P2 was then passed through preparative SFC (column model: DAICEL CHIRALPAK AD (250mm*30mm, 10μm), mobile phase: isopropanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 35%-35%, 4.1 minutes, 50 minutes ) was isolated and purified to obtain compound 15C and compound 15D.

化合物15A经SFC检测【柱型号：Chiralpak IC-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为甲醇(0.05％二乙胺)；梯度(B％)：40％-40％】得到：化合物15A的保留时间为0.760min，e.e.值为100％。Compound 15A was detected by SFC [column model: Chiralpak IC-3 50×4.6mm I.D., 3μm; mobile phase: phase A was supercritical carbon dioxide, phase B was methanol (0.05% diethylamine); gradient (B%): 40 %-40%] yielded: the retention time of compound 15A was 0.760 min, and the e.e. value was 100%.

化合物15B、化合物15C和化合物15D经SFC检测【柱型号：(s,s)Whelk-OI 100×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为乙醇(0.05％二乙胺)；梯度(B％)：40％-40％】得到：化合物15B的保留时间为2.255min，e.e.值为100％；化合物15C的保留时间为2.641min，e.e.值为100％；化合物15D的保留时间为2.503min，e.e.值为100％。Compound 15B, compound 15C and compound 15D were detected by SFC [column type: (s,s)Whelk-OI 100×4.6mm I.D., 3μm; mobile phase: supercritical carbon dioxide in phase A, ethanol (0.05% diethyl alcohol) in phase B Amine); Gradient (B%): 40%-40%] Obtained: Compound 15B has a retention time of 2.255 min, e.e. value is 100%; Compound 15C has a retention time of 2.641 min, e.e. value is 100%; The retention time was 2.503 min and the e.e. value was 100%.

化合物15A(保留时间＝0.760min)： ¹H NMR(400MHz,DMSO-d ₆)δ8.29(d,J＝4.8Hz,1H),7.30(dd,J＝2.2,11.0Hz,1H),7.10-7.03(m,1H),6.99(s,1H),6.89-6.75(m,2H),6.19(br d,J＝16.5Hz,1H),5.83-5.70(m,1H),5.66(s,2H),4.84-4.47(m,2H),4.20-3.64(m,4H),2.74(td,J＝3.3,6.4Hz,1H),2.01(br d,J＝4.0Hz,3H),1.33(br t,J＝6.7Hz,3H),1.25-1.15(m,3H),1.04(br d,J＝6.4Hz,3H),0.96(br d,J＝6.5Hz,3H)。LCMS(ESI)m/z:674.3(M+1) ⁺。 Compound 15A (retention time = 0.760 min): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.29 (d, J=4.8 Hz, 1H), 7.30 (dd, J=2.2, 11.0 Hz, 1H), 7.10 -7.03(m,1H),6.99(s,1H),6.89-6.75(m,2H),6.19(br d,J=16.5Hz,1H),5.83-5.70(m,1H),5.66(s, 2H), 4.84-4.47(m, 2H), 4.20-3.64(m, 4H), 2.74(td, J=3.3, 6.4Hz, 1H), 2.01(br d, J=4.0Hz, 3H), 1.33( br t, J=6.7Hz, 3H), 1.25-1.15 (m, 3H), 1.04 (br d, J=6.4Hz, 3H), 0.96 (br d, J=6.5Hz, 3H). LCMS (ESI) m/z: 674.3 (M+1) ⁺ .

化合物15B(保留时间＝2.255min)： ¹H NMR(400MHz,DMSO-d ₆)δ8.30(d,J＝4.9Hz,1H),7.30(dd,J＝2.2,10.9Hz,1H),7.14-7.06(m,1H),7.03(s,1H),6.92(s,1H),6.88-6.73(m,1H),6.26-6.15(m,1H),5.81-5.71(m,1H),5.62(s,2H),4.82-4.45(m,2H),4.10-3.76(m,4H),3.55-3.46(m,1H),2.16-2.06(m,3H),1.33(br t,J＝6.0Hz,3H),1.24-1.12(m,3H),0.98(br d,J＝6.6Hz,6H)。LCMS(ESI)m/z:674.2(M+1) ⁺。 Compound 15B (retention time=2.255 min): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.30 (d, J=4.9 Hz, 1H), 7.30 (dd, J=2.2, 10.9 Hz, 1H), 7.14 -7.06(m,1H),7.03(s,1H),6.92(s,1H),6.88-6.73(m,1H),6.26-6.15(m,1H),5.81-5.71(m,1H),5.62 (s,2H),4.82-4.45(m,2H),4.10-3.76(m,4H),3.55-3.46(m,1H),2.16-2.06(m,3H),1.33(br t,J=6.0 Hz, 3H), 1.24-1.12 (m, 3H), 0.98 (br d, J=6.6Hz, 6H). LCMS (ESI) m/z: 674.2 (M+1) ⁺ .

化合物15C(保留时间＝2.641min)： ¹H NMR(400MHz,DMSO-d ₆)δ8.30(d,J＝4.8Hz,1H),7.28(dd,J＝2.3,11.0Hz,1H),7.07-7.02(m,2H),7.01(s,1H),6.84(ddd,J＝5.6,10.6,16.5Hz,1H),6.20(br dd,J＝2.1,16.6Hz,1H),5.76(ddd,J＝2.2,7.4,10.0Hz,1H),5.60(s,2H),4.81-4.45(m,2H),4.17-3.68(m,4H),2.99(td,J＝6.4,13.1Hz,1H),1.91(d,J＝2.5Hz,3H),1.36-1.29(m,3H),1.22-1.13(m,3H),1.10-1.08(m,3H),1.05(s,3H)。LCMS(ESI)m/z:674.2(M+1) ⁺。 Compound 15C (retention time=2.641 min): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.30 (d, J=4.8 Hz, 1H), 7.28 (dd, J=2.3, 11.0 Hz, 1H), 7.07 -7.02(m,2H),7.01(s,1H),6.84(ddd,J=5.6,10.6,16.5Hz,1H),6.20(br dd,J=2.1,16.6Hz,1H),5.76(ddd, J=2.2,7.4,10.0Hz,1H),5.60(s,2H),4.81-4.45(m,2H),4.17-3.68(m,4H),2.99(td,J=6.4,13.1Hz,1H) , 1.91(d, J=2.5Hz, 3H), 1.36-1.29(m, 3H), 1.22-1.13(m, 3H), 1.10-1.08(m, 3H), 1.05(s, 3H). LCMS (ESI) m/z: 674.2 (M+1) ⁺ .

化合物15D(保留时间＝2.503min)： ¹H NMR(400MHz,DMSO-d ₆)δ8.30(d,J＝4.8Hz,1H),7.28(dd,J＝2.3,11.0Hz,1H),7.07-7.02(m,2H),7.01(s,1H),6.84(ddd,J＝5.6,10.6,16.5Hz,1H),6.20(br dd,J＝2.1,16.6Hz,1H),5.76(ddd,J＝2.2,7.4,10.0Hz,1H),5.60(s,2H),4.81-4.45(m,2H),4.17-3.75(m,4H),2.99(td,J＝6.4,13.1Hz,1H),1.91(d,J＝2.5Hz,3H),1.39-1.29(m,3H),1.23-1.13(m,3H),1.10-1.07(m,3H),1.05(s,3H)。LCMS(ESI)m/z:674.2(M+1) ⁺。 Compound 15D (retention time=2.503 min): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.30 (d, J=4.8 Hz, 1H), 7.28 (dd, J=2.3, 11.0 Hz, 1H), 7.07 -7.02(m,2H),7.01(s,1H),6.84(ddd,J=5.6,10.6,16.5Hz,1H),6.20(br dd,J=2.1,16.6Hz,1H),5.76(ddd, J=2.2,7.4,10.0Hz,1H),5.60(s,2H),4.81-4.45(m,2H),4.17-3.75(m,4H),2.99(td,J=6.4,13.1Hz,1H) , 1.91(d, J=2.5Hz, 3H), 1.39-1.29(m, 3H), 1.23-1.13(m, 3H), 1.10-1.07(m, 3H), 1.05(s, 3H). LCMS (ESI) m/z: 674.2 (M+1) ⁺ .

实施例16和实施例17Example 16 and Example 17

第一步：first step:

向中间体A(1.00克)的N,N-二甲基乙酰胺(10毫升)溶液中依次加入三吡咯烷基溴化鏻六氟磷酸盐(1.91克)、化合物3-1(1.75克)和DIEA(0.53克)，该反应在氮气保护下，70摄氏度反应10小时。将反应液倒入水(30毫升)中，有固体析出，过滤，滤饼干燥得到粗品。粗品通过制备的HPLC(色谱柱：Phenomenex luna C18(250*70mm,10μm)；流动相：[0.225％的甲酸水溶液-乙腈]；乙腈：30％-50％，35分钟)纯化得到消旋体。消旋体通过制备SFC(柱型号：DAICEL CHIRALPAK IC(250mm*30mm，10μm)，流动相：乙醇(0.1％氨水)，梯度：二氧化碳临界流体40％-40％，4.4分钟，45分钟)分离纯化得到化合物16-1A(保留时间＝0.615min)及化合物16-1B(保留时间＝1.066分钟)。To a solution of Intermediate A (1.00 g) in N,N-dimethylacetamide (10 mL) were added tripyrrolidinophosphonium bromide hexafluorophosphate (1.91 g), compound 3-1 (1.75 g) in this order and DIEA (0.53 g), the reaction was carried out under nitrogen protection at 70 degrees Celsius for 10 hours. The reaction solution was poured into water (30 mL), a solid was precipitated, filtered, and the filter cake was dried to obtain a crude product. The crude product was purified by preparative HPLC (column: Phenomenex luna C18 (250*70 mm, 10 μm); mobile phase: [0.225% formic acid in water-acetonitrile]; acetonitrile: 30%-50%, 35 minutes) to give the racemate. The racemate was separated and purified by preparative SFC (column type: DAICEL CHIRALPAK IC (250mm*30mm, 10μm), mobile phase: ethanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 40%-40%, 4.4 minutes, 45 minutes) Compound 16-1A (retention time=0.615 min) and compound 16-1B (retention time=1.066 min) were obtained.

化合物16-1A(保留时间＝0.615分钟)：LCMS m/z(ESI):686.3(M+1)+。Compound 16-1A (retention time = 0.615 min): LCMS m/z (ESI): 686.3 (M+1)+.

化合物16-1B(保留时间＝1.910分钟)：LCMS m/z(ESI):686.3(M+1)+。Compound 16-1B (retention time = 1.910 min): LCMS m/z (ESI): 686.3 (M+1)+.

第二步：Step 2:

分别向化合物16-1A和16-1B(280毫克)的乙腈(10毫升)溶液中依次加入N-氯代丁二酰亚胺(52.86毫克)和对甲基苯磺酸(68.17毫克)，该反应在氮气保护下，60摄氏度反应1小时。向反应液中加入饱和的亚硫酸钠水溶液(20毫升)，乙酸乙酯(30毫升*2)萃取两次。有机相用饱和食盐水(20毫升)洗涤一次，无水硫酸钠干燥，过滤，浓缩到残余物。残余物经硅胶板纯化(石油醚：乙酸乙酯：甲醇＝8：3：1)分别得到化合物16-2A和化合物17-1A、化合物16-2B和化合物17-1B。To a solution of compounds 16-1A and 16-1B (280 mg) in acetonitrile (10 mL), respectively, were added N-chlorosuccinimide (52.86 mg) and p-toluenesulfonic acid (68.17 mg), respectively. The reaction was carried out at 60 degrees Celsius for 1 hour under nitrogen protection. Saturated aqueous sodium sulfite solution (20 mL) was added to the reaction solution, followed by extraction with ethyl acetate (30 mL*2) twice. The organic phase was washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to a residue. The residue was purified by silica gel plate (petroleum ether:ethyl acetate:methanol=8:3:1) to obtain compound 16-2A and compound 17-1A, compound 16-2B and compound 17-1B, respectively.

16-2A和16-2B:LCMS m/z(ESI):720.3(M+1) ⁺。 16-2A and 16-2B: LCMS m/z (ESI): 720.3 (M+1) ⁺ .

17-1A和17-1B:LCMS m/z(ESI):720.1(M+1) ⁺。 17-1A and 17-1B: LCMS m/z (ESI): 720.1 (M+1) ⁺ .

化合物16-2A： ¹H NMR(400MHz,CHLOROFORM-d)δ8.37(d,J＝4.9Hz,1H),7.24-7.18(m,1H),6.96-6.88(m,2H),6.42(t,J＝8.9Hz,1H),4.83-4.62(m,1H),4.58-4.29(m,1H),3.97-3.84(m,1H),3.78-3.71(m,1H),3.48(br d,J＝13.5Hz,1H),2.63-2.57(m,1H),2.01(s,3H),1.44(s,9H),1.36(br d,J＝6.5Hz,3H),1.21-1.19(m,3H),1.12(d,J＝6.6Hz,3H),1.02(d,J＝6.8Hz,3H)。 Compound 16-2A: ¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.37 (d, J=4.9 Hz, 1H), 7.24-7.18 (m, 1H), 6.96-6.88 (m, 2H), 6.42 (t , J=8.9Hz, 1H), 4.83-4.62(m, 1H), 4.58-4.29(m, 1H), 3.97-3.84(m, 1H), 3.78-3.71(m, 1H), 3.48(br d, J=13.5Hz, 1H), 2.63-2.57(m, 1H), 2.01(s, 3H), 1.44(s, 9H), 1.36(br d, J=6.5Hz, 3H), 1.21-1.19(m, 3H), 1.12 (d, J=6.6 Hz, 3H), 1.02 (d, J=6.8 Hz, 3H).

第三步：third step:

分别向化合物16-2A、化合物17-1A、化合物16-2B和化合物17-1B(90毫克)的二氯甲烷(1.5毫升)溶液中加入三氟乙酸(770.00毫克)，该反应在氮气保护下，10摄氏度反应0.5小时。分别将反应液浓缩得到化合物16-3A的三氟乙酸盐、化合物17-2A的三氟乙酸盐、化合物16-3B的三氟乙酸盐和化合物17-2B的三氟乙酸盐，粗品直接用于下一步反应。To a solution of compound 16-2A, compound 17-1A, compound 16-2B and compound 17-1B (90 mg) in dichloromethane (1.5 mL) was added trifluoroacetic acid (770.00 mg), respectively, and the reaction was carried out under nitrogen protection , 10 degrees Celsius for 0.5 hours. The reaction solution was concentrated to obtain the trifluoroacetate salt of compound 16-3A, the trifluoroacetate salt of compound 17-2A, the trifluoroacetate salt of compound 16-3B and the trifluoroacetate salt of compound 17-2B, The crude product was directly used in the next reaction.

16-3A和16-3B:LCMS m/z(ESI):620.3(M+1) ⁺。 16-3A and 16-3B: LCMS m/z (ESI): 620.3 (M+1) ⁺ .

17-2A和17-2B:LCMS m/z(ESI):620.0(M+1) ⁺。 17-2A and 17-2B: LCMS m/z (ESI): 620.0 (M+1) ⁺ .

第四步：the fourth step:

分别向化合物16-3A、化合物17-2A、化合物16-3B和化合物17-2B(101.00毫克，三氟乙酸盐)的四氢呋喃(6毫升)和水(2毫升)混合溶液中依次加入碳酸钾(49.38毫克)和化合物1-5(10.78毫克)，该反应在10摄氏度下反应20分钟。向反应混合物中加入饱和碳酸氢钠水溶液(20毫升)，乙酸乙酯(20毫升*3)萃取三次。有机相用饱和食盐水(20毫升)洗涤一次，无水硫酸钠干燥，过滤，浓缩得到残余物。得到的残余物分别通过制备的HPLC(色谱柱：Phenomenex Luna C18 150*25mm*10μm)；流动相：[0.225％的甲酸水溶液-乙腈]；梯度：22％-52％，20分钟)纯化得到实施例16A、16B、17A和17B。To a mixed solution of compound 16-3A, compound 17-2A, compound 16-3B and compound 17-2B (101.00 mg, trifluoroacetate) in tetrahydrofuran (6 mL) and water (2 mL), potassium carbonate was sequentially added (49.38 mg) and compound 1-5 (10.78 mg), the reaction was carried out at 10 degrees Celsius for 20 minutes. Saturated aqueous sodium bicarbonate solution (20 mL) was added to the reaction mixture, which was extracted three times with ethyl acetate (20 mL*3). The organic phase was washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The obtained residues were purified by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10μm); mobile phase: [0.225% formic acid in water-acetonitrile]; gradient: 22%-52%, 20 minutes) Examples 16A, 16B, 17A and 17B.

化合物16A: ¹H NMR(400MHz,DMSO-d ₆)δ8.30(d,J＝4.9Hz,1H),7.35(dd,J＝5.8,8.9Hz,1H),7.12-7.00(m,2H),6.92-6.72(m,1H),6.46(t,J＝9.1Hz,1H),6.20(br d,J＝16.6Hz,1H),6.00(s,2H),5.81-5.67(m,1H),4.85-4.46(m,2H),4.21-3.66(m,4H),2.72-2.60(m,1H),2.03(d,J＝3.4Hz,3H),1.33(t,J＝7.4Hz,3H),1.28-1.17(m,3H),1.07-1.00(m,3H),0.93(d,J＝6.6Hz,3H)。LCMS m/z(ESI):674.2(M+1) ⁺。 Compound 16A: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.30 (d, J=4.9 Hz, 1H), 7.35 (dd, J=5.8, 8.9 Hz, 1H), 7.12-7.00 (m, 2H) ,6.92-6.72(m,1H),6.46(t,J＝9.1Hz,1H),6.20(br d,J＝16.6Hz,1H),6.00(s,2H),5.81-5.67(m,1H) ,4.85-4.46(m,2H),4.21-3.66(m,4H),2.72-2.60(m,1H),2.03(d,J=3.4Hz,3H),1.33(t,J=7.4Hz,3H ), 1.28-1.17 (m, 3H), 1.07-1.00 (m, 3H), 0.93 (d, J=6.6Hz, 3H). LCMS m/z (ESI): 674.2 (M+1) ⁺ .

化合物16B： ¹H NMR(400MHz,DMSO-d ₆)δ8.30(br d,J＝4.5Hz,1H),7.35(br dd,J＝5.8,8.3Hz,1H),7.06(br s,2H),6.92-6.75(m,1H),6.46(br t,J＝8.9Hz,1H),6.19(br d,J＝16.5Hz,1H),5.97(br s,2H),5.83-5.66(m,1H),4.834.44(m,2H),4.18-3.66(m,4H),2.90-2.73(m,1H),1.92(br s,3H),1.33(br t,J＝6.4Hz,3H),1.28-1.13(m,3H),1.03(br d,J＝5.8Hz,6H)。LCMS m/z(ESI):674.2(M+1) ⁺。 Compound 16B: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.30 (br d, J=4.5 Hz, 1H), 7.35 (br d, J=5.8, 8.3 Hz, 1H), 7.06 (br s, 2H) ),6.92-6.75(m,1H),6.46(br t,J=8.9Hz,1H),6.19(br d,J=16.5Hz,1H),5.97(br s,2H),5.83-5.66(m ,1H),4.834.44(m,2H),4.18-3.66(m,4H),2.90-2.73(m,1H),1.92(br s,3H),1.33(br t,J=6.4Hz,3H ), 1.28-1.13 (m, 3H), 1.03 (br d, J=5.8Hz, 6H). LCMS m/z (ESI): 674.2 (M+1) ⁺ .

化合物17A： ¹H NMR(400MHz,DMSO-d ₆)δ8.31(d,J＝4.8Hz,1H),7.26(t,J＝8.7Hz,1H),7.11-7.02(m,2H),6.83(td,J＝10.9,16.5Hz,1H),6.52(dd,J＝1.3,9.2Hz,1H),6.26-6.14(m,1H),5.89(s,2H),5.75(ddd,J＝2.3,6.1,10.3Hz,1H),4.85-4.45(m,2H),4.21-3.40(m,4H),2.73-2.61(m,1H),2.01(d,J＝3.5Hz,3H),1.37-1.28(m,3H),1.27-1.15(m,3H),1.04(d,J＝6.6Hz,3H),0.95(d,J＝6.6Hz,3H)。LCMS m/z(ESI):674.3(M+1) ⁺。 Compound 17A: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.31 (d, J=4.8 Hz, 1H), 7.26 (t, J=8.7 Hz, 1H), 7.11-7.02 (m, 2H), 6.83 (td, J=10.9, 16.5Hz, 1H), 6.52 (dd, J=1.3, 9.2Hz, 1H), 6.26-6.14 (m, 1H), 5.89 (s, 2H), 5.75 (ddd, J=2.3 ,6.1,10.3Hz,1H),4.85-4.45(m,2H),4.21-3.40(m,4H),2.73-2.61(m,1H),2.01(d,J=3.5Hz,3H),1.37- 1.28 (m, 3H), 1.27-1.15 (m, 3H), 1.04 (d, J=6.6 Hz, 3H), 0.95 (d, J=6.6 Hz, 3H). LCMS m/z (ESI): 674.3 (M+1) ⁺ .

化合物17B： ¹H NMR(400MHz,DMSO-d ₆)δ8.30(d,J＝4.9Hz,1H),7.25(t,J＝8.7Hz,1H),7.11-7.04(m,2H),6.83(td,J＝9.7,16.6Hz,1H),6.52(dd,J＝1.2,9.2Hz,1H),6.25-6.14(m,1H),5.88(s,2H), 5.80-5.70(m,1H),4.82-4.43(m,2H),4.14-3.47(m,4H),2.78(qd,J＝6.6,13.3Hz,1H),1.95(s,3H),1.37-1.29(m,3H),1.24-1.14(m,3H),1.03-0.97(m,6H)。LCMS m/z(ESI):674.3(M+1) ⁺。 Compound 17B: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.30 (d, J=4.9 Hz, 1H), 7.25 (t, J=8.7 Hz, 1H), 7.11-7.04 (m, 2H), 6.83 (td,J=9.7,16.6Hz,1H),6.52(dd,J=1.2,9.2Hz,1H),6.25-6.14(m,1H),5.88(s,2H), 5.80-5.70(m,1H) ), 4.82-4.43(m, 2H), 4.14-3.47(m, 4H), 2.78(qd, J=6.6, 13.3Hz, 1H), 1.95(s, 3H), 1.37-1.29(m, 3H), 1.24-1.14 (m, 3H), 1.03-0.97 (m, 6H). LCMS m/z (ESI): 674.3 (M+1) ⁺ .

实施例18Example 18

第一步：first step:

在0摄氏度下，向化合物18-1(5克)的乙腈(50毫升)溶液中一次性加入碳酸钾(1.59克)及化合物7-2(4.71克)。反应液在25-30摄氏度下反应12个小时。反应液浓缩得到残余物，用乙酸乙酯(20毫升*3)萃取，有机相用无水硫酸钠干燥，过滤，浓缩滤液得到化合物18-2。LCMS(ESI)m/z:275.04(M+1) ⁺。 To a solution of compound 18-1 (5 g) in acetonitrile (50 mL) at 0 degrees Celsius, potassium carbonate (1.59 g) and compound 7-2 (4.71 g) were added in one portion. The reaction solution was reacted at 25-30 degrees Celsius for 12 hours. The reaction solution was concentrated to obtain a residue, which was extracted with ethyl acetate (20 mL*3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 18-2. LCMS (ESI) m/z: 275.04 (M+1) ⁺ .

第二步：Step 2:

在0摄氏度下，向化合物18-2(5克)的乙腈(50毫升)溶液中一次性加入碳酸铯(5.94克)及4-乙氧基-1,1,1,-三氟-3-丁烯-2-酮(3.22克)。反应液在25-30摄氏度下反应1个小时。反应液浓缩得到残余物，用乙酸乙酯(20毫升*3)萃取，有机相用无水硫酸钠干燥，过滤，浓缩滤液得到化合物18-3。LCMS(ESI)m/z:397.04(M+1) ⁺。 To a solution of compound 18-2 (5 g) in acetonitrile (50 mL) at 0 degrees Celsius was added cesium carbonate (5.94 g) and 4-ethoxy-1,1,1,-trifluoro-3- in one portion Buten-2-one (3.22 g). The reaction solution was reacted at 25-30 degrees Celsius for 1 hour. The reaction solution was concentrated to obtain a residue, which was extracted with ethyl acetate (20 mL*3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 18-3. LCMS (ESI) m/z: 397.04 (M+1) ⁺ .

第三步：third step:

在20-30摄氏度下，向化合物18-3(5克)的三氟乙醇(50毫升)溶液中一次性加入三乙胺(2.55克)。反应液在80摄氏度下反应12个小时。反应液浓缩得到残余物，用水(50毫升)稀释后加氢氧化钠(4摩尔/升)调节pH到8，用乙酸乙酯(20毫升*3)萃取，合并水相用盐酸(1摩尔/升)调节pH 到3后，用乙酸乙酯(20毫升*3)萃取，合并有机相用无水硫酸钠干燥，过滤，浓缩滤液得到化合物18-4。LCMS(ESI)m/z:365.01(M+1) ⁺。 To a solution of compound 18-3 (5 g) in trifluoroethanol (50 mL) was added triethylamine (2.55 g) in one portion at 20-30 degrees Celsius. The reaction solution was reacted at 80 degrees Celsius for 12 hours. The reaction solution was concentrated to obtain a residue, which was diluted with water (50 mL) and sodium hydroxide (4 mol/L) was added to adjust the pH to 8, extracted with ethyl acetate (20 mL*3), and the combined aqueous phases were washed with hydrochloric acid (1 mol/L). L) after adjusting the pH to 3, extract with ethyl acetate (20 mL*3), combine the organic phases and dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain compound 18-4. LCMS (ESI) m/z: 365.01 (M+1) ⁺ .

第四步：the fourth step:

在0摄氏度下，向化合物18-4(2克)的乙腈(20毫升)溶液中一次性加入三溴吡啶(3.51克)及磷酸钾(1.40克)。反应液在80摄氏度下反应12个小时。反应液浓缩得到残余物，用水(20毫升)稀释后，用乙酸乙酯(10毫升*3)萃取，合并有机相用无水硫酸钠干燥，过滤，浓缩滤液得到化合物18-5。LCMS(ESI)m/z:398.93(M+1) ⁺。 To a solution of compound 18-4 (2 g) in acetonitrile (20 mL) at 0 degrees Celsius was added tribromopyridine (3.51 g) and potassium phosphate (1.40 g) in one portion. The reaction solution was reacted at 80 degrees Celsius for 12 hours. The reaction solution was concentrated to obtain a residue, diluted with water (20 mL), extracted with ethyl acetate (10 mL*3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 18-5. LCMS (ESI) m/z: 398.93 (M+1) ⁺ .

第五步：the fifth step:

在20-30摄氏度下，向化合物18-5(3.5克)的二氧六环(35毫升)溶液中一次性加入碳酸铯(5.72克)、4,5-双二苯基磷-9,9-二甲基杂氧杂蒽(507.48毫克)、三(二亚苄基丙酮)二钯(401.56毫克)及2-异丙基-4-甲基吡啶-3-胺(1.58克)。反应液在100摄氏度下反应12个小时。反应液浓缩得到残余物，用水(20毫升)稀释后，用乙酸乙酯(10毫升*3)萃取，合并有机相用无水硫酸钠干燥，过滤，浓缩滤液得到化合物18-6。LCMS(ESI)m/z:469.12(M+1) ⁺。 To a solution of compound 18-5 (3.5 g) in dioxane (35 ml) at 20-30 degrees Celsius was added cesium carbonate (5.72 g), 4,5-bisdiphenylphosphonium-9,9 in one portion - Dimethylxanthene (507.48 mg), tris(dibenzylideneacetone)dipalladium (401.56 mg) and 2-isopropyl-4-methylpyridin-3-amine (1.58 g). The reaction solution was reacted at 100 degrees Celsius for 12 hours. The reaction solution was concentrated to obtain a residue, diluted with water (20 mL), extracted with ethyl acetate (10 mL*3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 18-6. LCMS (ESI) m/z: 469.12 (M+1) ⁺ .

第六步：Step 6:

在0摄氏度下，向化合物18-6(275毫克)的二氯甲烷(5毫升)溶液中一次性加入N-溴代丁二酰亚胺(125.4毫克)。反应液在25摄氏度下反应2个小时。向反应液中加入饱和亚硫酸钠水溶液淬灭反应后，浓缩得到残余物，用水(20毫升)稀释，用乙酸乙酯(10毫升*3)萃取，合并有机相用无水硫酸钠干燥，过滤，浓缩滤液得到化合物18-7。LCMS(ESI)m/z:547.03(M+1) ⁺。 To a solution of compound 18-6 (275 mg) in dichloromethane (5 mL) at 0 degrees Celsius was added N-bromosuccinimide (125.4 mg) in one portion. The reaction solution was reacted at 25 degrees Celsius for 2 hours. After adding saturated aqueous sodium sulfite solution to the reaction solution to quench the reaction, the residue was concentrated to obtain a residue, which was diluted with water (20 mL), extracted with ethyl acetate (10 mL*3), the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated The filtrate gave compound 18-7. LCMS (ESI) m/z: 547.03 (M+1) ⁺ .

第七步：Step 7:

在20-30摄氏度下，向化合物18-7(300毫克)的乙醇与水(5:1)混合溶液中(5毫升)一次性加入氯化铵(146.61毫克)和还原性铁粉(153.06毫克。反应液在80摄氏度下反应12个小时。反应液过滤浓缩得到残余物，用水(10毫升)稀释，用乙酸乙酯(10毫升*3)萃取，合并有机相，用无水硫酸钠干燥，过滤，浓缩滤液得到化合物18-8。LCMS(ESI)m/z:517.06(M+1) ⁺。 To a mixed solution (5 mL) of compound 18-7 (300 mg) in ethanol and water (5:1) at 20-30 degrees Celsius, ammonium chloride (146.61 mg) and reduced iron powder (153.06 mg) were added in one portion The reaction solution was reacted at 80 degrees Celsius for 12 hours. The reaction solution was filtered and concentrated to obtain a residue, diluted with water (10 mL), extracted with ethyl acetate (10 mL*3), combined with the organic phases, dried over anhydrous sodium sulfate, Filtration and concentration of the filtrate gave compound 18-8. LCMS (ESI) m/z: 517.06 (M+1) ⁺ .

第八步：Step 8:

在20-30摄氏度下，向化合物18-8(354毫克)的N,N-二甲基甲酰胺(5毫升)溶液中一次性加入锌粉(22.37毫克)、氰化锌(64.29毫克)、溴化锌(7.71毫克)、三(二亚苄基丙酮)二钯(401.56毫克)及1,1-双(二苯基磷)二茂氯化钯(75.88克)。反应液在120摄氏度下反应12个小时。反应液过滤后用乙酸乙酯洗涤3次(5毫升*3)浓缩得到残余物，用水(10毫升)稀释后，用乙酸乙酯(10毫升*3)萃取，合并有机相用无水硫酸钠干燥，过滤，浓缩滤液得到化合物18-9。LCMS(ESI)m/z:464.14(M+1) ⁺。 To a solution of compound 18-8 (354 mg) in N,N-dimethylformamide (5 mL) at 20-30 degrees Celsius was added zinc powder (22.37 mg), zinc cyanide (64.29 mg), Zinc bromide (7.71 mg), tris(dibenzylideneacetone)dipalladium (401.56 mg) and 1,1-bis(diphenylphosphonium)bis(diphenylphosphonium)palladium chloride (75.88 g). The reaction solution was reacted at 120 degrees Celsius for 12 hours. The reaction solution was filtered, washed with ethyl acetate three times (5 mL*3) and concentrated to obtain a residue, diluted with water (10 mL), extracted with ethyl acetate (10 mL*3), and the organic phases were combined with anhydrous sodium sulfate. Dry, filter, and concentrate the filtrate to give compound 18-9. LCMS (ESI) m/z: 464.14 (M+1) ⁺ .

第九步：Step 9:

在20-30摄氏度下，将化合物18-9(2克)直接溶解在浓硫酸(5毫升)溶液中。反应液在60摄氏度下反应12个小时。反应液直接滴加到冰水(10毫升)溶液淬灭反应，用饱和的碳酸氢钠水溶液调节pH到8后，用乙酸乙酯(10毫升*3)萃取浓缩得到残余物，合并有机相用无水硫酸钠干燥，过滤，浓缩滤液得到化合物18-10。LCMS(ESI)m/z:482.15(M+1) ⁺。 Compound 18-9 (2 g) was directly dissolved in concentrated sulfuric acid (5 mL) solution at 20-30 degrees Celsius. The reaction solution was reacted at 60 degrees Celsius for 12 hours. The reaction solution was directly added dropwise to an ice-water (10 mL) solution to quench the reaction, adjusted to pH 8 with saturated aqueous sodium bicarbonate solution, extracted and concentrated with ethyl acetate (10 mL*3) to obtain a residue, and the organic phases were combined and used Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain compound 18-10. LCMS (ESI) m/z: 482.15 (M+1) ⁺ .

第十步：Step 10:

在0摄氏度下，向化合物18-10(1.16克)的四氢呋喃(12毫升)溶液中一次性加入羰基二咪唑(1.17克)及钠氢(481.91毫克，质量百分比：60％)。反应液在25摄氏度下反应2个小时。反应液加入到饱和氯化铵水溶液淬灭反应后，用乙酸乙酯(10毫升*3)萃取浓缩得到残余物，合并有机相用无水硫酸钠干燥，过滤，浓缩滤液得到化合物18-11。LCMS(ESI)m/z:508.13(M+1) ⁺。 To a solution of compound 18-10 (1.16 g) in tetrahydrofuran (12 mL) at 0 degrees Celsius, carbonyldiimidazole (1.17 g) and sodium hydrogen (481.91 mg, mass percentage: 60%) were added in one portion. The reaction solution was reacted at 25 degrees Celsius for 2 hours. The reaction solution was added to saturated aqueous ammonium chloride solution to quench the reaction, extracted and concentrated with ethyl acetate (10 mL*3) to obtain a residue, the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 18-11. LCMS (ESI) m/z: 508.13 (M+1) ⁺ .

第十一步：Step 11:

在20-30摄氏度下，向化合物18-11(300毫克)的四氢呋喃(3毫升)溶液中一次性加入三吡咯烷基溴化磷六氟磷酸盐(1.10克)、二异丙基乙胺(152.82毫克)及化合物3-1(633.54毫克)。反应液在60摄氏度下反应12个小时。反应液用水(20毫升)稀释后，用乙酸乙酯(10mL*3)萃取浓缩得到残余物，合并有机相用无水硫酸钠干燥，过滤，浓缩滤液得到化合物18-12。LCMS(ESI)m/z:704.29(M+1) ⁺。 To a solution of compound 18-11 (300 mg) in tetrahydrofuran (3 mL) at 20-30 °C was added tripyrrolidinophosphonium bromide hexafluorophosphate (1.10 g), diisopropylethylamine ( 152.82 mg) and compound 3-1 (633.54 mg). The reaction solution was reacted at 60 degrees Celsius for 12 hours. The reaction solution was diluted with water (20 mL), extracted with ethyl acetate (10 mL*3) and concentrated to obtain a residue. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 18-12. LCMS (ESI) m/z: 704.29 (M+1) ⁺ .

第十二步：Step 12:

在20-30摄氏度下，向化合物18-12(245毫克)的二氯甲烷(3毫升)溶液中一次性加入三氟乙酸(1.80克)。反应液在25摄氏度下反应1个小时。反应液浓缩得到化合物18-13的三氟乙酸盐。LCMS(ESI)m/z:604.24(M+1) ⁺。粗品直接用于下一步。 To a solution of compound 18-12 (245 mg) in dichloromethane (3 mL) was added trifluoroacetic acid (1.80 g) in one portion at 20-30 degrees Celsius. The reaction solution was reacted at 25 degrees Celsius for 1 hour. The reaction solution was concentrated to obtain the trifluoroacetate salt of compound 18-13. LCMS (ESI) m/z: 604.24 (M+1) ⁺ . The crude product was used directly in the next step.

第十三步：Step Thirteen:

在0摄氏度下，向化合物18-13(220毫克，TFA盐)的四氢呋喃(3.0毫升)和水(0.5毫升)的混合溶液中依次一次性加入无水碳酸钾(251.88毫克)，丙烯酰氯(16.49毫克)。反应液在0摄氏度下反应0.5小时。向反应液中加入水(10毫升)，用乙酸乙酯(10毫升*3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液浓缩得到残余物。残余物先经制备柱纯化HPLC(柱型号：Phenomenex Synergi C18150*25mm*10μm)，流动相(0.225％甲酸水：乙腈)，梯度：21％-54％，11分钟，得到化合物18。To a mixed solution of compound 18-13 (220 mg, TFA salt) in tetrahydrofuran (3.0 mL) and water (0.5 mL) at 0 degrees Celsius, anhydrous potassium carbonate (251.88 mg), acryloyl chloride (16.49 mL) were sequentially added in one portion. mg). The reaction solution was reacted at 0 degrees Celsius for 0.5 hours. Water (10 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was first purified by preparative column HPLC (column model: Phenomenex Synergi C18150*25mm*10μm), mobile phase (0.225% formic acid water:acetonitrile), gradient: 21%-54%, 11 minutes to obtain compound 18.

化合物18通过制备SFC(柱型号：DAICEL CHIRALPAK IC(250mm*30mm，10μm)，流动相：甲醇(0.1％氨水)，梯度：二氧化碳临界流体40％-40％，5分钟，40分钟)分离纯化得到化合物18A及18-P1。Compound 18 was isolated and purified by preparative SFC (column type: DAICEL CHIRALPAK IC (250mm*30mm, 10μm), mobile phase: methanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 40%-40%, 5 minutes, 40 minutes) Compounds 18A and 18-P1.

18-P1再通过制备SFC(柱型号：DAICEL CHIRALCELOD-H(250mm*30mm，5μm)，流动相：异丙醇(0.1％氨水)，梯度：二氧化碳临界流体30％-30％，5分钟，40分钟)分离纯化得到化合物18B，和18-P2。18-P1 was then passed through preparative SFC (column model: DAICEL CHIRALCELOD-H (250mm*30mm, 5μm), mobile phase: isopropanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 30%-30%, 5 minutes, 40 min) isolation and purification to obtain compound 18B, and 18-P2.

18-P2再通过制备SFC(柱型号：Kromasil(S,S)Whelk-O1(250mm*30mm，5μm)，流动相：异丙醇(0.05％二乙胺)，梯度：二氧化碳临界流体40％-40％，5分钟，40分钟)分离纯化得到化合物18C 和化合物18D。18-P2 was then passed through preparative SFC (column type: Kromasil (S, S) Whelk-O1 (250mm*30mm, 5μm), mobile phase: isopropanol (0.05% diethylamine), gradient: carbon dioxide critical fluid 40%- 40%, 5 min, 40 min) to separate and purify compound 18C and compound 18D.

化合物18A经SFC检测【柱型号：Chiralpak IC-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为甲醇(0.05％二乙胺)；梯度(B％)：5％-40％】得到：化合物18A的保留时间为1.952min，e.e.值为100％。Compound 18A was detected by SFC [column type: Chiralpak IC-3 50×4.6mm I.D., 3μm; mobile phase: phase A was supercritical carbon dioxide, phase B was methanol (0.05% diethylamine); gradient (B%): 5 %-40%] obtained: the retention time of compound 18A was 1.952 min, and the e.e. value was 100%.

化合物18B经SFC检测【柱型号：CHIRALPAK OD 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为乙醇(0.05％二乙胺)；梯度(B％)：5％-40％】得到：化合物18B的保留时间为1.471min，e.e.值为100％。Compound 18B was detected by SFC [column model: CHIRALPAK OD 50×4.6mm I.D., 3μm; mobile phase: phase A was supercritical carbon dioxide, phase B was ethanol (0.05% diethylamine); gradient (B%): 5%- 40%] obtained: the retention time of compound 18B was 1.471 min, and the e.e. value was 100%.

