WO2023280317A1

WO2023280317A1 - Benzylamino tricyclic compound and use thereof

Info

Publication number: WO2023280317A1
Application number: PCT/CN2022/104713
Authority: WO
Inventors: 吴凌云; 代天资; 赵乐乐; 展震; 孙建军; 钱薏; 陈曙辉
Original assignee: 南京明德新药研发有限公司
Priority date: 2021-07-09
Filing date: 2022-07-08
Publication date: 2023-01-12

Abstract

Provided are a benzylamino tricyclic compound and the use thereof, which in particular relate to a compound as represented by formula (Ⅹ), and a pharmaceutically acceptable salt thereof.

Description

苄氨基三并环类化合物及其应用Benzylamino tricyclic compound and its application

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

CN202110778940.3，2021年07月09日；CN202110778940.3, July 09, 2021;

CN202110949940.5，2021年08月18日；CN202110949940.5, August 18, 2021;

CN202110984116.3，2021年08月25日；CN202110984116.3, August 25, 2021;

CN202111058296.9，2021年09月09日；CN202111058296.9, September 9, 2021;

CN202111155118.8，2021年09月29日；CN202111155118.8, September 29, 2021;

CN202111223631.6，2021年10月20日；CN202111223631.6, October 20, 2021;

CN202111329065.7，2021年11月10日；CN202111329065.7, November 10, 2021;

CN202111653329.4，2021年12月30日；CN202111653329.4, December 30, 2021;

CN202210657741.1，2022年06月10日。CN202210657741.1, June 10, 2022.

技术领域technical field

本发明涉及苄氨基三并环类化合物及其应用，具体涉及式(Ⅹ)所示化合物及其药学上可接受的盐。The present invention relates to benzylaminotricyclic compounds and applications thereof, in particular to compounds represented by formula (X) and pharmaceutically acceptable salts thereof.

背景技术Background technique

RAS蛋白是一种21kDa大小，位于细胞膜上的，拥有鸟苷三磷酸水解酶(GTPase)活性的鸟嘌呤核苷结合蛋白。RAS家族主要包含三种亚型，KRAS，NRAS和HRAS。作为GDP/GTP循环控制的二进制分子开关，RAS蛋白可以在活性的GTP结合状态(GTP-RAS)和无活性的GDP结合状态(GDP-RAS)之间循环。当RAS-GDP与鸟嘌呤核苷交换因子(GEFs)如SOS1结合时，会迅速释放GDP并与细胞内高浓度的GTP结合进入“开”的状态，激活下游一系列信号通路，包括：MEK/ERK，PI3K/AKT/mTOR，RalGDS等。而在GTPase激活蛋白(GAPs)的作用下，RAS的GTPase的活性提高上千倍，与之结合的GTP被水解成GDP，RAS重新进入GDP结合的“关”的状态，从而完成一个完整的循环(Simanshu DK et al.,Cell,2017,170:17–33)。这一循环在细胞中具有重要的调控功能，同细胞的增殖，存活，代谢，迁移，免疫和生长密切相关。RAS protein is a 21kDa guanine nucleoside-binding protein located on the cell membrane and possessing guanosine triphosphate hydrolase (GTPase) activity. The RAS family mainly includes three subtypes, KRAS, NRAS and HRAS. As a binary molecular switch for GDP/GTP cycling control, RAS proteins can cycle between an active GTP-bound state (GTP-RAS) and an inactive GDP-bound state (GDP-RAS). When RAS-GDP binds to guanine nucleoside exchange factors (GEFs) such as SOS1, it will rapidly release GDP and combine with the high concentration of GTP in the cell to enter the "on" state, activating a series of downstream signaling pathways, including: MEK/ ERK, PI3K/AKT/mTOR, RalGDS, etc. Under the action of GTPase activating proteins (GAPs), the activity of GTPase in RAS is increased by thousands of times, the GTP bound to it is hydrolyzed into GDP, and RAS re-enters the "off" state of GDP binding, thus completing a complete cycle. (Simanshu DK et al., Cell, 2017, 170:17–33). This cycle has important regulatory functions in cells and is closely related to cell proliferation, survival, metabolism, migration, immunity and growth.

研究表明，约15％的肿瘤病例中存在RAS基因突变。致癌的RAS突变会同时抑制内在GTPase活性和GAP激活的GTPase活性，使RAS循环始终处于RAS-GTP的“开”状态，导致下游信号通路持续激活引发癌症。因此，抑制KRAS的突变体及下游通路的异常激活成为治疗癌症的热门靶点之一。Studies have shown that RAS gene mutations are present in about 15% of tumor cases. Oncogenic RAS mutations can simultaneously inhibit intrinsic GTPase activity and GAP-activated GTPase activity, making the RAS cycle always in the "on" state of RAS-GTP, resulting in continuous activation of downstream signaling pathways to cause cancer. Therefore, KRAS-inhibiting mutants and abnormal activation of downstream pathways have become one of the hot targets for cancer treatment.

SOS1(英文全称Son of Sevenless 1)是一类调控RAS蛋白GDP/GTP循环的GEF。通过结合在催化位点，SOS1抑制剂可以阻断SOS1与RAS蛋白的结合，降低RAS-GTP水平。这类抑制剂可以有效降低癌细胞中RAS下游信号通路的异常激活(如ERK磷酸化)，从而起到治疗癌症的作用。目前SOS1小分子抑制剂只有勃林格殷格翰公司开发的BI-1701963(WO2018115380，WO2019122129)进入了I期临床实验。近年来有研究认为，由于ERK磷酸化被抑制后会负反馈激活上游RAS通路，RAS通路的药物在临床应用中很容易产生耐药，而这一负反馈调节机制与SOS1密切相关。因此，开发SOS1小分子抑制剂具有广阔的应用前景。SOS1 (English full name Son of Sevenless 1) is a type of GEF that regulates the RAS protein GDP/GTP cycle. By binding to the catalytic site, SOS1 inhibitors can block the binding of SOS1 to RAS protein and reduce the level of RAS-GTP. Such inhibitors can effectively reduce the abnormal activation of RAS downstream signaling pathways (such as ERK phosphorylation) in cancer cells, thereby playing a role in the treatment of cancer. At present, only BI-1701963 (WO2018115380, WO2019122129) developed by Boehringer Ingelheim, a small molecule inhibitor of SOS1, has entered phase I clinical trials. In recent years, studies have suggested that since the inhibition of ERK phosphorylation will negatively activate the upstream RAS pathway, drugs in the RAS pathway are prone to drug resistance in clinical application, and this negative feedback regulation mechanism is closely related to SOS1. Therefore, the development of small molecule inhibitors of SOS1 has broad application prospects.