化合物18C和化合物18D经SFC检测【柱型号：Chiralpak IC-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为甲醇(0.05％二乙胺)；梯度(B％)：40％-40％】得到：化合物18C的保留时间为1.900min，e.e.值为100％；化合物18D的保留时间为2.322min，e.e.值为100％。化合物18A： ¹H NMR(400MHz,DMSO-d ₆)δ8.31-8.31(m,1H),7.06-7.03(m,2H),6.85-6.78(m,1H),6.38-6.19(m,3H),6.21-6.03(m,2H),6.17-5.13(m,1H),4.79-4.52(m,2H),3.93-3.92(m,3H),3.46-3.39(m,1H),3.25-3.24(m,1H),2.00-2.00(m,3H),1.34-1.31(m,3H),1.25-1.16(m,3H),1.05-1.03(m,3H),0.95-0.93(m,3H)。LCMS(ESI)m/z:658.2(M+1) ⁺。 Compound 18C and compound 18D were detected by SFC [column model: Chiralpak IC-3 50×4.6mm ID, 3μm; mobile phase: supercritical carbon dioxide in phase A, methanol (0.05% diethylamine) in phase B; gradient (B% ): 40%-40%] obtained: the retention time of compound 18C was 1.900 min, and the ee value was 100%; the retention time of compound 18D was 2.322 min, and the ee value was 100%. Compound 18A: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.31-8.31 (m, 1H), 7.06-7.03 (m, 2H), 6.85-6.78 (m, 1H), 6.38-6.19 (m, 3H) ), 6.21-6.03(m, 2H), 6.17-5.13(m, 1H), 4.79-4.52(m, 2H), 3.93-3.92(m, 3H), 3.46-3.39(m, 1H), 3.25-3.24 (m,1H),2.00-2.00(m,3H),1.34-1.31(m,3H),1.25-1.16(m,3H),1.05-1.03(m,3H),0.95-0.93(m,3H) . LCMS (ESI) m/z: 658.2 (M+1) ⁺ .

化合物18B： ¹H NMR(400MHz,DMSO-d ₆)δ8.32-8.30(m,1H),7.09-7.08(m,2H),6.84-6.77(m,1H),6.35-6.15(m,3H),6.02-5.99(m,2H),5.770-5.716(m,1H),4.74-4.46(m,2H),3.96-3.73(m,3H),3.46-3.43(m,1H),3.26-3.23(m,1H),2.09(m,3H),1.34-1.15(m,6H),0.90-0.91(m,6H)。LCMS(ESI)m/z:658.2(M+1) ⁺。 Compound 18B: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.32-8.30 (m, 1H), 7.09-7.08 (m, 2H), 6.84-6.77 (m, 1H), 6.35-6.15 (m, 3H) ),6.02-5.99(m,2H),5.770-5.716(m,1H),4.74-4.46(m,2H),3.96-3.73(m,3H),3.46-3.43(m,1H),3.26-3.23 (m, 1H), 2.09 (m, 3H), 1.34-1.15 (m, 6H), 0.90-0.91 (m, 6H). LCMS (ESI) m/z: 658.2 (M+1) ⁺ .

化合物18C：1H NMR(400MHz,DMSO-d ₆)δ8.30-8.29(m,1H),7.07-7.02(m,2H),6.85-6.78(m,1H),6.34-6.16(m,3H),6.01(m,2H),5.77-5.72(m,1H),4.74-4.48(m,2H),4.00-3.76(m,3H),3.48-3.45(m,1H),3.43-3.42(m,1H),1.85(m,3H),1.32-1.14(m,6H),1.08-1.00(m,6H)。LCMS(ESI)m/z:658.2(M+1) ⁺。 Compound 18C: 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.30-8.29 (m, 1H), 7.07-7.02 (m, 2H), 6.85-6.78 (m, 1H), 6.34-6.16 (m, 3H) ,6.01(m,2H),5.77-5.72(m,1H),4.74-4.48(m,2H),4.00-3.76(m,3H),3.48-3.45(m,1H),3.43-3.42(m, 1H), 1.85 (m, 3H), 1.32-1.14 (m, 6H), 1.08-1.00 (m, 6H). LCMS (ESI) m/z: 658.2 (M+1) ⁺ .

化合物18D：1H NMR(400MHz,DMSO-d ₆)δ8.31-8.29(m,1H),7.07-7.02(m,2H),6.85-6.78(m,1H),6.34-6.16(m,3H),6.01(m,2H),5.77-5.72(m,1H),4.74-4.48(m,2H),4.01-3.76(m,3H),3.48-3.45(m,1H),3.43-3.42(m,1H),1.85(m,3H),1.32-1.14(m,6H),1.08-1.02(m,6H)。LCMS(ESI)m/z:658.2(M+1) ⁺。 Compound 18D: 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.31-8.29 (m, 1H), 7.07-7.02 (m, 2H), 6.85-6.78 (m, 1H), 6.34-6.16 (m, 3H) ,6.01(m,2H),5.77-5.72(m,1H),4.74-4.48(m,2H),4.01-3.76(m,3H),3.48-3.45(m,1H),3.43-3.42(m, 1H), 1.85 (m, 3H), 1.32-1.14 (m, 6H), 1.08-1.02 (m, 6H). LCMS (ESI) m/z: 658.2 (M+1) ⁺ .

实施例19Example 19

第一步：first step:

在20-30摄氏度下，向化合物19-1(23克)的二氯甲烷(230毫升)溶液中依次加入三乙胺(10.7克)和丙二酸甲酯酰氯(78.04克)，反应液在20-30摄氏度下反应16小时。向反应液中加入柠檬酸至pH＝6-7，反应液分层，水相用二氯甲烷(50毫升)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液浓缩得到残余物。残余物经硅胶柱纯化(石油醚：乙酸乙酯＝5:1到2:1)得到化合物19-2。LCMS(ESI)m/z:274.9(M+1) ⁺。 To a solution of compound 19-1 (23 g) in dichloromethane (230 mL) at 20-30 degrees Celsius, triethylamine (10.7 g) and methyl malonate acid chloride (78.04 g) were sequentially added, and the reaction solution was React at 20-30 degrees Celsius for 16 hours. Citric acid was added to the reaction solution to pH=6-7, the reaction solution was separated, the aqueous phase was extracted with dichloromethane (50 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column (petroleum ether:ethyl acetate=5:1 to 2:1) to obtain compound 19-2. LCMS (ESI) m/z: 274.9 (M+1) ⁺ .

第二步：Step 2:

在20-30摄氏度下，向化合物19-2(14克)的甲醇(150毫升))溶液中加入Raney-Ni(1.4克)，反应液在15Psi的氢气氛围下25摄氏度下反应8小时。反应液过滤，滤液浓缩得到残余物。残余物经硅胶柱纯化(石油醚：乙酸乙酯＝10:1到3:1)得到化合物19-3。LCMS(ESI)m/z:245.0(M+1)+。Raney-Ni (1.4 g) was added to a solution of compound 19-2 (14 g) in methanol (150 ml) at 20-30 degrees Celsius, and the reaction solution was reacted at 25 degrees Celsius under a hydrogen atmosphere of 15 Psi for 8 hours. The reaction solution was filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column (petroleum ether:ethyl acetate=10:1 to 3:1) to obtain compound 19-3. LCMS (ESI) m/z: 245.0 (M+1)+.

第三步：third step:

在0摄氏度下，向化合物19-3(8克)的乙腈(100毫升)和溶液中加入吡啶溶液(5.18克)，逐滴滴加乙酰氯(3.09克)，反应液在15摄氏度下反应16小时。反应液加入水(100毫升)，用乙酸乙酯(50毫升*2)萃取。合并有机相，无水硫酸钠干燥，过滤，滤液浓缩得到残余物。残余物经硅胶柱纯化(石油醚：乙酸乙酯＝5:1到2:1)得到化合物19-4。 ¹H NMR(400MHz,DMSO-d6)δ9.69(s,1H),9.25(s,1H),7.70(br d,J＝11.0Hz,1H),7.19-6.97(m,1H),3.67(s,3H),3.62(s,2H),2.07(s,3H)。LCMS(ESI)m/z:287.1(M+1)+。 To the solution of compound 19-3 (8 g) in acetonitrile (100 mL) and the solution was added pyridine solution (5.18 g) at 0 degrees Celsius, acetyl chloride (3.09 g) was added dropwise, and the reaction solution was reacted at 15 degrees Celsius for 16 Hour. Water (100 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL*2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column (petroleum ether:ethyl acetate=5:1 to 2:1) to obtain compound 19-4. ¹ H NMR(400MHz,DMSO-d6)δ9.69(s,1H),9.25(s,1H),7.70(br d,J=11.0Hz,1H),7.19-6.97(m,1H),3.67( s, 3H), 3.62 (s, 2H), 2.07 (s, 3H). LCMS (ESI) m/z: 287.1 (M+1)+.

第四步：the fourth step:

在20-30摄氏度下，向化合物19-4(9克)的乙腈(100毫升)溶液中依次加入碳酸铯(10.24毫克)，4-乙氧基-1,1,1-三氟-3-丁烯-2-酮(5.81克)反应液在20-30摄氏度下反应3小时。向反应液中加入水(100毫升)，然后用乙酸乙酯(50毫升*3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液浓缩得到化合物19-5。LCMS(ESI)m/z:409.0(M+1) ⁺。 To a solution of compound 19-4 (9 g) in acetonitrile (100 mL) at 20-30 degrees Celsius was added cesium carbonate (10.24 mg), 4-ethoxy-1,1,1-trifluoro-3- The buten-2-one (5.81 g) reaction solution was reacted at 20-30 degrees Celsius for 3 hours. Water (100 mL) was added to the reaction solution, then extracted with ethyl acetate (50 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 19-5. LCMS (ESI) m/z: 409.0 (M+1) ⁺ .

第五步：the fifth step:

在20-30摄氏度下，向化合物19-5(15克)的三氟乙醇(150毫升)溶液中加入三乙胺(7.44克)。反应液在100摄氏度下反应12小时。向反应液中加入碳酸氢钠水溶液调节pH至8左右,然后用乙酸乙酯(50毫升*2)萃取，水相用0.1摩尔/升的稀盐酸调节pH至2左右，用乙酸乙酯(50毫升*2)萃取，有机相用无水硫酸钠干燥，过滤，滤液浓缩得到化合物19-6。LCMS(ESI)m/z:377.1(M+1) ⁺。 To a solution of compound 19-5 (15 g) in trifluoroethanol (150 mL) was added triethylamine (7.44 g) at 20-30 degrees Celsius. The reaction solution was reacted at 100 degrees Celsius for 12 hours. To the reaction solution, add aqueous sodium bicarbonate solution to adjust pH to about 8, then extract with ethyl acetate (50 mL*2), adjust pH to about 2 with 0.1 mol/L dilute hydrochloric acid, and use ethyl acetate (50 mL). mL*2) extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 19-6. LCMS (ESI) m/z: 377.1 (M+1) ⁺ .

第六步：Step 6:

在20-30摄氏度下，向化合物19-6(7.2克)的乙腈(80毫升)溶液中依次加入磷酸钾(12.19克)，三溴吡啶(24.48克)。反应液在氮气保护下于50摄氏度反应2小时。向反应液中加入亚硫酸钠溶液(100毫升)，然后用乙酸乙酯(50毫升*2)萃取，有机相用无水硫酸钠干燥，过滤，滤液浓缩得到化合物19-7。LCMS(ESI)m/z:412.9(M+3) ⁺。 To a solution of compound 19-6 (7.2 g) in acetonitrile (80 mL) at 20-30 degrees Celsius, potassium phosphate (12.19 g) and tribromopyridine (24.48 g) were sequentially added. The reaction solution was reacted at 50 degrees Celsius for 2 hours under nitrogen protection. Sodium sulfite solution (100 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL*2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 19-7. LCMS (ESI) m/z: 412.9 (M+3) ⁺ .

第七步：Step 7:

在20-30摄氏度下，向化合物19-7(3.51克)的二氧六环(40毫升)溶液中依次加入2-异丙基-4-甲基吡啶-3-胺(8克)，三(二亚苄基丙酮)二钯(1.78克)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(1.669克),碳酸铯(12.68克)。反应液在氮气保护下于100摄氏度反应16小时。反应液过滤，滤液浓缩得到残余物。残余物经硅胶柱纯化(石油醚：乙酸乙酯＝5:1到2:1)得到化合物19-8。LCMS(ESI)m/z:481.1(M+1) ⁺。 To a solution of compound 19-7 (3.51 g) in dioxane (40 mL) at 20-30 degrees Celsius was added 2-isopropyl-4-methylpyridin-3-amine (8 g), three (dibenzylideneacetone)dipalladium (1.78 g), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (1.669 g), cesium carbonate (12.68 g). The reaction solution was reacted at 100 degrees Celsius for 16 hours under nitrogen protection. The reaction solution was filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column (petroleum ether:ethyl acetate=5:1 to 2:1) to obtain compound 19-8. LCMS (ESI) m/z: 481.1 (M+1) ⁺ .

第八步：Step 8:

在0摄氏度下，向化合物19-8(4克)的二氯甲烷(50毫升)溶液中一次性加入N-溴代丁二酰亚胺(1.48克)。反应液在20摄氏度下反应一个小时。向反应液中加入亚硫酸钠溶液(50毫升)，然后用二氯甲烷(20毫升*2)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液浓缩得到19-9。LCMS(ESI)m/z:558.9(M+1) ⁺。 To a solution of compound 19-8 (4 g) in dichloromethane (50 mL) at 0 degrees Celsius was added N-bromosuccinimide (1.48 g) in one portion. The reaction solution was reacted at 20 degrees Celsius for one hour. Sodium sulfite solution (50 mL) was added to the reaction solution, then extracted with dichloromethane (20 mL*2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 19-9. LCMS (ESI) m/z: 558.9 (M+1) ⁺ .

第九步：Step 9:

在60摄氏度下，向化合物19-9(4克)的N,N-二甲基甲酰胺(40毫升)和溶液中依次一次性加入锌粉(526.09毫克)，氰化锌(1.89克)，溴化锌(362.36毫克)，1,1-双(二苯基膦基)二茂铁(892.04 毫克)和三(二亚苄基丙酮)二钯(736.73毫克)。反应液在120摄氏度下反应3个小时。反应液过滤，用乙酸乙酯(100毫升)稀释，用水(50毫升*3)和饱和食盐水(50毫升)洗涤，有机相用无水硫酸钠干燥，过滤，滤液浓缩得到滤液浓缩得到残余物。残余物经制备板纯化(石油醚：乙酸乙酯＝5:1到2:1)得到化合物19-10。LCMS(ESI)m/z:506.0(M+1) ⁺。 To the solution of compound 19-9 (4 g) in N,N-dimethylformamide (40 ml) at 60 degrees Celsius, zinc powder (526.09 mg), zinc cyanide (1.89 g) were added in one portion, Zinc bromide (362.36 mg), 1,1-bis(diphenylphosphino)ferrocene (892.04 mg) and tris(dibenzylideneacetone)dipalladium (736.73 mg). The reaction solution was reacted at 120 degrees Celsius for 3 hours. The reaction solution was filtered, diluted with ethyl acetate (100 mL), washed with water (50 mL*3) and saturated brine (50 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. . The residue was purified by preparative plate (petroleum ether:ethyl acetate=5:1 to 2:1) to give compound 19-10. LCMS (ESI) m/z: 506.0 (M+1) ⁺ .

第十步：Step 10:

化合物19-10(4克)的浓硫酸(20毫升)于60摄氏度下反应16小时。反应液加入到饱和碳酸氢钠水溶液(50毫升)中，用乙酸乙酯(20毫升*3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液浓缩得到化合物19-11。LCMS(ESI)m/z:481.9(M+1) ⁺。 Compounds 19-10 (4 g) in concentrated sulfuric acid (20 mL) were reacted at 60 degrees Celsius for 16 hours. The reaction solution was added to saturated aqueous sodium bicarbonate solution (50 mL), extracted with ethyl acetate (20 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 19-11. LCMS (ESI) m/z: 481.9 (M+1) ⁺ .

第十一步：Step 11:

在0摄氏度下，向化合物19-11(2.8克)的四氢呋喃(30毫升)溶液中一次性加入1,1-羰基二咪唑(2.83克)，反应液在0摄氏度下反应0.3小时，然后一次性加入氢化钠(697.87毫克，质量百分比：60％)。反应液在0-25摄氏度下反应0.7小时。将反应液加入到水(100毫升)中，用0.1摩尔/升的稀盐酸(30毫升)调节pH＝3-4，然后用饱和的碳酸氢钠(50毫升)水溶液调节pH＝7-8，用乙酸乙酯(30毫升*3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液浓缩得到残化合物19-12。LCMS(ESI)m/z:508.2(M+1) ⁺。 To a solution of compound 19-11 (2.8 g) in tetrahydrofuran (30 mL) at 0 degrees Celsius, 1,1-carbonyldiimidazole (2.83 g) was added in one portion, and the reaction solution was reacted at 0 degrees Celsius for 0.3 hours, and then one portion Sodium hydride (697.87 mg, mass percentage: 60%) was added. The reaction solution was reacted at 0-25 degrees Celsius for 0.7 hours. The reaction solution was added to water (100 mL), adjusted to pH=3-4 with 0.1 mol/L dilute hydrochloric acid (30 mL), and then adjusted to pH=7-8 with saturated aqueous sodium bicarbonate (50 mL) solution, Extract with ethyl acetate (30 mL*3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain residual compound 19-12. LCMS (ESI) m/z: 508.2 (M+1) ⁺ .

第十二步：Step 12:

向化合物19-12(1克)的四氢呋喃(15毫升)溶液中加入PYBROP(1.84克)，DIEA(764.11毫克)以及化合物3-1(1.06克)。反应液在70摄氏度下反应16小时，反应液浓缩得到残余物。残余物通过制备HPLC[柱型号：Phenomenex Synergi Max-RP(250*50mm*10μm)，流动相：水(0.225％甲酸)-乙腈：30％-60％，22分钟]纯化得到化合物19-13。LCMS(ESI)m/z:704.4(M+1) ⁺。 To a solution of compound 19-12 (1 g) in tetrahydrofuran (15 mL) were added PYBROP (1.84 g), DIEA (764.11 mg) and compound 3-1 (1.06 g). The reaction solution was reacted at 70 degrees Celsius for 16 hours, and the reaction solution was concentrated to obtain a residue. The residue was purified by preparative HPLC [column model: Phenomenex Synergi Max-RP (250*50mm*10μm), mobile phase: water (0.225% formic acid)-acetonitrile: 30%-60%, 22 minutes] to give compounds 19-13. LCMS (ESI) m/z: 704.4 (M+1) ⁺ .

化合物19-13通过制备SFC(柱型号：REGIS(R,R)WHELK-O1(250mm*25mm,10μm)，流动相：异丙醇(0.1％氨水异丙醇)，梯度：二氧化碳临界流体50％-50％，4.5分钟，90分钟)分离纯化得到化合物19-14A(保留时间＝1.098min)，和19-14M(保留时间＝1.869min，为19-14B、19-14C和19-14D的混合物)。Compounds 19-13 were prepared by preparative SFC (column type: REGIS(R,R) WHELK-O1 (250mm*25mm, 10μm), mobile phase: isopropanol (0.1% ammonia water isopropanol), gradient: carbon dioxide critical fluid 50% -50%, 4.5 minutes, 90 minutes) separation and purification to obtain compound 19-14A (retention time = 1.098 min), and 19-14M (retention time = 1.869 min, a mixture of 19-14B, 19-14C and 19-14D ).

第十三步：Step Thirteen:

在10-25摄氏度下，向化合物19-14A(460毫克)的二氯甲烷(1毫升)溶液中一次性加入三氟乙酸(0.5毫升)。反应液在10-25摄氏度下反应0.5小时。将反应液浓缩得到化合物19-15A的三氟乙酸盐，粗品直接用于下一步。To a solution of compound 19-14A (460 mg) in dichloromethane (1 mL) was added trifluoroacetic acid (0.5 mL) in one portion at 10-25 degrees Celsius. The reaction solution was reacted at 10-25 degrees Celsius for 0.5 hours. The reaction solution was concentrated to obtain the trifluoroacetate salt of compound 19-15A, and the crude product was directly used in the next step.

在10-25摄氏度下，向19-14M(420毫克)的二氯甲烷(2毫升)溶液中一次性加入三氟乙酸(1毫升)。反应液在10-25摄氏度下反应0.5小时。将反应液浓缩得到化合物19-15M(19-15B、19-15C和19-15D的混合物)的三氟乙酸盐，粗品直接用于下一步。To a solution of 19-14M (420 mg) in dichloromethane (2 mL) at 10-25 degrees Celsius was added trifluoroacetic acid (1 mL) in one portion. The reaction solution was reacted at 10-25 degrees Celsius for 0.5 hours. The reaction solution was concentrated to obtain the trifluoroacetate salt of compound 19-15M (a mixture of 19-15B, 19-15C and 19-15D), and the crude product was directly used in the next step.

第十四步Step 14

在0摄氏度下，向化合物19-15A(150毫克，2TFA盐)的四氢呋喃(2.0毫升)和水(0.5毫升)的混合溶液中依次一次性加入无水碳酸钾(74.79毫克)，丙烯酰氯(16.32毫克)。反应液在0摄氏度下反应0.25小时。向反应液中加入水(10毫升)，用乙酸乙酯(10毫升*3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液浓缩得到残余物。残余物通过制备SFC(柱型号：Phenomenex Gemini-NX C18(75mm*30mm，3μm)，流动相：水(0.225％甲酸)-乙腈，梯度：二氧化碳临界流体20％-50％，5分钟)分离纯化得到化合物19A。To a mixed solution of compound 19-15A (150 mg, 2TFA salt) in tetrahydrofuran (2.0 mL) and water (0.5 mL) at 0 degrees Celsius, anhydrous potassium carbonate (74.79 mg), acryloyl chloride (16.32 g mg). The reaction solution was reacted at 0 degrees Celsius for 0.25 hours. Water (10 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was separated and purified by preparative SFC (column type: Phenomenex Gemini-NX C18 (75mm*30mm, 3μm), mobile phase: water (0.225% formic acid)-acetonitrile, gradient: carbon dioxide critical fluid 20%-50%, 5 minutes) Compound 19A was obtained.

在0摄氏度下，向化合物19-15M(450毫克，2TFA盐)的四氢呋喃(2.0毫升)和水(0.5毫升)的混合溶液中依次一次性加入无水碳酸钾(224.36毫克)，丙烯酰氯(48.97毫克)。反应液在0摄氏度下反应0.25小时。向反应液中加入水(10毫升)，用乙酸乙酯(10毫升*3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液浓缩得到残余物。残余物通过制备SFC(柱型号：Phenomenex Gemini-NX C18(75mm*30mm，3μm)，流动相：水(0.225％甲酸)-乙腈，梯度：二氧化碳临界流体20％-50％，7分钟)分离纯化得到化合物19B和19-P1。To a mixed solution of compound 19-15M (450 mg, 2TFA salt) in tetrahydrofuran (2.0 mL) and water (0.5 mL) at 0 degrees Celsius, anhydrous potassium carbonate (224.36 mg), acryloyl chloride (48.97 g mg). The reaction solution was reacted at 0 degrees Celsius for 0.25 hours. Water (10 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was separated and purified by preparative SFC (column type: Phenomenex Gemini-NX C18 (75mm*30mm, 3μm), mobile phase: water (0.225% formic acid)-acetonitrile, gradient: carbon dioxide critical fluid 20%-50%, 7 minutes) Compounds 19B and 19-P1 were obtained.

19-P1再通过制备SFC(柱型号：DAICEL CHIRALPAK IC(250mm*30mm,10um)，流动相：乙醇(0.1％氨水)，梯度：二氧化碳临界流体35％-35％，4.9分钟，80分钟)分离纯化得到化合物19C和化合物19D。19-P1 was separated by preparative SFC (column type: DAICEL CHIRALPAK IC (250mm*30mm, 10um), mobile phase: ethanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 35%-35%, 4.9 minutes, 80 minutes) Purification gave compound 19C and compound 19D.

化合物19A经SFC检测【柱型号：(R,R)Whelk-O1-3 50×4.6mm I.D.,1.8μm；流动相：A相为超临界二氧化碳，B相为异丙醇(0.05％二乙胺)；梯度(B％)：40％-40％】得到：化合物19A的保留时间为1.653min。Compound 19A was detected by SFC [column type: (R,R)Whelk-O1-3 50×4.6mm I.D., 1.8μm; mobile phase: supercritical carbon dioxide in phase A, isopropanol (0.05% diethylamine in phase B) ); Gradient (B%): 40%-40%] Obtained: The retention time of compound 19A was 1.653 min.

化合物19B经SFC检测【柱型号：Chiralpak IC-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为甲醇(0.05％二乙胺)；梯度(B％)：5％-40％】得到：化合物19B的保留时间为2.22min，e.e.值为100％。Compound 19B was detected by SFC [column type: Chiralpak IC-3 50×4.6mm I.D., 3μm; mobile phase: phase A was supercritical carbon dioxide, phase B was methanol (0.05% diethylamine); gradient (B%): 5 %-40%] obtained: the retention time of compound 19B was 2.22 min, and the e.e. value was 100%.

化合物19C和化合物19D经SFC检测【柱型号：Chiralpak IC-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为乙醇(0.05％二乙胺)；梯度(B％)：40％-40％】得到：化合物19C的保留时间为1.653min，e.e.值为100％；化合物19D的保留时间为2.139min，e.e.值为100％。Compound 19C and compound 19D were detected by SFC [column model: Chiralpak IC-3 50×4.6mm I.D., 3μm; mobile phase: phase A was supercritical carbon dioxide, phase B was ethanol (0.05% diethylamine); gradient (B% ): 40%-40%] obtained: the retention time of compound 19C was 1.653 min, and the e.e. value was 100%; the retention time of compound 19D was 2.139 min, and the e.e. value was 100%.

化合物19A(保留时间＝0.967min)：LCMS(ESI)m/z:658.3(M+1) ⁺。 Compound 19A (retention time = 0.967 min): LCMS (ESI) m/z: 658.3 (M+1) ⁺ .

化合物19B(保留时间＝2.222min)：LCMS(ESI)m/z:658.3(M+1) ⁺。 Compound 19B (retention time = 2.222 min): LCMS (ESI) m/z: 658.3 (M+1) ⁺ .

化合物19C(保留时间＝1.653min)： ¹H NMR(400MHz,DMSO-d ₆)δ8.29(d,J＝4.8Hz,1H),7.30-7.15(m,1H),7.10-6.95(m,2H),6.93-6.70(m,2H),6.27-6.10(m,1H),5.83-5.63(m,1H),5.39-5.15(m,2H),4.83-4.39(m,2H),4.02-3.90(m,2H),3.59-3.40(m,1H),2.88-2.60(m,2H),2.04-1.96(m,3H),1.33-0.97(m,12H).LCMS(ESI)m/z:658.3(M+1) ⁺。 Compound 19C (retention time=1.653 min): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.29 (d, J=4.8 Hz, 1H), 7.30-7.15 (m, 1H), 7.10-6.95 (m, 2H), 6.93-6.70(m, 2H), 6.27-6.10(m, 1H), 5.83-5.63(m, 1H), 5.39-5.15(m, 2H), 4.83-4.39(m, 2H), 4.02- 3.90(m,2H),3.59-3.40(m,1H),2.88-2.60(m,2H),2.04-1.96(m,3H),1.33-0.97(m,12H).LCMS(ESI)m/z :658.3(M+1) ⁺ .

化合物19D(保留时间＝2.139min)： ¹H NMR(400MHz,DMSO-d ₆)δ8.30(br d,J＝4.8Hz,1H),7.29-7.15(m,1H),7.12-7.05(m,1H),7.00(s,1H),6.90-6.78(m,1H),6.76-6.70(m,1H),6.24-6.15(m,1H),5.80-5.71(m,1H),5.42-5.23(m,2H),4.85-4.47(m,2H),3.96-3.89(m,2H),3.53-3.43(m,1H),2.67(br s,2H),2.08-1.95(m,3H),1.33-0.95(m,12H)。LCMS(ESI)m/z:658.3(M+1) ⁺。 Compound 19D (retention time=2.139 min): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.30 (br d, J=4.8 Hz, 1H), 7.29-7.15 (m, 1H), 7.12-7.05 (m ,1H),7.00(s,1H),6.90-6.78(m,1H),6.76-6.70(m,1H),6.24-6.15(m,1H),5.80-5.71(m,1H),5.42-5.23 (m,2H),4.85-4.47(m,2H),3.96-3.89(m,2H),3.53-3.43(m,1H),2.67(br s,2H),2.08-1.95(m,3H), 1.33-0.95 (m, 12H). LCMS (ESI) m/z: 658.3 (M+1) ⁺ .

实施例20Example 20

第一步：first step:

在20-30摄氏度下，向化合物20-1(2.0克)的二氧六环(50毫升)和水(25毫升)溶液中加入化合物20-2(1.22克)、四三苯基膦钯(1.20克)和碳酸钾(4.30克)。反应液氮气置换三次后，在100摄氏度下反应2个小时。反应液浓缩得到残余物，用乙酸乙酯(30毫升)萃取，食盐水(30毫升)洗涤，有机相浓缩滤液得到残余物。残余物通过硅胶柱(洗脱剂：石油醚：乙酸乙酯＝10:1到3:1)纯化得到化合物20-3。LCMS(ESI)m/z:199.0(M+1) ⁺。 To a solution of compound 20-1 (2.0 g) in dioxane (50 mL) and water (25 mL) at 20-30 degrees Celsius was added compound 20-2 (1.22 g), tetrakistriphenylphosphine palladium ( 1.20 g) and potassium carbonate (4.30 g). After the reaction liquid was replaced with nitrogen three times, the reaction was carried out at 100 degrees Celsius for 2 hours. The reaction solution was concentrated to obtain a residue, which was extracted with ethyl acetate (30 mL), washed with brine (30 mL), and the organic phase was concentrated to the filtrate to obtain a residue. The residue was purified by silica gel column (eluent: petroleum ether: ethyl acetate=10:1 to 3:1) to obtain compound 20-3. LCMS (ESI) m/z: 199.0 (M+1) ⁺ .

第二步：Step 2:

在10-15摄氏度下，向化合物20-3(1.6克)的甲醇(10毫升)溶液中加入甲醇钠甲醇溶液(1.45克，10毫升，质量百分比：30％)。反应液在15摄氏度下反应0.5个小时。向反应液中加入水(10毫升)，乙酸乙酯(50毫升)萃取，食盐水(50毫升)洗涤，有机相浓缩滤液得到残余物。残余物通过硅胶柱(洗脱剂：石油醚：乙酸乙酯＝5:1到2:1)纯化得到化合物20-4。LCMS(ESI)m/z:195.1(M+1) ⁺。 To a methanol (10 mL) solution of compound 20-3 (1.6 g) was added sodium methoxide methanol solution (1.45 g, 10 mL, mass percentage: 30%) at 10-15 degrees Celsius. The reaction solution was reacted at 15 degrees Celsius for 0.5 hour. Water (10 mL) was added to the reaction solution, extracted with ethyl acetate (50 mL), washed with brine (50 mL), and the organic phase was concentrated to the filtrate to obtain a residue. The residue was purified by silica gel column (eluent: petroleum ether: ethyl acetate = 5:1 to 2:1) to obtain compound 20-4. LCMS (ESI) m/z: 195.1 (M+1) ⁺ .

第三步：third step:

在10-15摄氏度下，向化合物20-4(1.50克)的甲醇(20毫升)溶液中加入湿钯炭(0.5克，10％纯度)。反应液用氢气置换三次，在15摄氏度下反应2个小时。反应液过滤，滤饼用甲醇(20毫升)洗涤，滤液浓缩得到化合物20-5。LCMS(ESI)m/z:167.2(M+1) ⁺。 To a solution of compound 20-4 (1.50 g) in methanol (20 mL) was added wet palladium on carbon (0.5 g, 10% purity) at 10-15 degrees Celsius. The reaction solution was replaced with hydrogen three times, and the reaction was carried out at 15 degrees Celsius for 2 hours. The reaction solution was filtered, the filter cake was washed with methanol (20 mL), and the filtrate was concentrated to obtain compound 20-5. LCMS (ESI) m/z: 167.2 (M+1) ⁺ .

第四步：the fourth step:

在10-15摄氏度下，向化合物20-5(1.75克)的二氧六环(30毫升)溶液中加入化合物20-5A(0.76克)、Pd ₂(dba) ₃(420.52毫克)、Xantphos(531.43毫克)和碳酸铯(4.49克)。反应液氮气置换三次后在100摄氏度下反应2个小时。反应液浓缩得到残余物，残余物中加入水(100毫升)，乙酸乙酯(100毫升)，分离有机相，浓缩得到残余物。残余物通过硅胶柱(洗脱剂：石油醚：乙酸乙酯＝1:1)纯化得到化合物20-6。 ¹H NMR(400MHz,CHLOROFORM-d)δ8.48(d,J＝5.5Hz,1H),8.22-8.11(m,1H),7.73(dt,J＝5.3,8.4Hz,1H),7.63(dt,J＝1.2,8.3Hz,1H),6.81-6.74(m,2H),6.60(s,1H),5.96(d,J＝7.8Hz,1H),3.87(s,3H),3.29(td,J＝6.8,13.6Hz,1H),1.30-1.21(m,6H)。LCMS(ESI)m/z:467.0(M+1) ⁺。 To a solution of compound 20-5 (1.75 g) in dioxane (30 mL) at 10-15 degrees Celsius was added compound 20-5A (0.76 g), Pd ₂ (dba) ₃ (420.52 mg), Xantphos ( 531.43 mg) and cesium carbonate (4.49 g). The reaction liquid was replaced with nitrogen three times and then reacted at 100 degrees Celsius for 2 hours. The reaction solution was concentrated to obtain a residue. Water (100 mL) and ethyl acetate (100 mL) were added to the residue. The organic phase was separated and concentrated to obtain a residue. The residue was purified by silica gel column (eluent: petroleum ether: ethyl acetate=1:1) to obtain compound 20-6. ¹ H NMR(400MHz, CHLOROFORM-d)δ8.48(d,J=5.5Hz,1H),8.22-8.11(m,1H),7.73(dt,J=5.3,8.4Hz,1H),7.63(dt , J=1.2, 8.3Hz, 1H), 6.81-6.74(m, 2H), 6.60(s, 1H), 5.96(d, J=7.8Hz, 1H), 3.87(s, 3H), 3.29(td, J=6.8, 13.6Hz, 1H), 1.30-1.21 (m, 6H). LCMS (ESI) m/z: 467.0 (M+1) ⁺ .

第五步：the fifth step:

在10-15摄氏度下，向化合物20-6(0.8克)的二氯甲烷(10毫升)溶液中加入NBS(305.30毫克)。反应液氮气置换三次后，在15摄氏度下反应2个小时。向反应液中加入饱和亚硫酸钠水溶液(50毫升)，有机相分离，浓缩滤液得到残余物。残余物通过硅胶柱(洗脱剂：石油醚：乙酸乙酯＝10:1到1:1)纯化得到化合物20-7。LCMS(ESI)m/z:546.9(M+3) ⁺。 To a solution of compound 20-6 (0.8 g) in dichloromethane (10 mL) was added NBS (305.30 mg) at 10-15 degrees Celsius. After the reaction liquid was replaced with nitrogen three times, the reaction was carried out at 15 degrees Celsius for 2 hours. To the reaction solution was added saturated aqueous sodium sulfite solution (50 mL), the organic phase was separated, and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column (eluent: petroleum ether: ethyl acetate = 10:1 to 1:1) to obtain compound 20-7. LCMS (ESI) m/z: 546.9 (M+3) ⁺ .

第六步：Step 6:

在10-15摄氏度下，向化合物20-7(1.5克)的乙醇(50毫升)和水(25毫升)混合溶液中加入铁粉(768.11毫克)和氯化铵(735.74毫克)。反应液在60摄氏度下反应2个小时。反应液浓缩得到残余物，残余物中加入食盐水(50毫升)，乙酸乙酯(50毫升)，有机相分离，浓缩得到化合物20-8。LCMS(ESI)m/z:515.0(M+1) ⁺。 To a mixed solution of compound 20-7 (1.5 g) in ethanol (50 mL) and water (25 mL) was added iron powder (768.11 mg) and ammonium chloride (735.74 mg) at 10-15 degrees Celsius. The reaction solution was reacted at 60 degrees Celsius for 2 hours. The reaction solution was concentrated to obtain a residue, brine (50 mL) and ethyl acetate (50 mL) were added to the residue, the organic phase was separated, and concentrated to obtain compound 20-8. LCMS (ESI) m/z: 515.0 (M+1) ⁺ .

第七步：Step 7:

在10-15摄氏度下，向化合物20-8(1.4克)的N,N-二甲基甲酰胺(30毫升)溶液中加入锌粉(355.31毫克)、氰化锌(638.06毫克)、Pd ₂(dba) ₃(248.79毫克)、溴化锌(611.83毫克)和DPPF(301.24毫克)。反应液氮气置换三次后，在110摄氏度下反应12个小时。反应液中加入水(30毫升)，乙酸乙酯(30毫升)，混合物过滤，滤饼用乙酸乙酯(30毫升)洗涤，有机相分离，浓缩得到残余物。残余物通过硅胶柱(洗脱剂：石油醚：乙酸乙酯＝10:1到1:1)纯化得到化合物20-9。LCMS(ESI)m/z:462.1(M+1) ⁺。 To a solution of compound 20-8 (1.4 g) in N,N-dimethylformamide (30 mL) at 10-15 degrees Celsius was added zinc powder (355.31 mg), zinc cyanide (638.06 mg), Pd ₂ (dba) ₃ (248.79 mg), zinc bromide (611.83 mg) and DPPF (301.24 mg). After the reaction liquid was replaced with nitrogen three times, the reaction was carried out at 110 degrees Celsius for 12 hours. Water (30 mL) and ethyl acetate (30 mL) were added to the reaction solution, the mixture was filtered, the filter cake was washed with ethyl acetate (30 mL), the organic phase was separated, and concentrated to obtain a residue. The residue was purified by silica gel column (eluent: petroleum ether: ethyl acetate = 10:1 to 1:1) to obtain compound 20-9. LCMS (ESI) m/z: 462.1 (M+1) ⁺ .

第八步：Step 8:

在10-15摄氏度下，化合物20-9(1.1克)和浓硫酸(18.40克)的混合物在80摄氏度下反应2个小时。反应液缓慢倒入冰水(1.0升)中，搅拌下，分批加入碳酸钠固体，至pH约为9，乙酸乙酯(100毫升*2)萃取，合并有机相，浓缩得到化合物20-10。LCMS(ESI)m/z:480.1(M+1) ⁺。 A mixture of compound 20-9 (1.1 g) and concentrated sulfuric acid (18.40 g) was reacted at 80 degrees Celsius for 2 hours at 10-15 degrees Celsius. The reaction solution was slowly poured into ice water (1.0 L), and with stirring, solid sodium carbonate was added in batches until the pH was about 9, extracted with ethyl acetate (100 mL*2), the organic phases were combined, and concentrated to obtain compound 20-10 . LCMS (ESI) m/z: 480.1 (M+1) ⁺ .

第九步：Step 9:

在15摄氏度下，向化合物20-10(0.7克)的四氢呋喃(15毫升)溶液中加入氢化钠(116.80毫克，质量百分比：60％)和羰基二咪唑(473.50毫克)。反应液氮气置换三次后，在15摄氏度下反应2个小时。反应液倒入水(30毫升)中，乙酸乙酯(20毫升*2)萃取，合并有机相，饱和食盐水(30毫升)洗涤，有机相分离，浓缩得到化合物20-11。LCMS(ESI)m/z:506.1(M+1) ⁺。 To a solution of compound 20-10 (0.7 g) in tetrahydrofuran (15 mL) at 15 degrees Celsius was added sodium hydride (116.80 mg, mass percentage: 60%) and carbonyldiimidazole (473.50 mg). After the reaction liquid was replaced with nitrogen three times, the reaction was carried out at 15 degrees Celsius for 2 hours. The reaction solution was poured into water (30 mL), extracted with ethyl acetate (20 mL*2), the organic phases were combined, washed with saturated brine (30 mL), the organic phases were separated, and concentrated to obtain compound 20-11. LCMS (ESI) m/z: 506.1 (M+1) ⁺ .

第十步：Step 10:

在15摄氏度下，向化合物20-11(680毫克)的N,N-二甲基乙酰胺(30毫升)溶液中加入化合物3-1(864.98毫克)、PYBROP(1.25克)和DIPEA(521.66毫克)。反应液氮气置换三次后，在80摄氏度下反应2个小时。反应液倒入水(50毫升)中，乙酸乙酯(50毫升*2)萃取，合并有机相，饱和食盐水(50毫升)洗涤，有机相分离，浓缩得到残余物，残余物通过制备TLC(石油醚：乙酸乙酯＝0:1)纯化得到化合物20-12。LCMS(ESI)m/z:702.2(M+1) ⁺。 To a solution of compound 20-11 (680 mg) in N,N-dimethylacetamide (30 mL) at 15 degrees Celsius was added compound 3-1 (864.98 mg), PYBROP (1.25 g) and DIPEA (521.66 mg) ). After the reaction liquid was replaced with nitrogen three times, the reaction was carried out at 80 degrees Celsius for 2 hours. The reaction solution was poured into water (50 mL), extracted with ethyl acetate (50 mL*2), the organic phases were combined, washed with saturated brine (50 mL), the organic phases were separated, concentrated to obtain a residue, and the residue was passed through preparative TLC ( Petroleum ether: ethyl acetate=0:1) was purified to obtain compound 20-12. LCMS (ESI) m/z: 702.2 (M+1) ⁺ .