AMG-510是安进公司开发的一种有效的，口服生物可利用的，选择性的KRAS G12C共价抑制剂，用于治疗携带KRAS G12C突变的局部晚期或转移性非小细胞肺癌。其结构如下所示：AMG-510 is a potent, orally bioavailable, selective KRAS G12C covalent inhibitor developed by Amgen for the treatment of locally advanced or metastatic non-small cell lung cancer harboring a KRAS G12C mutation. Its structure is as follows:

发明内容Contents of the invention

本发明提供了式(X)所示化合物或其药学上可接受的盐，The present invention provides a compound represented by formula (X) or a pharmaceutically acceptable salt thereof,

其中，in,

R ₁₁、R ₁₂与它们相连的碳原子一起形成环A，其中环A选自

R ₁₁ , R ₁₂ form ring A together with the carbon atoms they are connected to, wherein ring A is selected from

E选自-(CH ₂CH ₂O) _m-； E is selected from -(CH ₂ CH ₂ O) _m -;

E ₁选自-(CR ₈R ₉) _n-； E ₁ is selected from -(CR ₈ R ₉ ) _n -;

E ₂选自-(CH ₂CH ₂O) _t-； E ₂ is selected from -(CH ₂ CH ₂ O) _t -;

R ₁选自H、F、Cl、Br、I、-OH、-NH ₂和-CN； R ₁ is selected from H, F, Cl, Br, I, -OH, -NH ₂ and -CN;

R ₂选自H、F、Cl、Br、I、-OH、-NH ₂、-CN和C _1-4烷基，其中所述C _1-4烷基任选被1、2或3个R _a取代； R ₂ is selected from H, F, Cl, Br, I, -OH, -NH ₂ , -CN and C _1-4 alkyl, wherein the C _1-4 alkyl is optionally replaced by 1, 2 or 3 R _a replaces;

R ₃选自H、F、Cl、Br、I、-OH、-NH ₂、-CN和C _1-4烷基，其中所述C _1-4烷基任选被1、2或3个R _b取代； R ₃ is selected from H, F, Cl, Br, I, -OH, -NH ₂ , -CN and C _1-4 alkyl, wherein the C _1-4 alkyl is optionally replaced by 1, 2 or 3 R _b replaces;

R ₄选自H和CH ₃； R ₄ is selected from H and CH ₃ ;

R ₅和R ₆分别独立地选自H、F、Cl、Br、I和-CN； R ₅ and R ₆ are independently selected from H, F, Cl, Br, I and -CN;

R ₇选自H、C _1-4烷基、C _3-8环烷基、3-8元杂环烷基、-CH ₂-C _3-8环烷基和-CH ₂-3-8元杂环烷基，其中所述C _1- ₄烷基、C _3-8环烷基、3-8元杂环烷基、-CH ₂-C _3-8环烷基和-CH ₂-3-8元杂环烷基分别独立地任选被1、2、3或4个R _c取代； R ₇ is selected from H, C _1-4 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocycloalkyl, -CH ₂ -C _3-8 cycloalkyl and -CH ₂ -3-8 membered Heterocycloalkyl, wherein the C _1-4 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocycloalkyl, -CH ₂ _-C _3-8 cycloalkyl and -CH ₂ -3- The 8-membered heterocycloalkyl group is independently optionally substituted by 1, 2, 3 or 4 R _c ;

各R ₈和R ₉分别独立地选自H、F、Cl、Br、I、-OH、-NH ₂、-CN、C _1-4烷基、C _1-4烷氧基、C _1-4烷氨基和-C(＝O)NR _fR _g，其中所述C _1-4烷基、C _1-4烷氧基和C _1-4烷氨基分别独立地任选被1、2或3个R _d取代； Each R ₈ and R ₉ are independently selected from H, F, Cl, Br, I, -OH, -NH ₂ , -CN, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 Alkylamino and -C(=O)NR _f R _g , wherein the C _1-4 alkyl, C _1-4 alkoxy and C _1-4 alkylamino are independently optionally replaced by 1, 2 or 3 _Rd replaces;

或者，R ₈、R ₉和与它们相连的碳原子一起形成

C _3-6环烷基或3-7元杂环烷基，其中所述C _3-6环烷基和3-7元杂环烷基分别独立地任选被1、2、3或4个R _e取代； Alternatively, R ₈ , R ₉ and the carbon atom to which they are attached together form

C _3-6 cycloalkyl or 3-7 membered heterocycloalkyl, wherein said C _3-6 cycloalkyl and 3-7 membered heterocycloalkyl are independently optionally replaced by 1, 2, 3 or 4 R _e replaces;

或者，R ₆、R ₁₁与它们相连的碳原子一起形成环B，其中环B选自

Or, R ₆ , R ₁₁ together with the carbon atoms they are attached to form ring B, wherein ring B is selected from

各R ₁₃分别独立地选自H、F、Cl、Br、I、-OH、-NH ₂、-CN、C _1-4烷基、C _1-4烷氧基和C _1-4烷氨基，其中所述C _1-4烷基、C _1-4烷氧基和C _1-4烷氨基分别独立地任选被1、2或3个R _h取代； Each R ₁₃ is independently selected from H, F, Cl, Br, I, -OH, -NH ₂ , -CN, C _1-4 alkyl, C _1-4 alkoxy and C _1-4 alkylamino, Wherein said C _1-4 alkyl, C _1-4 alkoxy and C _1-4 alkylamino are independently optionally substituted by 1, 2 or 3 _Rh ;

各R _a分别独立地选自F、Cl、Br、I、-OH、-NH ₂和-CN； Each _Ra is independently selected from F, Cl, Br, I, -OH, -NH ₂ and -CN;

各R _b分别独立地选自F、Cl、Br、I、-OH、-NH ₂和-CN； Each R _b is independently selected from F, Cl, Br, I, -OH, -NH ₂ and -CN;

各R _c分别独立地选自F、Cl、Br、I、-OH、-NH ₂、-CN、-OCH ₃、-N(CH ₃) ₂和C _1-4烷基； Each R _c is independently selected from F, Cl, Br, I, -OH, -NH ₂ , -CN, -OCH ₃ , -N(CH ₃ ) ₂ and C _1-4 alkyl;

各R _d分别独立地选自D、F、Cl、Br、I、-OH、-NH ₂、-CN、-CH ₃和-OCH ₃； Each R _d is independently selected from D, F, Cl, Br, I, -OH, -NH ₂ , -CN, -CH ₃ and -OCH ₃ ;

各R _e分别独立地选自F、Cl、Br、I、-OH、-NH ₂、-CN、-CH ₃和-OCH ₃； Each _Re is independently selected from F, Cl, Br, I, -OH, -NH ₂ , -CN, -CH ₃ and -OCH ₃ ;

R _f和R _g分别独立地选自H、C _1-4烷基和5-7元杂环烷基，其中C _1-4烷基和5-7元杂环烷基分别独立地任选被1、2、3或4个R _aa取代； R _f and R _g are independently selected from H, C _1-4 alkyl and 5-7 membered heterocycloalkyl, wherein C _1-4 alkyl and 5-7 membered heterocycloalkyl are independently optionally 1, 2, 3 or 4 R _aa substitutions;

或者，R _f、R _g和与它们相连的氮原子一起形成5-7元杂环烷基，其中所述5-7元杂环烷基任选被1、2、3或4个R _ab取代； Alternatively, R _f , R _g and the nitrogen atoms attached to them together form a 5-7 membered heterocycloalkyl group, wherein the 5-7 membered heterocycloalkyl group is optionally substituted by 1, 2, 3 or 4 _Rab ;

各R _h分别独立地选自F、Cl、Br、I、-OH、-NH ₂和-CN； Each _Rh is independently selected from F, Cl, Br, I, -OH, -NH ₂ and -CN;

各R _aa分别独立地选自F、Cl、Br、I、-OH、-NH ₂和-CN； Each R _aa is independently selected from F, Cl, Br, I, -OH, -NH ₂ and -CN;

各R _ab分别独立地选自F、Cl、Br、I、-OH、-NH ₂、-CN和C _1-4烷基； Each R _ab is independently selected from F, Cl, Br, I, -OH, -NH ₂ , -CN and C _1-4 alkyl;

m选自0、1或2；m is selected from 0, 1 or 2;

n选自2、3、4或5；n is selected from 2, 3, 4 or 5;

t选自0、1或2；t is selected from 0, 1 or 2;

所述3-8元杂环烷基、3-7元杂环烷基、-CH ₂-3-8元杂环烷基和5-7元杂环烷基中的“杂”表示1、2、3或4个分别独立地选自-O-、-NH-、-S-和-N-的杂原子或杂原子团。 The "hetero" in the 3-8 membered heterocycloalkyl, 3-7 membered heterocycloalkyl, -CH ₂ -3-8 membered heterocycloalkyl and 5-7 membered heterocycloalkyl means 1, 2 , 3 or 4 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -S- and -N-.

本发明提供了式(I)所示化合物或其药学上可接受的盐，The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

其中，in,

环A选自

Ring A is selected from

E选自-(CH ₂CH ₂O) _m-； E is selected from -(CH ₂ CH ₂ O) _m -;

E ₁选自-(CR ₈R ₉) _n-； E ₁ is selected from -(CR ₈ R ₉ ) _n -;

R ₄选自H和CH ₃； R ₄ is selected from H and CH ₃ ;

或者，R ₈、R ₉和与它们相连的碳原子一起形成

m选自0、1或2；m is selected from 0, 1 or 2;

n选自2、3、4或5；n is selected from 2, 3, 4 or 5;

t选自0、1或2；t is selected from 0, 1 or 2;

其中，in,

环A选自

Ring A is selected from

E选自-(CH ₂CH ₂O) _m-； E is selected from -(CH ₂ CH ₂ O) _m -;

E ₁选自-(CR ₈R ₉) _n-； E ₁ is selected from -(CR ₈ R ₉ ) _n -;

R ₄选自H和CH ₃； R ₄ is selected from H and CH ₃ ;

各R ₇选自H、C _1-4烷基、C _3-8环烷基、3-8元杂环烷基、-CH ₂-C _3-8环烷基和-CH ₂-3-8元杂环烷基，其中所述C _1-4烷基、C _3-8环烷基、3-8元杂环烷基、-CH ₂-C _3-8环烷基和-CH ₂-3-8元杂环烷基分别独立地任选被1、2、3或4个R _c取代； Each R ₇ is selected from H, C _1-4 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocycloalkyl, -CH ₂ -C _3-8 cycloalkyl and -CH ₂ -3-8 membered heterocycloalkyl, wherein the C _1-4 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocycloalkyl, -CH ₂ -C _3-8 cycloalkyl and -CH ₂ -3 -8-membered heterocycloalkyl is independently optionally substituted by 1, 2, 3 or 4 R _c ;

或者，R ₈、R ₉和与它们相连的碳原子一起形成

C _4-6环烷基或5-7元杂环烷基，其中所述C _4-6环烷基和5-7元杂环烷基分别独立地任选被1、2、3或4个R _e取代； Alternatively, R ₈ , R ₉ and the carbon atom to which they are attached together form

C _4-6 cycloalkyl or 5-7 membered heterocycloalkyl, wherein said C _4-6 cycloalkyl and 5-7 membered heterocycloalkyl are independently optionally replaced by 1, 2, 3 or 4 R _e replaces;

各R _d分别独立地选自D、F、Cl、Br、I、-OH、-NH ₂和-CN； Each R is independently selected from _D , F, Cl, Br, I, -OH, -NH ₂ and -CN;

各R _e分别独立地选自F、Cl、Br、I、-OH、-NH ₂和-CN； Each _Re is independently selected from F, Cl, Br, I, -OH, -NH ₂ and -CN;

m选自0、1或2；m is selected from 0, 1 or 2;

n选自2、3、4或5；n is selected from 2, 3, 4 or 5;

t选自0、1或2；t is selected from 0, 1 or 2;

所述3-8元杂环烷基、-CH ₂-3-8元杂环烷基和5-7元杂环烷基中的“杂”表示1、2、3或4个分别独立地选自-O-、-NH-、-S-和-N-的杂原子或杂原子团。 "Hetero" in the 3-8 membered heterocycloalkyl, -CH ₂ -3-8 membered heterocycloalkyl and 5-7 membered heterocycloalkyl means 1, 2, 3 or 4 independently selected A heteroatom or heteroatom group from -O-, -NH-, -S-, and -N-.

其中，in,

环A选自

Ring A is selected from

E选自-(CH ₂CH ₂O) _m-； E is selected from -(CH ₂ CH ₂ O) _m -;

E ₁选自-(CR ₈R ₉) _n-； E ₁ is selected from -(CR ₈ R ₉ ) _n -;

R ₄选自H和CH ₃； R ₄ is selected from H and CH ₃ ;

或者，各R ₈、R ₉和与它们相连的碳原子一起形成

C _4-6环烷基或5-7元杂环烷基，其中所述C _4-6环烷基和5-7元杂环烷基分别独立地任选被1、2、3或4个R _e取代； Alternatively, each R ₈ , R ₉ and the carbon atom to which they are attached together form

各R _d分别独立地选自F、Cl、Br、I、-OH、-NH ₂和-CN； Each R _is independently selected from F, Cl, Br, I, -OH, -NH ₂ and -CN;

m选自0、1或2；m is selected from 0, 1 or 2;

n选自2、3、4或5；n is selected from 2, 3, 4 or 5;

t选自0、1或2；t is selected from 0, 1 or 2;

其中，in,

环A选自

Ring A is selected from

R ₄选自H和CH ₃； R ₄ is selected from H and CH ₃ ;

或者，R ₈、R ₉和与它们相连的碳原子一起形成C _4-6环烷基或5-7元杂环烷基，其中所述C _4-6环烷基和5-7元杂环烷基分别独立地任选被1、2、3或4个R _e取代； Alternatively, R ₈ , R ₉ and the carbon atoms connected to them together form a C _4-6 cycloalkyl group or a 5-7 membered heterocycloalkyl group, wherein the C _4-6 cycloalkyl group and the 5-7 membered heterocycle group are Alkyl groups are independently optionally substituted by 1, 2, 3 or 4 _Re ;

其中，in,

环A选自

Ring A is selected from

R ₄选自H和CH ₃； R ₄ is selected from H and CH ₃ ;

各R ₇选自H、C _1-4烷基和-CH ₂-5-7元杂环烷基，其中所述C _1-4烷基和-CH ₂-5-7元杂环烷基分别独立地任选被1、2、3或4个R _c取代； Each R ₇ is selected from H, C _1-4 alkyl and -CH ₂ -5-7 membered heterocycloalkyl, wherein said C _1-4 alkyl and -CH ₂ -5-7 membered heterocycloalkyl are respectively independently optionally substituted with 1, 2, 3 or 4 _Rc ;

各R ₈和R ₉分别独立地选自H、F、Cl、Br、I、-OH、-NH ₂、-CN、C _1-4烷基、C _1-4烷氧基、C _1-4烷氨基和-C(＝O)NR _f(R _g)，其中所述C _1-4烷基、C _1-4烷氧基和C _1-4烷氨基分别独立地任选被1、2或3个R _d取代； Each R ₈ and R ₉ are independently selected from H, F, Cl, Br, I, -OH, -NH ₂ , -CN, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 Alkylamino and -C(=O)NR _f (R _g ), wherein the C _1-4 alkyl, C _1-4 alkoxy and C _1-4 alkylamino are independently optionally replaced by 1, 2 or 3 _Rd substitutions;