第十一步：Step 11:

在15摄氏度下，向化合物20-12(500毫克)的二氯甲烷(15毫升)溶液中加入三氟乙酸(4.81克)。反应液在15摄氏度下反应1个小时。反应液浓缩得到化合物20-13的三氟乙酸盐，粗品直接用于下一步。LCMS(ESI)m/z:602.2(M+1) ⁺。 To a solution of compound 20-12 (500 mg) in dichloromethane (15 mL) was added trifluoroacetic acid (4.81 g) at 15 degrees Celsius. The reaction solution was reacted at 15 degrees Celsius for 1 hour. The reaction solution was concentrated to obtain the trifluoroacetate salt of compound 20-13, and the crude product was directly used in the next step. LCMS (ESI) m/z: 602.2 (M+1) ⁺ .

第十二步：Step 12:

在15摄氏度下，向化合物20-13(500毫克)的四氢呋喃(10毫升)和水(10毫升)溶液中加入碳酸钾(193.13毫克)和丙烯酰氯(63.24毫克)。反应液在15摄氏度下反应15分钟。反应液中加入水(30毫升)，乙酸乙酯(30毫升)萃取，有机相分离，浓缩得到残余物，残余物通过制备HPLC(柱型号：Phenomenex Gemini-NX C18 75*30mm*3um，流动相：[水(0.225％甲酸-乙腈]；15％-45％,7分钟)纯化得到化合物20。To a solution of compound 20-13 (500 mg) in tetrahydrofuran (10 mL) and water (10 mL) at 15 degrees Celsius was added potassium carbonate (193.13 mg) and acryloyl chloride (63.24 mg). The reaction solution was reacted at 15 degrees Celsius for 15 minutes. Water (30 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL), the organic phase was separated, and concentrated to obtain a residue. The residue was subjected to preparative HPLC (column type: Phenomenex Gemini-NX C18 75*30mm*3um, mobile phase : [water (0.225% formic acid-acetonitrile]; 15%-45%, 7 min) purification gave compound 20.

化合物20通过SFC(柱型号：DAICEL CHIRALPAK IC(250mm*30mm,10μm)；流动相：0.1％氨水-甲醇，梯度：二氧化碳临界流体60％-60％，2.2分钟，50分钟)得到20A和20B。Compound 20 was obtained by SFC (column model: DAICEL CHIRALPAK IC (250mm*30mm, 10μm); mobile phase: 0.1% ammonia water-methanol, gradient: carbon dioxide critical fluid 60%-60%, 2.2 minutes, 50 minutes) to give 20A and 20B.

化合物20A和化合物20B经SFC检测【柱型号：Chiralpak IC-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为甲醇(0.05％二乙胺)；梯度(B％)：40％-40％】得到：化合物20A的保留时间为0.815min，e.e.值为100％；化合物20B的保留时间为2.118min，e.e.值为100％。Compound 20A and compound 20B were detected by SFC [column model: Chiralpak IC-3 50×4.6mm I.D., 3μm; mobile phase: phase A was supercritical carbon dioxide, phase B was methanol (0.05% diethylamine); gradient (B% ): 40%-40%] obtained: the retention time of compound 20A is 0.815min, and the e.e. value is 100%; the retention time of compound 20B is 2.118min, and the e.e. value is 100%.

化合物20A(保留时间＝0.815min)： ¹H NMR(400MHz,DMSO-d ₆)δ8.41-8.27(m,1H),7.09(dt,J＝6.8,8.2Hz,1H),7.01(s,1H),6.91(d,J＝5.8Hz,1H),6.89-6.75(m,1H),6.50(d,J＝8.4Hz,1H),6.38-6.29(m,1H),6.19(br d,J＝16.5Hz,1H),5.80-5.70(m,1H),5.63(s,2H),4.86-4.59(m,1H),4.83-4.43(m,1H),4.13(br dd,J＝2.4,13.8Hz,1H),3.95-3.75(m,3H),3.70(s,3H),2.71-2.59(m,1H),1.30(br t,J＝7.3Hz,3H),1.27-1.16(m,3H),1.06-1.01(m,3H),0.96(d,J＝6.6Hz,3H)。LCMS(ESI)m/z:656.3(M+1) ⁺。 Compound 20A (retention time = 0.815 min): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.41-8.27 (m, 1H), 7.09 (dt, J=6.8, 8.2 Hz, 1H), 7.01 (s, 1H), 6.91(d, J=5.8Hz, 1H), 6.89-6.75(m, 1H), 6.50(d, J=8.4Hz, 1H), 6.38-6.29(m, 1H), 6.19(br d, J=16.5Hz, 1H), 5.80-5.70(m, 1H), 5.63(s, 2H), 4.86-4.59(m, 1H), 4.83-4.43(m, 1H), 4.13(br dd, J=2.4 ,13.8Hz,1H),3.95-3.75(m,3H),3.70(s,3H),2.71-2.59(m,1H),1.30(br t,J＝7.3Hz,3H),1.27-1.16(m , 3H), 1.06-1.01 (m, 3H), 0.96 (d, J=6.6Hz, 3H). LCMS (ESI) m/z: 656.3 (M+1) ⁺ .

化合物20B(保留时间＝2.118min)： ¹H NMR(400MHz,DMSO-d ₆)δ8.39-8.28(m,1H),7.14-7.04(m,1H),7.03-6.98(m,1H),6.91-6.87(m,1H),6.82(br dd,J＝10.1,16.5Hz,1H),6.48(d,J＝8.3Hz,1H),6.38-6.29(m,1H),6.25-6.13(m,1H),5.81-5.70(m,1H),5.68-5.58(m,2H),4.82-4.43(m,2H),4.16-4.01(m,1H),3.93-3.84(m,1H),3.65(s,2H),3.74-3.58(m,1H),1.36-1.28(m,3H),1.27-1.27(m,1H),1.26-1.20(m, 1H),1.26-1.20(m,1H),1.16(br d,J＝6.5Hz,2H),1.11-1.05(m,4H),1.01(br d,J＝6.6Hz,3H)。LCMS(ESI)m/z:656.3(M+1) ⁺。 Compound 20B (retention time=2.118 min): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.39-8.28 (m, 1H), 7.14-7.04 (m, 1H), 7.03-6.98 (m, 1H), 6.91-6.87(m,1H),6.82(br dd,J=10.1,16.5Hz,1H),6.48(d,J=8.3Hz,1H),6.38-6.29(m,1H),6.25-6.13(m ,1H),5.81-5.70(m,1H),5.68-5.58(m,2H),4.82-4.43(m,2H),4.16-4.01(m,1H),3.93-3.84(m,1H),3.65 (s,2H),3.74-3.58(m,1H),1.36-1.28(m,3H),1.27-1.27(m,1H),1.26-1.20(m,1H),1.26-1.20(m,1H) , 1.16 (br d, J=6.5Hz, 2H), 1.11-1.05 (m, 4H), 1.01 (br d, J=6.6Hz, 3H). LCMS (ESI) m/z: 656.3 (M+1) ⁺ .

实施例21Example 21

第一步：first step:

在0摄氏度下，向化合物21-1(10克量)和碳酸钾(5.35克)的乙腈(100毫升)溶液中缓慢加入化合物7-2(12.69克)。反应液在20摄氏度下反应14个小时。反应液浓缩得到残余物，用乙酸乙酯(100mL)和饱和碳酸氢钠(100毫升)溶解。水相用乙酸乙酯(50毫升)萃取两次，合并有机相用水(50毫升)和饱和食盐水(50毫升)洗涤，有机相用无水硫酸钠干燥，过滤，浓缩滤液得到的残余物。向残余物中加入乙酸乙酯和石油醚(120毫升，1:5)搅拌一小时，过滤，滤饼减压干燥得到化合物21-2。LCMS(ESI)m/z:230.1(m+1) ⁺。 To a solution of compound 21-1 (10 g amount) and potassium carbonate (5.35 g) in acetonitrile (100 mL) was slowly added compound 7-2 (12.69 g) at 0 degrees Celsius. The reaction solution was reacted at 20 degrees Celsius for 14 hours. The reaction solution was concentrated to obtain a residue, which was dissolved in ethyl acetate (100 mL) and saturated sodium bicarbonate (100 mL). The aqueous phase was extracted twice with ethyl acetate (50 mL), the combined organic phases were washed with water (50 mL) and saturated brine (50 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. Ethyl acetate and petroleum ether (120 mL, 1:5) were added to the residue, stirred for one hour, filtered, and the filter cake was dried under reduced pressure to obtain compound 21-2. LCMS (ESI) m/z: 230.1 (m+1) ⁺ .

第二步：Step 2:

在0摄氏度下，向化合物21-2(13.18克)和碳酸铯(18.74克)的乙腈(140毫升)溶液中逐滴加入化合物7-4(9.86克)，反应液在15摄氏度下反应2小时。反应液过滤，滤液浓缩后加入水(100毫升)，用乙酸乙酯(50毫升)萃取两次。合并有机相用水(50毫升)和饱和食盐水(50毫升)洗涤，有机相用无水硫酸钠干燥，过滤，滤液浓缩得到残余物。向残余物中加入甲基叔丁基醚(40毫升)室温搅拌2小时，过滤，滤饼减压干燥得到化合物21-3。LCMS(ESI)m/z:352.1(m+1) ⁺。 To a solution of compound 21-2 (13.18 g) and cesium carbonate (18.74 g) in acetonitrile (140 mL) at 0 degrees Celsius, compound 7-4 (9.86 g) was added dropwise, and the reaction solution was reacted at 15 degrees Celsius for 2 hours . The reaction solution was filtered, the filtrate was concentrated, water (100 mL) was added, and the mixture was extracted twice with ethyl acetate (50 mL). The combined organic phase was washed with water (50 mL) and saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. Methyl tert-butyl ether (40 mL) was added to the residue, stirred at room temperature for 2 hours, filtered, and the filter cake was dried under reduced pressure to obtain compound 21-3. LCMS (ESI) m/z: 352.1 (m+1) ⁺ .

第三步：third step:

向化合物21-3(18.17克，100％纯度)的三氟乙醇(100毫升)溶液中加入三乙胺(10.47克)，反应液在80摄氏度下反14小时。反应液浓缩得到残余物。残余物用乙酸乙酯(50毫升)和饱和碳酸氢钠(100毫升)。水相用乙酸乙酯(50毫升)洗涤，水相用盐酸水溶液(3摩尔每升)调节pH到1，随后水相用乙酸乙酯(100毫升)萃取三次。合并有机相用无水硫酸钠干燥，过滤，滤液浓缩得到化合物21-4。LCMS(ESI)m/z:320.1(m+1) ⁺。 To a solution of compound 21-3 (18.17 g, 100% purity) in trifluoroethanol (100 mL) was added triethylamine (10.47 g), and the reaction solution was reacted at 80 degrees Celsius for 14 hours. The reaction solution was concentrated to obtain a residue. The residue was taken up with ethyl acetate (50 mL) and saturated sodium bicarbonate (100 mL). The aqueous phase was washed with ethyl acetate (50 mL), the pH of the aqueous phase was adjusted to 1 with aqueous hydrochloric acid (3 mol per liter), and the aqueous phase was extracted three times with ethyl acetate (100 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 21-4. LCMS (ESI) m/z: 320.1 (m+1) ⁺ .

第四步：the fourth step:

在向化合物21-4(13.9克)的乙腈(280毫升)的溶液中依次加入磷酸钾(18.49克)和三溴吡啶鎓盐(41.78克)，反应液在50摄氏度下反应2小时。反应液用饱和亚硫酸钠(200毫升)淬灭，随后用乙酸乙酯(100毫升)萃取两次。合并有机相用盐酸水溶液(150毫升，1摩尔每升)和饱和食盐水(150毫升)洗涤。有机相用无水硫酸钠干燥，过滤，滤液浓缩得到化合物21-5。LCMS(ESI)m/z:353.9(M+1) ⁺。 To a solution of compound 21-4 (13.9 g) in acetonitrile (280 ml) were sequentially added potassium phosphate (18.49 g) and pyridinium tribromide (41.78 g), and the reaction solution was reacted at 50 degrees Celsius for 2 hours. The reaction solution was quenched with saturated sodium sulfite (200 mL), followed by extraction twice with ethyl acetate (100 mL). The combined organic phases were washed with aqueous hydrochloric acid (150 mL, 1 mol per liter) and saturated brine (150 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 21-5. LCMS (ESI) m/z: 353.9 (M+1) ⁺ .

第五步：the fifth step:

在氮气氛围下，向化合物21-5(15.4克)和三(二亚苄基丙酮)二钯(3.98克)的二氧六环(300毫升)溶液中依次加入化合物6-4(7.84克)，Xantphos(5.03克)和碳酸铯(28.34克)，反应液在100摄氏度下反应2小时。反应液过滤，向滤液中加入盐酸乙酸乙酯溶液(200毫升，1摩尔每升)，15摄氏度下搅拌1小时。混合液过滤，滤饼用乙酸乙酯(100毫升)和饱和碳酸钠(200毫升)溶解。然后水相用乙酸乙酯(100毫升)萃取两次，合并有机相用饱和食盐水(200毫升)洗涤后用无水硫酸钠干燥，过滤，滤液浓缩得到残余物。向残余物中加入乙醇(30毫升)，室温搅拌1小时。过滤，滤饼减压干燥得到化合物21-6。LCMS(ESI)m/z:424.1(M+1) ⁺。 To a solution of compound 21-5 (15.4 g) and tris(dibenzylideneacetone)dipalladium (3.98 g) in dioxane (300 mL) was sequentially added compound 6-4 (7.84 g) under nitrogen atmosphere , Xantphos (5.03 g) and cesium carbonate (28.34 g), the reaction solution was reacted at 100 degrees Celsius for 2 hours. The reaction solution was filtered, and ethyl acetate hydrochloride solution (200 mL, 1 mol/L) was added to the filtrate, followed by stirring at 15°C for 1 hour. The mixture was filtered, and the filter cake was dissolved in ethyl acetate (100 mL) and saturated sodium carbonate (200 mL). Then the aqueous phase was extracted twice with ethyl acetate (100 mL), the combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. Ethanol (30 mL) was added to the residue, followed by stirring at room temperature for 1 hour. After filtration, the filter cake was dried under reduced pressure to obtain compound 21-6. LCMS (ESI) m/z: 424.1 (M+1) ⁺ .

第六步：Step 6:

在0摄氏度下，向化合物21-6(11.85克)的二氯甲烷(120毫升)溶液中一次性加入N-溴代丁二酰亚胺(6.48克)。反应液在15摄氏度下反应1小时。向反应液中加入饱和亚硫酸钠(200毫升),然后用二氯甲烷(100毫升)萃取两次，合并有机相用饱和食盐水(200毫升)洗涤，无水硫酸钠干燥，过滤，滤液浓缩得到残余物。向残余物中加入甲基叔丁基醚和石油醚(90毫升，1:5)搅拌12小时，过滤，滤饼减压干燥得到化合物21-7。LCMS(ESI)m/z:504.2(M+3) ⁺。 To a solution of compound 21-6 (11.85 g) in dichloromethane (120 mL) at 0 degrees Celsius was added N-bromosuccinimide (6.48 g) in one portion. The reaction solution was reacted at 15 degrees Celsius for 1 hour. Saturated sodium sulfite (200 mL) was added to the reaction solution, then extracted twice with dichloromethane (100 mL), the combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue thing. Methyl tert-butyl ether and petroleum ether (90 mL, 1:5) were added to the residue, stirred for 12 hours, filtered, and the filter cake was dried under reduced pressure to obtain compound 21-7. LCMS (ESI) m/z: 504.2 (M+3) ⁺ .

第七步：Step 7:

在氮气氛围下，向化合物21-7(14.15克)的N,N-二甲基甲酰胺(140毫升)溶液中依次加入锌粉(1.47克)，溴化锌(634.42毫克)，氰化锌(3.31克)，三(二亚苄基丙酮)二钯(1.29克)和DPPF(1.56克)。反应液在氮气保护下于120摄氏度反应3小时。反应液过滤，向滤液中加入饱和食盐水(400毫升)，然后用乙酸乙酯(200毫升)萃取两次，合并有机相用饱和食盐水(200毫升)洗涤两次，无水硫酸钠干燥，过滤，滤液浓缩得到残余物。残余物经硅胶柱纯化(洗脱剂：石油醚：乙酸乙酯＝5:1到3:1(含有5％的甲醇))得到化合物21-8。LCMS(ESI)m/z:449.1(M+1) ⁺。 To a solution of compound 21-7 (14.15 g) in N,N-dimethylformamide (140 mL) under nitrogen atmosphere were successively added zinc powder (1.47 g), zinc bromide (634.42 mg), zinc cyanide (3.31 g), tris(dibenzylideneacetone)dipalladium (1.29 g) and DPPF (1.56 g). The reaction solution was reacted at 120 degrees Celsius for 3 hours under nitrogen protection. The reaction solution was filtered, saturated brine (400 mL) was added to the filtrate, then extracted twice with ethyl acetate (200 mL), the combined organic phases were washed twice with saturated brine (200 mL), dried over anhydrous sodium sulfate, Filtration and concentration of the filtrate gave a residue. The residue was purified by silica gel column (eluent: petroleum ether: ethyl acetate = 5:1 to 3:1 (containing 5% methanol)) to give compound 21-8. LCMS (ESI) m/z: 449.1 (M+1) ⁺ .

第八步：Step 8:

化合物21-8(12.4克)的浓硫酸(128.8克)溶液在60摄氏度下反应3小时。反应液继续在60摄氏度下反应14小时。反应液冷却到15摄氏度。反应液加入到冰水(1000毫升)中，0摄氏度下缓慢加入氢氧化钠(100克)的水(300毫升)的溶液，随后用碳酸氢钠固体调pH到8。向混合液中加入乙酸乙酯(500毫升)，过滤，滤液用乙酸乙酯(200毫升*2)萃取，合并有机相用饱和食盐水(200毫升*2)洗涤，无水硫酸钠干燥，过滤，滤液浓缩得到化合物21-9。LCMS(ESI)m/z:467.2(M+1) ⁺。 A solution of compound 21-8 (12.4 g) in concentrated sulfuric acid (128.8 g) was reacted at 60 degrees Celsius for 3 hours. The reaction solution was continued to react at 60 degrees Celsius for 14 hours. The reaction solution was cooled to 15 degrees Celsius. The reaction solution was added to ice water (1000 mL), a solution of sodium hydroxide (100 g) in water (300 mL) was slowly added at 0°C, and then the pH was adjusted to 8 with solid sodium bicarbonate. Ethyl acetate (500 mL) was added to the mixture, filtered, the filtrate was extracted with ethyl acetate (200 mL*2), the combined organic phases were washed with saturated brine (200 mL*2), dried over anhydrous sodium sulfate, and filtered. , the filtrate was concentrated to obtain compound 21-9. LCMS (ESI) m/z: 467.2 (M+1) ⁺ .

第九步：Step 9:

在氮气氛围下，向化合物21-9(5.0克)的DMA(50毫升)溶液中加入CDI(5.21克)，随后缓慢加入氢化钠(1.29克，质量百分比：60％)。反应液在15摄氏度下反应1个小时)。反应液加入到冰水(200毫升)中，用盐酸水溶液(1摩尔每升)调pH到3，随后用碳酸氢钠固体调pH到8。混合液用乙酸乙酯(200毫升)萃取两次，合并有机相用饱和食盐水(200毫升)洗涤两次，无水硫酸钠干燥，过滤，滤液浓缩得到残余物，残余物中加入甲醇(15毫升)搅拌2小时。过滤，滤饼减压干燥得到21-10。LCMS(ESI)m/z:493.2(M+1) ⁺。 To a solution of compound 21-9 (5.0 g) in DMA (50 mL) was added CDI (5.21 g) under nitrogen atmosphere, followed by slowly adding sodium hydride (1.29 g, mass percent: 60%). The reaction solution was reacted at 15 degrees Celsius for 1 hour). The reaction solution was added to ice water (200 mL) and adjusted to pH 3 with aqueous hydrochloric acid (1 mol per liter), followed by pH 8 with solid sodium bicarbonate. The mixture was extracted twice with ethyl acetate (200 mL), the combined organic phases were washed twice with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue, to which was added methanol (15 mL) and stirred for 2 hours. After filtration, the filter cake was dried under reduced pressure to obtain 21-10. LCMS (ESI) m/z: 493.2 (M+1) ⁺ .

第十步：Step 10:

在氮气氛围下，向化合物21-10(0.6克)的四氢呋喃(10毫升)溶液中加入三吡咯烷基溴化鏻六氟磷酸盐(2.84克)和化合物1-1(2.27克)，反应液在60摄氏度下反应14小时。反应液过滤，滤液浓缩得到残余物。残余物经制备HPLC纯化[柱型号：Phenomenex luna C18(250*50mm*10μm)，流动相：水(0.225％甲酸)-乙腈，梯度：30％-60％，20分钟]纯化得到化合物21-11。LCMS(ESI)m/z:661.4(M+1) ⁺。 Under nitrogen atmosphere, to a solution of compound 21-10 (0.6 g) in tetrahydrofuran (10 mL) were added tripyrrolidinophosphonium bromide hexafluorophosphate (2.84 g) and compound 1-1 (2.27 g), the reaction solution was React at 60 degrees Celsius for 14 hours. The reaction solution was filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by preparative HPLC [column model: Phenomenex luna C18 (250*50mm*10μm), mobile phase: water (0.225% formic acid)-acetonitrile, gradient: 30%-60%, 20 minutes] to give compounds 21-11 . LCMS (ESI) m/z: 661.4 (M+1) ⁺ .

第十一步：Step 11:

向化合物21-11(0.9克)的二氯甲烷(10毫升)溶液中一次性加入三氟乙酸(4.62克)。反应液在15摄氏度下反应0.5小时。反应液浓缩后用乙酸乙酯(10毫升)溶解。将乙酸乙酯溶液逐滴加入到饱和碳酸氢钠(40毫升)中。混合液用乙酸乙酯(20毫升)萃取两次，合并有机相用饱和食盐水(20毫升)洗涤，无水硫酸钠干燥，过滤，滤液浓缩得到化合物21-12的三氟乙酸盐。LCMS(ESI)m/z:561.3(M+1) ⁺。 To a solution of compound 21-11 (0.9 g) in dichloromethane (10 mL) was added trifluoroacetic acid (4.62 g) in one portion. The reaction solution was reacted at 15 degrees Celsius for 0.5 hour. The reaction solution was concentrated and dissolved in ethyl acetate (10 mL). The ethyl acetate solution was added dropwise to saturated sodium bicarbonate (40 mL). The mixture was extracted twice with ethyl acetate (20 mL), the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the trifluoroacetate salt of compound 21-12. LCMS (ESI) m/z: 561.3 (M+1) ⁺ .

第十二步：Step 12:

在氮气氛围，0摄氏度下，向化合物21-12(0.37克)的四氢呋喃(8毫升)和水(2毫升)的混合溶液中加入碳酸钾(136.85毫克)，随后向反应液中加入化合物1-5(65.72毫克)。反应液在0摄氏度反应30分钟，向反应液中加入水(20毫升)，用乙酸乙酯(20毫升)萃取两次，有机相用饱和食盐水(20 毫升)洗后经无水硫酸钠干燥，过滤，滤液浓缩得到残余物。残余物通过制备HPLC[柱型号：Phenomenex luna C18(150*40mm*15um)，流动相：水(0.225％甲酸)-乙腈：28％-58％，13分钟]纯化，得到的产品用制备SFC(柱型号：DAICEL CHIRALPAK IC(250mm*30mm,10μm)，流动相：甲醇(0.1％氨水)，梯度：二氧化碳临界流体50％-50％，3.5分钟，20分钟)分离得到化合物21A和化合物21B。To a mixed solution of compound 21-12 (0.37 g) in tetrahydrofuran (8 mL) and water (2 mL) was added potassium carbonate (136.85 mg) under nitrogen atmosphere at 0 degrees Celsius, followed by compound 1- 5 (65.72 mg). The reaction solution was reacted at 0°C for 30 minutes, water (20 mL) was added to the reaction solution, extracted twice with ethyl acetate (20 mL), and the organic phase was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. , filtered, and the filtrate was concentrated to give a residue. The residue was purified by preparative HPLC [column type: Phenomenex luna C18 (150*40mm*15um), mobile phase: water (0.225% formic acid)-acetonitrile: 28%-58%, 13 minutes], and the obtained product was purified by preparative SFC ( Column model: DAICEL CHIRALPAK IC (250mm*30mm, 10μm), mobile phase: methanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 50%-50%, 3.5 minutes, 20 minutes) to separate compound 21A and compound 21B.

化合物21A和化合物21B经SFC检测【柱型号：Chiralpak IC-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为甲醇+乙腈(0.05％二乙胺)；梯度(B％)：40％甲醇+乙腈(0.05％二乙胺)】得到：化合物21A的保留时间为0.760min，e.e.值为100％；化合物21B的保留时间为1.548min，e.e.值为100％。Compound 21A and compound 21B were detected by SFC [column model: Chiralpak IC-3 50×4.6mm I.D., 3μm; mobile phase: phase A was supercritical carbon dioxide, phase B was methanol + acetonitrile (0.05% diethylamine); gradient ( B%): 40% methanol + acetonitrile (0.05% diethylamine)] yielded: compound 21A with a retention time of 0.760 min and an e.e. value of 100%; compound 21B with a retention time of 1.548 min and an e.e. value of 100%.

化合物21A(保留时间＝0.760min)： ¹H NMR(400MHz,MeOH-d ₄)δ8.32(d,J＝4.9Hz,1H),7.66-7.52(m,1H),7.32(s,1H),7.22-7.10(m,3H),6.81(dd,J＝16.8,10.6Hz,1H),6.29(dd,J＝16.8,1.7Hz,1H),5.82(dd,J＝10.6,1.7Hz,1H),4.04(br d,J＝5.9Hz,4H),3.92(br s,4H),2.84(td,J＝13.5,6.7Hz,1H),2.09(s,3H),1.18(d,J＝6.8Hz,3H),1.09(d,J＝6.8Hz,3H)。LCMS(ESI)m/z:615.3(m+1) ⁺。 Compound 21A (retention time = 0.760 min): ¹ H NMR (400 MHz, MeOH-d ₄ ) δ 8.32 (d, J=4.9 Hz, 1H), 7.66-7.52 (m, 1H), 7.32 (s, 1H) ,7.22-7.10(m,3H),6.81(dd,J＝16.8,10.6Hz,1H),6.29(dd,J＝16.8,1.7Hz,1H),5.82(dd,J＝10.6,1.7Hz,1H) ), 4.04(br d, J=5.9Hz, 4H), 3.92(br s, 4H), 2.84(td, J=13.5, 6.7Hz, 1H), 2.09(s, 3H), 1.18(d, J= 6.8Hz, 3H), 1.09 (d, J=6.8Hz, 3H). LCMS (ESI) m/z: 615.3 (m+1) ⁺ .

化合物21B(保留时间＝1.548min)： ¹H NMR(400MHz,MeOH-d ₄)δ8.32(d,J＝4.9Hz,1H),7.66-7.53(m,1H),7.32(s,1H),7.23-7.11(m,3H),6.82(dd,J＝16.8,10.6Hz,1H),6.29(dd,J＝16.8,1.6Hz,1H),5.82(dd,J＝10.5,1.6Hz,1H),4.12-4.00(m,4H),3.92(br s,4H),2.84(td,J＝13.6,6.8Hz,1H),2.09(s,3H),1.18(d,J＝6.7Hz,3H),1.08(d,J＝6.8Hz,3H)。LCMS(ESI)m/z:615.3(m+1) ⁺。 Compound 21B (retention time=1.548 min): ¹ H NMR (400 MHz, MeOH-d ₄ ) δ 8.32 (d, J=4.9 Hz, 1H), 7.66-7.53 (m, 1H), 7.32 (s, 1H) ,7.23-7.11(m,3H),6.82(dd,J＝16.8,10.6Hz,1H),6.29(dd,J＝16.8,1.6Hz,1H),5.82(dd,J＝10.5,1.6Hz,1H) ),4.12-4.00(m,4H),3.92(br s,4H),2.84(td,J=13.6,6.8Hz,1H),2.09(s,3H),1.18(d,J=6.7Hz,3H ), 1.08 (d, J=6.8 Hz, 3H). LCMS (ESI) m/z: 615.3 (m+1) ⁺ .

实施例22Example 22

第一步：first step:

在氮气氛围下，向化合物21-10(0.5克)的DMAc(10毫升)溶液中加入三吡咯烷基溴化鏻六氟磷酸盐(951.01毫克)和DIPEA(263.66毫克)反应液在15摄氏度下反应1小时，加入化合物3-1(655.77毫克)，反应液在100摄氏度下反应14小时。向反应液中加入水(20毫升)，用乙酸乙酯(20 毫升)萃取两次，合并有机相用饱和食盐水(20毫升)洗涤，无水硫酸钠干燥，过滤，滤液浓缩得到化合物22-1。LCMS(ESI)m/z:689.4(M+1) ⁺。 To a solution of compound 21-10 (0.5 g) in DMAc (10 mL) was added tripyrrolidinophosphonium bromide hexafluorophosphate (951.01 mg) and DIPEA (263.66 mg) under nitrogen atmosphere at 15°C. After reacting for 1 hour, compound 3-1 (655.77 mg) was added, and the reaction solution was reacted at 100 degrees Celsius for 14 hours. Water (20 mL) was added to the reaction solution, extracted twice with ethyl acetate (20 mL), the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 22- 1. LCMS (ESI) m/z: 689.4 (M+1) ⁺ .

第二步：Step 2:

在0摄氏度下，向化合物22-1(0.9克)的二氯甲烷(10毫升)溶液中一次性加入三氟乙酸(4.62克)。反应液在15摄氏度下反应0.5小时。反应液旋干后用乙酸乙酯(10毫升)溶解。将乙酸乙酯溶液逐滴加入到饱和碳酸氢钠(40毫升)中。混合液用乙酸乙酯(20毫升)萃取两次，合并有机相用饱和食盐水(20毫升)洗涤，无水硫酸钠干燥，过滤，滤液浓缩得到化合物22-2。LCMS(ESI)m/z:589.4(M+1) ⁺。 To a solution of compound 22-1 (0.9 g) in dichloromethane (10 mL) at 0 degrees Celsius was added trifluoroacetic acid (4.62 g) in one portion. The reaction solution was reacted at 15 degrees Celsius for 0.5 hour. The reaction solution was spin-dried and dissolved in ethyl acetate (10 mL). The ethyl acetate solution was added dropwise to saturated sodium bicarbonate (40 mL). The mixture was extracted twice with ethyl acetate (20 mL), the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 22-2. LCMS (ESI) m/z: 589.4 (M+1) ⁺ .

第三步：third step:

在氮气氛围，0摄氏度下，向化合物22-2(0.55克)的四氢呋喃(4毫升)和水(1毫升)的混合溶液中加入碳酸钾(193.72毫克)，随后向反应液中加入化合物1-5(93.03毫克)。反应液在0摄氏度反应30分钟，向反应液中加入水(10毫升)，用乙酸乙酯(10毫升)萃取两次，有机相用饱和食盐水(10毫升)洗后经无水硫酸钠干燥，过滤，滤液浓缩得到残余物。残余物通过制备HPLC[柱型号：Phenomenex luna C18(150*40mm*15um)，流动相：水(0.225％甲酸)-乙腈，梯度：25％-55％，13分钟]纯化，得到化合物22。To a mixed solution of compound 22-2 (0.55 g) in tetrahydrofuran (4 mL) and water (1 mL) was added potassium carbonate (193.72 mg) under nitrogen atmosphere at 0 degrees Celsius, followed by adding compound 1- 5 (93.03 mg). The reaction solution was reacted at 0°C for 30 minutes, water (10 mL) was added to the reaction solution, extracted twice with ethyl acetate (10 mL), and the organic phase was washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. , filtered, and the filtrate was concentrated to give a residue. The residue was purified by preparative HPLC [column model: Phenomenex luna C18 (150*40mm*15um), mobile phase: water (0.225% formic acid)-acetonitrile, gradient: 25%-55%, 13 minutes] to give compound 22.

化合物22用制备SFC(柱型号：DAICEL CHIRALPAK IC(250mm*30mm,10μm)，流动相：甲醇(0.1％氨水)，梯度：二氧化碳临界流体50％-50％，8.0分钟，40分钟)分离得到化合物22A和化合物22B。Compound 22 was separated by preparative SFC (column type: DAICEL CHIRALPAK IC (250mm*30mm, 10μm), mobile phase: methanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 50%-50%, 8.0 minutes, 40 minutes) to obtain the compound 22A and Compound 22B.

化合物22A和化合物22B经SFC检测【柱型号：Column:Chiralpak IC-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为乙醇(0.05％二乙胺)；梯度(B％)：40％-40％】得到：化合物22A的保留时间为1.478min，e.e.值为100％；化合物22B的保留时间为2.993min，e.e.值为99.47％。化合物22A(保留时间＝1.478min)： ¹H NMR(400MHz,MeOD-d ₄)δ8.33(d,J＝5.0Hz,1H),7.70-7.52(m,1H),7.25-7.10(m,4H),6.95-6.73(m,1H),6.29(ddd,J＝16.7,6.1,1.8Hz,1H),5.82(ddd,J＝10.6,7.0,1.8Hz,1H),5.02-4.90(m,2H),4.62-4.14(m,2H),3.98-3.81(m,2H),2.87(qd,J＝11.0,6.8Hz,1H),2.07(s,3H),1.49(d,J＝6.6Hz,3H),1.41-1.29(m,3H),1.18(dd,J＝6.7,1.6Hz,3H),1.09(dd,J＝6.7,1.6Hz,3H)。LCMS(ESI)m/z:643.4(m+1) ⁺。 Compound 22A and compound 22B were detected by SFC [Column model: Column: Chiralpak IC-3 50×4.6mm ID, 3μm; mobile phase: phase A was supercritical carbon dioxide, phase B was ethanol (0.05% diethylamine); gradient ( B%): 40%-40%] Obtained: the retention time of compound 22A is 1.478min, and the ee value is 100%; the retention time of compound 22B is 2.993min, and the ee value is 99.47%. Compound 22A (retention time=1.478 min): ¹ H NMR (400 MHz, MeOD-d ₄ ) δ 8.33 (d, J=5.0 Hz, 1H), 7.70-7.52 (m, 1H), 7.25-7.10 (m, 4H),6.95-6.73(m,1H),6.29(ddd,J=16.7,6.1,1.8Hz,1H),5.82(ddd,J=10.6,7.0,1.8Hz,1H),5.02-4.90(m, 2H), 4.62-4.14(m, 2H), 3.98-3.81(m, 2H), 2.87(qd, J=11.0, 6.8Hz, 1H), 2.07(s, 3H), 1.49(d, J=6.6Hz , 3H), 1.41-1.29 (m, 3H), 1.18 (dd, J=6.7, 1.6 Hz, 3H), 1.09 (dd, J=6.7, 1.6 Hz, 3H). LCMS (ESI) m/z: 643.4 (m+1) ⁺ .

化合物22B(保留时间＝2.993min)： ¹H NMR(400MHz,MeOD-d ₄)δ8.33(d,J＝4.9Hz,1H),7.68-7.54(m,1H),7.24-7.13(m,4H),6.92-6.74(m,1H),6.30(ddd,J＝16.8,6.4,1.8Hz,1H),5.87-5.77(m,1H), 4.98-4.89(m,2H),4.60-4.16(m,2H),3.97-3.80(m,2H),2.73(quin,J＝6.8Hz,1H),2.13(s,3H),1.48(d,J＝6.6Hz,3H),1.40-1.28(m,3H),1.16(d,J＝6.7Hz,3H),1.07(d,J＝6.8Hz,3H)。LCMS(ESI)m/z:643.4(m+1) ⁺。 Compound 22B (retention time = 2.993 min): ¹ H NMR (400 MHz, MeOD-d ₄ ) δ 8.33 (d, J=4.9 Hz, 1H), 7.68-7.54 (m, 1H), 7.24-7.13 (m, 4H), 6.92-6.74(m, 1H), 6.30(ddd, J=16.8, 6.4, 1.8Hz, 1H), 5.87-5.77(m, 1H), 4.98-4.89(m, 2H), 4.60-4.16( m, 2H), 3.97-3.80(m, 2H), 2.73(quin, J=6.8Hz, 1H), 2.13(s, 3H), 1.48(d, J=6.6Hz, 3H), 1.40-1.28(m , 3H), 1.16 (d, J=6.7Hz, 3H), 1.07 (d, J=6.8Hz, 3H). LCMS (ESI) m/z: 643.4 (m+1) ⁺ .

实施例23Example 23

第一步：first step:

在化合物23-1(5克)的乙腈(50毫升)溶液中加入碳酸钾(2.35克)，冷却到0摄氏度，分批加入化合物7-2(5.57克)，然后在25摄氏度搅拌16小时。过滤，浓缩干，浓缩干后在乙酸乙酯和石油醚(体积比1:1)的混合溶剂中室温打浆2小时，过滤浓缩得到化合物23-2。LCMS(ESI)m/z:248.0(M+1) ⁺。 Potassium carbonate (2.35 g) was added to a solution of compound 23-1 (5 g) in acetonitrile (50 mL), cooled to 0°C, compound 7-2 (5.57 g) was added in portions, followed by stirring at 25°C for 16 hours. Filtration, concentrated to dryness, concentrated to dryness, slurried in a mixed solvent of ethyl acetate and petroleum ether (volume ratio 1:1) at room temperature for 2 hours, filtered and concentrated to obtain compound 23-2. LCMS (ESI) m/z: 248.0 (M+1) ⁺ .

第二步：Step 2:

在化合物23-2(6.7克)的乙腈(100毫升)中加入碳酸铯(8.83克)，然后在0-5摄氏度分批加入化合物7-4(4.65克)，在25摄氏度搅拌2小时，过滤浓缩干得化合物23-3。LCMS(ESI)m/z:369.9(M+1) ⁺。 Cesium carbonate (8.83 g) was added to compound 23-2 (6.7 g) in acetonitrile (100 mL), then compound 7-4 (4.65 g) was added in portions at 0-5 degrees Celsius, stirred at 25 degrees Celsius for 2 hours, and filtered. Concentrate to dryness to obtain compound 23-3. LCMS (ESI) m/z: 369.9 (M+1) ⁺ .

第三步：third step:

在化合物23-3(10克)的三氟乙醇(50毫升)溶液中加入三乙胺(5.48g)，混合体系在90摄氏度搅拌16小时。浓缩干，用50毫升的水稀释，用1摩尔/升的氢氧化钠水溶液调节pH到8，用乙酸乙酯(50毫升)萃取丢弃，水相用1摩尔/升的盐酸水溶液调节pH到3～4，黄色的固体析出，用乙酸乙酯(100毫升)萃取，食盐水(20毫升)洗涤，无水硫酸钠干燥浓缩得到化合物23-4。 ¹H NMR(400MHz,CHLOROFORM-d)δ13.10-12.64(m,1H),8.84-8.67(m,1H),7.55-7.40(m,1H),7.23-7.10(m,2H)。LCMS(ESI)m/z:337.9(M+1) ⁺。 To a solution of compound 23-3 (10 g) in trifluoroethanol (50 ml) was added triethylamine (5.48 g), and the mixed system was stirred at 90 degrees Celsius for 16 hours. Concentrated to dryness, diluted with 50 mL of water, adjusted to pH 8 with 1 mol/L aqueous sodium hydroxide solution, extracted with ethyl acetate (50 mL) and discarded, and the aqueous phase adjusted to pH 3 with 1 mol/L aqueous hydrochloric acid solution ~4, a yellow solid was precipitated, extracted with ethyl acetate (100 mL), washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated to obtain compound 23-4. ¹ H NMR (400 MHz, CHLOROFORM-d) δ 13.10-12.64 (m, 1H), 8.84-8.67 (m, 1H), 7.55-7.40 (m, 1H), 7.23-7.10 (m, 2H). LCMS (ESI) m/z: 337.9 (M+1) ⁺ .