各R _c分别独立地选自F、Cl、Br、I、-OH、-NH ₂、-CN、-OCH ₃和-N(CH ₃) ₂； Each R _c is independently selected from F, Cl, Br, I, -OH, -NH ₂ , -CN, -OCH ₃ and -N(CH ₃ ) ₂ ;

或者，R _f、R _g和与它们相连的氮原子一起形成5-7元杂环烷基，其中所述5-7元杂环烷基任选被1、2、3或4个R _ab取代； Alternatively, R _f , R _g and the nitrogen atom attached to them together form a 5-7 membered heterocycloalkyl, wherein the 5-7 membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 _Rab ;

所述-CH ₂-5-7元杂环烷基和5-7元杂环烷基中的“杂”表示1、2、3或4个分别独立地选自-O-、-NH-、-S-和-N-的杂原子或杂原子团。 The "hetero" in the -CH ₂ -5-7 membered heterocycloalkyl and 5-7 membered heterocycloalkyl means 1, 2, 3 or 4 are independently selected from -O-, -NH-, Heteroatoms or heteroatom groups of -S- and -N-.

在本发明的一些方案中，上述化合物具有式(Ⅹ-1)和(Ⅹ-2)所示结构：In some schemes of the present invention, the above-mentioned compounds have structures shown in formulas (X-1) and (X-2):

其中，R ₁、R ₂、R ₃、R ₄、R ₅、R ₆、R ₁₁和R ₁₂如本发明所定义。 Wherein, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₁₁ and R ₁₂ are as defined in the present invention.

在本发明的一些方案中，上述化合物具有式(I-1)和(I-2)所示结构：In some schemes of the present invention, the above-mentioned compounds have structures shown in formulas (I-1) and (I-2):

其中，环A、R ₁、R ₂、R ₃、R ₄、R ₅和R ₆如本发明所定义。 Wherein, ring A, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are as defined in the present invention.

本发明的一些方案中，上述各R _a分别独立地选自F和-OH，其他变量如本发明所定义。 In some solutions of the present invention, each R _a above is independently selected from F and -OH, and other variables are as defined in the present invention.

本发明的一些方案中，上述各R _c分别独立地选自F、Cl、Br、-CH ₃、-OCH ₃和-N(CH ₃) ₂，其他变量如本发明所定义。 In some solutions of the present invention, each R _c mentioned above is independently selected from F, Cl, Br, -CH ₃ , -OCH ₃ and -N(CH ₃ ) ₂ , and other variables are as defined in the present invention.

本发明的一些方案中，上述各R _c分别独立地选自-OCH ₃和-N(CH ₃) ₂，其他变量如本发明所定义。 In some solutions of the present invention, each R _c mentioned above is independently selected from -OCH ₃ and -N(CH ₃ ) ₂ , and other variables are as defined in the present invention.

本发明的一些方案中，上述各R _d分别独立地选自-OCH ₃，其他变量如本发明所定义。 In some solutions of the present invention, each R _d above is independently selected from -OCH ₃ , and other variables are as defined in the present invention.

本发明的一些方案中，上述各R _aa、R _b、R _d和R _e分别独立地选自F，其他变量如本发明所定义。 In some solutions of the present invention, each of the above-mentioned R _aa , R _b , R _d and _Re is independently selected from F, and other variables are as defined in the present invention.

本发明的一些方案中，上述各R _ab分别独立地选自-CH ₃，其他变量如本发明所定义。 In some solutions of the present invention, each _Rab mentioned above is independently selected from -CH ₃ , and other variables are as defined in the present invention.

本发明的一些方案中，上述R _f和R _g分别独立地选自H、-CH ₃和

其他变量如本发明所定义。 In some schemes of the present invention, above-mentioned R _f and R _g are independently selected from H, -CH ₃ and

Other variables are as defined herein.

本发明的一些方案中，上述R _f、R _g和与它们相连的氮原子一起形成

其中所述

分别独立地任选被1、2、3或4个R _ab取代，R _ab及其他变量如本发明所定义。 In some schemes of the present invention, the above-mentioned R _f , R _g and the nitrogen atoms connected to them together form

which stated

are independently and optionally substituted by 1, 2, 3 or 4 _{Rabs, and Rab} _and other variables are as defined in the present invention.

其他变量如本发明所定义。 In some schemes of the present invention, the above-mentioned R _f , R _g and the nitrogen atoms connected to them together form

Other variables are as defined herein.

本发明的一些方案中，上述R ₁选自H、-NH ₂和-CN，其他变量如本发明所定义。 In some solutions of the present invention, the above-mentioned R ₁ is selected from H, -NH ₂ and -CN, and other variables are as defined in the present invention.

本发明的一些方案中，上述R ₁选自H和-NH ₂，其他变量如本发明所定义。 In some solutions of the present invention, the above-mentioned R ₁ is selected from H and -NH ₂ , and other variables are as defined in the present invention.

本发明的一些方案中，上述R ₂选自H、F、-CN、-CH ₃、-CH ₂CH ₃和-CH ₂CH(CH ₃) ₂，其中所述-CH ₃、-CH ₂CH ₃和-CH ₂CH(CH ₃) ₂分别独立地任选被1、2、或3个R _a取代，R _a及其他变量如本发明所定义。 In some solutions of the present invention, the above-mentioned R ₂ is selected from H, F, -CN, -CH ₃ , -CH ₂ CH ₃ and -CH ₂ CH(CH ₃ ) ₂ , wherein -CH ₃ , -CH ₂ CH ₃ and -CH ₂ CH(CH ₃ ) ₂ are each independently optionally substituted by 1, 2, or 3 R _a , and R _a and other variables are as defined in the present invention.

本发明的一些方案中，上述R ₂选自H、F、-CN、、

R _a及其他变量如本发明所定义。 In some solutions of the present invention, the above-mentioned R ₂ is selected from H, F, -CN,,

_Ra and other variables are as defined herein.

本发明的一些方案中，上述R ₂选自H、F、-CN、-CHF ₂、-CF ₃、

其他变量如本发明所定义。 In some solutions of the present invention, the above-mentioned R ₂ is selected from H, F, -CN, -CHF ₂ , -CF ₃ ,

Other variables are as defined herein.

本发明的一些方案中，上述R ₃选自H、F和-CH ₃，其他变量如本发明所定义。 In some solutions of the present invention, the above-mentioned R ₃ is selected from H, F and -CH ₃ , and other variables are as defined in the present invention.

本发明的一些方案中，上述R ₄选自-CH ₃，其他变量如本发明所定义。 In some solutions of the present invention, the above R ₄ is selected from -CH ₃ , and other variables are as defined in the present invention.

本发明的一些方案中，上述R ₅和R ₆分别独立地选自H和F，其他变量如本发明所定义。 In some solutions of the present invention, the above-mentioned R ₅ and R ₆ are independently selected from H and F, and other variables are as defined in the present invention.

本发明的一些方案中，上述R ₅和R ₆分别独立地选自H，其他变量如本发明所定义。 In some solutions of the present invention, the above-mentioned R ₅ and R ₆ are independently selected from H, and other variables are as defined in the present invention.

本发明的一些方案中，上述各R ₇选自H、-CH ₃、-CH ₂CH ₃、

其中所述-CH ₃、-CH ₂CH ₃、

分别独立地任选被1、2、3或4个R _c取代，R _c及其他变量如本发明所定义。 In some schemes of the present invention, each R ₇ above is selected from H, -CH ₃ , -CH ₂ CH ₃ ,

Wherein -CH ₃ , -CH ₂ CH ₃ ,

are independently and optionally substituted by 1, 2, 3 or 4 R _c , R _c and other variables are as defined in the present invention.

其中所述-CH ₃、-CH ₂CH ₃、

Wherein -CH ₃ , -CH ₂ CH ₃ ,

其中所述-CH ₃、-CH ₂CH ₃、

Wherein -CH ₃ , -CH ₂ CH ₃ ,

本发明的一些方案中，上述各R ₇选自H、-CH ₃、-CH ₂CH ₃和

其中所述-CH ₃、-CH ₂CH ₃和

分别独立地任选被1、2、3或4个R _c取代，R _c及其他变量如本发明所定义。 In some solutions of the present invention, each R ₇ above is selected from H, -CH ₃ , -CH ₂ CH ₃ and

Wherein -CH ₃ , -CH ₂ CH ₃ and

本发明的一些方案中，上述各R ₇选自H、-CH ₃、-CH ₂CH ₃、-CH ₂CF ₃、-CH ₂CH ₂OCH ₃、-CH ₂CH ₂N(CH ₃) ₂、

其他变量如本发明所定义。 In some solutions of the present invention, each R ₇ above is selected from H, -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CF ₃ , -CH ₂ CH ₂ OCH ₃ , -CH ₂ CH ₂ N(CH ₃ ) ₂ ,

Other variables are as defined herein.

Other variables are as defined herein.

Other variables are as defined herein.

本发明的一些方案中，上述各R ₇选自H、-CH ₃、-CH ₂CH ₂OCH ₃、-CH ₂CH ₂N(CH ₃) ₂和

其他变量如本发明所定义。 In some schemes of the present invention, each R ₇ above is selected from H, -CH ₃ , -CH ₂ CH ₂ OCH ₃ , -CH ₂ CH ₂ N(CH ₃ ) ₂ and

Other variables are as defined herein.

本发明的一些方案中，上述各R ₈和R ₉分别独立地选自H、F、-CH ₃、-OCH ₃、-CH ₂CH ₃、

其中所述-CH ₃、-OCH ₃和-CH ₂CH ₃分别独立地任选被1、2或3个R _d取代，R _d及其他变量如本发明所定义。 In some solutions of the present invention, each of the above-mentioned R ₈ and R ₉ is independently selected from H, F, -CH ₃ , -OCH ₃ , -CH ₂ CH ₃ ,

Wherein said -CH ₃ , -OCH ₃ and -CH ₂ CH ₃ are independently optionally substituted by 1, 2 or 3 R _d , R _d and other variables are as defined in the present invention.

本发明的一些方案中，上述各R ₈和R ₉分别独立地选自H、F、-CH ₃、-OCH ₃、-CH ₂CH ₂OCH ₃、

其他变量如本发明所定义。 In some solutions of the present invention, each of the above-mentioned R ₈ and R ₉ is independently selected from H, F, -CH ₃ , -OCH ₃ , -CH ₂ CH ₂ OCH ₃ ,

Other variables are as defined herein.

本发明的一些方案中，上述各R ₈和R ₉分别独立地选自H、-CH ₃、-OCH ₃、

其他变量如本发明所定义。 In some solutions of the present invention, each of the above-mentioned R ₈ and R ₉ is independently selected from H, -CH ₃ , -OCH ₃ ,

Other variables are as defined herein.

本发明的一些方案中，上述各R ₈分别独立地选自H、-CH ₃、-OCH ₃、

其他变量如本发明所定义。 In some solutions of the present invention, each R ₈ above is independently selected from H, -CH ₃ , -OCH ₃ ,

Other variables are as defined herein.

本发明的一些方案中，上述各R ₉分别独立地选自H和-CH ₃，其他变量如本发明所定义。 In some solutions of the present invention, each R ₉ above is independently selected from H and -CH ₃ , and other variables are as defined in the present invention.

本发明的一些方案中，上述R ₈、R ₉和与它们相连的碳原子一起形成

其中所述

分别独立地任选被1、2、3或4个R _e取代，R _e及其他变量如本发明所定义。 In some schemes of the present invention, the above-mentioned R ₈ , R ₉ and the carbon atoms connected to them together form

which stated

are independently optionally substituted by 1, 2, 3 or 4 _Re , _Re and other variables are as defined in the present invention.

其中所述

which stated

其中所述

which stated

其他变量如本发明所定义。 In some schemes of the present invention, the above-mentioned R ₈ , R ₉ and the carbon atoms connected to them together form

Other variables are as defined herein.

Other variables are as defined herein.

Other variables are as defined herein.

本发明的一些方案中，上述各R ₁₃分别独立地选自H和-CH ₃，其他变量如本发明所定义。 In some solutions of the present invention, each R ₁₃ above is independently selected from H and -CH ₃ , and other variables are as defined in the present invention.

本发明的一些方案中，上述结构单元

选自

R ₈、R ₉及其他变量如本发明所定义。 In some solutions of the present invention, the above structural units

selected from

R ₈ , R ₉ and other variables are as defined herein.

本发明的一些方案中，上述环A选自

其他变量如本发明所定义。 In some schemes of the present invention, the above-mentioned ring A is selected from

Other variables are as defined herein.

本发明的一些方案中，上述环A选自

Other variables are as defined herein.

本发明的一些方案中，上述环A选自

Other variables are as defined herein.

本发明的一些方案中，上述环A选自

Other variables are as defined herein.

本发明的一些方案中，上述环A选自

Other variables are as defined herein.

本发明的一些方案中，上述环A选自

Other variables are as defined herein.

本发明的一些方案中，上述环B选自

其他变量如本发明所定义。 In some schemes of the present invention, the above ring B is selected from

Other variables are as defined herein.

在本发明的一些方案中，上述化合物具有式(X-3)、(X-4)、(X-5)、(X-6)、(X-7)、(X-8)或(X-9)所示结构：In some aspects of the present invention, the above compound has the formula (X-3), (X-4), (X-5), (X-6), (X-7), (X-8) or (X -9) The structure shown:

其中，R ₁、R ₂、R ₃、R ₄、R ₇、R ₈、R ₉和R ₁₃如本发明所定义。 Wherein, R ₁ , R ₂ , R ₃ , R ₄ , R ₇ , R ₈ , R ₉ and R ₁₃ are as defined in the present invention.

在本发明的一些方案中，上述化合物具有式(X-3A)、(X-3B)、(X-4A)、(X-4B)、(X-5A)、(X-5B)、(X-6A)、(X-6B)、(X-7A)、(X-7B)、(X-8A)、(X-8B)、(X-9A)或(X-9B)所示结构：In some aspects of the present invention, the compounds described above have the formula (X-3A), (X-3B), (X-4A), (X-4B), (X-5A), (X-5B), (X -6A), (X-6B), (X-7A), (X-7B), (X-8A), (X-8B), (X-9A) or (X-9B):

本发明还有一些方案是由上述各变量任意组合而来。Some schemes of the present invention are formed by any combination of the above-mentioned variables.