第四步：the fourth step:

在化合物23-4(6.7克)的乙腈(100毫升)溶液中加入磷酸钾(8.44克)和三溴吡啶嗡盐(19.07克)，然后在50摄氏度搅拌2小时，用亚硫酸钠水溶液(50毫升)淬灭反应，用乙酸乙酯(50毫升*3)萃取三次，合并有机相用饱和食盐水(20毫升)洗涤一次，无水硫酸钠干燥，浓缩得到化合物23-5。LCMS(ESI)m/z:371.7(M+1) ⁺。 Potassium phosphate (8.44 g) and pyridinium tribromide (19.07 g) were added to a solution of compound 23-4 (6.7 g) in acetonitrile (100 ml), followed by stirring at 50 degrees Celsius for 2 hours, and adding sodium sulfite aqueous solution (50 ml) The reaction was quenched, extracted three times with ethyl acetate (50 mL*3), the combined organic phases were washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain compound 23-5. LCMS (ESI) m/z: 371.7 (M+1) ⁺ .

第五步：the fifth step:

在化合物23-5(7克)和2-异丙基-4-甲基-吡啶-3-胺(3.11克)的二氧六环(20毫升)中加入Pd ₂(dba) ₃(861.42毫克)和Xantphos(1.09克，碳酸铯(12.26克)，反应体系用氮气置换，加热到100摄氏度搅拌反应18小时。降温到25摄氏度，过滤，浓缩，加入盐酸乙酸乙酯溶液((1摩尔/升，120毫升)，固体过滤，悬浊在水(100毫升)和乙酸乙酯(200毫升)溶液中，用饱和亚硫酸钠水溶液调节pH＝8～9，有机相用水(50毫升)洗涤，然后用饱和食盐水(50毫升)洗涤，无水硫酸干燥，过滤，浓缩得到化合物23-6。LCMS(ESI)m/z:442.0(M+1) ⁺. To compound 23-5 (7 g) and 2-isopropyl-4-methyl-pyridin-3-amine (3.11 g) in dioxane (20 mL) was added Pd ₂ (dba) ₃ (861.42 mg) ) and Xantphos (1.09 g, cesium carbonate (12.26 g), the reaction system was replaced with nitrogen, heated to 100 degrees Celsius and stirred for 18 hours. Cool to 25 degrees Celsius, filter, concentrate, add hydrochloric acid ethyl acetate solution ((1 mol/L , 120 mL), the solid was filtered, suspended in a solution of water (100 mL) and ethyl acetate (200 mL), adjusted to pH=8~9 with saturated aqueous sodium sulfite solution, the organic phase was washed with water (50 mL), and then saturated with Washed with brine (50 mL), dried with anhydrous sulfuric acid, filtered, and concentrated to obtain compound 23-6. LCMS (ESI) m/z: 442.0 (M+1) ⁺ .

第六步：Step 6:

在0摄氏度，向化合物23-6(8.1克)的二氯甲烷(100毫升)溶液中分批加入NBS(3.48克)，在0-25摄氏度搅拌半小时，加入饱和亚硫酸钠(50毫升)水溶液，分离的有机相用饱和食盐水(50毫升)洗涤1次，无水硫酸钠干燥，浓缩干得粗品，用石油醚和甲基叔丁基醚混合体系室温打浆12小时，过滤，干燥得到化合物23-7。 ¹H NMR(400MHz,CHLOROFORM-d)δ8.44(d,J＝4.9Hz,1H),7.48-7.35(m,1H),7.16-6.97(m,3H),6.96-6.91(m,1H),3.45-3.32(m,1H),2.20(d,J＝2.8Hz,3H),1.36-1.31(m,3H),1.26-1.20(m,3H)。LCMS(ESI)m/z:521.9(M+3) ⁺。 To a solution of compound 23-6 (8.1 g) in dichloromethane (100 mL) at 0 degrees Celsius, NBS (3.48 g) was added in portions, stirred at 0-25 degrees Celsius for half an hour, and a saturated aqueous solution of sodium sulfite (50 mL) was added, The separated organic phase was washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to dryness to obtain a crude product, which was slurried at room temperature with a mixed system of petroleum ether and methyl tert-butyl ether for 12 hours, filtered, and dried to obtain compound 23 -7. ¹ H NMR(400MHz, CHLOROFORM-d)δ8.44(d,J=4.9Hz,1H),7.48-7.35(m,1H),7.16-6.97(m,3H),6.96-6.91(m,1H) , 3.45-3.32(m, 1H), 2.20(d, J=2.8Hz, 3H), 1.36-1.31(m, 3H), 1.26-1.20(m, 3H). LCMS (ESI) m/z: 521.9 (M+3) ⁺ .

第七步：Step 7:

在化合物23-7(7.5克)，氰化锌(3.21克)，锌粉(894.00毫克)的N,N-二甲基甲酰胺(100毫升)溶液中，加入溴化锌(153.94毫克)，氮气置换，加入DPPF(1.52克)和Pd ₂(dba) ₃(1.25克)，氮气置换后在100摄氏度搅拌16小时。冷却到室温，过滤后母液倒入纯水(300毫升)中，固体过滤，溶解到乙酸乙酯(200毫升)中，水(50毫升*3)洗涤三次，用无水硫酸钠干燥，过滤浓缩干，用石油醚和甲基叔丁基醚混合体系室温打浆1小时，过滤浓缩得到化合物23-8。LCMS(ESI)m/z:466.9(M+1) ⁺。 To a solution of compound 23-7 (7.5 g), zinc cyanide (3.21 g), zinc powder (894.00 mg) in N,N-dimethylformamide (100 mL) was added zinc bromide (153.94 mg), After nitrogen replacement, DPPF (1.52 g) and Pd ₂ (dba) ₃ (1.25 g) were added, and the mixture was stirred at 100° C. for 16 hours after nitrogen replacement. Cool to room temperature, pour the mother liquor into pure water (300 ml) after filtration, filter the solid, dissolve in ethyl acetate (200 ml), wash three times with water (50 ml*3), dry with anhydrous sodium sulfate, filter and concentrate After drying, the mixture was slurried with petroleum ether and methyl tert-butyl ether at room temperature for 1 hour, filtered and concentrated to obtain compound 23-8. LCMS (ESI) m/z: 466.9 (M+1) ⁺ .

第八步：Step 8:

化合物23-8(7克)分批加入到浓硫酸(35毫升)中，加热到60摄氏度搅拌16小时，冷却到室温，倒入冰水(300毫升)中，加入10％的氢氧化钠水溶液至pH为8到9，用乙酸乙酯(500毫升*2)萃取，合并的有机相浓缩得到化合物23-9。LCMS(ESI)m/z:484.9(M+1) ⁺。 Compound 23-8 (7 g) was added to concentrated sulfuric acid (35 mL) in batches, heated to 60 degrees Celsius, stirred for 16 hours, cooled to room temperature, poured into ice water (300 mL), and added with 10% aqueous sodium hydroxide solution To pH 8 to 9, extracted with ethyl acetate (500 mL*2), the combined organic phases were concentrated to give compound 23-9. LCMS (ESI) m/z: 484.9 (M+1) ⁺ .

第九步：Step 9:

在0摄氏度，向化合物23-9(6.1克)的DMA(65毫升)溶液中加入氢化钠(1.51克，质量百分比：60％)和羰基二咪唑(6.13克)，在0-25摄氏度搅拌1小时，倒入冰水(200毫升)中，用1摩尔的盐酸水溶液调节pH到4，然后用固体碳酸氢钠调节pH＝8，用乙酸乙酯(100毫升*2)萃取，合并有机相用食盐水(20毫升)洗涤一次，无水硫酸钠干燥，浓缩得到化合物23-10。LCMS(ESI)m/z:511.0(M+1) ⁺。 To a solution of compound 23-9 (6.1 g) in DMA (65 mL) at 0 degrees Celsius, sodium hydride (1.51 g, mass percentage: 60%) and carbonyldiimidazole (6.13 g) were added, and stirred at 0-25 degrees Celsius for 1 hours, poured into ice water (200 ml), adjusted pH to 4 with 1 molar hydrochloric acid aqueous solution, then adjusted pH=8 with solid sodium bicarbonate, extracted with ethyl acetate (100 ml*2), combined the organic phases and used Washed with brine (20 mL) once, dried over anhydrous sodium sulfate, and concentrated to obtain compound 23-10. LCMS (ESI) m/z: 511.0 (M+1) ⁺ .

第十步：Step 10:

向化合物23-10(3.0克)的DMAc(30毫升)溶液中加入PYBROP(5.48克)和DIEA(2.28克)，在25摄氏度搅拌2小时。加入化合物1-1(3.29克)，加热至100摄氏度反应12小时。反应液倒入水(100毫升)中，固体用乙酸乙酯(50毫升)溶解，饱和食盐水(20毫升*3)洗涤，有机相浓缩得到残余物，残余物通过柱层析纯化(洗脱剂：石油醚：乙酸乙酯＝1:1)得到化合物23-11。LCMS(ESI)m/z:679.1(M+1) ⁺。 To a solution of compound 23-10 (3.0 g) in DMAc (30 mL) were added PYBROP (5.48 g) and DIEA (2.28 g) and stirred at 25°C for 2 hours. Compound 1-1 (3.29 g) was added, heated to 100 degrees Celsius and reacted for 12 hours. The reaction solution was poured into water (100 mL), the solid was dissolved in ethyl acetate (50 mL), washed with saturated brine (20 mL*3), the organic phase was concentrated to obtain a residue, and the residue was purified by column chromatography (eluting) Reagent: petroleum ether:ethyl acetate=1:1) to obtain compound 23-11. LCMS (ESI) m/z: 679.1 (M+1) ⁺ .

第十一步：Step 11:

化合物23-11(4.0克)的二氯甲烷(30毫升)溶液中，加入三氟乙酸(10毫升)，反应液在25摄氏度搅拌30分钟，浓缩得到化合物23-12的三氟乙酸盐。粗品直接用于下一步。LCMS(ESI)m/z:579.0(M+1) ⁺。 To a solution of compound 23-11 (4.0 g) in dichloromethane (30 mL), trifluoroacetic acid (10 mL) was added, the reaction solution was stirred at 25°C for 30 minutes, and concentrated to obtain the trifluoroacetic acid salt of compound 23-12. The crude product was used directly in the next step. LCMS (ESI) m/z: 579.0 (M+1) ⁺ .

第十二步：Step 12:

化合物23-12(3.0克，三氟乙酸盐)的四氢呋喃(20毫升)和水(10毫升)溶液中，加入碳酸钾(1.54克)，混合物在25摄氏度搅拌10分钟，然后加入化合物1-5(504.97毫克)，在25摄氏度搅拌30分钟。反应液用乙酸乙酯(50毫升)萃取，然后用饱和食盐水(10毫升)洗涤，浓缩得粗品。粗品通过制备HPLC(柱型号:Phenomenex Synergi Max-RP(250*50mm*10μm)；流动相:[水(0.225％甲酸)-乙腈]；梯度：25％-55％，25分钟)纯化得到化合物23。LCMS(ESI)m/z:633.1(M+1) ⁺。 To a solution of compound 23-12 (3.0 g, trifluoroacetate) in tetrahydrofuran (20 mL) and water (10 mL), potassium carbonate (1.54 g) was added, the mixture was stirred at 25°C for 10 minutes, and then compound 1- 5 (504.97 mg), stirred at 25 degrees Celsius for 30 minutes. The reaction solution was extracted with ethyl acetate (50 mL), washed with saturated brine (10 mL), and concentrated to obtain a crude product. The crude product was purified by preparative HPLC (column type: Phenomenex Synergi Max-RP (250*50mm*10μm); mobile phase: [water (0.225% formic acid)-acetonitrile]; gradient: 25%-55%, 25 minutes) to give compound 23 . LCMS (ESI) m/z: 633.1 (M+1) ⁺ .

第十三步：Step Thirteen:

通过制备SFC(柱型号：DAICEL CHIRALPAK IC(250mm*30mm，10μm)，流动相：甲醇(0.1％氨水)，梯度：二氧化碳临界流体50％-50％，4分钟，120分钟)分离纯化得到23M-1(保留时间＝1.904和保留时间＝2.01min的混合物)及23M-2(保留时间＝1.463min和保留时间＝1.569min的混合物)。23M-23M- 1 (mixture of RT=1.904 and RT=2.01 min) and 23M-2 (mixture of RT=1.463 min and RT=1.569 min).

23M-1通过制备SFC(柱型号：DAICEL CHIRALPAK AD(250mm*30mm，10μm)，流动相：乙醇(0.1％氨水)，梯度：二氧化碳临界流体15％-15％，5.7分钟，800分钟)分离纯化得到化合物23A和化合物23B。23M-1 was separated and purified by preparative SFC (column type: DAICEL CHIRALPAK AD (250mm*30mm, 10μm), mobile phase: ethanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 15%-15%, 5.7 minutes, 800 minutes) Compound 23A and compound 23B were obtained.

23M-2通过制备SFC(柱型号：DAICEL CHIRALPAK IG(250mm*30mm，10μm)，流动相：异丙醇(0.1％氨水)，梯度：二氧化碳临界流体15％-15％，9分钟，530分钟)分离纯化得到化合物23C和化合物23D。23M-2 was prepared by SFC (column model: DAICEL CHIRALPAK IG (250mm*30mm, 10μm), mobile phase: isopropanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 15%-15%, 9 minutes, 530 minutes) Compound 23C and compound 23D were obtained by separation and purification.

化合物23A和化合物23B经SFC检测【柱型号：Column:Chiralpak IG-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为乙醇(0.05％二乙胺)；梯度(B％)：40％-40％】得到：化合物23A的保留时间为1.904min，e.e.值为95.12％；化合物23B的保留时间为2.017min，e.e.值为99.47％。Compound 23A and compound 23B were detected by SFC [Column model: Column: Chiralpak IG-3 50 × 4.6 mm I.D., 3 μm; mobile phase: phase A was supercritical carbon dioxide, phase B was ethanol (0.05% diethylamine); gradient ( B%): 40%-40%] Obtained: Compound 23A has a retention time of 1.904 min and an e.e. value of 95.12%; Compound 23B has a retention time of 2.017 min and an e.e. value of 99.47%.

化合物23C和化合物23D经SFC检测【柱型号：Column:Chiralpak IG-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为异丙醇(0.05％二乙胺)；梯度(B％)：15％-15％】得到：化合物23C的保留时间为1.463min；化合物23D的保留时间为1.569min。Compound 23C and compound 23D were detected by SFC [Column model: Column: Chiralpak IG-3 50×4.6mm I.D., 3μm; mobile phase: A phase was supercritical carbon dioxide, and B phase was isopropanol (0.05% diethylamine); Gradient (B%): 15%-15%] yielded: the retention time of compound 23C was 1.463 min; the retention time of compound 23D was 1.569 min.

化合物23A： ¹H NMR(400MHz,DMSO-d ₆)δ8.33(d,J＝4.8Hz,1H),7.90-7.77(m,1H),7.52-7.42(m,1H),7.32(s,1H),7.10(d,J＝4.9Hz,1H),6.90-6.79(m,1H),6.24-6.15(m,1H),5.81-5.73(m,1H),3.99-3.76(m,8H),2.79-2.69(m,1H),1.99(s,3H),1.10-0.93(m,6H)。LCMS(ESI)m/z:633.1(M+1) ⁺。 Compound 23A: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.33 (d, J=4.8 Hz, 1H), 7.90-7.77 (m, 1H), 7.52-7.42 (m, 1H), 7.32 (s, 1H), 7.10(d, J＝4.9Hz, 1H), 6.90-6.79(m, 1H), 6.24-6.15(m, 1H), 5.81-5.73(m, 1H), 3.99-3.76(m, 8H) , 2.79-2.69(m, 1H), 1.99(s, 3H), 1.10-0.93(m, 6H). LCMS (ESI) m/z: 633.1 (M+1) ⁺ .

化合物23B： ¹H NMR(400MHz,DMSO-d ₆)δ8.33(d,J＝4.9Hz,1H),7.9-7.78(m,1H),7.47(br t,J＝8.8Hz,1H),7.32(s,1H),7.09(d,J＝4.9Hz,1H),6.96-6.79(m,1H),6.29-6.17(m,1H),5.92-5.70(m,1H),3.99-3.77(m,8H),2.85-2.68(m,1H),2.03-1.93(m,3H),1.13-0.93(m,6H)。LCMS(ESI)m/z:633.1(M+1) ⁺。 Compound 23B: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.33 (d, J=4.9 Hz, 1H), 7.9-7.78 (m, 1H), 7.47 (br t, J=8.8 Hz, 1H), 7.32(s, 1H), 7.09(d, J=4.9Hz, 1H), 6.96-6.79(m, 1H), 6.29-6.17(m, 1H), 5.92-5.70(m, 1H), 3.99-3.77( m, 8H), 2.85-2.68 (m, 1H), 2.03-1.93 (m, 3H), 1.13-0.93 (m, 6H). LCMS (ESI) m/z: 633.1 (M+1) ⁺ .

化合物23C： ¹H NMR(400MHz,DMSO-d ₆)δ8.33(d,J＝4.8Hz,1H),7.90-7.78(m,1H),7.53-7.44(m,1H),7.32(s,1H),7.10(d,J＝4.9Hz,1H),6.93-6.76(m,1H),6.27-6.15(m,1H),5.84-5.70(m,1H),3.99-3.73(m,8H),2.78-2.69(m,1H),1.99(s,3H),0.94-1.06(m,6H)。LCMS(ESI)m/z:633.1(M+1) ⁺。 Compound 23C: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.33 (d, J=4.8 Hz, 1H), 7.90-7.78 (m, 1H), 7.53-7.44 (m, 1H), 7.32 (s, 1H), 7.10(d, J＝4.9Hz, 1H), 6.93-6.76(m, 1H), 6.27-6.15(m, 1H), 5.84-5.70(m, 1H), 3.99-3.73(m, 8H) ,2.78-2.69(m,1H),1.99(s,3H),0.94-1.06(m,6H). LCMS (ESI) m/z: 633.1 (M+1) ⁺ .

化合物23D： ¹H NMR(400MHz,DMSO-d ₆)δ8.33(d,J＝4.8Hz,1H),7.92-7.80(m,1H),7.56-7.44(m,1H),7.32(s,1H),7.09(d,J＝5.0Hz,1H),6.94-6.78(m,1H),6.30-6.12(m,1H),5.86-5.70(m,1H),4.04-3.72(m,8H),2.84-2.68(m,1H),1.97(s,3H),1.13-0.94(m,6H)。LCMS(ESI)m/z:633.1(M+1) ⁺。 Compound 23D: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.33 (d, J=4.8 Hz, 1H), 7.92-7.80 (m, 1H), 7.56-7.44 (m, 1H), 7.32 (s, 1H), 7.09(d, J＝5.0Hz, 1H), 6.94-6.78(m, 1H), 6.30-6.12(m, 1H), 5.86-5.70(m, 1H), 4.04-3.72(m, 8H) , 2.84-2.68 (m, 1H), 1.97 (s, 3H), 1.13-0.94 (m, 6H). LCMS (ESI) m/z: 633.1 (M+1) ⁺ .

实施例24Example 24

第一步：first step:

在0-10摄氏度下，向化合物24-1(4克)的乙腈(40毫升)溶液中加入碳酸钾(1.93克)，化合物7-2(5.72克)，加完后反应液在25摄氏度下反应12个小时。将反应液过滤，滤饼用乙酸乙酯(20毫升*3)淋洗，滤液减压浓缩得到残留物。残留物中加入石油醚(40毫升)室温搅拌半小时，过滤，滤饼用石油醚(20毫升*3)淋洗并减压浓缩得到化合物24-2。LCMS(ESI)m/z:244.2(M+1)+。Potassium carbonate (1.93 g) and compound 7-2 (5.72 g) were added to a solution of compound 24-1 (4 g) in acetonitrile (40 mL) at 0-10 degrees Celsius. After the addition, the reaction solution was heated at 25 degrees Celsius. React for 12 hours. The reaction solution was filtered, the filter cake was rinsed with ethyl acetate (20 mL*3), and the filtrate was concentrated under reduced pressure to obtain a residue. Petroleum ether (40 mL) was added to the residue, stirred at room temperature for half an hour, filtered, and the filter cake was rinsed with petroleum ether (20 mL*3) and concentrated under reduced pressure to obtain compound 24-2. LCMS (ESI) m/z: 244.2 (M+1)+.

第二步：Step 2:

在0-10摄氏度下，向化合物24-2(8.33克)的乙腈(85毫升)溶液中加入碳酸铯(11.16克)，化合物7-4(5.87克)，加完反应液在10-15摄氏度下反应1小时。将反应液垫硅藻土过滤，滤饼用乙酸乙酯(30毫升*3)淋洗，滤液减压浓缩得到化合物24-3。LCMS(ESI)m/z:366.1(M+1) ⁺。 To a solution of compound 24-2 (8.33 g) in acetonitrile (85 ml) was added cesium carbonate (11.16 g), compound 7-4 (5.87 g) at 0-10 degrees Celsius, and the reaction solution was added at 10-15 degrees Celsius. React for 1 hour. The reaction solution was filtered through a pad of celite, the filter cake was rinsed with ethyl acetate (30 mL*3), and the filtrate was concentrated under reduced pressure to obtain compound 24-3. LCMS (ESI) m/z: 366.1 (M+1) ⁺ .

第三步：third step:

向化合物24-3(13克)的三氟乙醇(65毫升)溶液中加入三乙胺(7.20克)，反应液在80摄氏度下反应11小时。反应液减压浓缩得到残余物，残余物经乙酸乙酯(200毫升)和盐酸(1摩尔/升，50毫升)溶液稀释，静置分层，有机相依次用盐酸(1摩尔/升，50毫升)溶液，饱和食盐水(50毫升)洗涤，然后经无水硫酸钠干燥，过滤，减压浓缩得到残留物，在10-15摄氏度下，向残留物中加入甲基叔丁基醚(50毫升)，搅拌半小时，过滤，滤饼用甲基叔丁基醚(10毫升*3)淋洗，并减压浓缩得到化合物24-4。LCMS(ESI)m/z:334.0(M+1) ⁺。 To a solution of compound 24-3 (13 g) in trifluoroethanol (65 ml) was added triethylamine (7.20 g), and the reaction solution was reacted at 80 degrees Celsius for 11 hours. The reaction solution was concentrated under reduced pressure to obtain a residue. The residue was diluted with a solution of ethyl acetate (200 mL) and hydrochloric acid (1 mol/L, 50 mL). mL) solution, washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. To the residue was added methyl tert-butyl ether (50 °C) at 10-15 °C. mL), stirred for half an hour, filtered, and the filter cake was rinsed with methyl tert-butyl ether (10 mL*3), and concentrated under reduced pressure to obtain compound 24-4. LCMS (ESI) m/z: 334.0 (M+1) ⁺ .

第四步：the fourth step:

向化合物24-4(5.5克)的乙腈(55毫升)溶液中加入三溴吡啶鎓盐(10.56克)和磷酸钾(7.01克)，然后反应液在50摄氏度下反应2小时。将亚硫酸钠(6克)溶于水(30毫升)中淬灭反应，然后混合物过滤，滤饼用乙酸乙酯(10毫升*3)淋洗，滤液减压浓缩得到残留物。残留物用乙酸乙酯(200毫升)稀释，混合物用盐酸(1摩尔/升，50毫升*2)溶液洗涤，有机相用饱和食盐水(50毫升)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到残留物。残余物经硅胶柱纯化(石油醚：乙酸乙酯＝10:1到8:1)得到化合物24-5。LCMS(ESI)m/z:367.8(M+1) ⁺。 To a solution of compound 24-4 (5.5 g) in acetonitrile (55 ml) were added pyridinium tribromide (10.56 g) and potassium phosphate (7.01 g), and the reaction solution was reacted at 50 degrees Celsius for 2 hours. The reaction was quenched by dissolving sodium sulfite (6 g) in water (30 mL), then the mixture was filtered, the filter cake was rinsed with ethyl acetate (10 mL*3), and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was diluted with ethyl acetate (200 mL), the mixture was washed with hydrochloric acid (1 mol/L, 50 mL*2) solution, the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and reduced Concentration under pressure gave a residue. The residue was purified by silica gel column (petroleum ether:ethyl acetate=10:1 to 8:1) to obtain compound 24-5. LCMS (ESI) m/z: 367.8 (M+1) ⁺ .

第五步：the fifth step:

向化合物24-5(6克)的二氧六环(60毫升)溶液中依次加入2-异丙基-4-甲基吡啶-3-胺(2.45克)，碳酸铯(10.62克)，三(二亚苄基丙酮)二钯(1.49克)和4,5-双二苯基膦-9,9-二甲基氧杂蒽(1.89克)，反应液在氮气保护下于100摄氏度反应12小时。反应液垫硅藻土过滤，滤饼用乙酸乙酯(30毫升*3)洗涤，滤液减压浓缩得到残留物，残留物经硅胶柱纯化(石油醚：乙酸乙酯＝10:1到3:1)得到化合物24-6。LCMS(ESI)m/z:438.3(M+1) ⁺。 To a solution of compound 24-5 (6 g) in dioxane (60 mL) were successively added 2-isopropyl-4-methylpyridin-3-amine (2.45 g), cesium carbonate (10.62 g), tris (dibenzylideneacetone)dipalladium (1.49 g) and 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (1.89 g), the reaction solution was reacted at 100 degrees Celsius under nitrogen protection for 12 Hour. The reaction solution was filtered through a pad of celite, the filter cake was washed with ethyl acetate (30 mL*3), the filtrate was concentrated under reduced pressure to obtain a residue, and the residue was purified by silica gel column (petroleum ether:ethyl acetate=10:1 to 3:1) 1) Compound 24-6 is obtained. LCMS (ESI) m/z: 438.3 (M+1) ⁺ .

第六步：Step 6:

在0-10摄氏度下，向化合物24-6(5克)的二氯甲烷(50毫升)溶液中加入N-溴代丁二酰亚胺(2.03克)，反应液在0-10摄氏度下反应1小时，反应液用饱和亚硫酸钠水溶液(20毫升)淬灭，然后静置分层，有机相用饱和食盐水(20毫升)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到化合物24-7。LCMS(ESI)m/z:518.1(M+3) ⁺。 N-bromosuccinimide (2.03 g) was added to a solution of compound 24-6 (5 g) in dichloromethane (50 mL) at 0-10 degrees Celsius, and the reaction solution was reacted at 0-10 degrees Celsius For 1 hour, the reaction solution was quenched with saturated aqueous sodium sulfite solution (20 mL), then allowed to stand for layers, the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 24-7 . LCMS (ESI) m/z: 518.1 (M+3) ⁺ .

第七步：Step 7:

向化合物24-7(6.12克)的N,N-二甲基甲酰胺(60毫升)溶液中依次一次性加入锌粉(0.46克)，氰化锌(0.79克)，溴化锌(124.66毫克)，1,1-双(二苯基膦基)二茂铁(1.23克)和三(二亚苄基丙酮)二钯(1.01克)。反应液在氮气保护下于120摄氏度下反应2个小时。反应液垫硅藻土过滤，滤饼用乙酸乙酯(60毫升*3)淋洗，滤液用水(240毫升)稀释，静置分层，有机相用饱和食盐水(60毫升*2)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到残余物。残余物经硅胶柱纯化(洗脱剂：石油醚：乙酸乙酯＝10:1到3:1)得到化合物24-8。LCMS(ESI)m/z:463.0(M+1) ⁺。 To a solution of compound 24-7 (6.12 g) in N,N-dimethylformamide (60 mL) were added zinc powder (0.46 g), zinc cyanide (0.79 g), and zinc bromide (124.66 mg) in one portion. ), 1,1-bis(diphenylphosphino)ferrocene (1.23 g) and tris(dibenzylideneacetone)dipalladium (1.01 g). The reaction solution was reacted at 120 degrees Celsius for 2 hours under nitrogen protection. The reaction solution was filtered through a pad of celite, the filter cake was rinsed with ethyl acetate (60 mL*3), the filtrate was diluted with water (240 mL), the layers were left to stand, and the organic phase was washed with saturated brine (60 mL*2). Dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a residue. The residue was purified by silica gel column (eluent: petroleum ether: ethyl acetate = 10:1 to 3:1) to give compound 24-8. LCMS (ESI) m/z: 463.0 (M+1) ⁺ .

第八步：Step 8:

化合物24-8(5.8克)的浓硫酸(55.20g)溶液于60摄氏度下反应7小时。反应液加到冰水(300毫升)和乙酸乙酯(200毫升)中，在0-10摄氏度下将氢氧化钠(40克)溶解到水(200毫升)缓慢滴加至上面的混合物中，用碳酸氢钠固体调节水相的pH值到7-8，将混合物过滤，滤饼用乙酸乙酯(100毫升*3)淋洗，滤液静置分层，合并有机相用饱和食盐水(150毫升)洗涤，无水硫酸钠干燥，过滤，减压滤液浓缩得到化合物24-9。LCMS(ESI)m/z:481.2(M+1) ⁺。 A solution of compound 24-8 (5.8 g) in concentrated sulfuric acid (55.20 g) was reacted at 60 degrees Celsius for 7 hours. The reaction solution was added to ice water (300 mL) and ethyl acetate (200 mL), and sodium hydroxide (40 g) was dissolved in water (200 mL) at 0-10 degrees Celsius and slowly added dropwise to the above mixture, The pH value of the aqueous phase was adjusted to 7-8 with solid sodium bicarbonate, the mixture was filtered, the filter cake was rinsed with ethyl acetate (100 mL*3), the filtrate was allowed to stand for layers, and the organic phases were combined with saturated brine (150 mL). mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 24-9. LCMS (ESI) m/z: 481.2 (M+1) ⁺ .

第九步：Step 9:

向化合物24-9(4克)的N,N-二甲基甲酰胺(40毫升)溶液中加入1,1-羰基二咪唑(4.46克)，在10-15摄氏度下将钠氢(1.10克，质量百分比：60％)加入到上面混合物，反应液在10-15摄氏度下反应0.5小时。反应液缓慢加入到水(200毫升)中，混合物用乙酸乙酯(100毫升)稀释，用盐酸(1摩尔/升)溶液调节水相的pH值到2-3，然后再用碳酸氢钠固体调节水相的pH值到7-8。静置分层，水相用乙酸乙酯(100毫升)萃取，合并有机相用水(50毫升*2)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到化合物24-10。LCMS(ESI)m/z:507.0(M+1) ⁺。 To a solution of compound 24-9 (4 g) in N,N-dimethylformamide (40 mL) was added 1,1-carbonyldiimidazole (4.46 g), and sodium hydrogen (1.10 g) was added at 10-15 degrees Celsius. , mass percentage: 60%) was added to the above mixture, and the reaction solution was reacted at 10-15 degrees Celsius for 0.5 hours. The reaction solution was slowly added to water (200 mL), the mixture was diluted with ethyl acetate (100 mL), the pH of the aqueous phase was adjusted to 2-3 with a solution of hydrochloric acid (1 mol/L), and then solidified with sodium bicarbonate. Adjust the pH of the aqueous phase to 7-8. The layers were left to stand, the aqueous phase was extracted with ethyl acetate (100 mL), the combined organic phases were washed with water (50 mL*2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 24-10. LCMS (ESI) m/z: 507.0 (M+1) ⁺ .

第十步Step 10

向化合物24-10(637毫克)的N，N-二甲基乙酰胺(7毫升)溶液中加入二异丙基乙胺(483.80毫克)和三吡咯烷基溴化鏻六氟磷酸盐(872.53毫克)，然后反应液在15摄氏度下反应1小时。化合物1-1(697.20毫克)加入到上面的混合物中，反应液在60摄氏度下反应12个小时。反应液用水(50毫升)和乙酸乙酯(50毫升)稀释，水相用乙酸乙酯(25毫升)萃取，合并有机相用饱和食盐水(25毫升)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到残留物。残留物经制备HPLC纯化(柱型号：Phenomenex Synergi Max-RP(250*50mm*10μm)；流动相：[水(0.225％甲酸)-乙腈]；梯度：30％-60％，22分钟)得到化合物24-11。LCMS(ESI)m/z:675.3(M+1) ⁺。 To a solution of compound 24-10 (637 mg) in N,N-dimethylacetamide (7 mL) was added diisopropylethylamine (483.80 mg) and tripyrrolidinophosphonium bromide hexafluorophosphate (872.53 mg), and then the reaction solution was reacted at 15 degrees Celsius for 1 hour. Compound 1-1 (697.20 mg) was added to the above mixture, and the reaction solution was reacted at 60 degrees Celsius for 12 hours. The reaction solution was diluted with water (50 mL) and ethyl acetate (50 mL), the aqueous phase was extracted with ethyl acetate (25 mL), the combined organic phases were washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, and Concentration under reduced pressure gave a residue. The residue was purified by preparative HPLC (column type: Phenomenex Synergi Max-RP (250*50mm*10μm); mobile phase: [water (0.225% formic acid)-acetonitrile]; gradient: 30%-60% in 22 minutes) to give the compound 24-11. LCMS (ESI) m/z: 675.3 (M+1) ⁺ .

第十一步Step 11

向化合物24-11(600毫克)的二氯甲烷(6毫升)溶液中加入三氟乙酸(3.08克)，反应液在15摄氏度下反应0.5小时。反应液减压浓缩得到残留物，残留物经饱和碳酸氢钠(40毫升)溶液和乙酸乙酯(40毫升)稀释后，有机相用饱和食盐水(10毫升)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到化合物24-12。LCMS(ESI)m/z:575.2(M+1) ⁺。 To a solution of compound 24-11 (600 mg) in dichloromethane (6 mL) was added trifluoroacetic acid (3.08 g), and the reaction solution was reacted at 15 degrees Celsius for 0.5 hour. The reaction solution was concentrated under reduced pressure to obtain a residue. The residue was diluted with saturated sodium bicarbonate (40 mL) solution and ethyl acetate (40 mL). The organic phase was washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave compound 24-12. LCMS (ESI) m/z: 575.2 (M+1) ⁺ .

第十二步Step 12

向化合物24-12的四氢呋喃(8毫升)和水(2毫升)的混合溶液中加入碳酸钾(114.74毫克)，然后在15摄氏度下加入丙烯酰氯(75.14毫克)，反应液在15摄氏度下反应10分钟。反应液减压浓缩得到残留物，残留物用乙酸乙酯(40毫升)和饱和食盐水(20毫升)稀释，有机相用无水硫酸钠干燥，过滤，减压浓缩得到化合物24。LCMS(ESI)m/z:629.3(M+1) ⁺。 Potassium carbonate (114.74 mg) was added to a mixed solution of compound 24-12 in tetrahydrofuran (8 mL) and water (2 mL), then acryloyl chloride (75.14 mg) was added at 15 degrees Celsius, and the reaction solution was reacted at 15 degrees Celsius for 10 minute. The reaction solution was concentrated under reduced pressure to obtain a residue. The residue was diluted with ethyl acetate (40 mL) and saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 24. LCMS (ESI) m/z: 629.3 (M+1) ⁺ .

实施例25Example 25

第一步：first step:

在氮气氛围下，向化合物25-1(23克)的甲苯(230毫升)溶液中依次加入2-苯基碳二亚胺(16.07克)，碳酸铯(43.33克)，醋酸钯(995.23毫克)和BINAP(5.52克)。反应液在90摄氏度下反应14个小时。反应液浓缩得到残余物，用乙酸乙酯(100mL)和水(100毫升)溶解。混合液过滤，滤液分层，水相用乙酸乙酯(100毫升)萃取两次，合并有机相用无水硫酸钠干燥，过滤，浓缩滤液得到化合物25-2。LCMS(ESI)m/z:360.2(m+1) ⁺。 To a solution of compound 25-1 (23 g) in toluene (230 ml) were added 2-phenylcarbodiimide (16.07 g), cesium carbonate (43.33 g), palladium acetate (995.23 mg) in this order under nitrogen atmosphere and BINAP (5.52 g). The reaction solution was reacted at 90 degrees Celsius for 14 hours. The reaction solution was concentrated to obtain a residue, which was dissolved in ethyl acetate (100 mL) and water (100 mL). The mixture was filtered, the filtrate was separated, the aqueous phase was extracted twice with ethyl acetate (100 mL), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 25-2. LCMS (ESI) m/z: 360.2 (m+1) ⁺ .

第二步：Step 2:

向化合物25-2(32克)的四氢呋喃(600毫升)溶液中加入盐酸水溶液(4摩尔每升，130毫升，)。反应液在15摄氏度下反应2个小时。反应液中加入水(500毫升)，用氢氧化钠水溶液(1摩尔/升)调节pH到5，随后用碳酸氢钠固体调节pH到7。用乙酸乙酯(500mL)萃取两次，合并有机相用饱和食盐水(500毫升)洗涤两次，有机相用无水硫酸钠干燥，过滤，浓缩滤液得到的残余物。残余物用硅胶柱(洗脱剂：石油醚：乙酸乙酯＝50:1)纯化得到化合物25-3。To a solution of compound 25-2 (32 g) in tetrahydrofuran (600 mL) was added aqueous hydrochloric acid (4 mol per liter, 130 mL,). The reaction solution was reacted at 15 degrees Celsius for 2 hours. Water (500 mL) was added to the reaction solution, and the pH was adjusted to 5 with aqueous sodium hydroxide solution (1 mol/L), followed by pH adjustment to 7 with solid sodium bicarbonate. It was extracted twice with ethyl acetate (500 mL), the combined organic phases were washed twice with saturated brine (500 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the residue obtained by concentrating the filtrate. The residue was purified by silica gel column (eluent: petroleum ether: ethyl acetate=50:1) to obtain compound 25-3.

第三步：third step:

在0摄氏度下，向化合物25-3(35克)和碳酸钾(12.37克)的乙腈(350毫升)溶液中缓慢加入化合物7-2(29.32克)。反应液在25摄氏度下反应14个小时。反应液浓缩得到残余物，用乙酸乙酯(200mL)和饱和碳酸氢钠(200毫升)溶解。水相用乙酸乙酯(100毫升)萃取两次，合并有机相用水(200毫升)和饱和食盐水(200毫升)洗涤，有机相用无水硫酸钠干燥，过滤，浓缩滤液得到的残余物。残余物用乙酸乙酯和石油醚(200毫升，1:5)打浆1小时，过滤，滤饼减压干燥得到化合物25-4。LCMS(ESI)m/z:296.0(M+1) ⁺。 To a solution of compound 25-3 (35 g) and potassium carbonate (12.37 g) in acetonitrile (350 mL) was slowly added compound 7-2 (29.32 g) at 0 degrees Celsius. The reaction solution was reacted at 25 degrees Celsius for 14 hours. The reaction solution was concentrated to obtain a residue, which was dissolved in ethyl acetate (200 mL) and saturated sodium bicarbonate (200 mL). The aqueous phase was extracted twice with ethyl acetate (100 mL), the combined organic phases were washed with water (200 mL) and saturated brine (200 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was slurried with ethyl acetate and petroleum ether (200 mL, 1:5) for 1 hour, filtered, and the filter cake was dried under reduced pressure to obtain compound 25-4. LCMS (ESI) m/z: 296.0 (M+1) ⁺ .

第四步：the fourth step:

在0摄氏度下，向化合物25-4(24.9克)和碳酸铯(27.44克)的乙腈(250毫升)溶液中逐滴加入化合物7-4(14.44克)，反应液在15摄氏度下反应2小时。反应液过滤，滤液浓缩后加入水(200毫升)，用乙酸乙酯(200毫升)萃取两次。合并有机相用水(200毫升)和饱和食盐水(200毫升)洗涤，有机相用无水硫酸钠干燥，过滤，滤液浓缩得到化合物25-5。LCMS(ESI)m/z:418.1(M+1) ⁺。 To a solution of compound 25-4 (24.9 g) and cesium carbonate (27.44 g) in acetonitrile (250 mL) at 0 degrees Celsius, compound 7-4 (14.44 g) was added dropwise, and the reaction solution was reacted at 15 degrees Celsius for 2 hours . The reaction solution was filtered, the filtrate was concentrated, water (200 mL) was added, and the mixture was extracted twice with ethyl acetate (200 mL). The combined organic phases were washed with water (200 mL) and saturated brine (200 mL). The organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 25-5. LCMS (ESI) m/z: 418.1 (M+1) ⁺ .

第五步：the fifth step:

向化合物25-5(36克)的三氟乙醇(180毫升)溶液中加入三乙胺(17.44克)，反应液在80摄氏度下反14小时。反应液浓缩得到残余物。残余物用乙酸乙酯(500毫升)溶解，随后用盐酸水溶液(200毫升，1摩尔每升)洗涤两次，有机相用无水硫酸钠干燥，过滤，滤液浓缩得到的残余物。向残余物中加入甲基叔丁基醚和石油醚(240毫升，1:5)，室温搅拌1小时，过滤，滤饼减压干燥得到化合物25-6。LCMS(ESI)m/z:386.1(M+1) ⁺。 To a solution of compound 25-5 (36 g) in trifluoroethanol (180 ml) was added triethylamine (17.44 g), and the reaction solution was reacted at 80 degrees Celsius for 14 hours. The reaction solution was concentrated to obtain a residue. The residue was dissolved in ethyl acetate (500 mL), then washed twice with aqueous hydrochloric acid (200 mL, 1 mol per liter), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a residue. Methyl tert-butyl ether and petroleum ether (240 mL, 1:5) were added to the residue, stirred at room temperature for 1 hour, filtered, and the filter cake was dried under reduced pressure to obtain compound 25-6. LCMS (ESI) m/z: 386.1 (M+1) ⁺ .

第六步：Step 6:

向化合物25-6(10克)的乙腈(200毫升)的溶液中依次加入磷酸钾(11.01克)和三溴吡啶鎓盐(24.88克)，反应液在50摄氏度下反应14小时。反应液用饱和亚硫酸钠(200毫升)淬灭，随后用乙酸乙酯(100毫升)萃取两次。合并有机相用盐酸水溶液(200毫升，1摩尔每升)和饱和食盐水(100毫升)洗涤。有机相用无水硫酸钠干燥，过滤，滤液浓缩得到化合物25-7。LCMS(ESI)m/z:421.7(M+3) ⁺。第七步： To a solution of compound 25-6 (10 g) in acetonitrile (200 ml) were sequentially added potassium phosphate (11.01 g) and pyridinium tribromide (24.88 g), and the reaction solution was reacted at 50 degrees Celsius for 14 hours. The reaction solution was quenched with saturated sodium sulfite (200 mL), then extracted twice with ethyl acetate (100 mL). The combined organic phases were washed with aqueous hydrochloric acid (200 mL, 1 mol per liter) and saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 25-7. LCMS (ESI) m/z: 421.7 (M+3) ⁺ . Step 7:

在氮气氛围下，向化合物25-7(8.89克)和三(二亚苄基丙酮)二钯(1.94克)的二氧六环(90毫升)溶液中依次加入化合物6-4(3.18克)，Xantphos(2.45克)和碳酸铯(13.78克)，反应液在100摄氏度下反应14小时。反应液过滤，向滤液中加入盐酸乙酸乙酯溶液(100毫升，1摩尔每升)，15摄氏度下搅拌1小时。混合液过滤，滤饼用乙酸乙酯(100毫升)和饱和碳酸钠(100毫升)溶解。然后水相用乙酸乙酯(100毫升)萃取两次，合并有机相用饱和食盐水(50毫升)洗涤后用无水硫酸钠干燥，过滤，滤液浓缩得到残余物。向残余物中加入石油醚(50毫升)，室温搅拌1小时。过滤，滤饼减压干燥得到化合物25-8。LCMS(ESI)m/z:490.2(M+1) ⁺。 To a solution of compound 25-7 (8.89 g) and tris(dibenzylideneacetone)dipalladium (1.94 g) in dioxane (90 mL) was sequentially added compound 6-4 (3.18 g) under nitrogen atmosphere , Xantphos (2.45 g) and cesium carbonate (13.78 g), the reaction solution was reacted at 100 degrees Celsius for 14 hours. The reaction solution was filtered, and ethyl acetate hydrochloride solution (100 mL, 1 mol per liter) was added to the filtrate, followed by stirring at 15 degrees Celsius for 1 hour. The mixture was filtered, and the filter cake was dissolved in ethyl acetate (100 mL) and saturated sodium carbonate (100 mL). The aqueous phase was then extracted twice with ethyl acetate (100 mL), the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. Petroleum ether (50 mL) was added to the residue, followed by stirring at room temperature for 1 hour. After filtration, the filter cake was dried under reduced pressure to obtain compound 25-8. LCMS (ESI) m/z: 490.2 (M+1) ⁺ .

第八步：Step 8:

在0摄氏度下，向化合物25-8(8.68克)的二氯甲烷(86毫升)溶液中一次性加入N-溴代丁二酰亚胺(3.15克)。反应液在15摄氏度下反应1小时。向反应液中加入饱和亚硫酸钠(100毫升),然后用二氯甲烷(100毫升)萃取两次，合并有机相用饱和食盐水(200毫升)洗涤，无水硫酸钠干燥，过滤，滤液浓缩得到残余物。残余物用硅胶柱(二氧化硅，石油醚：乙酸乙酯＝3:1)纯化得到化合物25-9。LCMS(ESI)m/z:570.2(M+3) ⁺。 To a solution of compound 25-8 (8.68 g) in dichloromethane (86 mL) at 0 degrees Celsius was added N-bromosuccinimide (3.15 g) in one portion. The reaction solution was reacted at 15 degrees Celsius for 1 hour. Saturated sodium sulfite (100 mL) was added to the reaction solution, then extracted twice with dichloromethane (100 mL), the combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue thing. The residue was purified by silica gel column (silica, petroleum ether:ethyl acetate=3:1) to obtain compound 25-9. LCMS (ESI) m/z: 570.2 (M+3) ⁺ .

第九步：Step 9:

在氮气氛围下，向化合物25-9(6.5克)的N,N-二甲基甲酰胺(65毫升)溶液中依次加入锌粉(747.33毫克)，溴化锌(257.38毫克)，氰化锌(1.34克)，三(二亚苄基丙酮)二钯(523.28毫克)和DPPF(633.59毫克)。反应液在氮气保护下于120摄氏度反应2小时。反应液过滤，向滤液中加入水(100毫升)，然后用乙酸乙酯(100毫升)萃取两次，合并有机相用水(100毫升)和饱和食盐水(100毫升)洗涤，无水硫酸钠干燥，过滤，滤液浓缩得到残余物。残余物经硅胶柱纯化(石油醚：乙酸乙酯＝5:1到3:1(含有5％的甲醇))得到化合物25-10。LCMS(ESI)m/z:515.0(M+1) ⁺。 To a solution of compound 25-9 (6.5 g) in N,N-dimethylformamide (65 mL) under nitrogen atmosphere were sequentially added zinc powder (747.33 mg), zinc bromide (257.38 mg), zinc cyanide (1.34 g), tris(dibenzylideneacetone)dipalladium (523.28 mg) and DPPF (633.59 mg). The reaction solution was reacted at 120 degrees Celsius for 2 hours under nitrogen protection. The reaction solution was filtered, water (100 mL) was added to the filtrate, then extracted twice with ethyl acetate (100 mL), the combined organic phases were washed with water (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. , filtered, and the filtrate was concentrated to give a residue. The residue was purified by silica gel column (petroleum ether:ethyl acetate=5:1 to 3:1 (containing 5% methanol)) to give compound 25-10. LCMS (ESI) m/z: 515.0 (M+1) ⁺ .

第十步：Step 10:

化合物25-10(400毫克)分批加入到浓硫酸(2毫升，98％纯度)中，加热到60摄氏度搅拌14小时，冷却到室温，倒入冰水(10毫升)中，加入饱和碳酸氢钠水溶液至pH为8，乙酸乙酯(20毫升)萃取，无水硫酸钠干燥，过滤浓缩干，得化合物25-11。LCMS(ESI)m/z:532.9(M+1) ⁺。 Compound 25-10 (400 mg) was added to concentrated sulfuric acid (2 mL, 98% purity) in batches, heated to 60 degrees Celsius, stirred for 14 hours, cooled to room temperature, poured into ice water (10 mL), and saturated bicarbonate was added Aqueous sodium solution to pH 8, extracted with ethyl acetate (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness to obtain compound 25-11. LCMS (ESI) m/z: 532.9 (M+1) ⁺ .

第十一步：Step 11:

在0摄氏度下，向化合物25-11(400毫克)的四氢呋喃(10毫升)溶液中加入氢化钠(120.09毫克，质量百分比：60％)，加入羰基二咪唑(365.16毫克)，在25摄氏度下搅拌30分钟，倒入到冰水(20毫升)中，用1摩尔/升的盐酸调节pH到3-4，然后用饱和碳酸氢钠溶液调节pH＝7-8,用乙酸乙酯(20毫升)萃取两次，有机相用无水硫酸钠干燥，浓缩干得到化合物25-12。LCMS(ESI)m/z:558.9(M+1) ⁺。 To a solution of compound 25-11 (400 mg) in tetrahydrofuran (10 mL) at 0 degrees Celsius, sodium hydride (120.09 mg, mass percentage: 60%) was added, carbonyldiimidazole (365.16 mg) was added, and the mixture was stirred at 25 degrees Celsius. 30 minutes, pour into ice water (20 mL), adjust pH to 3-4 with 1 mol/L hydrochloric acid, then adjust pH=7-8 with saturated sodium bicarbonate solution, and use ethyl acetate (20 mL) After extraction twice, the organic phase was dried over anhydrous sodium sulfate and concentrated to dryness to obtain compound 25-12. LCMS (ESI) m/z: 558.9 (M+1) ⁺ .

第十二步：Step 12:

化合物25-12(400毫克)的四氢呋喃(10毫升)溶液中加入PYBROP(667.33毫克)和DIEA(277.51毫克)和化合物1-1(399.92毫克)，加热到60摄氏度反应12小时。浓缩干，用甲醇(20毫升)溶解，过滤掉不溶解的固体，母液浓缩干得到残余物。残余物通过制备HPLC(柱型号：Phenomenex Gemini-NX C18(75*30mm*3um)；流动相：[水(0.225％甲酸)-乙腈]；梯度：40％-70％，7分钟))纯化得到化合物25-13。LCMS(ESI)m/z:727.0(M+1) ⁺。 PYBROP (667.33 mg), DIEA (277.51 mg) and compound 1-1 (399.92 mg) were added to a solution of compound 25-12 (400 mg) in tetrahydrofuran (10 mL), and the reaction was heated to 60 degrees Celsius for 12 hours. Concentrate to dryness, dissolve with methanol (20 mL), filter off insoluble solids, and concentrate the mother liquor to dryness to obtain a residue. The residue was purified by preparative HPLC (column type: Phenomenex Gemini-NX C18 (75*30mm*3um); mobile phase: [water (0.225% formic acid)-acetonitrile]; gradient: 40%-70%, 7 minutes)) to give Compounds 25-13. LCMS (ESI) m/z: 727.0 (M+1) ⁺ .

第十三步：Step Thirteen:

在20-30摄氏度下，向化合物25-13(200毫克)的二氯甲烷(3毫升)溶液中一次性加入三氟乙酸(1.54克)。反应液在25摄氏度下反应1个小时。反应液浓缩得到化合物25-14的三氟乙酸盐。LCMS(ESI)m/z:627.0(M+1) ⁺。粗品直接用于下一步。 To a solution of compound 25-13 (200 mg) in dichloromethane (3 mL) was added trifluoroacetic acid (1.54 g) in one portion at 20-30 degrees Celsius. The reaction solution was reacted at 25 degrees Celsius for 1 hour. The reaction solution was concentrated to obtain the trifluoroacetate salt of compound 25-14. LCMS (ESI) m/z: 627.0 (M+1) ⁺ . The crude product was used directly in the next step.

第十四步：Step 14:

在0摄氏度下，向化合物25-14(150毫克，TFA盐)的四氢呋喃(3.0毫升)和水(0.5毫升)的混合溶液中依次一次性加入无水碳酸钾(99.19毫克)，化合物1-5(21.65毫克)。反应液在0摄氏度下反应0.5小时。向反应液中加入水(10毫升)，用乙酸乙酯(10毫升*3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液浓缩得到残余物。残余物先经制备柱纯化HPLC(柱型号：Shim-pack C18 150*25mm*10 μm)，流动相(0.225％甲酸水：乙腈)，梯度：8％-38％，10分钟)。得化合物25。 ¹H NMR(400MHz,DMSO-d ₆)δ8.32-8.31(m,1H),7.56-7.52(m,1H),7.28-7.23(m,1H),7.18(m,1H),7.07-7.05(m,2H),6.87-6.78(m,1H),6.01-5.96(m,1H),5.48-5.43(m,1H),3.49-3.49(m,1H),3.25-3.24(m,4H),2.99-2.97(m,4H),2.22(m,3H),1.38-1.17(m,6H)。LCMS(ESI)m/z:681.17(M+1) ⁺。 To a mixed solution of compound 25-14 (150 mg, TFA salt) in tetrahydrofuran (3.0 mL) and water (0.5 mL) at 0 degrees Celsius, anhydrous potassium carbonate (99.19 mg) was sequentially added in one portion, compound 1-5 (21.65 mg). The reaction solution was reacted at 0 degrees Celsius for 0.5 hours. Water (10 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was first purified by HPLC on a preparative column (column type: Shim-pack C18 150*25mm*10 μm), mobile phase (0.225% formic acid in water:acetonitrile), gradient: 8%-38% in 10 minutes). Compound 25 was obtained. ¹ H NMR (400MHz, DMSO-d ₆ )δ8.32-8.31(m,1H), 7.56-7.52(m,1H), 7.28-7.23(m,1H), 7.18(m,1H), 7.07-7.05 (m,2H),6.87-6.78(m,1H),6.01-5.96(m,1H),5.48-5.43(m,1H),3.49-3.49(m,1H),3.25-3.24(m,4H) , 2.99-2.97 (m, 4H), 2.22 (m, 3H), 1.38-1.17 (m, 6H). LCMS (ESI) m/z: 681.17 (M+1) ⁺ .

实施例26Example 26

第一步：first step:

在化合物26-1(10克)的乙腈(100毫升)溶液中加入碳酸钾(4.275克)，冷却到0度，分批加入化合物7-2(10.11克)，然后在25摄氏度搅拌16小时。过滤，浓缩干，在乙酸乙酯和石油醚(体积比1:1，200毫升)的混合溶剂中25摄氏度打浆2小时，过滤浓缩得到化合物26-2。LCMS(ESI)m/z:261.9(M+1) ⁺。 Potassium carbonate (4.275 g) was added to a solution of compound 26-1 (10 g) in acetonitrile (100 ml), cooled to 0°C, compound 7-2 (10.11 g) was added in portions, followed by stirring at 25°C for 16 hours. It was filtered, concentrated to dryness, slurried in a mixed solvent of ethyl acetate and petroleum ether (1:1 by volume, 200 ml) at 25 degrees Celsius for 2 hours, filtered and concentrated to obtain compound 26-2. LCMS (ESI) m/z: 261.9 (M+1) ⁺ .

第二步：Step 2:

在0摄氏度，化合物26-2(13.3克)的乙腈(150毫升)中加入碳酸铯(16.15克)，然后在分批加入三氟乙酰乙烯基烯醚(8.50克)，在25摄氏度搅拌2小时，过滤浓缩干得化合物26-3。LCMS(ESI)m/z: 401.8(M+1+H ₂O) ⁺。 At 0°C, cesium carbonate (16.15g) was added to compound 26-2 (13.3g) in acetonitrile (150ml), then trifluoroacetyl vinylene ether (8.50g) was added in portions, and the mixture was stirred at 25°C for 2 hours , filtered and concentrated to give compound 26-3. LCMS (ESI) m/z: 401.8 (M+1+H ₂ O) ⁺ .

第三步：third step:

在化合物26-3(20克)的三氟乙醇(100毫升)溶液中加入三乙胺(10.54克)，混合体系在80摄氏度搅拌12小时。浓缩干，用水(200毫升)和乙酸乙酯(200毫升)稀释，用1摩尔/升的盐酸水溶液调节pH到3，乙酸乙酯萃取，丢弃有机相，水相用1摩尔/升的氢氧化钠水溶液调节pH到8，黄色的固体析出，过滤固体，固体悬浊在水(300毫升)中，用1摩尔的盐酸调节pH到2，用乙酸乙酯(100毫升*2)萃取，合并的有机相用无水硫酸钠干燥，过滤浓缩干得化合物26-4。LCMS(ESI)m/z:351.8(M+1) ⁺。 To a solution of compound 26-3 (20 g) in trifluoroethanol (100 mL) was added triethylamine (10.54 g), and the mixed system was stirred at 80 degrees Celsius for 12 hours. Concentrate to dryness, dilute with water (200 mL) and ethyl acetate (200 mL), adjust the pH to 3 with 1 mol/L aqueous hydrochloric acid, extract with ethyl acetate, discard the organic phase, and use 1 mol/L hydrochloric acid for the aqueous phase Aqueous sodium solution was adjusted to pH 8, a yellow solid was precipitated, the solid was filtered, the solid was suspended in water (300 mL), the pH was adjusted to 2 with 1 molar hydrochloric acid, extracted with ethyl acetate (100 mL*2), and the combined The organic phase was dried with anhydrous sodium sulfate, filtered and concentrated to dryness to obtain compound 26-4. LCMS (ESI) m/z: 351.8 (M+1) ⁺ .

第四步：the fourth step:

在化合物26-4(12克)的乙腈(180毫升)溶液中加入磷酸钾(14.47克)和三溴吡啶嗡盐(32.70克)，然后在50摄氏度搅拌3小时，用饱和亚硫酸钠(100毫升)淬灭反应，乙酸乙酯(100毫升)萃取，有机相用饱和食盐水(50毫升)洗涤，无水硫酸钠(10克)干燥，浓缩干得粗品，粗品在50毫升甲基叔丁基醚中25摄氏度搅拌16小时，过滤，滤饼干燥得到化合物26-5。LCMS(ESI)m/z:387.7(M+3) ⁺。 Potassium phosphate (14.47 g) and pyridinium tribromide (32.70 g) were added to a solution of compound 26-4 (12 g) in acetonitrile (180 ml), followed by stirring at 50 degrees Celsius for 3 hours, using saturated sodium sulfite (100 ml) The reaction was quenched, extracted with ethyl acetate (100 mL), the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate (10 g), and concentrated to dryness to obtain the crude product, which was dissolved in 50 mL of methyl tert-butyl ether. The mixture was stirred at 25 degrees Celsius for 16 hours, filtered, and the filter cake was dried to obtain compound 26-5. LCMS (ESI) m/z: 387.7 (M+3) ⁺ .

第五步：the fifth step:

在化合物26-5(8克)和化合物6-4(3.11克)的二氧六环(150毫升)中加Pd ₂(dba) ₃(1.89克)和Xantphos(2.39克)，碳酸铯(13.47克)，反应体系用氮气置换，加热到100摄氏度搅拌16小时。降温到25摄氏度，过滤，浓缩干，用乙酸乙酯(200毫升)稀释，用水(20毫升)洗涤，饱和食盐水(20毫升)洗涤，浓缩干得粗品，柱层析(洗脱剂：石油醚：乙酸乙酯＝10:1到20:1)纯化得到化合物26-6。 ¹H NMR(400MHz,CHLOROFORM-d)δ8.40(d,J＝4.9Hz,1H),7.52-7.39(m,1H),7.23(s,2H),7.03(d,J＝4.8Hz,1H),6.70(br d,J＝4.4Hz,1H),6.62(d,J＝7.8Hz,1H),5.73(d,J＝7.8Hz,1H),3.25-3.06(m,1H),2.20-2.11(m,3H),1.21-1.07(m,6H)。LCMS(ESI)m/z:455.9(M+1) ⁺。 To compound 26-5 (8 g) and compound 6-4 (3.11 g) in dioxane (150 ml) were added Pd ₂ (dba) ₃ (1.89 g) and Xantphos (2.39 g), cesium carbonate (13.47 g) g), the reaction system was replaced with nitrogen, heated to 100 degrees Celsius and stirred for 16 hours. Cooled to 25 degrees Celsius, filtered, concentrated to dryness, diluted with ethyl acetate (200 mL), washed with water (20 mL), washed with saturated brine (20 mL), concentrated to dryness to obtain the crude product, column chromatography (eluent: petroleum ether:ethyl acetate=10:1 to 20:1) was purified to give compound 26-6. ¹ H NMR(400MHz, CHLOROFORM-d)δ8.40(d,J=4.9Hz,1H),7.52-7.39(m,1H),7.23(s,2H),7.03(d,J=4.8Hz,1H) ),6.70(br d,J=4.4Hz,1H),6.62(d,J=7.8Hz,1H),5.73(d,J=7.8Hz,1H),3.25-3.06(m,1H),2.20- 2.11 (m, 3H), 1.21-1.07 (m, 6H). LCMS (ESI) m/z: 455.9 (M+1) ⁺ .

第六步：Step 6:

在0摄氏度，向化合物26-6(3.4克)的二氯甲烷(60毫升)溶液中分批加入NBS(1.33克)，在28摄氏度搅拌30分钟，加入饱和亚硫酸钠(20毫升) _，分离的有机相用饱和食盐水(20毫升)洗涤，无水硫酸钠干燥，浓缩干得粗品，用石油醚和甲基叔丁基醚混合体系(体积比1:1,50毫升)25摄氏度打浆2小时，过滤，干燥得到化合物26-7。LCMS(ESI)m/z:535.8(M+3) ⁺。 To a solution of compound 26-6 (3.4 g) in dichloromethane (60 mL) at 0 °C was added NBS (1.33 g) portionwise, stirred at 28 °C for 30 min, saturated sodium sulfite (20 mL) was added _{, and} the separated organic The phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to dryness to obtain a crude product, which was slurried at 25°C for 2 hours with a mixed system of petroleum ether and methyl tert-butyl ether (volume ratio 1:1, 50 mL). Filtration and drying gave compound 26-7. LCMS (ESI) m/z: 535.8 (M+3) ⁺ .

第七步：Step 7:

在化合物26-7(4克)，氰化锌(438.82毫克)，锌粉(488.73毫克)的二甲基甲酰胺(60毫升)溶液中加入溴化锌(168.31毫克)，氮气置换，加入DPPF(828.69克)和Pd ₂(dba) ₃(684.41毫克)，氮气置换后在120摄氏度搅拌2小时。冷却到室温，过滤后母液浓缩干除去二甲基甲酰胺，然后用乙酸乙酯(150毫升)稀释，用饱和食盐水(50毫升)洗涤，浓缩干得粗品，通过柱层析(洗脱剂乙酸乙酯：石油醚＝1:10到1:3)得到纯化得到化合物26-8。LCMS(ESI)m/z:480.9(M+1) ⁺。 To a solution of compound 26-7 (4 g), zinc cyanide (438.82 mg), zinc powder (488.73 mg) in dimethylformamide (60 mL) was added zinc bromide (168.31 mg), nitrogen was replaced, DPPF was added (828.69 g) and Pd ₂ (dba) ₃ (684.41 mg), and stirred at 120° C. for 2 hours after nitrogen replacement. After cooling to room temperature, the mother liquor was filtered and concentrated to dryness to remove dimethylformamide, then diluted with ethyl acetate (150 mL), washed with saturated brine (50 mL), and concentrated to dryness to obtain crude product, which was subjected to column chromatography (eluent). ethyl acetate:petroleum ether=1:10 to 1:3) was purified to obtain compound 26-8. LCMS (ESI) m/z: 480.9 (M+1) ⁺ .

第八步：Step 8:

化合物26-8(1.7克)分批加入到浓硫酸(35毫升，纯度98％)中，加热到60摄氏度搅拌16小时，冷却到室温，倒入的冰水(200毫升)中，加入5摩尔/升的氢氧化钠水溶液至pH为8，用的乙酸乙酯 (200毫升)萃取，合并的有机相用食盐水(120毫升)洗涤，无水硫酸钠(10克)干燥，过滤浓缩得到化合物26-9。LCMS(ESI)m/z:498.9(M+1) ⁺。 Compound 26-8 (1.7 g) was added to concentrated sulfuric acid (35 mL, purity 98%) in batches, heated to 60 degrees Celsius, stirred for 16 hours, cooled to room temperature, poured into ice water (200 mL), and added 5 mol /L aqueous sodium hydroxide solution to pH 8, extracted with ethyl acetate (200 mL), the combined organic phases were washed with brine (120 mL), dried over anhydrous sodium sulfate (10 g), filtered and concentrated to obtain the compound 26-9. LCMS (ESI) m/z: 498.9 (M+1) ⁺ .

第九步：Step 9:

在0摄氏度，向化合物26-9(1.7克)的N,N-二甲基乙酰胺(20毫升)溶液中加氢化钠(408.52毫克，质量百分比：60％)，反应液在室温搅拌10分钟，分批加入羰基二咪唑(1.66克)，反应液在0-25摄氏度搅拌50分钟。反应液倒入到冰水(100毫升)中，用1摩尔/升的盐酸水溶液调节pH到3-4，然后用饱和碳酸氢钠水溶液调节pH＝7-8，用乙酸乙酯(100毫升)萃取，有机相用无水硫酸钠干燥，浓缩干得化合物26-10。LCMS(ESI)m/z:524.9(M+1) ⁺。 To a solution of compound 26-9 (1.7 g) in N,N-dimethylacetamide (20 mL) at 0 degrees Celsius, sodium hydride (408.52 mg, mass percentage: 60%) was added, and the reaction solution was stirred at room temperature for 10 minutes, carbonyldiimidazole (1.66 g) was added in portions, and the reaction solution was stirred at 0-25 degrees Celsius for 50 minutes. The reaction solution was poured into ice water (100 mL), adjusted to pH 3-4 with 1 mol/L aqueous hydrochloric acid solution, then adjusted to pH=7-8 with saturated aqueous sodium bicarbonate solution, and then adjusted to pH=7-8 with ethyl acetate (100 mL) After extraction, the organic phase was dried over anhydrous sodium sulfate, and concentrated to dryness to obtain compound 26-10. LCMS (ESI) m/z: 524.9 (M+1) ⁺ .

第十步：Step 10:

向化合物26-10(1.0克)的N,N-二甲基甲酰胺(10毫升)溶液中加PyBrOP(1.77克)和二异丙基乙胺(738.10毫克)，在25摄氏度搅拌1小时。加入化合物1-1(1.06克)加热到100摄氏度反应12小时。冷却到25度，用乙酸乙酯(100毫升)稀释，用水(20毫升*3)洗涤，再用饱和食盐水(50毫升)洗涤，有机相浓缩得到粗品通过制备HPLC((柱型号:Phenomenex Synergi Max-RP(250*50mm*10μm)；流动相:[水(0.225％甲酸)-乙腈]；梯度：35％-65％，22分钟))纯化得到化合物26-11。LCMS(ESI)m/z:693.0(M+1) ⁺。 To a solution of compound 26-10 (1.0 g) in N,N-dimethylformamide (10 mL) were added PyBrOP (1.77 g) and diisopropylethylamine (738.10 mg) and stirred at 25°C for 1 hour. Compound 1-1 (1.06 g) was added and heated to 100 degrees Celsius to react for 12 hours. Cooled to 25 degrees, diluted with ethyl acetate (100 mL), washed with water (20 mL*3), then with saturated brine (50 mL), the organic phase was concentrated to obtain the crude product by preparative HPLC ((column type: Phenomenex Synergi) Max-RP (250*50mm*10μm); mobile phase: [water (0.225% formic acid)-acetonitrile]; gradient: 35%-65%, 22 minutes)) purification gave compound 26-11. LCMS (ESI) m/z: 693.0 (M+1) ⁺ .

第十一步：Step 11:

向化合物26-11(800毫克)的二氯甲烷(6毫升)溶液中，加入三氟乙酸(3毫升)，反应液在25摄氏度搅拌30分钟，浓缩干得化合物26-12的三氟乙酸盐。粗品直接用于下一步。LCMS(ESI)m/z:593.1(M+1) ⁺。 To a solution of compound 26-11 (800 mg) in dichloromethane (6 mL), trifluoroacetic acid (3 mL) was added, the reaction solution was stirred at 25 degrees Celsius for 30 minutes, and concentrated to dryness to obtain compound 26-12 in trifluoroacetic acid Salt. The crude product was used directly in the next step. LCMS (ESI) m/z: 593.1 (M+1) ⁺ .

第十二步：Step 12:

向化合物26-12(940毫克，2三氟乙酸盐)的四氢呋喃(20毫升)和水(10毫升)溶液中加入碳酸钾(316.29毫克)，混合物在25摄氏度搅拌10分钟，然后加入化合物1-5(124.28毫克)，在25摄氏度搅拌20分钟。用乙酸乙酯(50毫升)萃取，然后用饱和食盐水(10毫升)洗涤，有机相浓缩得到化合物26。To a solution of compound 26-12 (940 mg, 2-trifluoroacetate) in tetrahydrofuran (20 mL) and water (10 mL) was added potassium carbonate (316.29 mg), the mixture was stirred at 25°C for 10 minutes, and then compound 1 was added -5 (124.28 mg), stirred at 25 degrees Celsius for 20 minutes. Extracted with ethyl acetate (50 mL), washed with saturated brine (10 mL), and concentrated the organic phase to obtain compound 26.

化合物26通过制备SFC(柱型号：DAICEL CHIRALPAK IC(250mm*30mm，5μm)，流动相：甲醇(0.1％氨水)，梯度：二氧化碳临界流体25％-25％，6.7分钟，730分钟)分离纯化得化合物26A及化合物26B。Compound 26 was isolated and purified by preparative SFC (column type: DAICEL CHIRALPAK IC (250mm*30mm, 5μm), mobile phase: methanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 25%-25%, 6.7 minutes, 730 minutes) Compound 26A and Compound 26B.

化合物26A和化合物26B经SFC检测【柱型号：Column:Chiralceel OD-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为甲醇(0.05％二乙胺)；梯度(B％)：5％-40％】得到：化合物26A的保留时间为1.62min，e.e.值为100％；化合物26B的保留时间为1.74min，e.e.值为100％。Compound 26A and compound 26B were detected by SFC [Column model: Column: Chiralceel OD-3 50×4.6mm I.D., 3μm; mobile phase: phase A was supercritical carbon dioxide, phase B was methanol (0.05% diethylamine); gradient ( B%): 5%-40%] Obtained: Compound 26A has a retention time of 1.62 min and an e.e. value of 100%; Compound 26B has a retention time of 1.74 min and an e.e. value of 100%.

化合物26A(保留时间＝1.62min)： ¹H NMR(400MHz,DMSO-d ₆)δ8.31(d,J＝4.8Hz,1H),7.82(t,J＝1.8Hz,1H),7.62(s,1H),7.44(s,1H),7.17(s,1H),7.07(d,J＝4.9Hz,1H),6.93-6.79(m,1H),6.27-6.12(m,1H),5.83-5.71(m,1H),4.06-3.73(m,8H),2.72-2.79(m,1H),2.00(s,3H),1.17-0.92(m,6H)。LCMS(ESI)m/z:647.0(M+1) ⁺。 Compound 26A (retention time=1.62 min): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.31 (d, J=4.8 Hz, 1H), 7.82 (t, J=1.8 Hz, 1H), 7.62 (s ,1H),7.44(s,1H),7.17(s,1H),7.07(d,J=4.9Hz,1H),6.93-6.79(m,1H),6.27-6.12(m,1H),5.83- 5.71(m,1H), 4.06-3.73(m,8H), 2.72-2.79(m,1H), 2.00(s,3H), 1.17-0.92(m,6H). LCMS (ESI) m/z: 647.0 (M+1) ⁺ .

化合物26B(保留时间＝1.74min)： ¹H NMR(400MHz,DMSO-d ₆)δ8.31(d,J＝4.9Hz,1H),7.93-7.77(m,1H),7.62(s,1H),7.44(s,1H),7.29-7.00(m,2H),6.97-6.79(m,1H),6.26-6.12(m,1H),5.89-5.61(m,1H),4.02-3.75(m,8H),2.81-2.71(m,1H),2.04-1.94(m,3H),1.12-0.95(m,6H)。LCMS(ESI)m/z:647.0(M+1) ⁺。 Compound 26B (retention time=1.74 min): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.31 (d, J=4.9 Hz, 1H), 7.93-7.77 (m, 1H), 7.62 (s, 1H) ,7.44(s,1H),7.29-7.00(m,2H),6.97-6.79(m,1H),6.26-6.12(m,1H),5.89-5.61(m,1H),4.02-3.75(m, 8H), 2.81-2.71 (m, 1H), 2.04-1.94 (m, 3H), 1.12-0.95 (m, 6H). LCMS (ESI) m/z: 647.0 (M+1) ⁺ .

实施例27Example 27

第一步：first step:

在20-30摄氏度下，向化合物26-10(300毫克)的四氢呋喃(3毫升)溶液中一次性加入三吡咯烷基溴化磷六氟磷酸盐(532.47毫克)、二异丙基乙胺(221.43毫克)及化合物3-1(367.16毫克)。反应液在60摄氏度下反应12个小时。反应液物用水(20毫升)稀释后，用乙酸乙酯(10毫升*3)萃取，合并有机相用无水硫酸钠干燥，过滤，浓缩滤液得到化合物27-1。LCMS(ESI)m/z:721.4(M+1) ⁺。 To a solution of compound 26-10 (300 mg) in tetrahydrofuran (3 mL) at 20-30 degrees Celsius was added tripyrrolidinophosphonium bromide hexafluorophosphate (532.47 mg), diisopropylethylamine ( 221.43 mg) and compound 3-1 (367.16 mg). The reaction solution was reacted at 60 degrees Celsius for 12 hours. The reaction solution was diluted with water (20 mL), extracted with ethyl acetate (10 mL*3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 27-1. LCMS (ESI) m/z: 721.4 (M+1) ⁺ .

第二步：Step 2:

在20-30摄氏度下，向化合物27-1(380毫克)的二氯甲烷(3毫升)溶液中一次性加入三氟乙酸(2.93克)。反应液在25摄氏度下反应1个小时。反应液浓缩得到化合物27-2的三氟乙酸盐。LCMS(ESI)m/z:621.1(M+1) ⁺。粗品直接用于下一步。 To a solution of compound 27-1 (380 mg) in dichloromethane (3 mL) was added trifluoroacetic acid (2.93 g) in one portion at 20-30 degrees Celsius. The reaction solution was reacted at 25 degrees Celsius for 1 hour. The reaction solution was concentrated to obtain the trifluoroacetate salt of compound 27-2. LCMS (ESI) m/z: 621.1 (M+1) ⁺ . The crude product was used directly in the next step.

第三步：third step:

在0摄氏度下，向化合物27-2(290毫克，三氟乙酸盐)的四氢呋喃(3.0毫升)和水(0.5毫升)的混合溶液中依次一次性加入无水碳酸钾(64.49毫克)，丙烯酰氯(42.23毫克)。反应液在0摄氏度下反应0.5小时。向反应液中加入水(10毫升)，用乙酸乙酯(10毫升*3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液浓缩得到残余物。残余物先经制备HPLC(柱型号：Phenomenex Gemini-NX C18 75*30mm*3μm)，流动相(0.225％甲酸水：乙腈)，梯度：32％-62％，7分钟)纯化得到化合物27。To a mixed solution of compound 27-2 (290 mg, trifluoroacetate) in tetrahydrofuran (3.0 mL) and water (0.5 mL) at 0 degrees Celsius, anhydrous potassium carbonate (64.49 mg), propylene Acid chloride (42.23 mg). The reaction solution was reacted at 0 degrees Celsius for 0.5 hours. Water (10 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was first purified by preparative HPLC (column type: Phenomenex Gemini-NX C18 75*30mm*3μm), mobile phase (0.225% formic acid water:acetonitrile), gradient: 32%-62%, 7 minutes) to obtain compound 27.

化合物27再通过SFC(柱型号：Chiralpak IC-3(250*30mm I.D.,5μm)，流动相：异丙醇(0.05％二乙胺)，梯度：二氧化碳临界流体40％-40％，5分钟，40分钟)分离纯化得到化合物27A及化合物27B。Compound 27 was then passed through SFC (column type: Chiralpak IC-3 (250*30mm I.D., 5μm), mobile phase: isopropanol (0.05% diethylamine), gradient: carbon dioxide critical fluid 40%-40%, 5 minutes, 40 minutes) separation and purification to obtain compound 27A and compound 27B.

化合物27A和化合物27B经SFC检测【柱型号：Column:Chiralpak IC-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为乙醇(0.05％二乙胺)；梯度(B％)：50％-50％】得到：化合物27A的保留时间为2.933min，e.e.值为100％；化合物27B的保留时间为4.568min，e.e.值为100％。Compound 27A and compound 27B were detected by SFC [Column model: Column: Chiralpak IC-3 50×4.6mm I.D., 3μm; mobile phase: phase A was supercritical carbon dioxide, phase B was ethanol (0.05% diethylamine); gradient ( B%): 50%-50%] Obtained: Compound 27A has a retention time of 2.933 min and an e.e. value of 100%; Compound 27B has a retention time of 4.568 min and an e.e. value of 100%.

化合物27A(保留时间＝2.933min)：LCMS(ESI)m/z:675.18(M+1) ⁺。 Compound 27A (retention time = 2.933 min): LCMS (ESI) m/z: 675.18 (M+1) ⁺ .

化合物27B(保留时间＝4.568min)： ¹H NMR(400MHz,DMSO-d ₆)δ8.304-8.292(m,1H),7.812(m,1H),7.826(m,1H),7.418(m,1H),7.067-7.054(m,2H),6.880-6.788(m,1H),6.211-6.189(m,1H),5.770-5.735(m,1H),4.751-4.457(m,2H),4.137-3.745(m,4H),3.553-3.455(m,1H),1.956(m,3H),1.338-1.132(m,6H),1.072-0.989(m,6H)。LCMS(ESI)m/z:675.18(M+1) ⁺。 Compound 27B (retention time = 4.568 min): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.304-8.292 (m, 1H), 7.812 (m, 1H), 7.826 (m, 1H), 7.418 (m, 1H), 7.067-7.054(m, 2H), 6.880-6.788(m, 1H), 6.211-6.189(m, 1H), 5.770-5.735(m, 1H), 4.751-4.457(m, 2H), 4.137- 3.745(m,4H), 3.553-3.455(m,1H), 1.956(m,3H), 1.338-1.132(m,6H), 1.072-0.989(m,6H). LCMS (ESI) m/z: 675.18 (M+1) ⁺ .

实施例28Example 28

第一步：first step:

在10-25摄氏度下，向化合物7-13(0.5克)的DMAC(5毫升)溶液中一次性加入三吡咯烷基溴化鏻六氟磷酸盐(1.77克)，化合物2-1(1.52克，7.59毫摩尔，8.0当量)，反应液在60摄氏度下反应12小时。向反应液中缓慢加入水(10毫升)，用乙酸乙酯(5毫升*3)萃取，合并有机相，盐水洗涤(5毫升*3)无水硫酸钠干燥，过滤，滤液浓缩得到残余物。残余物经制备纯化得到化合物28-1。LCMS(ESI)m/z:709.2(M+1) ⁺。 To a solution of compound 7-13 (0.5 g) in DMAC (5 mL) at 10-25 degrees Celsius, tripyrrolidinophosphonium bromide hexafluorophosphate (1.77 g), compound 2-1 (1.52 g) was added in one portion , 7.59 mmol, 8.0 equiv), the reaction solution was reacted at 60 degrees Celsius for 12 hours. Water (10 mL) was slowly added to the reaction solution, extracted with ethyl acetate (5 mL*3), the organic phases were combined, washed with brine (5 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was preparatively purified to give compound 28-1. LCMS (ESI) m/z: 709.2 (M+1) ⁺ .

第二步：Step 2:

在10-25摄氏度下，向化合物28-1(230毫克)的二氯甲烷(5毫升)溶液中一次性加入三氟乙酸(1.54克)。反应液在15摄氏度下反应0.5小时。将反应液浓缩得到残余物。向残余物中加入水(10毫升)，水相用碳酸氢钠固体调至pH＝8，乙酸乙酯(5毫升*3)萃取，合并有机相，盐水洗涤(10毫升)无水硫酸钠干燥，过滤，滤液浓缩得到化合物28-2。LCMS(ESI)m/z:609.2(M+1) ⁺。 To a solution of compound 28-1 (230 mg) in dichloromethane (5 mL) was added trifluoroacetic acid (1.54 g) in one portion at 10-25 degrees Celsius. The reaction solution was reacted at 15 degrees Celsius for 0.5 hour. The reaction solution was concentrated to obtain a residue. To the residue was added water (10 mL), the aqueous phase was adjusted to pH=8 with solid sodium bicarbonate, extracted with ethyl acetate (5 mL*3), the organic phases were combined, washed with brine (10 mL) and dried over anhydrous sodium sulfate , filtered, and the filtrate was concentrated to obtain compound 28-2. LCMS (ESI) m/z: 609.2 (M+1) ⁺ .