本发明还提供了下式化合物或其药学上可接受的盐，The present invention also provides a compound of the following formula or a pharmaceutically acceptable salt thereof,

本发明还提供了上述化合物或其药学上可接受的盐在制备治疗KRAS突变实体瘤药物中的应用。The present invention also provides the use of the above compound or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating KRAS mutant solid tumors.

本申请还提供了一种在需要的受试者中治疗KRAS突变实体瘤的方法，包括向受试者提供有效剂量的上述化合物或其药学上可接受的盐。The present application also provides a method for treating KRAS mutant solid tumors in a subject in need, comprising providing the subject with an effective dose of the above-mentioned compound or a pharmaceutically acceptable salt thereof.

本发明还提供了上述化合物的合成实验方案：The present invention also provides the synthetic experimental scheme of above-mentioned compound:

中间体的合成：Synthesis of intermediates:

合成路线方案1：Synthetic Route Scheme 1:

或者：or:

合成路线方案2：Synthetic route scheme 2:

或者：or:

合成路线方案3：Synthetic route scheme 3:

或者：or:

合成路线方案4：Synthetic route scheme 4:

或者：or:

合成路线方案5：Synthetic route scheme 5:

或者：or:

合成路线方案6：Synthetic route scheme 6:

其中，X为卤素；Wherein, X is a halogen;

R’为C _1-6烷基； R' is C _1-6 alkyl;

R"和R'"分别独立选自H、C _1-6烷基和5-7元杂环烷基，其中C _1-6烷基和5-7元杂环烷基分别独立地任选被1、2、3或4个R _aa取代； R" and R'" are independently selected from H, C _1-6 alkyl and 5-7 membered heterocycloalkyl, wherein C _1-6 alkyl and 5-7 membered heterocycloalkyl are independently optionally 1, 2, 3 or 4 R _aa substitutions;

或者，R"、R'"和与它们相连的氮原子一起形成C _4-6环烷基或5-7元杂环烷基，其中所述C _4-6环烷基和5-7元杂环烷基分别独立地任选被1、2、3或4个R _e取代； Alternatively, R", R'" and the nitrogen atoms connected to them together form a C _4-6 cycloalkyl group or a 5-7 membered heterocycloalkyl group, wherein the C _4-6 cycloalkyl group and the 5-7 membered heterocycloalkyl group are Cycloalkyl is independently optionally substituted by 1, 2, 3 or 4 _Re ;

R ₁、R ₂、R ₃、R ₄、R ₅、R ₆、R ₇、R ₈、R ₉、R _aa和R _e如本发明所定义。 R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R _aa and _Re are as defined in the present invention.

本发明还提供了上述化合物的生物实验测试方法：The present invention also provides the biological experiment testing method of above-mentioned compound:

实验测试方法1：H358细胞3D增殖抑制活性测试Experimental test method 1: 3D proliferation inhibitory activity test of H358 cells

实验原理：Experimental principle:

KRAS(G12C)突变的H358细胞中,KRAS信号通路异常激活。小分子SOS1抑制剂通过抑制SOS1与RAS蛋白的结合,降低其GEF活性,减少激活状态RAS-GTP的比例。进一步下调RAS下游的MEK/ERK通路的磷酸化水平,达到抑制细胞增殖的效果。将小分子与H358细胞在3D空间内共培养,然后通过细胞读数,间接反映SOS1抑制剂对H358细胞的增殖抑制活性。In H358 cells with KRAS(G12C) mutation, the KRAS signaling pathway was abnormally activated. Small molecule SOS1 inhibitors inhibit the combination of SOS1 and RAS protein, reduce its GEF activity, and reduce the ratio of activated RAS-GTP. Further down-regulate the phosphorylation level of MEK/ERK pathway downstream of RAS to achieve the effect of inhibiting cell proliferation. Small molecules were co-cultured with H358 cells in a 3D space, and then the cells were read out to indirectly reflect the proliferation inhibitory activity of SOS1 inhibitors on H358 cells.

实验材料：Experimental Materials:

RPMI1640培养基,胎牛血清,盘尼西林/链霉素抗生素购自维森特,低熔点琼脂糖购自Sigma。Almar blue试剂购自Invitrogen。NCI-H358细胞系购自南京科佰生物科技有限公司。Nivo多标记分析仪(PerkinElmer)。RPMI1640 medium, fetal bovine serum, penicillin/streptomycin antibiotics were purchased from Vicente, and low-melting point agarose was purchased from Sigma. Almar blue reagent was purchased from Invitrogen. NCI-H358 cell line was purchased from Nanjing Kebai Biotechnology Co., Ltd. Nivo Multilabel Analyzer (PerkinElmer).

实验方法：experimental method:

将H358细胞种于96孔U型板中,先将低熔点琼脂糖配成2％的母液,使用时先将琼脂糖母液在微波炉中加热使其完全融化,之后至于42℃水浴锅中使琼脂糖保持液体状态。将凝胶加入含血清的培养基中配成凝胶浓度为0.6％作为底层胶,按照每孔50μL铺到96孔U型板中。待底层胶凝固后,再将2％凝胶加入到含细胞的培养基中,配成凝胶浓度为0.4％的含细胞的上层胶,细胞密度为4×10 ⁴细胞/毫升,按照每孔75μl加到铺有底层胶的96孔U型板中,细胞密度为3000个每孔。待上层胶凝固后细胞板置于二氧化碳培养箱中过夜培养。 Plant H358 cells in a 96-well U-shaped plate, first make a 2% mother solution of low-melting point agarose, heat the agarose mother solution in a microwave oven to completely melt it, and then put the agarose in a 42°C water bath Sugar remains in a liquid state. Add the gel into the serum-containing medium to prepare a gel concentration of 0.6% as the bottom layer gel, and spread it into a 96-well U-shaped plate according to 50 μL per well. After the bottom gel is solidified, add 2% gel to the cell-containing medium to prepare a cell-containing upper gel with a gel concentration of 0.4%, and a cell density of ⁴ ×104 cells/ml. 75μl was added to the 96-well U-plate covered with bottom glue, and the cell density was 3000 cells per well. After the supernatant gel was solidified, the cell plate was cultured overnight in a carbon dioxide incubator.