第三步：third step:

在0摄氏度下，向化合物28-2(0.2克)的四氢呋喃(4毫升)和水(1毫升)的混合溶液中依次加入无水碳酸钾(136.17毫克)，丙烯酰氯(29.72毫克)。反应液在15摄氏度下反应15分钟。向反应液中加入水(10毫升)，用乙酸乙酯(5毫升*3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液浓缩得到残余物。残余物先经制备板纯化(石油醚：乙酸乙酯：甲醇＝3：4：1)，得到的化合物28。To a mixed solution of compound 28-2 (0.2 g) in tetrahydrofuran (4 mL) and water (1 mL) at 0 degrees Celsius were sequentially added anhydrous potassium carbonate (136.17 mg) and acryloyl chloride (29.72 mg). The reaction solution was reacted at 15 degrees Celsius for 15 minutes. Water (10 mL) was added to the reaction solution, extracted with ethyl acetate (5 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was first purified by preparative plate (petroleum ether:ethyl acetate:methanol=3:4:1) to obtain compound 28.

化合物28再通过制备SFC(柱型号：DAICEL CHIRALPAK IC(250mm*30mm，10μm)，流动相：甲醇(0.1％氨水)，梯度：二氧化碳临界流体60％-60％，2.6分钟，50分钟)分离纯化得到28-P1(保留时间＝3.397min和保留时间＝3.789min的混合物)及28-P2(保留时间＝1.402min和保留时间＝1.565min的混合物)。Compound 28 was then separated and purified by preparative SFC (column type: DAICEL CHIRALPAK IC (250mm*30mm, 10μm), mobile phase: methanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 60%-60%, 2.6 minutes, 50 minutes) 28-P1 (mixture of RT=3.397 min and RT=3.789 min) and 28-P2 (mixture of RT=1.402 min and RT=1.565 min) were obtained.

28-P1再通过制备SFC(柱型号：DAICEL CHIRALPAK AD(250mm*30mm，5μm)，流动相：异丙醇(0.1％氨水)，梯度：二氧化碳临界流体20％-20％，4.6分钟，120分钟)分离纯化得到化合物28A，和化合物28B。28-P1 was then passed through preparative SFC (column type: DAICEL CHIRALPAK AD (250mm*30mm, 5μm), mobile phase: isopropanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 20%-20%, 4.6 minutes, 120 minutes ) was isolated and purified to obtain compound 28A and compound 28B.

28-P2再通过制备SFC(柱型号：DAICEL CHIRALPAK IG(250mm*30mm，10μm)，流动相：异丙醇(0.1％氨水)，梯度：二氧化碳临界流体25％-25％，5分钟，45分钟)分离纯化得到化合物28C和化合物28D。28-P2 was then passed through preparative SFC (column model: DAICEL CHIRALPAK IG (250mm*30mm, 10μm), mobile phase: isopropanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 25%-25%, 5 minutes, 45 minutes ) was isolated and purified to obtain compound 28C and compound 28D.

化合物28A和化合物28B经SFC检测【柱型号：Column:Chiralpak AD-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为异丙醇(0.05％二乙胺)；梯度(B％)：5％-15％】得到：化合物28A的保留时间为3.376min，e.e.值为100％；化合物28B的保留时间为3.789min，e.e.值为100％。Compound 28A and Compound 28B were detected by SFC [Column model: Column: Chiralpak AD-3 50×4.6mm I.D., 3μm; mobile phase: A phase was supercritical carbon dioxide, and B phase was isopropanol (0.05% diethylamine); Gradient (B%): 5%-15%] Obtained: Compound 28A has a retention time of 3.376 min and an e.e. value of 100%; Compound 28B has a retention time of 3.789 min and an e.e. value of 100%.

化合物28C和化合物28D经SFC检测【柱型号：Column:Chiralpak AD-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为异丙醇(0.05％二乙胺)；梯度(B％)：5％-40％】得到：化合物29C的保留时间为1.408min，e.e.值为100％；化合物29D的保留时间为1.571min，e.e.值为100％。化合物28A： ¹H NMR(400MHz,METHANOL-d ₄)δ8.23(d,J＝5.0Hz,1H),7.64(ddd,J＝5.5,8.3,9.1Hz,1H),7.19-7.09(m,2H),7.06(d,J＝5.0Hz,1H),6.81-6.65(m,1H),6.21(br dd,J＝3.3,16.9Hz,1H),5.77-5.67(m,1H),4.83-4.79(m,1H),4.47(s,1H),4.31-4.19(m,1H),3.98(br d,J＝13.4Hz,1H),3.70-3.55(m,2H),3.15-3.02(m,1H),2.79-2.69(m,1H),2.00(s,3H),1.37(d,J＝6.6Hz,3H),1.12-1.05(m,3H),0.97(d,J＝6.9Hz,3H)。LCMS(ESI)m/z:663.3(M+1) ⁺。 Compound 28C and Compound 28D were detected by SFC [Column model: Column: Chiralpak AD-3 50×4.6 mm ID, 3 μm; Mobile phase: A phase was supercritical carbon dioxide, and B phase was isopropanol (0.05% diethylamine); Gradient (B%): 5%-40%] Obtained: compound 29C has a retention time of 1.408 min and an ee value of 100%; compound 29D has a retention time of 1.571 min and an ee value of 100%. Compound 28A: ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ 8.23 (d, J=5.0 Hz, 1H), 7.64 (ddd, J=5.5, 8.3, 9.1 Hz, 1H), 7.19-7.09 (m, 2H),7.06(d,J=5.0Hz,1H),6.81-6.65(m,1H),6.21(br dd,J=3.3,16.9Hz,1H),5.77-5.67(m,1H),4.83- 4.79(m, 1H), 4.47(s, 1H), 4.31-4.19(m, 1H), 3.98(br d, J=13.4Hz, 1H), 3.70-3.55(m, 2H), 3.15-3.02(m ,1H),2.79-2.69(m,1H),2.00(s,3H),1.37(d,J=6.6Hz,3H),1.12-1.05(m,3H),0.97(d,J=6.9Hz, 3H). LCMS (ESI) m/z: 663.3 (M+1) ⁺ .

化合物28B： ¹H NMR(400MHz,METHANOL-d ₄)δ8.23(d,J＝5.0Hz,1H),7.70-7.59(m,1H),7.20-7.08(m,2H),7.04(d,J＝5.0Hz,1H),6.82-6.65(m,1H),6.26-6.14(m,1H),5.73(dd,J＝1.9,10.5Hz,1H),4.79(br s,1H),4.53-4.31(m,1H),4.30-4.17(m,1H),4.17-3.92(m,1H),3.72-3.55(m,2H),3.14-3.02(m,1H),2.80-2.71(m,1H),1.98(s,3H),1.37(d,J＝6.8Hz,3H),1.11-1.06(m,3H),1.02-0.97(m,3H)。LCMS(ESI)m/z:663.4(M+1) ⁺。 Compound 28B: ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ 8.23 (d, J=5.0 Hz, 1H), 7.70-7.59 (m, 1H), 7.20-7.08 (m, 2H), 7.04 (d, J=5.0Hz,1H),6.82-6.65(m,1H),6.26-6.14(m,1H),5.73(dd,J=1.9,10.5Hz,1H),4.79(br s,1H),4.53- 4.31(m,1H),4.30-4.17(m,1H),4.17-3.92(m,1H),3.72-3.55(m,2H),3.14-3.02(m,1H),2.80-2.71(m,1H ), 1.98(s, 3H), 1.37(d, J=6.8Hz, 3H), 1.11-1.06(m, 3H), 1.02-0.97(m, 3H). LCMS (ESI) m/z: 663.4 (M+1) ⁺ .

化合物28C： ¹H NMR(400MHz,METHANOL-d ₄)δ8.23(d,J＝5.0Hz,1H),7.65(dt,J＝5.5,8.7Hz,1H),7.18-7.09(m,2H),7.06(d,J＝5.0Hz,1H),6.81-6.64(m,1H),6.26-6.15(m,1H),5.73(dd,J＝1.9,10.6Hz,1H),4.81(br s,1H),4.53-4.31(m,1H),4.30-4.20(m,1H),4.16-3.94(m,1H),3.70-3.44(m,2H),3.19-3.00(m,1H),2.76-2.64(m,1H),2.01(s,3H),1.38(d,J＝6.6Hz,3H),1.10-1.06(m,3H),0.97(d,J＝6.8Hz,3H)。LCMS(ESI)m/z:663.2(M+1) ⁺。 Compound 28C: ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ 8.23 (d, J=5.0 Hz, 1H), 7.65 (dt, J=5.5, 8.7 Hz, 1H), 7.18-7.09 (m, 2H) ,7.06(d,J＝5.0Hz,1H),6.81-6.64(m,1H),6.26-6.15(m,1H),5.73(dd,J＝1.9,10.6Hz,1H),4.81(br s, 1H), 4.53-4.31(m, 1H), 4.30-4.20(m, 1H), 4.16-3.94(m, 1H), 3.70-3.44(m, 2H), 3.19-3.00(m, 1H), 2.76- 2.64(m, 1H), 2.01(s, 3H), 1.38(d, J=6.6Hz, 3H), 1.10-1.06(m, 3H), 0.97(d, J=6.8Hz, 3H). LCMS (ESI) m/z: 663.2 (M+1) ⁺ .

化合物28D： ¹H NMR(400MHz,METHANOL-d ₄)δ8.23(d,J＝5.0Hz,1H),7.64(dt,J＝5.5,8.7Hz, 1H),7.18-7.09(m,2H),7.04(d,J＝5.0Hz,1H),6.73(dt,J＝10.9,17.5Hz,1H),6.21(br d,J＝17.2Hz,1H),5.77-5.68(m,1H),4.83-4.77(m,1H),4.53-4.32(m,1H),4.31-4.20(m,1H),4.17-3.93(m,1H),3.70-3.43(m,2H),3.20-3.02(m,1H),2.72(br s,1H),1.99(s,3H),1.37(br d,J＝6.6Hz,3H),1.11-1.06(m,3H),0.99(d,J＝6.7Hz,3H)。LCMS(ESI)m/z:663.1(M+1) ⁺。 Compound 28D: ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ 8.23 (d, J=5.0 Hz, 1H), 7.64 (dt, J=5.5, 8.7 Hz, 1H), 7.18-7.09 (m, 2H) ,7.04(d,J＝5.0Hz,1H),6.73(dt,J＝10.9,17.5Hz,1H),6.21(br d,J＝17.2Hz,1H),5.77-5.68(m,1H),4.83 -4.77(m, 1H), 4.53-4.32(m, 1H), 4.31-4.20(m, 1H), 4.17-3.93(m, 1H), 3.70-3.43(m, 2H), 3.20-3.02(m, 1H), 2.72(br s, 1H), 1.99(s, 3H), 1.37(br d, J=6.6Hz, 3H), 1.11-1.06(m, 3H), 0.99(d, J=6.7Hz, 3H) ). LCMS (ESI) m/z: 663.1 (M+1) ⁺ .

实施例29Example 29

第一步：first step:

在10-25摄氏度下，向化合物7-13(0.5克)的DMAC(10毫升)溶液中一次性加入三吡咯烷基溴化鏻六氟磷酸盐(1.77克)，化合物3-1(1.63克)，反应液在60摄氏度下反应12小时。向反应液中缓慢加入水(10毫升)，用乙酸乙酯(5毫升*3)萃取，合并有机相，盐水洗涤(5毫升*3)无水硫酸钠干燥，过滤，滤液浓缩得到残余物。残余物经制备纯化得到化合物29-1。LCMS(ESI)m/z:723.2(M+1) ⁺。 Tripyrrolidinophosphonium bromide hexafluorophosphate (1.77 g), compound 3-1 (1.63 g) were added in one portion to a solution of compound 7-13 (0.5 g) in DMAC (10 mL) at 10-25 degrees Celsius ), the reaction solution was reacted at 60 degrees Celsius for 12 hours. Water (10 mL) was slowly added to the reaction solution, extracted with ethyl acetate (5 mL*3), the organic phases were combined, washed with brine (5 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was preparatively purified to give compound 29-1. LCMS (ESI) m/z: 723.2 (M+1) ⁺ .

第二步：Step 2:

在10-25摄氏度下，向化合物29-1(0.26克)的二氯甲烷(5毫升)溶液中一次性加入三氟乙酸(1.54克)。反应液在15摄氏度下反应0.5小时。将反应液浓缩得到残余物。向残余物中加入水(10毫升)，水相用碳酸氢钠固体调至pH＝8，乙酸乙酯(5毫升*3)萃取，合并有机相，盐水洗涤(10毫升*1)无水硫酸钠干燥，过滤，滤液浓缩得到化合物29-2。LCMS(ESI)m/z:623.3(M+1) ⁺。 To a solution of compound 29-1 (0.26 g) in dichloromethane (5 mL) was added trifluoroacetic acid (1.54 g) in one portion at 10-25 degrees Celsius. The reaction solution was reacted at 15 degrees Celsius for 0.5 hour. The reaction solution was concentrated to obtain a residue. To the residue was added water (10 mL), the aqueous phase was adjusted to pH=8 with solid sodium bicarbonate, extracted with ethyl acetate (5 mL*3), the organic phases were combined, washed with brine (10 mL*1) anhydrous sulfuric acid Dry over sodium, filter, and concentrate the filtrate to give compound 29-2. LCMS (ESI) m/z: 623.3 (M+1) ⁺ .

第三步：third step:

在0摄氏度下，向化合物29-2(0.24克)的四氢呋喃(4毫升)和水(1毫升)的混合溶液中依次加入无水碳酸钾(159.73毫克)，丙烯酰氯(34.87毫克)。反应液在15摄氏度下反应15分钟。向反应液中加入水(10毫升)，用乙酸乙酯(5毫升*3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液浓缩得到残余物。残余物先经制备板纯化(石油醚：乙酸乙酯：甲醇＝3：4：1)，得到的化合物29。To a mixed solution of compound 29-2 (0.24 g) in tetrahydrofuran (4 mL) and water (1 mL) at 0 degrees Celsius were sequentially added anhydrous potassium carbonate (159.73 mg) and acryloyl chloride (34.87 mg). The reaction solution was reacted at 15 degrees Celsius for 15 minutes. Water (10 mL) was added to the reaction solution, extracted with ethyl acetate (5 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was first purified by preparative plate (petroleum ether:ethyl acetate:methanol=3:4:1) to obtain compound 29.

化合物29通过制备SFC(柱型号：DAICEL CHIRALPAK IC(250mm*30mm，10μm)，流动相：甲醇(0.1％氨水)，梯度：二氧化碳临界流体50％-50％，3.0分钟，40分钟)分离纯化得到实施例29-P1(及实施例29-P2。Compound 29 was isolated and purified by preparative SFC (column type: DAICEL CHIRALPAK IC (250mm*30mm, 10μm), mobile phase: methanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 50%-50%, 3.0 minutes, 40 minutes) Example 29-P1 (and Example 29-P2.

29-P1再通过制备SFC(柱型号：DAICEL CHIRALPAK AD(250mm*30mm，5μm)，流动相：异丙醇(0.1％氨水)，梯度：二氧化碳临界流体15％-15％，5.3分钟，260分钟)分离纯化得到化合物29A和化合物29B。29-P1 was then passed through preparative SFC (column model: DAICEL CHIRALPAK AD (250mm*30mm, 5μm), mobile phase: isopropanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 15%-15%, 5.3 minutes, 260 minutes ) was isolated and purified to obtain compound 29A and compound 29B.

29-P2再通过制备SFC(柱型号：DAICEL CHIRALPAK IG(250mm*30mm，10μm)，流动相：异丙醇(0.1％氨水)，梯度：二氧化碳临界流体25％-25％，5.9分钟，240分钟)分离纯化得到化合物29C和化合物29D。29-P2 was then passed through preparative SFC (column model: DAICEL CHIRALPAK IG (250mm*30mm, 10μm), mobile phase: isopropanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 25%-25%, 5.9 minutes, 240 minutes ) was isolated and purified to obtain compound 29C and compound 29D.

化合物29A和化合物29B经SFC检测【柱型号：Column:Chiralpak AD-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为异丙醇(0.05％二乙胺)；梯度(B％)：5％-15％】得到：化合物29A的保留时间为3.020min，e.e.值为100％；化合物29B的保留时间为3.171min，e.e.值为100％。Compound 29A and compound 29B were detected by SFC [Column model: Column: Chiralpak AD-3 50×4.6mm I.D., 3μm; mobile phase: A phase is supercritical carbon dioxide, and B phase is isopropanol (0.05% diethylamine); Gradient (B%): 5%-15%] Obtained: Compound 29A has a retention time of 3.020 min and an e.e. value of 100%; Compound 29B has a retention time of 3.171 min and an e.e. value of 100%.

化合物29C和化合物29D经SFC检测【柱型号：Column:Chiralpak AD-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为异丙醇(0.05％二乙胺)；梯度(B％)：5％-40％】得到：化合物29C的保留时间为1.346min，e.e.值为100％；化合物29D的保留时间为1.483min，e.e.值为100％。Compound 29C and compound 29D were detected by SFC [Column model: Column: Chiralpak AD-3 50×4.6mm I.D., 3μm; mobile phase: A phase was supercritical carbon dioxide, and B phase was isopropanol (0.05% diethylamine); Gradient (B%): 5%-40%] Obtained: Compound 29C has a retention time of 1.346 min and an e.e. value of 100%; Compound 29D has a retention time of 1.483 min and an e.e. value of 100%.

化合物29A： ¹H NMR(400MHz,METHANOL-d ₄)δ8.23(d,J＝5.0Hz,1H),7.64(dt,J＝5.5,8.7Hz,1H),7.18-7.10(m,2H),7.06(d,J＝5.1Hz,1H),6.81-6.63(m,1H),6.24-6.14(m,1H),5.72(ddd,J＝1.8,7.1,10.6Hz,1H),4.88-4.77(m,1H),4.50-4.39(m,1H),4.29-4.18(m,1H),4.13(br d,J＝14.0Hz,1H),3.86-3.70(m,2H),2.76(qd,J＝6.7,10.6Hz,1H),1.93(s,3H),1.38(d,J＝6.6Hz,3H),1.30-1.19(m,3H),1.08(dd,J＝1.6,6.7Hz,3H),0.98(dd,J＝1.8,6.7Hz,3H)。LCMS(ESI)m/z:677.1(M+1) ⁺。 Compound 29A: ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ 8.23 (d, J=5.0 Hz, 1H), 7.64 (dt, J=5.5, 8.7 Hz, 1H), 7.18-7.10 (m, 2H) ,7.06(d,J＝5.1Hz,1H),6.81-6.63(m,1H),6.24-6.14(m,1H),5.72(ddd,J＝1.8,7.1,10.6Hz,1H),4.88-4.77 (m,1H),4.50-4.39(m,1H),4.29-4.18(m,1H),4.13(br d,J=14.0Hz,1H),3.86-3.70(m,2H),2.76(qd, J=6.7, 10.6Hz, 1H), 1.93(s, 3H), 1.38(d, J=6.6Hz, 3H), 1.30-1.19(m, 3H), 1.08(dd, J=1.6, 6.7Hz, 3H) ), 0.98 (dd, J=1.8, 6.7 Hz, 3H). LCMS (ESI) m/z: 677.1 (M+1) ⁺ .

化合物29B： ¹H NMR(400MHz,METHANOL-d ₄)δ8.23(d,J＝5.0Hz,1H),7.68-7.60(m,1H),7.18-7.09(m,2H),7.04(d,J＝5.5Hz,1H),6.80-6.62(m,1H),6.23-6.14(m,1H),5.77-5.67(m,1H),4.87-4.77(m,1H),4.50-4.40(m,1H),4.28-4.19(m,1H),4.16-4.08(m,1H),3.86-3.68(m,2H),,2.85-2.72(m,1H),1.95(s,3H),1.38(d,J＝6.6Hz,3H),1.32-1.19(m,3H),1.08(dd,J＝1.7,6.7Hz,3H),1.00(dd,J＝1.5,6.8Hz,3H)。 LCMS(ESI)m/z:677.1(M+1) ⁺。 Compound 29B: ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ 8.23 (d, J=5.0 Hz, 1H), 7.68-7.60 (m, 1H), 7.18-7.09 (m, 2H), 7.04 (d, J=5.5Hz, 1H), 6.80-6.62(m, 1H), 6.23-6.14(m, 1H), 5.77-5.67(m, 1H), 4.87-4.77(m, 1H), 4.50-4.40(m, 1H),4.28-4.19(m,1H),4.16-4.08(m,1H),3.86-3.68(m,2H),,2.85-2.72(m,1H),1.95(s,3H),1.38(d , J=6.6Hz, 3H), 1.32-1.19 (m, 3H), 1.08 (dd, J=1.7, 6.7Hz, 3H), 1.00 (dd, J=1.5, 6.8Hz, 3H). LCMS (ESI) m/z: 677.1 (M+1) ⁺ .

化合物29C： ¹H NMR(400MHz,METHANOL-d ₄)δ8.23(d,J＝5.0Hz,1H),7.64(dt,J＝5.6,8.7Hz,1H),7.19-7.03(m,3H),6.81-6.62(m,1H),6.19(ddd,J＝1.7,6.3,16.7Hz,1H),5.72(ddd,J＝1.7,7.0,10.5Hz,1H),4.86-4.80(m,1H),4.48-4.40(m,1H),4.27-4.07(m,2H),3.90-3.69(m,2H),2.63(quin,J＝6.8Hz,1H),1.98(s,3H),1.38(d,J＝6.6Hz,3H),1.28-1.19(m,3H),1.05(d,J＝6.7Hz,3H),0.96(d,J＝6.8Hz,3H)。LCMS(ESI)m/z:677.3(M+1) ⁺。 Compound 29C: ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ 8.23 (d, J=5.0 Hz, 1H), 7.64 (dt, J=5.6, 8.7 Hz, 1H), 7.19-7.03 (m, 3H) ,6.81-6.62(m,1H),6.19(ddd,J＝1.7,6.3,16.7Hz,1H),5.72(ddd,J＝1.7,7.0,10.5Hz,1H),4.86-4.80(m,1H) ,4.48-4.40(m,1H),4.27-4.07(m,2H),3.90-3.69(m,2H),2.63(quin,J=6.8Hz,1H),1.98(s,3H),1.38(d , J=6.6Hz, 3H), 1.28-1.19 (m, 3H), 1.05 (d, J=6.7Hz, 3H), 0.96 (d, J=6.8Hz, 3H). LCMS (ESI) m/z: 677.3 (M+1) ⁺ .

化合物29D： ¹H NMR(400MHz,METHANOL-d ₄)δ8.24(d,J＝4.9Hz,1H),7.65(dt,J＝5.6,8.7Hz,1H),7.21-7.01(m,3H),6.81-6.61(m,1H),6.19(ddd,J＝1.5,6.2,16.7Hz,1H),5.77-5.67(m,1H),4.88-4.82(m,1H),4.49-4.40(m,1H),4.28-4.07(m,2H),3.87-3.71(m,2H),,2.65(td,J＝6.7,13.5Hz,1H),1.96(s,3H),1.38(d,J＝6.7Hz,3H),1.28(br d,J＝6.7Hz,2H),1.22(s,1H),1.06(d,J＝6.7Hz,3H),0.99(d,J＝6.8Hz,3H)。LCMS(ESI)m/z:677.3(M+1) ⁺。 Compound 29D: ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ 8.24 (d, J=4.9 Hz, 1H), 7.65 (dt, J=5.6, 8.7 Hz, 1H), 7.21-7.01 (m, 3H) ,6.81-6.61(m,1H),6.19(ddd,J=1.5,6.2,16.7Hz,1H),5.77-5.67(m,1H),4.88-4.82(m,1H),4.49-4.40(m, 1H),4.28-4.07(m,2H),3.87-3.71(m,2H),,2.65(td,J=6.7,13.5Hz,1H),1.96(s,3H),1.38(d,J=6.7 Hz, 3H), 1.28 (br d, J=6.7Hz, 2H), 1.22 (s, 1H), 1.06 (d, J=6.7Hz, 3H), 0.99 (d, J=6.8Hz, 3H). LCMS (ESI) m/z: 677.3 (M+1) ⁺ .

实施例30Example 30

第一步：first step:

在20-30摄氏度下，向化合物30-1(14克)的乙腈(140毫升)溶液中加入化合物7-2(17.77克)和碳酸钾(7.49克)，反应液在15摄氏度下反应16小时。向反应液中加入乙酸乙酯(300毫升)和水(300毫升)，有机相分离，饱和食盐水(300毫升)洗涤，有机相减压浓缩得到残余物。残余物用石油醚(100毫升)打浆半小时，过滤，滤饼干燥得到化合物30-2。LCMS(ESI)m/z:230.1(M+1) ⁺。 Compound 7-2 (17.77 g) and potassium carbonate (7.49 g) were added to a solution of compound 30-1 (14 g) in acetonitrile (140 ml) at 20-30 degrees Celsius, and the reaction solution was reacted at 15 degrees Celsius for 16 hours . Ethyl acetate (300 mL) and water (300 mL) were added to the reaction solution, the organic phase was separated, washed with saturated brine (300 mL), and the organic phase was concentrated under reduced pressure to obtain a residue. The residue was slurried with petroleum ether (100 mL) for half an hour, filtered, and the filter cake was dried to obtain compound 30-2. LCMS (ESI) m/z: 230.1 (M+1) ⁺ .

第二步：Step 2:

在20-30摄氏度下，向化合物30-2(24.50克)的乙腈(245毫升)溶液中依次加入碳酸铯(34.83 克)和化合物7-4(18.87克)，反应液在氮气保护下于15摄氏度下反应3小时。向反应液中加入乙酸乙酯(200毫升)和水(200毫升)，有机相分离，饱和食盐水(200毫升)洗涤，有机相减压浓缩得到残余物。向残余物中加入石油醚：乙酸乙酯＝10:1(60毫升)搅拌半小时，过滤，滤饼干燥得到化合物30-3。LCMS(ESI)m/z:352.2(M+1) ⁺。 To a solution of compound 30-2 (24.50 g) in acetonitrile (245 ml) at 20-30 degrees Celsius, cesium carbonate (34.83 g) and compound 7-4 (18.87 g) were sequentially added, and the reaction solution was heated under nitrogen protection at 15 The reaction was carried out at degrees Celsius for 3 hours. Ethyl acetate (200 mL) and water (200 mL) were added to the reaction solution, the organic phase was separated, washed with saturated brine (200 mL), and the organic phase was concentrated under reduced pressure to obtain a residue. Petroleum ether:ethyl acetate=10:1 (60 mL) was added to the residue, stirred for half an hour, filtered, and the filter cake was dried to obtain compound 30-3. LCMS (ESI) m/z: 352.2 (M+1) ⁺ .

第三步：third step:

在20-30摄氏度下，向化合物30-3(20克)的三氟乙醇(200毫升)溶液中加入三乙胺(17.29克)，反应液在氮气保护下于95摄氏度下反应16小时。反应液浓缩得到残余物，向残余物中加入石油醚(100毫升)搅拌1小时，混合物过滤，滤饼干燥得到化合物30-4。LCMS(ESI)m/z:320.2(M+1) ⁺。 Triethylamine (17.29 g) was added to a solution of compound 30-3 (20 g) in trifluoroethanol (200 ml) at 20-30 degrees Celsius, and the reaction solution was reacted at 95 degrees Celsius for 16 hours under nitrogen protection. The reaction solution was concentrated to obtain a residue. Petroleum ether (100 mL) was added to the residue and stirred for 1 hour. The mixture was filtered, and the filter cake was dried to obtain compound 30-4. LCMS (ESI) m/z: 320.2 (M+1) ⁺ .

第四步：the fourth step:

在20-30摄氏度下，向化合物30-4(12克)的乙腈(150毫升)溶液中依次加入三溴吡啶嗡盐(24.05克)和磷酸钾(11.97克)，反应液在15摄氏度下反应18小时。向反应液中加入饱和亚硫酸钠水溶液(100毫升)，混合物用乙酸乙酯(200毫升)萃取，有机相用饱和食盐水(200毫升)洗涤，有机相减压浓缩得到化合物30-5。粗品直接用于下一步。LCMS(ESI)m/z:353.9(M+1) ⁺。 To a solution of compound 30-4 (12 g) in acetonitrile (150 ml) at 20-30 degrees Celsius, pyridinium tribromide (24.05 g) and potassium phosphate (11.97 g) were sequentially added, and the reaction solution was reacted at 15 degrees Celsius 18 hours. To the reaction solution was added saturated aqueous sodium sulfite solution (100 mL), the mixture was extracted with ethyl acetate (200 mL), the organic phase was washed with saturated brine (200 mL), and the organic phase was concentrated under reduced pressure to obtain compound 30-5. The crude product was used directly in the next step. LCMS (ESI) m/z: 353.9 (M+1) ⁺ .

第五步：the fifth step:

在20-30摄氏度下，向化合物30-5(10克)的二氧六环(140毫升)溶液中依次加入化合物6-4(4.67克)，Pd ₂(dba) ₃(2.59克)，Xantphos(3.27克)和碳酸铯(18.40克)，反应液氮气保护，在100摄氏度下反应2小时。反应液浓缩得到残余物，残余物通过硅胶柱(洗脱剂：石油醚：乙酸乙酯＝10:1到3:1)纯化得到化合物30-6。LCMS(ESI)m/z:424.1(M+1) ⁺。 To a solution of compound 30-5 (10 g) in dioxane (140 mL) at 20-30 degrees Celsius was added compound 6-4 (4.67 g), Pd ₂ (dba) ₃ (2.59 g), Xantphos (3.27 g) and cesium carbonate (18.40 g), the reaction liquid was protected by nitrogen, and reacted at 100 degrees Celsius for 2 hours. The reaction solution was concentrated to obtain a residue, and the residue was purified by silica gel column (eluent: petroleum ether: ethyl acetate=10:1 to 3:1) to obtain compound 30-6. LCMS (ESI) m/z: 424.1 (M+1) ⁺ .

第六步：Step 6:

在20-30摄氏度下，向化合物30-6(1.0克)的二氯甲烷(10毫升)溶液中加入NBS(420.39毫克)，反应液氮气保护，在15摄氏度下反应13小时。向反应液中加入饱和亚硫酸钠水溶液(15毫升)，有机相分离，食盐水(20毫升)洗涤。有机相浓缩得到残余物，向残余物中加入甲醇(3毫升)搅拌0.5小时，混合物过滤，滤饼干燥得到化合物30-7。LCMS(ESI)m/z:503.9(M+3) ⁺。 At 20-30 degrees Celsius, NBS (420.39 mg) was added to a solution of compound 30-6 (1.0 g) in dichloromethane (10 mL), and the reaction solution was protected with nitrogen and reacted at 15 degrees Celsius for 13 hours. To the reaction solution was added saturated aqueous sodium sulfite solution (15 mL), the organic phase was separated, and washed with brine (20 mL). The organic phase was concentrated to obtain a residue, methanol (3 mL) was added to the residue and stirred for 0.5 hours, the mixture was filtered, and the filter cake was dried to obtain compound 30-7. LCMS (ESI) m/z: 503.9 (M+3) ⁺ .

第七步：Step 7:

在20-30摄氏度下，向化合物30-7(600毫克)的N,N-二甲基甲酰胺(6毫升)溶液中依次加入锌粉(78.11毫克)、氰化锌(140.27毫克)、Pd ₂(dba) ₃(109.39毫克)、DPPF(132.45毫克)和溴化锌(53.80毫克)，反应液氮气保护，在110摄氏度下反应2小时。反应液过滤，滤饼用乙酸乙酯(15毫升)洗涤，滤液用食盐水(30毫升)洗涤，分离有机相，浓缩得到残余物，残余物用硅胶柱(洗脱剂：石油醚：乙酸乙酯＝10:1到3:1)纯化得到化合物30-8。LCMS(ESI)m/z:449.0(M+1) ⁺。 To a solution of compound 30-7 (600 mg) in N,N-dimethylformamide (6 mL) at 20-30 degrees Celsius was added zinc powder (78.11 mg), zinc cyanide (140.27 mg), Pd ₂ (dba) ₃ (109.39 mg), DPPF (132.45 mg) and zinc bromide (53.80 mg), the reaction liquid was protected with nitrogen, and reacted at 110 degrees Celsius for 2 hours. The reaction solution was filtered, the filter cake was washed with ethyl acetate (15 mL), the filtrate was washed with brine (30 mL), the organic phase was separated and concentrated to obtain a residue, which was applied to a silica gel column (eluent: petroleum ether: ethyl acetate) Ester = 10:1 to 3:1) was purified to give compound 30-8. LCMS (ESI) m/z: 449.0 (M+1) ⁺ .

第八步：Step 8:

化合物30-8(0.5克)的浓硫酸(4.60g)溶液于90摄氏度下反应1.5小时。反应液加入到饱和碳酸氢钠水溶液(250毫升)中，用乙酸乙酯(20毫升*2)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液浓缩得到化合物30-9。LCMS(ESI)m/z:467.1(M+1) ⁺。 A solution of compound 30-8 (0.5 g) in concentrated sulfuric acid (4.60 g) was reacted at 90 degrees Celsius for 1.5 hours. The reaction solution was added to saturated aqueous sodium bicarbonate solution (250 mL), extracted with ethyl acetate (20 mL*2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 30-9. LCMS (ESI) m/z: 467.1 (M+1) ⁺ .

第九步：Step 9:

在0摄氏度下，向化合物30-9(0.4克)的N,N-二甲基乙酰胺(4毫升)溶液中加入羰基二咪唑 (417.19毫克)和氢化钠(102.91毫克，质量百分比：60％)，反应液在15摄氏度下反应0.5小时。反应液倒入水(30毫升)中，缓慢滴加盐酸(2摩尔/升)至pH约为1。向混合物中加入饱和碳酸氢钠水溶液至pH约为10，混合物用乙酸乙酯(30毫升*2)萃取，合并有机相，饱和食盐水(50毫升)洗涤，分出有机相，无水硫酸钠干燥，过滤，滤液浓缩得到化合物30-10。粗品直接用于下一步。LCMS(ESI)m/z:493.1(M+1) ⁺。 To a solution of compound 30-9 (0.4 g) in N,N-dimethylacetamide (4 mL) at 0 degrees Celsius was added carbonyldiimidazole (417.19 mg) and sodium hydride (102.91 mg, mass percentage: 60%) ), the reaction solution was reacted at 15 degrees Celsius for 0.5 hours. The reaction solution was poured into water (30 mL), and hydrochloric acid (2 mol/L) was slowly added dropwise to pH about 1. Saturated aqueous sodium bicarbonate solution was added to the mixture until the pH was about 10, the mixture was extracted with ethyl acetate (30 mL*2), the organic phases were combined, washed with saturated brine (50 mL), the organic phase was separated, and anhydrous sodium sulfate was used. Dry, filter, and concentrate the filtrate to give compound 30-10. The crude product was used directly in the next step. LCMS (ESI) m/z: 493.1 (M+1) ⁺ .

第十步：Step 10:

在10-15摄氏度下，向化合物30-10(500毫克)的N,N-二甲基乙酰胺(5毫升)溶液中加入N,N-二异丙基乙胺(393.72毫克)和三吡咯烷基溴化鏻六氟磷酸盐(946.76毫克)和化合物1-1(567毫克)，反应液在氮气保护下，110摄氏度反应12个小时。反应液倒入水(100毫升)中，乙酸乙酯(40毫升*2)萃取，合并有机相，饱和食盐水(50毫升)洗涤，分出有机相，浓缩得到残余物。残余物通过硅胶柱(洗脱剂：石油醚：乙酸乙酯＝1:1到0:1)纯化得到化合物30-11。LCMS(ESI)m/z:661.1(M+1) ⁺。 To a solution of compound 30-10 (500 mg) in N,N-dimethylacetamide (5 mL) at 10-15 degrees Celsius was added N,N-diisopropylethylamine (393.72 mg) and tripyrrole Alkylphosphonium bromide hexafluorophosphate (946.76 mg) and compound 1-1 (567 mg), the reaction solution was reacted under nitrogen protection at 110 degrees Celsius for 12 hours. The reaction solution was poured into water (100 mL), extracted with ethyl acetate (40 mL*2), the organic phases were combined, washed with saturated brine (50 mL), the organic phase was separated, and concentrated to obtain a residue. The residue was purified by silica gel column (eluent: petroleum ether: ethyl acetate = 1:1 to 0:1) to obtain compound 30-11. LCMS (ESI) m/z: 661.1 (M+1) ⁺ .

第十一步：Step 11:

在10-15摄氏度下，向化合物30-11(550毫克)的二氯甲烷(12毫升)溶液中加入三氟乙酸(6.16克，54.02微摩尔，4毫升，64.89当量)。反应液在氮气保护下，15摄氏度反应1个小时。反应液浓缩得到化合物30-12的三氟乙酸盐。粗品直接用于下一步。LCMS(ESI)m/z:561.1(M+1) ⁺。 To a solution of compound 30-11 (550 mg) in dichloromethane (12 mL) was added trifluoroacetic acid (6.16 g, 54.02 μmol, 4 mL, 64.89 equiv) at 10-15 degrees Celsius. The reaction solution was reacted at 15°C for 1 hour under nitrogen protection. The reaction solution was concentrated to obtain the trifluoroacetate salt of compound 30-12. The crude product was used directly in the next step. LCMS (ESI) m/z: 561.1 (M+1) ⁺ .

第十二步：Step 12:

在10-15摄氏度下，向化合物30-12(700毫克，三氟乙酸盐)的四氢呋喃(14毫升)和水(7毫升)溶液中加入碳酸钾(286.84毫克)和丙烯酰氯(93.92毫克)。反应液在氮气保护下，15摄氏度反应15分钟。向反应液中加入乙酸乙酯(30毫升)和水(30毫升)，分离有机相，饱和食盐水(50毫升)洗涤，有机相浓缩得到消旋体化合物30。化合物30通过制备SFC(柱型号：DAICEL CHIRALPAK IG(250*30mm,10μm)，流动相：乙醇(0.1％氨水)，梯度：二氧化碳临界流体40％-40％，4分钟，30分钟)分离纯化得到化合物30A(保留时间＝0.540min)及化合物30B(保留时间＝0.735min)。To a solution of compound 30-12 (700 mg, trifluoroacetate) in tetrahydrofuran (14 mL) and water (7 mL) at 10-15 degrees Celsius was added potassium carbonate (286.84 mg) and acryloyl chloride (93.92 mg) . The reaction solution was reacted at 15 degrees Celsius for 15 minutes under nitrogen protection. Ethyl acetate (30 mL) and water (30 mL) were added to the reaction solution, the organic phase was separated, washed with saturated brine (50 mL), and the organic phase was concentrated to obtain the racemate compound 30. Compound 30 was isolated and purified by preparative SFC (column type: DAICEL CHIRALPAK IG (250*30mm, 10μm), mobile phase: ethanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 40%-40%, 4 minutes, 30 minutes) Compound 30A (retention time = 0.540 min) and compound 30B (retention time = 0.735 min).

化合物30A和化合物30B经SFC检测【柱型号：Column:Chiralpak IG-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为乙醇(0.05％二乙胺)；梯度(B％)：40％-40％】得到：化合物30A的保留时间为0.540min，e.e.值为100％；化合物30B的保留时间为0.753min，e.e.值为100％。Compound 30A and compound 30B were detected by SFC [Column model: Column: Chiralpak IG-3 50 × 4.6 mm I.D., 3 μm; mobile phase: phase A was supercritical carbon dioxide, phase B was ethanol (0.05% diethylamine); gradient ( B%): 40%-40%] Obtained: the retention time of compound 30A is 0.540min, and the e.e. value is 100%; the retention time of compound 30B is 0.753min, and the e.e. value is 100%.

化合物30A(保留时间＝0.540min)： ¹H NMR(400MHz,DMSO-d ₆)δ8.30(d,J＝4.9Hz,1H),7.47(tt,J＝2.2,9.3Hz,1H),7.29(br d,J＝8.6Hz,1H),7.16(s,1H),7.14(br d,J＝8.6Hz,1H),7.06(d,J＝4.9Hz,1H),6.85(dd,J＝10.4,16.7Hz,1H),6.19(dd,J＝2.3,16.7Hz,1H),5.78-5.74(m,1H),3.98-3.72(m,8H), 2.75(quin,J＝6.7Hz,1H),1.99(s,3H),1.08-0.97(m,6H)。LCMS(ESI)m/z:615.1(M+1) ⁺。 Compound 30A (retention time = 0.540 min): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.30 (d, J=4.9 Hz, 1H), 7.47 (tt, J=2.2, 9.3 Hz, 1H), 7.29 (br d,J=8.6Hz,1H),7.16(s,1H),7.14(br d,J=8.6Hz,1H),7.06(d,J=4.9Hz,1H),6.85(dd,J= 10.4,16.7Hz,1H),6.19(dd,J=2.3,16.7Hz,1H),5.78-5.74(m,1H),3.98-3.72(m,8H), 2.75(quin,J=6.7Hz,1H ), 1.99(s, 3H), 1.08-0.97(m, 6H). LCMS (ESI) m/z: 615.1 (M+1) ⁺ .