加化合物当天,在铺好细胞的96孔U型板中加入85μL液体培养基。将待测化合物用排枪进行3倍稀释至第9个浓度,即从6mM稀释至0.9μM，设置双复孔实验。向中间板中加入97μL培养基,再按照对应位置,转移2.5μL每孔的梯度稀释化合物至中间板,混匀后转移40μL每孔到细胞板中。转移到细胞板中的化合物浓度范围是30μM至4.5nM。细胞板置于二氧化碳培养箱中培养7天,第8天,将待测化合物用排枪进行3倍稀释至第九个浓度,即从6mM稀释至0.9μM,设置双复孔实验。像中间板中加入198μL培养基,再按照对应位置,转移2μL每孔的梯度稀释化合物至第一块中间板中,再向第二块中间板中加入100μL培养基,取第一块中间板中的混匀化合物100μL加入,混匀后转移40μL每孔到细胞板中。转移到细胞板中的化合物浓度范围是30μM至4.5nM。细胞板置于二氧化碳培养箱中再培养7天。化合物与细胞共孵育14天,向细胞板中加入每孔20μL的Almar blue检测试剂,将加染料的板子置于水平摇床上震荡15分钟,再将板子至于室温孵育至5小时使发光信号稳定。采用多标记分析仪读数。On the day of adding the compound, add 85 μL of liquid culture medium to the 96-well U-plate with cells laid out. The compound to be tested was diluted 3 times to the 9th concentration with a row gun, that is, diluted from 6mM to 0.9μM, and a double-well experiment was set up. Add 97 μL of medium to the middle plate, and transfer 2.5 μL of each well of the gradient dilution compound to the middle plate according to the corresponding position, transfer 40 μL of each well to the cell plate after mixing. Compound concentrations ranged from 30 [mu]M to 4.5 nM transferred to the cell plate. The cell plate was cultured in a carbon dioxide incubator for 7 days. On the 8th day, the compound to be tested was diluted 3 times to the ninth concentration with a row gun, that is, diluted from 6mM to 0.9μM, and a double-well experiment was set up. Add 198 μL medium to the middle plate, and then transfer 2 μL of each well of the gradient dilution compound to the first middle plate according to the corresponding position, then add 100 μL medium to the second middle plate, and take the first middle plate. Add 100 μL of the mixed compound, transfer 40 μL per well to the cell plate after mixing. Compound concentrations ranged from 30 [mu]M to 4.5 nM transferred to the cell plate. The cell plates were placed in a carbon dioxide incubator and cultured for another 7 days. The compound was co-incubated with the cells for 14 days, and 20 μL of Almar blue detection reagent per well was added to the cell plate, and the dyed plate was placed on a horizontal shaker for 15 minutes, and then the plate was incubated at room temperature for 5 hours to stabilize the luminescent 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 original data into inhibition rate, the value of _IC50 can be obtained by curve fitting with four parameters ("log(inhibitor) vs. response--Variable slope" mode).

技术效果technical effect

本发明化合物具有良好的KRAS(G12C)-SOS1结合抑制活性，以及对KRAS(G12C)突变的H358细胞和DLD-1细胞p-ERK增殖具有显著的抑制活性，进而获得了优良的抑制肿瘤生长的活性。The compound of the present invention has good KRAS(G12C)-SOS1 binding inhibitory activity, and has significant inhibitory activity on KRAS(G12C) mutated H358 cells and DLD-1 cell p-ERK proliferation, and then obtains excellent tumor growth inhibitory activity active.

定义和说明Definition and Description

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 stated, the following terms and phrases used herein are intended to have the following meanings. A specific term or phrase should not be considered indeterminate or unclear if it is not specifically defined, but should be understood according to its ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding trade name 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。The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and/or dosage forms, which are suitable for use in contact with human and animal tissues within the scope of sound medical judgment , without undue toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit/risk ratio.

术语“药学上可接受的盐”是指本发明化合物的盐，由本发明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。当本发明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。当本发明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。本发明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 salt" refers to a salt of a compound of the present invention, which is prepared from a compound having a specific substituent found in the present invention and a relatively non-toxic acid or base. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds with a sufficient amount of base, either neat solution or in a suitable inert solvent. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting such compounds with a sufficient amount of the acid, either neat solution or in a suitable inert solvent. Certain specific compounds of the present invention contain basic and acidic functional groups and can thus be converted into either base or acid addition salts.

本发明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 invention can be synthesized from the parent compound containing acid groups or bases by conventional chemical methods. In general, 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 both.

本发明的化合物可以存在特定的几何或立体异构体形式。本发明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发明的范围之内。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，均包括在本发明的范围之内。The compounds of the invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and their racemic and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are subject to the present within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.

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 stated, the terms "enantiomer" or "optical isomer" 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 stated, the terms "cis-trans isomers" or "geometric isomers" arise from the inability to rotate freely due to the double bond or the single bond of the carbon atoms forming the ring.

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 "diastereoisomer" refers to stereoisomers whose molecules have two or more chiral centers and which are not mirror images of the molecules.

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

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

和直形虚线键

Unless otherwise noted, keys with wedge-shaped solid lines

and dotted wedge keys

Indicates the absolute configuration of a stereocenter, with a straight solid-line bond

and straight dashed keys

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

Indicates wedge-shaped solid-line bond

or dotted wedge key

or with tilde

Indicates a straight solid line key

and straight dashed keys

本发明的化合物可以存在特定的。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。Compounds of the invention may exist specific. Unless otherwise stated, the term "tautomer" or "tautomeric form" means that isomers with different functional groups are in dynamic equilibrium at room temperature and are rapidly interconvertible. If tautomerism is possible (eg, in solution), then chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also called prototropic tautomers) include interconversions via migration of a proton, such as keto-enol isomerization and imine-ene Amine isomerization. Valence isomers (valence tautomers) involve interconversions by recombination of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between two tautomers of 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 stated, the terms "enriched in an isomer", "enriched in an isomer", "enriched in an enantiomer" or "enantiomerically enriched" refer to one of the isomers or enantiomers The content of the enantiomer is less than 100%, and the content of the isomer or enantiomer 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 stated, the terms "isomer excess" or "enantiomeric excess" refer to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the other isomer or enantiomer is 10%, then 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。如果想得到本发明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 one enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, wherein the resulting diastereomeric mixture 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 diastereoisomeric salt is formed with an appropriate optically active acid or base, and then a diastereomeric salt is formed by a conventional method known in the art. Diastereomeric resolution was performed and the pure enantiomers recovered. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally in combination with chemical derivatization methods (e.g. amines to amino groups formate).

本发明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。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。 The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds. For example, compounds may be labeled with radioactive isotopes such as tritium ( ³ H), iodine-125 ( ¹²⁵ I) or C-14 ( ¹⁴ C). For another example, heavy hydrogen can be used to replace hydrogen to form deuterated drugs. The bond formed by deuterium and carbon is stronger than the bond 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 changes in isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.

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 term "optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where said event or circumstance occurs and instances where said event or circumstance does not occur .

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，取代基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。氧取代不会发生在芳香基上。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. When a substituent is oxygen (ie =0), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups.

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 realizable 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 (eg, R) occurs more than once in the composition or structure of a compound, its definition is independent at each occurrence. Thus, for example, if a group is substituted with 0-2 R, said group may optionally be substituted with up to two R, with independent options for each occurrence of R. Also, combinations of substituents and/or variations thereof are permissible only if such combinations result in stable compounds.

当一个连接基团的数量为0时，比如-(CRR) ₀-，表示该连接基团为单键。 When the number of a linking group is 0, such as -(CRR) ₀ -, it means that the linking group is a single bond.

当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。When one of the variables is selected from a single bond, it means that the two groups connected are directly connected. For example, when L in A-L-Z represents a single bond, it means that the structure is actually A-Z.

当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。When a substituent is vacant, it means that the substituent does not exist. For example, when X in A-X is vacant, it means that the structure is actually A. When the enumerated substituent does not indicate which atom it is connected to the substituted group, this substituent can be bonded through any atom, for example, pyridyl as a substituent can be connected to any atom on the pyridine ring. The carbon atom is attached to the group being substituted.