化合物30B(保留时间＝0.735min)： ¹H NMR(400MHz,DMSO-d ₆)δ8.29(d,J＝4.9Hz,1H),7.47(tt,J＝2.3,9.3Hz,1H),7.29(br d,J＝8.6Hz,1H),7.19-7.10(m,2H),7.06(d,J＝5.4Hz,1H),6.85(dd,J＝10.4,16.7Hz,1H),6.18(dd,J＝2.3,16.7Hz,1H),5.79-5.68(m,1H),3.97-3.71(m,8H),2.74(quin,J＝6.6Hz,1H),1.98(s,3H),1.12-0.94(m,6H)。LCMS(ESI)m/z:615.1(M+1) ⁺。 Compound 30B (retention time = 0.735 min): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.29 (d, J=4.9 Hz, 1H), 7.47 (tt, J=2.3, 9.3 Hz, 1H), 7.29 (br d,J＝8.6Hz,1H),7.19-7.10(m,2H),7.06(d,J＝5.4Hz,1H),6.85(dd,J＝10.4,16.7Hz,1H),6.18(dd , J=2.3, 16.7Hz, 1H), 5.79-5.68(m, 1H), 3.97-3.71(m, 8H), 2.74(quin, J=6.6Hz, 1H), 1.98(s, 3H), 1.12- 0.94 (m, 6H). LCMS (ESI) m/z: 615.1 (M+1) ⁺ .

实施例31Example 31

第一步：first step:

向化合物30-10(300毫克)的DMAC(5毫升)溶液中加入PYBROP(568.05毫克)，DIEA(157.49毫克)以及化合物3-1(391.70毫克)。反应液在100摄氏度下反应16小时，反应液浓缩得到残余物。残余物通过制备HPLC[柱型号：Phenomenex luna C18(150*40mm*15μm)，流动相：水(0.1％三氟乙酸)-乙腈，梯度：29％-59％，11分钟]纯化得到化合物31-1。LCMS(ESI)m/z:689.3.(M+1) ⁺。 To a solution of compound 30-10 (300 mg) in DMAC (5 mL) was added PYBROP (568.05 mg), DIEA (157.49 mg) and compound 3-1 (391.70 mg). The reaction solution was reacted at 100 degrees Celsius for 16 hours, and the reaction solution was concentrated to obtain a residue. The residue was purified by preparative HPLC [column model: Phenomenex luna C18 (150*40mm*15μm), mobile phase: water (0.1% trifluoroacetic acid)-acetonitrile, gradient: 29%-59%, 11 minutes] to give compound 31- 1. LCMS (ESI) m/z: 689.3.(M+1) ⁺ .

第二步：Step 2:

将化合物31-1(120毫克)溶解在二氯甲烷(2毫升)和三氟乙酸(0.5毫升)的混合溶液中。反应液在25摄氏度下反应1小时，反应液浓缩得到化合物31-2的三氟乙酸盐，粗品直接用于下一步。LCMS(ESI)m/z:589.3(M+1) ⁺。 Compound 31-1 (120 mg) was dissolved in a mixed solution of dichloromethane (2 mL) and trifluoroacetic acid (0.5 mL). The reaction solution was reacted at 25 degrees Celsius for 1 hour, the reaction solution was concentrated to obtain the trifluoroacetate salt of compound 31-2, and the crude product was directly used in the next step. LCMS (ESI) m/z: 589.3 (M+1) ⁺ .

第三步：third step:

向化合物31-2(150毫克)的四氢呋喃(4毫升)和水(1毫升)的混合溶液中加入碳酸钾(35.22毫克)，调节pH至8后，向反应液中加入化合物1-5(23.07毫克)。反应液在0摄氏度反应15分钟，向反应液中加入饱和碳酸氢钠水溶液，调节pH到8，用乙酸乙酯(10毫升*2)萃取，有机相用饱和食盐水(5毫升*2)洗后经无水硫酸钠干燥后浓缩得到化合物31。Potassium carbonate (35.22 mg) was added to a mixed solution of compound 31-2 (150 mg) in tetrahydrofuran (4 mL) and water (1 mL) to adjust the pH to 8, and compound 1-5 (23.07 mg) was added to the reaction solution. mg). The reaction solution was reacted at 0 degrees Celsius for 15 minutes, a saturated aqueous sodium bicarbonate solution was added to the reaction solution, the pH was adjusted to 8, extracted with ethyl acetate (10 mL*2), and the organic phase was washed with saturated brine (5 mL*2). Then, it was dried over anhydrous sodium sulfate and concentrated to obtain compound 31.

化合物31用制备SFC(柱型号：DAICEL CHIRALPAK IC(250mm*30mm,10um)，流动相：乙醇(0.1％氨水)，梯度：二氧化碳临界流体50％-50％，6.7分钟，50分钟)分离得到化合物31A和化合物31B。Compound 31 was separated by preparative SFC (column type: DAICEL CHIRALPAK IC (250mm*30mm, 10um), mobile phase: ethanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 50%-50%, 6.7 minutes, 50 minutes) to obtain the compound 31A and compound 31B.

化合物31A和化合物31B经SFC检测【柱型号：Column:Chiralpak IC-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为乙醇(0.05％二乙胺)；梯度(B％)：40％-40％】得到：化合物31A的保留时间为1.845min；化合物31B的保留时间为2.980min。Compound 31A and compound 31B were detected by SFC [Column model: Column: Chiralpak IC-3 50×4.6mm I.D., 3μm; mobile phase: phase A was supercritical carbon dioxide, phase B was ethanol (0.05% diethylamine); gradient ( B%): 40%-40%] Obtained: the retention time of compound 31A is 1.845min; the retention time of compound 31B is 2.980min.

化合物31A(保留时间＝1.845min)：LCMS(ESI)m/z:643.3.(M+1) ⁺。 Compound 31A (retention time = 1.845 min): LCMS (ESI) m/z: 643.3. (M+1) ⁺ .

化合物31B(保留时间＝2.980min)：LCMS(ESI)m/z:643.3.(M+1) ⁺。 Compound 31B (retention time = 2.980 min): LCMS (ESI) m/z: 643.3. (M+1) ⁺ .

实施例32Example 32

第一步：first step:

将化合物32-1(10克)和丙二酸甲酯酰氯(11.26克)溶于二氯甲烷(100毫升)中，反应液在20摄氏度下反应1小时。反应液浓缩得粗品化合物32-2，粗品直接用于下一步。LCMS(ESI)m/z:246.0.(M+1) ⁺。 Compound 32-1 (10 g) and methyl malonate acid chloride (11.26 g) were dissolved in dichloromethane (100 mL), and the reaction solution was reacted at 20 degrees Celsius for 1 hour. The reaction solution was concentrated to obtain the crude compound 32-2, which was directly used in the next step. LCMS (ESI) m/z: 246.0.(M+1) ⁺ .

第二步：Step 2:

向化合物32-2(17克)的乙腈(200毫升)溶液中依次加入碳酸铯(22.55克)和4-乙氧基-1,1,1-三氟-3-丁烯-2-酮(12.22克)，反应液在20摄氏度下反应1小时。反应液倒入水(250毫升)中，然后用乙酸乙酯(250毫升*3)萃取，合并有机相经饱和食盐水(250毫升)洗涤后用无水硫酸钠干燥，过滤，滤液浓缩得粗品化合物32-3，粗品直接用于下一步。LCMS(ESI)m/z:368.0.(M+1) ⁺。 To a solution of compound 32-2 (17 g) in acetonitrile (200 mL) were added cesium carbonate (22.55 g) followed by 4-ethoxy-1,1,1-trifluoro-3-buten-2-one ( 12.22 g), the reaction solution was reacted at 20 degrees Celsius for 1 hour. The reaction solution was poured into water (250 mL), then extracted with ethyl acetate (250 mL*3), the combined organic phases were washed with saturated brine (250 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product Compound 32-3, crude product was used directly in the next step. LCMS (ESI) m/z: 368.0.(M+1) ⁺ .

第三步：third step:

将化合物32-3(25克)和三乙胺(13.76克)溶于三氟乙醇(250毫升)中，反应液在80摄氏度下搅拌12小时。反应液用1摩尔/升的盐酸水溶液(250毫升)酸化，然后用乙酸乙酯(250毫升*2)萃取，所得有机相经饱和食盐水(250毫升)洗涤后用无水硫酸钠干燥，过滤，滤液浓缩得粗品化合物32-4，粗品直接用于下一步。LCMS(ESI)m/z:336.0.(M+1) ⁺。 Compound 32-3 (25 g) and triethylamine (13.76 g) were dissolved in trifluoroethanol (250 mL), and the reaction solution was stirred at 80 degrees Celsius for 12 hours. The reaction solution was acidified with 1 mol/L hydrochloric acid aqueous solution (250 mL), and then extracted with ethyl acetate (250 mL*2). The obtained organic phase was washed with saturated brine (250 mL), dried with anhydrous sodium sulfate, and filtered. , the filtrate was concentrated to obtain the crude compound 32-4, which was directly used in the next step. LCMS (ESI) m/z: 336.0.(M+1) ⁺ .

第四步：the fourth step:

向化合物32-4(23克)的乙腈(250毫升)溶液中加入三溴化吡啶鎓(43.83克)和磷酸钾(29.09克)，反应液在50摄氏度下搅拌12小时。反应液倒入水(200毫升)中，然后用乙酸乙酯(200毫升*3)萃取，所得有机相经饱和食盐水(250毫升)洗涤后用无水硫酸钠干燥，过滤，滤液浓缩得粗品化合物32-5，粗品直接用于下一步。LCMS(ESI)m/z:369.9.(M+1) ⁺。 To a solution of compound 32-4 (23 g) in acetonitrile (250 mL) were added pyridinium tribromide (43.83 g) and potassium phosphate (29.09 g), and the reaction solution was stirred at 50°C for 12 hours. The reaction solution was poured into water (200 mL), and then extracted with ethyl acetate (200 mL*3). The obtained organic phase was washed with saturated brine (250 mL), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product Compound 32-5, crude was used directly in the next step. LCMS (ESI) m/z: 369.9. (M+1) ⁺ .

第五步：the fifth step:

向化合物32-5(20克)的二氧六环(200毫升)溶液中加入2-异丙基-4-甲基吡啶-3-胺(8.51克)，碳酸铯(4.54克)，三(二亚苄基丙酮)二钯(4.94克)和4,5-双(二苯基磷)-9,9-二甲基氧杂蒽(6.25克)，反应液在100摄氏度下，氮气保护条件下搅拌12小时。反应液过滤，滤饼用乙酸乙酯(150毫升*3)洗涤，滤液浓缩得残余物，向残余物中加入石油醚/乙酸乙酯(200毫升/200毫升)搅拌1小时，混合物过滤，滤饼烘干得到化合物32-6。LCMS(ESI)m/z:440.1(M+1) ⁺。 To a solution of compound 32-5 (20 g) in dioxane (200 mL) was added 2-isopropyl-4-methylpyridin-3-amine (8.51 g), cesium carbonate (4.54 g), tris( Dibenzylideneacetone) dipalladium (4.94 g) and 4,5-bis(diphenylphosphonium)-9,9-dimethylxanthene (6.25 g), the reaction solution was at 100 degrees Celsius under nitrogen protection under stirring for 12 hours. The reaction solution was filtered, the filter cake was washed with ethyl acetate (150 mL*3), and the filtrate was concentrated to obtain a residue. To the residue was added petroleum ether/ethyl acetate (200 mL/200 mL) and stirred for 1 hour. The mixture was filtered and filtered. The cake was dried to obtain compound 32-6. LCMS (ESI) m/z: 440.1 (M+1) ⁺ .

第六步：Step 6:

在0摄氏度下，向化合物32-6(11克)的二氯甲烷(120毫升)溶液中加入N-溴代丁二酰亚胺(4.45克)，反应液在0摄氏度下搅拌0.5小时。反应液在0摄氏度条件下用饱和亚硫酸钠水溶液(150毫升)淬灭，经饱和食盐水(150毫升)洗涤后用无水硫酸钠干燥，过滤，滤液浓缩得粗品化合物32-7，粗品直接用于下一步。LCMS(ESI)m/z:518.0.(M+1) ⁺。 To a solution of compound 32-6 (11 g) in dichloromethane (120 mL) was added N-bromosuccinimide (4.45 g) at 0 degrees Celsius, and the reaction solution was stirred at 0 degrees Celsius for 0.5 hours. The reaction solution was quenched with saturated aqueous sodium sulfite solution (150 mL) at 0 degrees Celsius, washed with saturated brine (150 mL), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain crude compound 32-7, which was directly used for Next step. LCMS (ESI) m/z: 518.0.(M+1) ⁺ .

第七步：Step 7:

向化合物32-7(13克)的N,N-二甲基甲酰胺(150毫升)溶液中加入锌粉(1.10克)，氰化锌(2.5克)，溴化锌(282.19毫克)，1,1’-双(二苯基膦)二茂铁(2.78克)和三(二亚苄基丙酮)二钯(2.29克)，反应液在120摄氏度，氮气保护条件下搅拌2小时。反应液过滤，滤饼用乙酸乙酯(250毫升*3)洗涤，滤液浓缩得残余物，向残余物中加入甲醇(50毫升)搅拌0.5小时，混合物过滤，滤饼烘干得到化合物32-8。LCMS(ESI)m/z:465.1(M+1) ⁺。 To a solution of compound 32-7 (13 g) in N,N-dimethylformamide (150 mL) was added zinc powder (1.10 g), zinc cyanide (2.5 g), zinc bromide (282.19 mg), 1 , 1'-bis(diphenylphosphino)ferrocene (2.78 g) and tris(dibenzylideneacetone)dipalladium (2.29 g), the reaction solution was stirred at 120 degrees Celsius under nitrogen protection for 2 hours. The reaction solution was filtered, the filter cake was washed with ethyl acetate (250 ml*3), the filtrate was concentrated to obtain a residue, methanol (50 ml) was added to the residue and stirred for 0.5 hours, the mixture was filtered, and the filter cake was dried to obtain compound 32-8 . LCMS (ESI) m/z: 465.1 (M+1) ⁺ .

第八步：Step 8:

化合物32-8(8克)的浓硫酸(40毫升)溶液于60摄氏度下反应12小时。反应液缓慢滴加到2摩尔/升的氢氧化钠(600毫升)水溶液中，然后用乙酸乙酯(250毫升*3)萃取，所得有机相经饱和食盐水(250毫升)洗涤后用无水硫酸钠干燥，过滤，滤液浓缩得到粗品化合物32-9，粗品直接用于下一步。LCMS(ESI)m/z:483.1.(M+1) ⁺。 A solution of compound 32-8 (8 g) in concentrated sulfuric acid (40 mL) was reacted at 60 degrees Celsius for 12 hours. The reaction solution was slowly added dropwise to a 2 mol/L aqueous solution of sodium hydroxide (600 mL), and then extracted with ethyl acetate (250 mL*3). The obtained organic phase was washed with saturated brine (250 mL) and then washed with anhydrous Dry over sodium sulfate, filter, and concentrate the filtrate to obtain crude compound 32-9, which is used directly in the next step. LCMS (ESI) m/z: 483.1.(M+1) ⁺ .

第九步：Step 9:

向化合物32-9(8克)的四氢呋喃(100毫升)溶液中一次性加入氢化钠(1.99毫克，质量百分比：60％)和1,1-羰基二咪唑(5.37克)，反应液在20摄氏度下搅拌0.5小时。反应液倒入水(250毫升)中，用1摩尔/升的盐酸(50毫升)酸化，然后用乙酸乙酯(150毫升*3)萃取，所得有机相经饱和食盐水(200毫升)洗涤后用无水硫酸钠干燥，过滤，滤液浓缩得到粗品化合物32-10，粗品直接用于下一步。LCMS(ESI)m/z:508.9.(M+1) ⁺。 To a solution of compound 32-9 (8 g) in tetrahydrofuran (100 mL) was added sodium hydride (1.99 mg, mass percentage: 60%) and 1,1-carbonyldiimidazole (5.37 g) at one time, and the reaction solution was heated at 20 degrees Celsius. under stirring for 0.5 hours. The reaction solution was poured into water (250 mL), acidified with 1 mol/L hydrochloric acid (50 mL), and then extracted with ethyl acetate (150 mL*3). The obtained organic phase was washed with saturated brine (200 mL). Dry with anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain crude compound 32-10, which is used directly in the next step. LCMS (ESI) m/z: 508.9. (M+1) ⁺ .

第十步：Step 10:

向化合物32-10(8.5克)的N,N-二甲基乙酰胺(100毫升)溶液中加入N,N-二异丙基乙胺(6.48克)和三吡咯烷基溴化鏻六氟磷酸盐(15.57克)。反应液在20摄氏度下反应2小时后加入化合物1-1(9.33克)。反应液在80摄氏度下反应10小时。反应液倒入水(300毫升)中，然后用乙酸乙酯(150 毫升*3)萃取，所得有机相经饱和食盐水(250毫升)洗涤后用无水硫酸钠干燥，过滤，滤液浓缩得到残余物。残余物通过制备HPLC[柱型号：Phenomenex luna C18(250*50mm*10μm)，流动相：水(0.1％三氟乙酸)-乙腈，梯度：25％-55％，20分钟]纯化得到化合物32-11。LCMS(ESI)m/z:677.3.(M+1) ⁺。 To a solution of compound 32-10 (8.5 g) in N,N-dimethylacetamide (100 mL) were added N,N-diisopropylethylamine (6.48 g) and tripyrrolidinophosphonium bromide hexafluoro Phosphate (15.57 g). The reaction solution was reacted at 20 degrees Celsius for 2 hours, and then compound 1-1 (9.33 g) was added. The reaction solution was reacted at 80 degrees Celsius for 10 hours. The reaction solution was poured into water (300 mL), and then extracted with ethyl acetate (150 mL*3). The resulting organic phase was washed with saturated brine (250 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain residues thing. The residue was purified by preparative HPLC [column model: Phenomenex luna C18 (250*50mm*10μm), mobile phase: water (0.1% trifluoroacetic acid)-acetonitrile, gradient: 25%-55%, 20 minutes] to give compound 32- 11. LCMS (ESI) m/z: 677.3. (M+1) ⁺ .

第十一步：Step 11:

向化合物32-11(11克)的二氯甲烷(100毫升)溶液中加入三氟乙酸(30.80克)。反应液在20摄氏度下反应0.5小时，反应液浓缩得到化合物32-12的三氟乙酸盐，粗品直接用于下一步。LCMS(ESI)m/z:577.3.(M+1) ⁺。 To a solution of compound 32-11 (11 g) in dichloromethane (100 mL) was added trifluoroacetic acid (30.80 g). The reaction solution was reacted at 20 degrees Celsius for 0.5 hours, and the reaction solution was concentrated to obtain the trifluoroacetate salt of compound 32-12, and the crude product was directly used in the next step. LCMS (ESI) m/z: 577.3. (M+1) ⁺ .

第十二步：Step 12:

在0摄氏度下，向化合物32-12(11克，三氟乙酸盐)的四氢呋喃(100.0毫升)和水(20毫升)的混合溶液中依次加入无水碳酸钾(11.0克)，丙烯酰氯(1.44克)。反应液在0摄氏度下反应0.5小时。向反应液中加入水(250毫升)，用乙酸乙酯(250毫升*3)萃取，所得有机相经饱和食盐水(250毫升)洗涤后用无水硫酸钠干燥，过滤，滤液浓缩得到化合物32。化合物32通过制备SFC(柱型号：DAICEL CHIRALPAK IC(250mm*30mm，10μm)，流动相：甲醇(0.1％氨水)，梯度：二氧化碳临界流体60％-60％，5.5分钟，150分钟)分离纯化得到32-P1(保留时间＝1.956min)及32-P2(保留时间＝4.491min)。To a mixed solution of compound 32-12 (11 g, trifluoroacetate) in tetrahydrofuran (100.0 mL) and water (20 mL) at 0 degrees Celsius, anhydrous potassium carbonate (11.0 g), acryloyl chloride ( 1.44 grams). The reaction solution was reacted at 0 degrees Celsius for 0.5 hours. Water (250 mL) was added to the reaction solution, extracted with ethyl acetate (250 mL*3), the obtained organic phase was washed with saturated brine (250 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 32 . Compound 32 was isolated and purified by preparative SFC (column type: DAICEL CHIRALPAK IC (250mm*30mm, 10μm), mobile phase: methanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 60%-60%, 5.5 minutes, 150 minutes) 32-P1 (retention time = 1.956 min) and 32-P2 (retention time = 4.491 min).

32-P1再通过制备SFC(柱型号：DAICEL CHIRALPAK IG(250mm*30mm，10μm)，流动相：异丙醇(0.1％氨水)，梯度：二氧化碳临界流体40％-40％，6.0分钟，95分钟)分离纯化得到32A和32B。32-P1 was then passed through preparative SFC (column model: DAICEL CHIRALPAK IG (250mm*30mm, 10μm), mobile phase: isopropanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 40%-40%, 6.0 minutes, 95 minutes ) were separated and purified to obtain 32A and 32B.

32-P2再通过制备SFC(柱型号：DAICEL CHIRALPAK OD(250mm*30mm，10μm)，流动相：乙醇(0.1％氨水)，梯度：二氧化碳临界流体30％-30％，6.2分钟，180分钟)分离纯化得到化合物32C和化合物32D。32-P2 was separated by preparative SFC (column model: DAICEL CHIRALPAK OD (250mm*30mm, 10μm), mobile phase: ethanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 30%-30%, 6.2 minutes, 180 minutes) Purification gave compound 32C and compound 32D.

化合物32A和化合物32B经SFC检测【柱型号：Column:Chiralpak IG-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为异丙醇(0.05％二乙胺)；梯度(B％)：5％-40％】得到：化合物32A的保留时间为2.274min，e.e.值为56.29％；化合物32B的保留时间为2.642min，e.e.值为28.83％。Compound 32A and compound 32B were detected by SFC [Column model: Column: Chiralpak IG-3 50×4.6mm I.D., 3μm; mobile phase: A phase was supercritical carbon dioxide, and B phase was isopropanol (0.05% diethylamine); Gradient (B%): 5%-40%] Obtained: Compound 32A has a retention time of 2.274 min and an e.e. value of 56.29%; Compound 32B has a retention time of 2.642 min and an e.e. value of 28.83%.

化合物32C和化合物32D经SFC检测【柱型号：Column:Chiralpak IC-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为乙醇(0.05％二乙胺)；梯度(B％)：5％-40％】得到：化合物32C的保留时间为1.724min，e.e.值为66.46％；化合物32D的保留时间为1.915min，e.e.值为38.83％。化合物32A： ¹H NMR(400MHz,DMSO-d ₆)δ8.43-8.20(m,1H),7.92-7.72(m,1H),7.52(br t,J＝7.5Hz,2H),7.30-7.18(m,1H),7.14-7.00(m,1H),6.92-6.76(m,1H),6.28-6.13(m,1H),5.83-5.69(m,1H),3.97-3.74(m,8H),2.84-2.68(m,1H),2.05-1.92(m,3H),1.10-1.04(m,3H),1.02-0.95(m,3H)。LCMS(ESI)m/z: 631.2(M+1) ⁺。 Compound 32C and compound 32D were detected by SFC [Column model: Column: Chiralpak IC-3 50×4.6 mm ID, 3 μm; mobile phase: phase A was supercritical carbon dioxide, phase B was ethanol (0.05% diethylamine); gradient ( B%): 5%-40%] Obtained: compound 32C has a retention time of 1.724 min and an ee value of 66.46%; compound 32D has a retention time of 1.915 min and an ee value of 38.83%. Compound 32A: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.43-8.20 (m, 1H), 7.92-7.72 (m, 1H), 7.52 (br t, J=7.5Hz, 2H), 7.30-7.18 (m,1H),7.14-7.00(m,1H),6.92-6.76(m,1H),6.28-6.13(m,1H),5.83-5.69(m,1H),3.97-3.74(m,8H) , 2.84-2.68(m, 1H), 2.05-1.92(m, 3H), 1.10-1.04(m, 3H), 1.02-0.95(m, 3H). LCMS(ESI) m/z: 631.2(M+1) ⁺ .

化合物32B： ¹H NMR(400MHz,DMSO-d ₆)δ8.35-8.27(m,1H),7.86-7.70(m,1H),7.55-7.36(m,2H),7.30-7.21(m,1H),7.14-7.02(m,1H),6.93-6.78(m,1H),6.28-6.13(m,1H),5.83-5.70(m,1H),3.97-3.77(m,8H),2.74-2.67(m,1H),2.04-1.94(m,3H),1.10-0.97(m,6H)。LCMS(ESI)m/z:631.2(M+1) ⁺。 Compound 32B: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.35-8.27 (m, 1H), 7.86-7.70 (m, 1H), 7.55-7.36 (m, 2H), 7.30-7.21 (m, 1H) ),7.14-7.02(m,1H),6.93-6.78(m,1H),6.28-6.13(m,1H),5.83-5.70(m,1H),3.97-3.77(m,8H),2.74-2.67 (m, 1H), 2.04-1.94 (m, 3H), 1.10-0.97 (m, 6H). LCMS (ESI) m/z: 631.2 (M+1) ⁺ .

化合物32C： ¹H NMR(400MHz,DMSO-d ₆)δ8.36-8.28(m,1H),7.85-7.75(m,1H),7.54-7.37(m,2H),7.28-7.20(m,1H),7.14-7.04(m,1H),6.92-6.79(m,1H),6.26-6.13(m,1H),5.82-5.71(m,1H),3.96-3.75(m,8H),2.84-2.70(m,1H),2.03-1.93(m,3H),1.09-1.04(m,3H),1.01-0.96(m,3H)。LCMS(ESI)m/z:631.2(M+1) ⁺。 Compound 32C: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.36-8.28 (m, 1H), 7.85-7.75 (m, 1H), 7.54-7.37 (m, 2H), 7.28-7.20 (m, 1H) ),7.14-7.04(m,1H),6.92-6.79(m,1H),6.26-6.13(m,1H),5.82-5.71(m,1H),3.96-3.75(m,8H),2.84-2.70 (m, 1H), 2.03-1.93 (m, 3H), 1.09-1.04 (m, 3H), 1.01-0.96 (m, 3H). LCMS (ESI) m/z: 631.2 (M+1) ⁺ .

化合物32D： ¹H NMR(400MHz,DMSO-d ₆)δ8.35-8.30(m,1H),7.84-7.72(m,1H),7.55-7.34(m,2H),7.28-7.20(m,1H),7.12-7.03(m,1H),6.91-6.79(m,1H),6.26-6.14(m,1H),5.80-5.72(m,1H),3.99-3.76(m,8H),2.78-2.67(m,1H),2.03-1.94(m,3H),1.08-0.97(m,6H)。LCMS(ESI)m/z:631.2(M+1) ⁺。 Compound 32D: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.35-8.30 (m, 1H), 7.84-7.72 (m, 1H), 7.55-7.34 (m, 2H), 7.28-7.20 (m, 1H) ),7.12-7.03(m,1H),6.91-6.79(m,1H),6.26-6.14(m,1H),5.80-5.72(m,1H),3.99-3.76(m,8H),2.78-2.67 (m, 1H), 2.03-1.94 (m, 3H), 1.08-0.97 (m, 6H). LCMS (ESI) m/z: 631.2 (M+1) ⁺ .

实施例33Example 33

第一步：first step:

向化合物21-10(500毫克)的DMAC(10毫升)溶液中加入PYBROP(1.42克)，DIEA(328.10毫克)以及化合物4-2(870.45毫克)。反应液在100摄氏度下反应16小时，反应液浓缩得到残余物。残余物通过制备HPLC[柱型号：Phenomenex Synergi Max-RP 250*50mm*10μm，流动相：水(0.225％甲酸-乙腈，梯度：32％-62％，20分钟]纯化得到化合物33-1。LCMS(ESI)m/z:689.1.(M+1) ⁺。 To a solution of compound 21-10 (500 mg) in DMAC (10 mL) was added PYBROP (1.42 g), DIEA (328.10 mg) and compound 4-2 (870.45 mg). The reaction solution was reacted at 100 degrees Celsius for 16 hours, and the reaction solution was concentrated to obtain a residue. The residue was purified by preparative HPLC [column model: Phenomenex Synergi Max-RP 250*50mm*10μm, mobile phase: water (0.225% formic acid-acetonitrile, gradient: 32%-62%, 20 minutes] to give compound 33-1. LCMS (ESI) m/z: 689.1.(M+1) ⁺ .

第二步：Step 2:

将化合物33-1(100毫克)溶解在二氯甲烷(3毫升)和三氟乙酸(1毫升)的混合溶液中。反应液在25摄氏度下反应1小时，反应液浓缩得到化合物33-2的三氟乙酸盐，粗品直接用于下一步。LCMS(ESI)m/z:589.2(M+1) ⁺。 Compound 33-1 (100 mg) was dissolved in a mixed solution of dichloromethane (3 mL) and trifluoroacetic acid (1 mL). The reaction solution was reacted at 25 degrees Celsius for 1 hour, the reaction solution was concentrated to obtain the trifluoroacetate salt of compound 33-2, and the crude product was directly used in the next step. LCMS (ESI) m/z: 589.2 (M+1) ⁺ .

第三步：third step:

向化合物33-2(140毫克)的四氢呋喃(4毫升)和水(1毫升)的混合溶液中加入碳酸钾(71.08毫克)，调节pH至8后，向反应液中加入化合物1-5(15.52毫克)。反应液在0摄氏度反应15分钟，向反应液中加入饱和碳酸氢钠水溶液，调节pH到8，用乙酸乙酯(10毫升*2)萃取，有机相用饱和食盐水(5毫升*2)洗后经无水硫酸钠干燥后浓缩得到化合物33。化合物33用制备SFC(柱型号：Phenomenex Gemini-NX C18(75*30mm*3um)，流动相：水0.225％甲酸)乙腈，梯度：二氧化碳临界流体28％-58％，7分钟)分离得到化合物33A和化合物33B。To a mixed solution of compound 33-2 (140 mg) in tetrahydrofuran (4 mL) and water (1 mL), potassium carbonate (71.08 mg) was added to adjust the pH to 8, and compound 1-5 (15.52 mg) was added to the reaction solution. mg). The reaction solution was reacted at 0 degrees Celsius for 15 minutes, a saturated aqueous sodium bicarbonate solution was added to the reaction solution, the pH was adjusted to 8, extracted with ethyl acetate (10 mL*2), and the organic phase was washed with saturated brine (5 mL*2). Then, it was dried over anhydrous sodium sulfate and concentrated to obtain compound 33. Compound 33 was separated by preparative SFC (column type: Phenomenex Gemini-NX C18 (75*30mm*3um), mobile phase: water 0.225% formic acid) acetonitrile, gradient: carbon dioxide critical fluid 28%-58%, 7 minutes) to obtain compound 33A and compound 33B.

化合物33A和化合物33B经SFC检测【柱型号：Column:Chiralpak IG-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为甲醇+乙腈(0.05％二乙胺)；梯度(B％)：40％甲醇+(0.05％二乙胺)】得到：化合物33A的保留时间为0.663min；化合物33B的保留时间为1.128min。Compound 33A and compound 33B were detected by SFC [Column model: Column: Chiralpak IG-3 50×4.6mm I.D., 3μm; mobile phase: A phase was supercritical carbon dioxide, and B phase was methanol + acetonitrile (0.05% diethylamine); Gradient (B%): 40% methanol + (0.05% diethylamine)] yielded: the retention time of compound 33A was 0.663 min; the retention time of compound 33B was 1.128 min.

化合物33A(保留时间＝0.663min)： ¹H NMR(400MHz,DMSO-d ₆)δ8.32(d,J＝4.9Hz,1H),7.77-7.61(m,1H),7.44-7.30(m,3H),7.16-7.05(m,1H),6.89-6.74(m,1H),6.30-6.10(m,1H),5.89-5.68(m,1H),4.70-4.51(m,2H),4.40-4.04(m,3H),2.78-2.63(m,2H),2.02-1.94(m,3H),1.43-1.34(m,6H),1.06-0.94(m,6H)。LCMS(ESI)m/z:643.2.(M+1) ⁺ Compound 33A (retention time=0.663 min): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.32 (d, J=4.9 Hz, 1H), 7.77-7.61 (m, 1H), 7.44-7.30 (m, 3H), 7.16-7.05(m, 1H), 6.89-6.74(m, 1H), 6.30-6.10(m, 1H), 5.89-5.68(m, 1H), 4.70-4.51(m, 2H), 4.40- 4.04 (m, 3H), 2.78-2.63 (m, 2H), 2.02-1.94 (m, 3H), 1.43-1.34 (m, 6H), 1.06-0.94 (m, 6H). LCMS(ESI)m/z:643.2.(M+1) ⁺

化合物33B(保留时间＝1.128min)： ¹H NMR(400MHz,DMSO-d ₆)δ8.36-8.25(m,1H),7.75-7.60(m,1H),7.42-7.30(m,3H),7.13-7.05(m,1H),6.89-6.74(m,1H),6.24-6.14(m,1H),5.79-5.70(m,1H),4.73-4.51(m,2H),4.36-3.97(m,3H),2.75-2.67(m,2H),1.99-1.97(m,3H),1.42-1.36(m,6H),1.06-0.95(m,6H)。LCMS(ESI)m/z:643.2.(M+1) ⁺。 Compound 33B (retention time = 1.128 min): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.36-8.25 (m, 1H), 7.75-7.60 (m, 1H), 7.42-7.30 (m, 3H), 7.13-7.05(m, 1H), 6.89-6.74(m, 1H), 6.24-6.14(m, 1H), 5.79-5.70(m, 1H), 4.73-4.51(m, 2H), 4.36-3.97(m , 3H), 2.75-2.67 (m, 2H), 1.99-1.97 (m, 3H), 1.42-1.36 (m, 6H), 1.06-0.95 (m, 6H). LCMS (ESI) m/z: 643.2.(M+1) ⁺ .

实施例34Example 34

第一步：first step:

向化合物23-10(2克)的二甲基甲酰胺(20毫升)溶液中加入PYBROP(3.64克)，二异丙基乙胺(1.51克)，在25摄++氏度搅拌1小时，加入化合物3-1(2.10克)。反应液在100摄氏度下反应12小时，反应液倒入水(50毫升)中，固体过滤，滤饼溶解在乙酸乙酯(100毫升)中，通过柱层析分离纯化(洗脱剂：石油醚：乙酸乙酯＝5:1到2:1)得到化合物34-1。LCMS(ESI)m/z:707.0(M+1) ⁺。 To a solution of compound 23-10 (2 g) in dimethylformamide (20 mL) was added PYBROP (3.64 g), diisopropylethylamine (1.51 g), and stirred at 25°C for 1 hour, Compound 3-1 (2.10 g) was added. The reaction solution was reacted at 100 degrees Celsius for 12 hours, the reaction solution was poured into water (50 mL), the solid was filtered, the filter cake was dissolved in ethyl acetate (100 mL), and separated and purified by column chromatography (eluent: petroleum ether). : ethyl acetate=5:1 to 2:1) to obtain compound 34-1. LCMS (ESI) m/z: 707.0 (M+1) ⁺ .

第二步：Step 2:

向化合物34-1(3.0克)的二氯甲烷(20毫升)溶液中加入三氟乙酸(10毫升)。反应液在25摄氏度下反应1小时，反应液浓缩得到化合物34-2的三氟乙酸盐，粗品直接用于下一步。LCMS(ESI)m/z:607.0(M+1) ⁺。 To a solution of compound 34-1 (3.0 g) in dichloromethane (20 mL) was added trifluoroacetic acid (10 mL). The reaction solution was reacted at 25 degrees Celsius for 1 hour, and the reaction solution was concentrated to obtain the trifluoroacetate salt of compound 34-2, and the crude product was directly used in the next step. LCMS (ESI) m/z: 607.0 (M+1) ⁺ .

第三步：third step:

向化合物34-2(3.0克)的四氢呋喃(20毫升)和水(10毫升)的混合溶液中加入碳酸钾(1.49克)和化合物1-5(389.46毫克)。反应液在25摄氏度反应30分钟，用乙酸乙酯(10毫升*2)萃取，有机相用饱和食盐水(5毫升*2)洗后经无水硫酸钠干燥后浓缩得到残余物。残余物通过制备HPLC(柱型号:Phenomenex luna C18(250*70mm,10μm)；流动相：[水(0.225％甲酸)-乙腈]；梯度：30％-60％，20分钟)纯化得到化合物34。得到的产品用制备SFC(柱型号：DAICEL CHIRALPAK AS-H(250mm*30mm,10μm)，流动相：甲醇(0.1％氨水)，梯度：二氧化碳临界流体45％-45％，5分钟，605分钟)分离得到34-P1(34C和34D的混合物)和34-P2。To a mixed solution of compound 34-2 (3.0 g) in tetrahydrofuran (20 mL) and water (10 mL) were added potassium carbonate (1.49 g) and compound 1-5 (389.46 mg). The reaction solution was reacted at 25 degrees Celsius for 30 minutes, extracted with ethyl acetate (10 mL*2), the organic phase was washed with saturated brine (5 mL*2), dried over anhydrous sodium sulfate, and concentrated to obtain a residue. The residue was purified by preparative HPLC (column model: Phenomenex luna C18 (250*70 mm, 10 μm); mobile phase: [water (0.225% formic acid)-acetonitrile]; gradient: 30%-60%, 20 minutes) to give compound 34. The obtained product was prepared by preparative SFC (column type: DAICEL CHIRALPAK AS-H (250mm*30mm, 10μm), mobile phase: methanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 45%-45%, 5 minutes, 605 minutes) 34-P1 (a mixture of 34C and 34D) and 34-P2 were isolated.

化合物34-P1(34C和34D的混合物)经SFC检测【柱型号：Column:Chiralpak IC-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为甲醇(0.05％二乙胺)；梯度(B％)：40％-40％】得到：化合物34-P1的保留时间为0.977min。Compound 34-P1 (a mixture of 34C and 34D) was detected by SFC [Column model: Column: Chiralpak IC-3 50×4.6mm I.D., 3μm; mobile phase: A phase was supercritical carbon dioxide, and B phase was methanol (0.05% ethylamine); gradient (B%): 40%-40%] yielded: the retention time of compound 34-P1 was 0.977 min.

34-P1(34C和34D的混合物)： ¹H NMR(400MHz,DMSO-d ₆)δ8.33(d,J＝4.9Hz,1H),7.94-7.76(m,1H),7.57-7.42(m,1H),7.21(s,1H),7.14-7.06(m,1H),6.92-6.72(m,1H),6.28-6.16(m,1H),5.88-5.65(m,1H),4.87-4.42(m,2H),4.19-3.73(m,4H),2.84-2.71(m,1H),2.00-1.91(m,3H),1.38-1.31(m,3H),1.27-1.16(m,3H),1.11-1.04(m,3H),1.03-0.95(m,3H)。LCMS(ESI)m/z:661.1(M+1) ⁺。 34-P1 (mixture of 34C and 34D): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.33 (d, J=4.9 Hz, 1H), 7.94-7.76 (m, 1H), 7.57-7.42 (m ,1H),7.21(s,1H),7.14-7.06(m,1H),6.92-6.72(m,1H),6.28-6.16(m,1H),5.88-5.65(m,1H),4.87-4.42 (m, 2H), 4.19-3.73 (m, 4H), 2.84-2.71 (m, 1H), 2.00-1.91 (m, 3H), 1.38-1.31 (m, 3H), 1.27-1.16 (m, 3H) , 1.11-1.04 (m, 3H), 1.03-0.95 (m, 3H). LCMS (ESI) m/z: 661.1 (M+1) ⁺ .

34-P2(保留时间＝1.425min)再通过SFC(柱型号：DAICEL CHIRALPAK AS-H(250mm*30mm,5μm)，流动相：异丙醇(0.1％氨水)，梯度：二氧化碳临界流体5％-40％，3分钟，510分钟)分离得到化合物34A(保留时间＝1.217min)和化合物34B(保留时间＝1.401min)。34-P2 (retention time=1.425min) passed through SFC (column type: DAICEL CHIRALPAK AS-H (250mm*30mm, 5μm), mobile phase: isopropanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 5%- 40%, 3 min, 510 min) isolated compound 34A (retention time=1.217 min) and compound 34B (retention time=1.401 min).

化合物34A和化合物34B经SFC检测【柱型号：Column:Chiralpak AD-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为异丙醇(0.05％二乙胺)；梯度(B％)：5％-40％】得到：化合物34A的保留时间为1.217min，ee值为100％；化合物34B的保留时间为1.401min，ee值为93.15％。Compound 34A and Compound 34B were detected by SFC [Column model: Column: Chiralpak AD-3 50×4.6mm I.D., 3μm; Mobile phase: A phase is supercritical carbon dioxide, and B phase is isopropanol (0.05% diethylamine); Gradient (B%): 5%-40%] Obtained: Compound 34A has a retention time of 1.217 min and an ee value of 100%; Compound 34B has a retention time of 1.401 min and an ee value of 93.15%.

化合物34A： ¹H NMR(400MHz,DMSO-d ₆)δ8.33(d,J＝4.9Hz,1H),7.94-7.76(m,1H),7.57-7.42(m,1H),7.21(s,1H),7.14-7.06(m,1H),6.92-6.72(m,1H),6.28-6.16(m,1H),5.88-5.65(m,1H),4.87-4.42(m,2H),4.19-3.73(m,4H),2.84-2.71(m,1H),2.00-1.91(m,3H),1.38-1.31(m,3H),1.27-1.16(m,3H),1.11-1.04(m,3H),1.03-0.95(m,3H)。LCMS(ESI)m/z:661.1(M+1) ⁺。 Compound 34A: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.33 (d, J=4.9 Hz, 1H), 7.94-7.76 (m, 1H), 7.57-7.42 (m, 1H), 7.21 (s, 1H), 7.14-7.06(m, 1H), 6.92-6.72(m, 1H), 6.28-6.16(m, 1H), 5.88-5.65(m, 1H), 4.87-4.42(m, 2H), 4.19- 3.73(m,4H), 2.84-2.71(m,1H), 2.00-1.91(m,3H), 1.38-1.31(m,3H), 1.27-1.16(m,3H), 1.11-1.04(m,3H) ), 1.03-0.95 (m, 3H). LCMS (ESI) m/z: 661.1 (M+1) ⁺ .

化合物34B： ¹H NMR(400MHz,DMSO-d ₆)δ8.39-8.29(m,1H),7.95-7.75(m,1H),7.58-7.42(m,1H),7.25-7.20(m,1H),7.14-7.08(m,1H),6.92-6.75(m,1H),6.26-6.15(m,1H),5.86-5.72(m,1H),4.88-4.43(m,2H),4.20-3.98(m,1H),3.94-3.70(m,2H),3.48-3.38(m,1H),2.72-2.59(m,1H),2.07-1.99(m,3H),1.39-1.32(m,3H),1.27-1.17(m,3H),1.06-0.95(m,6H)。LCMS(ESI)m/z:661.1(M+1) ⁺。 Compound 34B: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.39-8.29 (m, 1H), 7.95-7.75 (m, 1H), 7.58-7.42 (m, 1H), 7.25-7.20 (m, 1H) ),7.14-7.08(m,1H),6.92-6.75(m,1H),6.26-6.15(m,1H),5.86-5.72(m,1H),4.88-4.43(m,2H),4.20-3.98 (m,1H),3.94-3.70(m,2H),3.48-3.38(m,1H),2.72-2.59(m,1H),2.07-1.99(m,3H),1.39-1.32(m,3H) , 1.27-1.17 (m, 3H), 1.06-0.95 (m, 6H). LCMS (ESI) m/z: 661.1 (M+1) ⁺ .

实验例1：细胞实验Experimental Example 1: Cell Experiment

实验目的：Purpose:

本实验旨在验证本申请化合物对KRAS G12C突变的NCI-H358人非小细胞肺癌细胞和KRAS野生型的A375人恶性黑色素瘤细胞的增殖抑制效果。The purpose of this experiment is to verify the proliferation inhibitory effect of the compounds of the present application on KRAS G12C-mutated NCI-H358 human non-small cell lung cancer cells and KRAS wild-type A375 human malignant melanoma cells.

实验材料：Experimental Materials:

细胞株NCI-H358(购自中国科学院细胞库)、细胞株A375(购自中国科学院细胞库)、DMEM培养基，盘尼西林/链霉素抗生素购自维森特，胎牛血清购自Biosera。CellTiter-Glo(细胞活率化学发光检测试剂)试剂购自Promega。Cell line NCI-H358 (purchased from Cell Bank of Chinese Academy of Sciences), cell line A375 (purchased from Cell Bank of Chinese Academy of Sciences), DMEM medium, penicillin/streptomycin antibiotics were purchased from Vicente, and fetal bovine serum was purchased from Biosera. CellTiter-Glo (Cell Viability Chemiluminescence Detection Reagent) reagent was purchased from Promega.

实验方法：experimental method:

1)NCI-H358细胞抗增殖实验：1) Anti-proliferation experiment of NCI-H358 cells:

将NCI-H358细胞种于白色96孔板中，80μL细胞悬液每孔，其中包含4000个NCI-H358细胞。细胞板置于二氧化碳培养箱中过夜培养。将待测化合物用排枪进3倍稀释至第9个浓度，即从2mM稀释至304nM，设置双复孔实验。向中间板中加入78μL培养基，再按照对应位置，转移2μL每孔的梯度稀释化合物至中间板，混匀后转移20μL每孔到细胞板中。转移到细胞板中的化合物浓度范围是10μM至1.52nM。细胞板置于二氧化碳培养箱中培养5天。另准备一块细胞板，在加药当天读取信号值作为最大值(下面方程式中Max值)参与数据分析。向此细胞板每孔加入25μL细胞活率化学发光检测试剂，室温孵育10分钟使发光信号稳定。采用多标记分析仪读数。向细胞板中加入每孔25μL的细胞活率化学发光检测试剂，室温孵育10分钟使发光信号稳定。采用多标记分析仪读数。NCI-H358 cells were seeded in a white 96-well plate, 80 μL of cell suspension per well, which contained 4000 NCI-H358 cells. Cell plates were incubated overnight in a carbon dioxide incubator. The compounds to be tested were diluted 3-fold to the ninth concentration, that is, from 2 mM to 304 nM, and a double-well experiment was set up. Add 78 μL of medium to the middle plate, and then transfer 2 μL of each well of the compound to the middle plate according to the corresponding position. After mixing, transfer 20 μL of each well to the cell plate. Compound concentrations transferred to cell plates ranged from 10 [mu]M to 1.52 nM. The cell plates were placed in a carbon dioxide incubator for 5 days. Another cell plate was prepared, and the signal value was read on the day of drug addition as the maximum value (Max value in the following equation) to participate in data analysis. Add 25 μL of cell viability chemiluminescence detection reagent to each well of the cell plate, and incubate at room temperature for 10 minutes to stabilize the luminescence signal. Read using a multi-label analyzer. Add 25 μL of cell viability chemiluminescence detection reagent per well to the cell plate, and incubate at room temperature for 10 minutes to stabilize the luminescence signal. Read using a multi-label analyzer.

2)A375细胞抗增殖实验：2) Anti-proliferation experiment of A375 cells:

将A375细胞种于白色96孔板中，80μL细胞悬液每孔，其中包含2000个A375细胞。细胞板置于二氧化碳培养箱中过夜培养。将待测化合物用排枪进3倍稀释至第9个浓度，即从2mM稀释至304nM，设置双复孔实验。向中间板中加入78μL培养基，再按照对应位置，转移2μL每孔的梯度稀释化合物至中间板，混匀后转移20μL每孔到细胞板中。转移到细胞板中的化合物浓度范围是10μM至1.52nM。细胞板置于二氧化碳培养箱中培养5天。另准备一块细胞板，在加药当天读取信号值作为最大值(下面方程式中Max值)参与数据分析。向此细胞板每孔加入25μL细胞活率化学发光检测试剂，室温孵育10分钟使发光信号稳定。采用多标记分析仪读数。向细胞板中加入每孔25μL的细胞活率化学发光检测试剂，室温孵育10分钟使发光信号稳定。采用多标记分析仪读数。A375 cells were seeded in white 96-well plates, 80 μL of cell suspension per well, which contained 2000 A375 cells. Cell plates were incubated overnight in a carbon dioxide incubator. The compounds to be tested were diluted 3-fold to the ninth concentration, that is, from 2 mM to 304 nM, and a double-well experiment was set up. Add 78 μL of medium to the middle plate, and then transfer 2 μL of each well of the compound to the middle plate according to the corresponding position. After mixing, transfer 20 μL of each well to the cell plate. Compound concentrations transferred to cell plates ranged from 10 [mu]M to 1.52 nM. The cell plates were placed in a carbon dioxide incubator for 5 days. Another cell plate was prepared, and the signal value was read on the day of drug addition as the maximum value (Max value in the following equation) to participate in data analysis. Add 25 μL of cell viability chemiluminescence detection reagent to each well of the cell plate, and incubate at room temperature for 10 minutes to stabilize the luminescence signal. Read using a multi-label analyzer. Add 25 μL of cell viability chemiluminescence detection reagent per well to the cell plate, and incubate at room temperature for 10 minutes to stabilize the luminescence signal. Read using a multi-label analyzer.

数据分析：data analysis:

利用方程式(Sample-Min)/(Max-Min)*100％将原始数据换算成抑制率，IC ₅₀的值即可通过四参数进行曲线拟合得出(GraphPad Prism中"log(inhibitor)vs.response--Variable slope"模式得出)。 Using the equation (Sample-Min)/(Max-Min)*100% to convert the raw data into inhibition rate, the IC ₅₀ value can be obtained by curve fitting with four parameters ("log(inhibitor) vs. response--Variable slope" mode).

实验结果：Experimental results:

本申请化合物对NCI-H358(G12C突变)细胞和A375(野生型)细胞的抗增殖活性IC ₅₀的数据在表1中展示。 The _IC50 data of the antiproliferative activity of the compounds of the present application on NCI-H358 (G12C mutant) cells and A375 (wild type) cells are shown in Table 1.

实验结论：Experimental results:

本申请化合物对于KRAS G12C突变型细胞NCI-H358显示了较高的细胞抗增殖活性，同时对于野生型的A375细胞抗增殖活性较弱，体现了高的选择性。The compounds of the present application show high cell anti-proliferation activity on KRAS G12C mutant cells NCI-H358, and at the same time have weak anti-proliferative activity on wild-type A375 cells, showing high selectivity.

表1细胞实验结果Table 1 Cell test results

受试化合物test compound	NCI-H358 IC ₅₀(nM) NCI-H358 IC ₅₀ (nM)	A375 IC ₅₀(nM) A375 IC ₅₀ (nM)
1A1A	1.61.6	95909590
1B1B	3.23.2	----
2A2A	1.51.5	>10000>10000
2B2B	44	----
3A3A	<1.5<1.5	45614561
3B3B	1.81.8	----
4A4A	<0.2<0.2	----

4B4B	0.30.3	----
5A5A	22	----
5B5B	33	----
8A8A	7.87.8	----
9A9A	1.21.2	----
9B9B	3.63.6	----
12B12B	44	----
14B14B	1212	----
15A15A	1515	----
16A16A	7.67.6	----
16B16B	21twenty one	----
17A17A	5.45.4	----
18A18A	1010	----
20A20A	1212	----
22A22A	44	>10000>10000
26A26A	1010	----
27A27A	1111	----
28B28B	88	----
29B29B	55	----

“--”表示尚未检测。"--" means not yet detected.

实验例2：血浆蛋白结合试验Experimental Example 2: Plasma Protein Binding Test

实验目的：采用平衡透析法测定受试化合物在CD-1小鼠、SD大鼠、比格犬、食蟹猴和人血浆中的蛋白结合率。OBJECTIVE: To determine the protein binding rate of test compounds in CD-1 mice, SD rats, beagle dogs, cynomolgus monkeys and human plasma by equilibrium dialysis.

实验方法：首先，采用上述五个物种的血浆分别配制受试化合物和对照化合物浓度为2μM的血浆样品；其次，将这些血浆样品放置于培养箱中在37±1℃预孵育4h；然后，测定缓冲液样品和透析后的血浆样品。本实验采用华法林作为对照化合物。样品中待测物的浓度用LC-MS/MS法进行测定。Experimental method: First, the plasma samples of the test compound and the control compound with a concentration of 2 μM were prepared by using the plasma of the above five species; secondly, these plasma samples were placed in an incubator at 37±1°C for pre-incubation for 4 hours; then, the assay was performed. Buffer samples and dialyzed plasma samples. Warfarin was used as the control compound in this experiment. The concentration of the analyte in the sample was determined by LC-MS/MS method.

实验结果：实验结果见表2。Experimental results: The experimental results are shown in Table 2.

表2化合物血浆蛋白结合试验结果Table 2 Compound plasma protein binding test results

实验结论：本申请化合物在五个物种中表现出适中的血浆蛋白结合率。Experimental conclusion: The compound of the present application showed moderate plasma protein binding rate in five species.

实验例3：雄性CD-1小鼠单次静脉推注与灌胃给予受试化合物的药代动力学研究Experimental Example 3: Pharmacokinetic study of test compounds administered by single intravenous bolus injection and gavage to male CD-1 mice

实验目的：Purpose:

以雄性CD-1小鼠为试验动物，评价受试化合物单次静脉推注和灌胃给药后的药代动力学行为，考察灌胃给药后的生物利用度，为临床研究提供动物试验资料。Male CD-1 mice were used as experimental animals to evaluate the pharmacokinetic behavior of the test compounds after single intravenous injection and intragastric administration, and to investigate the bioavailability after intragastric administration to provide animal experiments for clinical research. material.

实验方案：Experimental program:

试验动物：雄性CD-1小鼠6只，周龄7-9周，分成2组，IV组3只，PO组3只。动物购买自维通利华实验动物技术有限公司。Experimental animals: 6 male CD-1 mice, aged 7-9 weeks, were divided into 2 groups, 3 in IV group and 3 in PO group. Animals were purchased from Weitong Lihua Laboratory Animal Technology Co., Ltd.

药物配制：IV组：溶媒为10％DMSO+30％PEG400+60％Water。称量适量化合物，加入相应体积溶媒，涡旋得到澄清溶液，用0.22μm滤膜过滤。Drug preparation: Group IV: vehicle is 10% DMSO+30% PEG400+60% Water. Weigh an appropriate amount of compound, add the corresponding volume of solvent, and vortex to obtain a clear solution, which is filtered through a 0.22 μm filter.

PO组：溶媒为10％DMSO+30％PEG400+60％Water。称量适量化合物，加入相应体积溶媒，涡旋得到澄清溶液。PO group: the solvent was 10% DMSO+30% PEG400+60% Water. An appropriate amount of compound was weighed, the corresponding volume of solvent was added, and a clear solution was obtained by vortexing.

给药：3只静脉推注给药组动物给药前不禁食，3只灌胃给药组动物在给药前禁食至少12小时，给药4小时后恢复供食，禁食时间不超过20小时。试验当天，IV组动物通过尾静脉单次注射给予受试化合物；PO组通过单次灌胃给予受试化合物，Administration: 3 animals in the intravenous bolus administration group did not fast before administration, and 3 animals in the gavage administration group fasted for at least 12 hours before administration, and resumed feeding 4 hours after administration, and the fasting time was not long. more than 20 hours. On the test day, animals in IV group were given the test compound by a single injection through the tail vein; PO group was given the test compound by a single gavage,

实验操作：Experimental operation:

雄性CD-1小鼠静脉推注组分别给与受试化合物后，通过隐静脉分别0.083，0.25，0.5，1，2，4，8，及24小时采集全血样品(约0.03mL)；灌胃给药组分别给与受试化合物后，分别在0.25，0.5，1，2，4，8，12，及24小时采集全血样品(约0.03mL)，并记录实际采血时间。所有血样立即转移至贴有标签的含K2-EDTA的商品化离心管中。血样采集后，4℃，3200g离心10分钟吸取上清血浆，迅速置于干冰中，然后保存在-60℃或更低温度，用于LC-MS/MS分析。Male CD-1 mice in the intravenous bolus group were administered with test compounds, and whole blood samples (about 0.03 mL) were collected through saphenous vein for 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours, respectively; Whole blood samples (about 0.03 mL) were collected at 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours after administration of the test compound in the gastric administration group, and the actual blood collection time was recorded. All blood samples were immediately transferred to labeled commercial centrifuge tubes containing K2-EDTA. After blood sample collection, centrifuge at 3200g at 4°C for 10 minutes to aspirate the supernatant plasma, quickly place it in dry ice, and then store it at -60°C or lower for LC-MS/MS analysis.

实验结果：见表3。Experimental results: see Table 3.

表3雄性CD-1小鼠单次静脉推注与灌胃给予受试化合物的药代动力学研究结果Table 3 Results of pharmacokinetic studies of test compounds administered by single intravenous bolus injection and gavage to male CD-1 mice

注：Cl：清除率；V _d：分布容积；AUC：暴露量；T _1/2：半衰期；C _max：口服给药后化合物浓度最大值；T _max：达到C _max的时间；F：生物利用度。 Note: Cl: clearance; _Vd : volume of distribution; AUC: exposure; T1 _/2 : half-life; _Cmax : maximum compound concentration after oral administration; _Tmax : time to reach _Cmax ; F: bioavailability Spend.

实验结论：本申请化合物显示出较高的暴露量和口服生物利用度，具有较好的药代动力学性质。Experimental conclusion: The compound of the present application shows high exposure and oral bioavailability, and has good pharmacokinetic properties.

实验例4：雄性SD大鼠单次静脉推注与灌胃给予受试化合物的药代动力学研究Experimental Example 4: Pharmacokinetic study of test compounds administered by single intravenous bolus injection and gavage to male SD rats

实验目的：Purpose:

以雄性SD大鼠为试验动物，评价受试化合物单次静脉推注和灌胃给药后的药代动力学行为，考察灌胃给药后的生物利用度，为临床研究提供动物试验资料。Male SD rats were used as experimental animals to evaluate the pharmacokinetic behavior of the test compounds after single intravenous injection and intragastric administration, and to investigate the bioavailability after intragastric administration, so as to provide animal test data for clinical research.

实验方案：Experimental program:

试验动物：雄性SD大鼠6只，周龄7-9周，分成2组，IV组3只，PO组3只。动物购买自维通利华实验动物技术有限公司Experimental animals: 6 male SD rats, aged 7-9 weeks, were divided into 2 groups, 3 in IV group and 3 in PO group. Animals were purchased from Weitong Lihua Laboratory Animal Technology Co., Ltd.

实验操作：Experimental operation:

雄性SD大鼠静脉推注组分别给与受试化合物后，通过隐静脉分别0.083，0.25，0.5，1，2，4，6，8，及24小时采集全血样品(约0.2mL)；灌胃给药组分别给与受试化合物后，分别在0.25，0.5，1，2，4，6，8，及24小时采集全血样品(约0.2mL)，并记录实际采血时间。所有血样立即转移至贴有标签的含K2-EDTA的商品化离心管中。血样采集后，4℃，3200g离心10分钟吸取上清血浆，迅速置于干冰中，然后保存在-60℃或更低温度，用于LC-MS/MS分析。Male SD rats in the intravenous bolus group were administered with test compounds, and whole blood samples (about 0.2 mL) were collected through saphenous vein for 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours, respectively; Whole blood samples (about 0.2 mL) were collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration of the test compound in the gastric administration group, and the actual blood collection time was recorded. All blood samples were immediately transferred to labeled commercial centrifuge tubes containing K2-EDTA. After blood sample collection, centrifuge at 3200g at 4°C for 10 minutes to aspirate the supernatant plasma, quickly place it in dry ice, and then store it at -60°C or lower for LC-MS/MS analysis.

实验例5：雄性食蟹猴单次静脉注射或灌胃给予受试化合物后的药代动力学研究Experimental Example 5: Pharmacokinetic study of male cynomolgus monkeys after single intravenous injection or intragastric administration of test compounds

实验目的：Purpose:

以雄性食蟹猴为试验动物，评价单次静脉注射或灌胃给予受试化合物后雄性食蟹猴的药代动力学行为。Male cynomolgus monkeys were used as experimental animals to evaluate the pharmacokinetic behavior of male cynomolgus monkeys after single intravenous injection or gavage administration of test compounds.

实验方案：Experimental program:

试验动物：静脉注射采用2只雄性食蟹猴，口服给药采用雄性食蟹猴3只，年龄2-5年。Experimental animals: 2 male cynomolgus monkeys were used for intravenous injection, and 3 male cynomolgus monkeys were used for oral administration, aged 2-5 years.

药物配制：静脉注射溶媒：10％DMSO+30％PEG400+60％Water。称量适量化合物，加入相应体积溶媒，涡旋得到澄清溶液，用0.22μm滤膜过滤。Drug preparation: Intravenous injection Vehicle: 10% DMSO+30% PEG400+60% Water. Weigh an appropriate amount of compound, add the corresponding volume of solvent, and vortex to obtain a clear solution, which is filtered through a 0.22 μm filter.

口服溶媒：10％DMSO+30％PEG400+60％Water。称量适量化合物，加入相应体积溶媒，通过搅拌、超声得到澄清溶液。Oral vehicle: 10% DMSO+30% PEG400+60% Water. Weigh an appropriate amount of the compound, add the corresponding volume of solvent, and obtain a clear solution by stirring and sonicating.

实验操作：Experimental operation:

静脉注射：静脉注射给与受试化合物后，试验动物均将在未被麻醉状态下，通过外周静脉采集血样，分别在0.083，0.25，0.5，1，2，4，6，8，及24小时采集全血样品(约0.5mL)，并记录实际采血时间。血样采集后转移至含K2-EDTA抗凝剂的商品化离心管中，血样采集后，4℃，3200g离心10分钟吸取上清血浆，迅速置于干冰中，然后保存在-60℃或更低温度，用于LC-MS/MS分析。Intravenous injection: After intravenous administration of the test compound, the experimental animals will be under anesthesia, and blood samples will be collected through peripheral veins at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours, respectively. A whole blood sample (approximately 0.5 mL) was collected and the actual blood collection time was recorded. After blood sample collection, transfer it to a commercial centrifuge tube containing K2-EDTA anticoagulant. After blood sample collection, centrifuge at 3200g for 10 minutes at 4°C to absorb the supernatant plasma, quickly place it in dry ice, and then store it at -60°C or lower. temperature for LC-MS/MS analysis.

口服：灌胃给药给与受试化合物后，试验动物均将在未被麻醉状态下，通过外周静脉采集血样，分别在0.25，0.5，1，2，4，6，8，及24小时采集全血样品(约0.5mL)，并记录实际采血时间。血样采集后转移至含K2-EDTA抗凝剂的商品化离心管中，血样采集后，4℃，3200g离心10分钟吸取上清血浆，迅速置于干冰中，然后保存在-60℃或更低温度，用于LC-MS/MS分析。Oral: After the test compound is administered by gavage, the test animals will collect blood samples through peripheral veins without anesthesia at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours, respectively. Whole blood samples (approximately 0.5 mL) were recorded and the actual blood collection time was recorded. After blood sample collection, transfer it to a commercial centrifuge tube containing K2-EDTA anticoagulant. After blood sample collection, centrifuge at 3200g for 10 minutes at 4°C to absorb the supernatant plasma, quickly place it in dry ice, and then store it at -60°C or lower. temperature for LC-MS/MS analysis.

实验例6：比格犬单次静脉注射或灌胃给予受试化合物后的药代动力学研究Experimental Example 6: Pharmacokinetic study after single intravenous injection or intragastric administration of test compounds in beagle dogs

实验目的：Purpose:

以比格犬为试验动物评价单次静脉注射或灌胃给予受试化合物后雄性比格犬的药代动力学行为。试验动物：静脉注射采用2只雄性比格犬，口服给药采用3只雄性比格犬。溶媒：The pharmacokinetic behavior of male Beagle dogs after a single intravenous injection or intragastric administration of test compounds was evaluated by using Beagle dogs as experimental animals. Experimental animals: 2 male Beagle dogs were used for intravenous injection, and 3 male Beagle dogs were used for oral administration. Solvent:

静脉注射溶媒：10％DMSO+30％PEG400+60％水。称量适量化合物，加入相应体积溶媒，涡旋得到澄清溶液，用0.22μm滤膜过滤。Intravenous vehicle: 10% DMSO + 30% PEG400 + 60% water. Weigh an appropriate amount of compound, add the corresponding volume of solvent, and vortex to obtain a clear solution, which is filtered through a 0.22 μm filter.

口服溶媒：10％DMSO+30％PEG400+60％水。称量适量化合物，加入相应体积溶媒，通过搅拌、超声得到澄清溶液。Oral vehicle: 10% DMSO+30% PEG400+60% water. Weigh an appropriate amount of the compound, add the corresponding volume of solvent, and obtain a clear solution by stirring and sonicating.

实验方案：Experimental program:

静脉注射：静脉注射给与受试化合物后，通过外周静脉采集血样，分别在0.083，0.25，0.5，1，2，4，8，及24小时采集全血样品，并记录实际采血时间。血样采集后转移至含K2-EDTA抗凝剂的商品化离心管中，血样采集后，4℃，3200g离心10分钟吸取上清血浆，迅速置于干冰中，然后保存在-60℃或更低温度，用于LC-MS/MS分析。Intravenous injection: After intravenous administration of the test compound, blood samples were collected from peripheral veins, and whole blood samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours, and the actual blood collection time was recorded. After blood sample collection, transfer it to a commercial centrifuge tube containing K2-EDTA anticoagulant. After blood sample collection, centrifuge at 3200g for 10 minutes at 4°C to absorb the supernatant plasma, quickly place it in dry ice, and then store it at -60°C or lower. temperature for LC-MS/MS analysis.

口服：灌胃给药给与受试化合物后，试验动物均将在未被麻醉状态下，通过外周静脉采集血样，分别在0.083，0.25，0.5，1，2，4，8，及24小时采集全血样品，并记录实际采血时间。血样采集后转移至含K2-EDTA抗凝剂的商品化离心管中，血样采集后，4℃，3200g离心10分钟吸取上清血浆，迅速置于干冰中，然后保存在-60℃或更低温度，用于LC-MS/MS分析。Oral: After the test compound is administered by gavage, the test animals will collect blood samples through peripheral veins without anesthesia at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours, respectively. Whole blood samples were taken, and the actual blood collection time was recorded. After blood sample collection, transfer it to a commercial centrifuge tube containing K2-EDTA anticoagulant. After blood sample collection, centrifuge at 3200g for 10 minutes at 4°C to absorb the supernatant plasma, quickly place it in dry ice, and then store it at -60°C or lower. temperature for LC-MS/MS analysis.

实验例7：体内药效试验(一)Experimental Example 7: In vivo efficacy test (1)

实验目的：Purpose:

评价受试化合物在人非小细胞肺癌NCI-H358皮下异体移植肿瘤模型上的体内药效。The in vivo efficacy of the test compounds on the human non-small cell lung cancer NCI-H358 subcutaneous xenograft tumor model was evaluated.

实验操作：Experimental operation:

BALB/c裸小鼠，雌性，6-8周龄，体重18-23克。共需48只。由上海市计划生育科学研究所实验动物经营部提供。将NCI-H358肿瘤细胞重悬于PBS中，制备成0.2mL(1×10 ⁷个)的细胞悬液，皮下接种于每只小鼠的右后背(1×10 ⁷/只)等待肿瘤生长。在肿瘤平均体积达到约100-150mm ³时开始进行随机分组给药，每组8只动物，口服灌胃给药频率为一天一次，给药剂量如表4所示。每周两次用游标卡尺测量肿瘤直径。肿瘤体积的计算公式为：V＝0.5a×b ²，a和b分别表示肿瘤的长径和短径。化合物的抑瘤疗效用TGI(％)评价。TGI(％)，反映肿瘤生长抑制率。TGI(％)的计算：TGI(％)＝[(1- (某处理组给药结束时平均瘤体积－该处理组开始给药时平均瘤体积)/(溶剂对照组治疗结束时平均瘤体积－溶剂对照组开始治疗时平均瘤体积)]×100％。 BALB/c nude mice, female, 6-8 weeks old, weighing 18-23 grams. A total of 48 are required. Provided by the Laboratory Animal Management Department of Shanghai Institute of Family Planning. The NCI-H358 tumor cells were resuspended in PBS, prepared into 0.2 mL (1×10 ⁷ cells) of cell suspension, and subcutaneously inoculated into the right back of each mouse (1×10 ⁷ /mice) to wait for tumor growth . When the average tumor volume reached about 100-150 mm ³ , the patients were randomly divided into groups, with 8 animals in each group, and the frequency of oral gavage was once a day. Tumor diameters were measured with vernier calipers twice a week. The calculation formula of tumor volume is: V=0.5a×b ² , a and b represent the long and short diameters of the tumor, respectively. The tumor-inhibitory efficacy of the compounds was evaluated by TGI (%). TGI (%), reflecting tumor growth inhibition rate. Calculation of TGI(%): TGI(%)=[(1-(average tumor volume at the end of administration of a certain treatment group-average tumor volume at the beginning of administration of this treatment group)/(average tumor volume at the end of treatment in the solvent control group) - Average tumor volume at the start of treatment in the solvent control group)] × 100%.

实验结果：见表4。Experimental results: see Table 4.

实验结论：本申请化合物在人非小细胞肺癌NCI-H358皮下异体移植肿瘤模型中展示出显著的抑瘤效果。Experimental conclusion: The compound of the present application shows a significant tumor inhibitory effect in the human non-small cell lung cancer NCI-H358 subcutaneous xenograft tumor model.

表4非小细胞肺癌NCI-H358皮下异体移植肿瘤模型试验结果Table 4 The results of the non-small cell lung cancer NCI-H358 subcutaneous allograft tumor model test

实验例8：体内药效试验(二)Experimental Example 8: In vivo efficacy test (2)

实验目的：Purpose:

评价受试化合物在人结肠癌CO-04-0070皮下异体移植肿瘤模型上的体内药效。The in vivo efficacy of the test compounds on the human colon cancer CO-04-0070 subcutaneous xenograft tumor model was evaluated.

实验操作：Experimental operation:

BALB/c裸小鼠，雌性，6-8周龄，体重18-20克。共需48只。由上海灵畅生物科技有限公司提供。将20～30mm ³的CO-04-0070FP4肿瘤组织块皮下接种于的每只小鼠的右后背等待肿瘤生长，肿瘤平均体积达到约153mm ³时开始进行随机分组给药，每组8只动物，口服给药频率为一天一次，给药剂量如表5所示。每周两次用游标卡尺测量肿瘤直径。肿瘤体积的计算公式为：V＝0.5a×b ²，a和b分别表示肿瘤的长径和短径。化合物的抑瘤疗效用TGI(％)评价。TGI(％)，反映肿瘤生长抑制率。TGI(％)的计算：TGI(％)＝[(1-(某处理组给药结束时平均瘤体积－该处理组开始给药时平均瘤体积)/(溶剂对照组治疗结束时平均瘤体积－溶剂对照组开始治疗时平均瘤体积)]×100％。 BALB/c nude mice, female, 6-8 weeks old, weighing 18-20 grams. A total of 48 are required. Provided by Shanghai Lingchang Biotechnology Co., Ltd. A ^20-30mm3 CO-04-0070FP4 tumor tissue block was subcutaneously inoculated into the right back of each mouse to wait for tumor growth. When the average tumor volume reached about ^153mm3 , random group administration began, with 8 animals in each group , the oral administration frequency is once a day, and the dosage is shown in Table 5. Tumor diameters were measured with vernier calipers twice a week. The calculation formula of tumor volume is: V=0.5a×b ² , a and b represent the long and short diameters of the tumor, respectively. The tumor-inhibitory efficacy of the compounds was evaluated by TGI (%). TGI (%), reflecting tumor growth inhibition rate. Calculation of TGI (%): TGI (%)=[(1-(average tumor volume at the end of administration of a certain treatment group - average tumor volume at the beginning of administration of this treatment group)/(average tumor volume at the end of treatment in the solvent control group) - Average tumor volume at the start of treatment in the solvent control group)] × 100%.

实验结果：见表5。Experimental results: see Table 5.

实验结论：本申请化合物在人结肠癌CO-04-0070皮下异体移植肿瘤模型中展示出显著的抑瘤效果，且量效关系明确。Experimental conclusion: The compound of the present application shows a significant tumor inhibitory effect in the human colon cancer CO-04-0070 subcutaneous xenograft tumor model, and the dose-effect relationship is clear.

表5人结肠癌CO-04-0070皮下异体移植肿瘤模型试验结果Table 5. Results of the test of the subcutaneous xenograft tumor model of human colon cancer CO-04-0070

实验例9：体内药效试验(三)Experimental Example 9: In vivo efficacy test (3)

实验目的：Purpose:

评价受试化合物在人胰腺癌MIAPACA2细胞BALB/c裸小鼠皮下异体移植肿瘤模型上的体内药效。To evaluate the in vivo efficacy of the test compounds on the human pancreatic cancer MIAPACA2 cell BALB/c nude mouse subcutaneous xenograft tumor model.

实验操作：Experimental operation:

BALB/c裸小鼠，雌性，7-8周龄。共需48只。由上海市计划生育科学研究所实验动物经营部提供。在小鼠腋下接种MIAPACA2细胞，接种量为5×10 ⁶/0.2mL，肿瘤平均体积达到约125mm ³时开始进行随机分组给药，每组8只动物，口服灌胃给药频率为一天一次，给药剂量如表6所示。每周两次用游标卡尺测量肿瘤直径。肿瘤体积的计算公式为：V＝0.5a×b ²，a和b分别表示肿瘤的长径和短径。化合物的抑瘤疗效用TGI(％)评价。TGI(％)，反映肿瘤生长抑制率。TGI(％)的计算：TGI(％)＝[(1-(某处理组给药结束时平均瘤体积－该处理组开始给药时平均瘤体积)/(溶剂对照组治疗结束时平均瘤体积－溶剂对照组开始治疗时平均瘤体积)]×100％。 BALB/c nude mice, female, 7-8 weeks old. A total of 48 are required. Provided by the Laboratory Animal Management Department of Shanghai Institute of Family Planning. MIAPACA2 cells were inoculated in the armpits of mice with an inoculation volume of 5×10 ⁶ /0.2 mL, and the average tumor volume reached about 125 mm ³ , and then the mice were randomly divided into groups, 8 animals in each group, and the frequency of oral gavage was once a day. , the doses are shown in Table 6. Tumor diameters were measured with vernier calipers twice a week. The calculation formula of tumor volume is: V=0.5a×b ² , a and b represent the long and short diameters of the tumor, respectively. The tumor-inhibitory efficacy of the compounds was evaluated by TGI (%). TGI (%), reflecting tumor growth inhibition rate. Calculation of TGI (%): TGI (%)=[(1-(average tumor volume at the end of administration of a certain treatment group - average tumor volume at the beginning of administration of this treatment group)/(average tumor volume at the end of treatment in the solvent control group) - Average tumor volume at the start of treatment in the solvent control group)] × 100%.

实验结果：见表6。Experimental results: see Table 6.

实验结论：Experimental results:

本申请化合物在人胰腺癌MIAPACA2皮下异体移植肿瘤模型中展示出显著的抑瘤效果，且量效关系明确。The compounds of the present application show a significant tumor inhibitory effect in the human pancreatic cancer MIAPACA2 subcutaneous xenograft tumor model, and the dose-effect relationship is clear.

表6人胰腺癌MIAPACA2皮下异体移植肿瘤模型试验结果Table 6. Results of the test of human pancreatic cancer MIAPACA2 subcutaneous xenograft tumor model

Claims

式(I)化合物或其药学上可接受的盐，a compound of formula (I) or a pharmaceutically acceptable salt thereof,

其中，in,

X选自CR ₁₃和N； X is selected from CR ₁₃ and N;

Q和Y分别独立地选自CH和N；Q and Y are independently selected from CH and N, respectively;

R ₁选自H、F、Cl、Br、I、C _1-3烷基，所述C _1-3烷基任选被1、2或3个卤素取代； R ₁ is selected from H, F, Cl, Br, I, C _1-3 alkyl optionally substituted with ₁ , 2 or 3 halogens;

R ₂、R ₃、R ₄、R ₅和R ₆分别独立地选自H、F、Cl、Br、I、OH、C _1-3烷基、NH ₂和-NH-C _1-3烷基，所述C _1-3烷基任选被1、2或3个卤素取代； R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are each independently selected from H, F, Cl, Br, I, OH, C _1-3 alkyl, NH ₂ and -NH-C _1-3 alkyl , the C _1-3 alkyl is optionally substituted by 1, 2 or 3 halogens;

R ₇、R ₈、R ₉和R ₁₀分别独立地选自H和CH ₃； R ₇ , R ₈ , R ₉ and R ₁₀ are each independently selected from H and CH ₃ ;

R ₁₁选自H和F； R ₁₁ is selected from H and F;

R ₁₂和R ₁₃分别独立地选自H、C _1-6烷基、环丙基和C _1-3烷氧基。 R ₁₂ and R ₁₃ are each independently selected from H, C _1-6 alkyl, cyclopropyl and C _1-3 alkoxy.
根据权利要求1所述的化合物或其药学上可接受的盐，其中，化合物选自The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from

其中，R ₁、R ₂、R ₃、R ₄、R ₅、R ₆、R ₇、R ₈、R ₉、R ₁₀、R ₁₁、R ₁₂和R ₁₃如权利要求1所定义。 wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ are as defined in claim 1 .
根据权利要求1或2所述的化合物或其药学上可接受的盐，其中，R ₁选自H、F、Cl、Br、I、CH ₃，所述CH ₃任选被1、2或3个卤素取代。 The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R ₁ is selected from H, F, Cl, Br, I, CH ₃ , wherein CH ₃ is optionally replaced by 1, 2 or 3 halogen substituted.
根据权利要求3所述的化合物或其药学上可接受的盐，其中，R ₁选自H、F和CF ₃。 The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein R ₁ is selected from H, F and CF ₃ .
根据权利要求1或2所述的化合物或其药学上可接受的盐，其中，R ₂、R ₃、R ₄、R ₅和R ₆分别独立地选自H、F、Cl、Br、I、OH、CF ₃、CH ₃、NH ₂和-NHCH ₃。 The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are each independently selected from H, F, Cl, Br, I, OH, _CF3 , _CH3 , _NH2 and _-NHCH3 .
根据权利要求5所述的化合物或其药学上可接受的盐，其中，R ₂选自H、F、NH ₂和-NHCH ₃。 The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein R ₂ is selected from the group consisting of H, F, NH ₂ and -NHCH ₃ .
根据权利要求5所述的化合物或其药学上可接受的盐，其中，R ₃选自H、F和Cl。 The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein _R3 is selected from the group consisting of H, F and Cl.
根据权利要求5所述的化合物或其药学上可接受的盐，其中，R ₄选自H和F。 The compound of claim ₅ , or a pharmaceutically acceptable salt thereof, wherein R4 is selected from H and F.
根据权利要求5所述的化合物或其药学上可接受的盐，其中，R ₅选自H、F、Cl和CH ₃。 The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein R ₅ is selected from H, F, Cl and CH ₃ .
根据权利要求5所述的化合物或其药学上可接受的盐，其中，R ₆选自H、F和CF ₃。 The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein R ₆ is selected from H, F and CF ₃ .
根据权利要求1或2所述的化合物或其药学上可接受的盐，其中，R ₁₂选自
The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R ₁₂ is selected from
根据权利要求1或2所述的化合物或其药学上可接受的盐，其中，R ₁₃选自CH ₃和OCH ₃。 The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R ₁₃ is selected from CH ₃ and OCH ₃ .
根据权利要求1或2所述的化合物或其药学上可接受的盐，其中，结构单元
选自
The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein the structural unit
selected from
根据权利要求1或2所述的化合物或其药学上可接受的盐，其中，结构单元
选自
The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein the structural unit
selected from
根据权利要求1所述的化合物或其药学上可接受的盐，其中，结构单元
选自
The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the structural unit
selected from
化合物或其药学上可接受的盐，其选自A compound or a pharmaceutically acceptable salt thereof selected from
根据权利要求16所述的化合物或其药学上可接受的盐，其选自The compound of claim 16, or a pharmaceutically acceptable salt thereof, selected from
根据权利要求1～16任意一项所述的化合物或其药学上可接受的盐在制备KRAS G12C突变蛋白抑制剂的应用。Use of the compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof in the preparation of a KRAS G12C mutein inhibitor.
根据权利要求1～16任意一项所述的化合物或其药学上可接受的盐在制备治疗非小细胞肺癌药物中的应用。Use of the compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating non-small cell lung cancer.