当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，

中连接基团L为-M-W-，此时-M-W-既可以按与从左往右的读取顺序相同的方向连接环A和环B构成

也可以按照与从左往右的读取顺序相反的方向连接环A和环B构成

所述连接基团、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 the linking group listed does not indicate its linking direction, its linking direction is arbitrary, for example,

The connecting group L in the middle is -MW-, at this time -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form

It can also be formed by connecting loop A and loop B in the opposite direction to the reading order from left to right

Combinations of the described linking groups, substituents and/or variations thereof are permissible only if such combinations result in stable compounds.

当所列举的连接并环基团没有指明连接方向，其连接方向是任意的，例如，

中并环C为

此时

包含

两种结构片段。所述连接基团、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 the linking ring group is listed without specifying the linking direction, the linking direction is arbitrary, for example,

In the ring C is

at this time

Include

Two structural fragments. Combinations of the described linking groups, substituents and/or variations 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 linkable sites, any one or more sites of the group can be linked to other groups through chemical bonds. When the connection method of the chemical bond is not positioned, and there is an H atom at the connectable site, when the chemical bond is connected, the number of H atoms at the site will decrease correspondingly with the number of chemical bonds connected to become the corresponding valence group. The chemical bonds that the site connects with other groups can use straight solid line bonds

Straight dotted key

or tilde

express. For example, the straight-shaped solid-line bond in _-OCH3 indicates that it is connected to other groups through the oxygen atom in the group;

The straight dotted line bond in indicates that the two ends of the nitrogen atom in the group are connected to other groups;

The wavy lines in indicate that the 1 and 2 carbon atoms in the phenyl group are connected to other groups.

Indicates that any connectable 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 include

For groups with this connection method, only when a chemical bond is connected, the H at this site will be reduced by one to become the corresponding monovalent piperidinyl group.

除非另有规定，术语“C _1-4烷基”用于表示直链或支链的由1至4个碳原子组成的饱和碳氢基团。所述C _1-4烷基包括C _1-2、C _1-3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 _1-4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)等。 Unless otherwise specified, the term "C _1-4 alkyl" is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 4 carbon atoms. The C _1-4 alkyl group includes C _1-2 , C _1-3 and C _2-3 alkyl groups, etc.; it may be monovalent (such as methyl), divalent (such as methylene) or multivalent ( such as methine). Examples of C _1-4 alkyl groups 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) and so on.

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 group 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, etc.; it can be Is monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine). Examples of C _1-6 alkyl groups 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, etc.

除非另有规定，术语“C _1-4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4个碳原子的烷基基团。所述C _1-4烷氧基包括C _1-3、C _1-2、C _2-4、C ₄和C ₃烷氧基等。C _1-6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)、丁氧基(包括n-丁氧基、异丁氧基、s-丁氧基和t-丁氧基)、戊氧基(包括n-戊氧基、异戊氧基和新戊氧基)、己氧基等。 Unless otherwise specified, the term "C _1-4 alkoxy" denotes those alkyl groups containing 1 to 4 carbon atoms attached to the rest of the molecule through an oxygen atom. The C _1-4 alkoxy group includes C _1-3 , C _1-2 , C _2-4 , C ₄ and C ₃ alkoxy groups and the like. Examples of C _1-6 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, oxy, s-butoxy and t-butoxy), pentyloxy (including n-pentyloxy, isopentyloxy and neopentyloxy), hexyloxy and the like.

除非另有规定，术语“C _1-4烷氨基”表示通过氨基连接到分子的其余部分的那些包含1至4个碳原子的烷基基团。所述C _1-4烷氨基包括C _1-3、C _1-2、C _2-4、C ₄、C ₃和C ₂烷氨基等。C _1-4烷氨基的实例包括但不限于-NHCH ₃、-N(CH ₃) ₂、-NHCH ₂CH ₃、-N(CH ₃)CH ₂CH ₃、-N(CH ₂CH ₃)(CH ₂CH ₃)、-NHCH ₂CH ₂CH ₃、-NHCH ₂(CH ₃) ₂、-NHCH ₂CH ₂CH ₂CH ₃等。 Unless otherwise specified, the term "C _1-4 alkylamino" denotes those alkyl groups containing 1 to 4 carbon atoms attached to the rest of the molecule through an amino group. The C _1-4 alkylamino group includes C _1-3 , C _1-2 , C _2-4 , C ₄ , C ₃ and C ₂ alkylamino groups and the like. Examples of C _1-4 alkylamino include, but are not limited to, -NHCH ₃ , -N(CH ₃ ) ₂ , -NHCH ₂ CH ₃ , -N(CH ₃ )CH ₂ CH ₃ , -N(CH ₂ CH ₃ )( CH ₂ CH ₃ ), -NHCH ₂ CH ₂ CH ₃ , -NHCH ₂ (CH ₃ ) ₂ , -NHCH ₂ CH ₂ CH ₂ CH ₃ 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.

除非另有规定，“C _3-8环烷基”表示由3至8个碳原子组成的饱和环状碳氢基团，其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。所述C _3-8环烷基包括C _3-6、C _3-5、C _4-8、C _4-6、C _4-5、C _5-8或C _5-6环烷基等；其可以是一价、二价或者多价。C _3-8环烷基的实例包括，但不限于，环丙基、环丁基、环戊基、环己基、环庚基、降冰片烷基、、螺庚烷等。 Unless otherwise specified, "C _3-8 cycloalkyl" means a saturated cyclic hydrocarbon group composed of 3 to 8 carbon atoms, which includes monocyclic and bicyclic systems, wherein bicyclic systems include spiro rings, fused rings and bridge ring. The C _3-8 cycloalkyl group includes C _3-6 , C _3-5 , C _4-8 , C _4-6 , C _4-5 , C _5-8 or C _5-6 cycloalkyl group, etc.; Can be monovalent, divalent or polyvalent. Examples of C _3-8 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, spiroheptyl, and the like.

除非另有规定，“C _4-6环烷基”表示由4至6个碳原子组成的饱和环状碳氢基团，其为单环和双环体系，所述C _3-6环烷基包括C _4-5和C _5-6环烷基等；其可以是一价、二价或者多价。C _4-6环烷基的实例包括，但不限于，环丁基、环戊基、环己基等。 Unless otherwise specified, "C _4-6 cycloalkyl" means a saturated cyclic hydrocarbon group composed of 4 to 6 carbon atoms, which is a monocyclic and bicyclic ring system, and the C _3-6 cycloalkyl includes C _4-5 and C _5-6 cycloalkyl, etc.; it may be monovalent, divalent or multivalent. Examples of C _4-6 cycloalkyl include, but are not limited to, cyclobutyl, cyclopentyl, cyclohexyl and the like.

除非另有规定，环上原子的数目通常被定义为环的元数，例如，“5-7元环”是指环绕排列5-7个原子的“环”。Unless otherwise specified, the number of atoms in a ring is generally defined as the number of ring members, eg, "5-7 membered ring" means a "ring" with 5-7 atoms arranged around it.

除非另有规定，术语“3-8元杂环烷基”本身或者与其他术语联合分别表示由3至8个环原子组成的饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，碳、氮和硫杂原子可任选被氧化(即C(＝O)、NO和S(＝O) _p，p是1或2)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。此外，就该“3-8元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。所述3-8元杂环烷基包括3-6元、3-5元、4-6元、5-6元、4元、5元、6元、7元、8元杂环烷基等。3-8元杂环烷基的实例包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基、高哌嗪基、高哌啶基或二氧杂环庚烷基等。 Unless otherwise specified, the term "3-8 membered heterocycloalkyl" by itself or in combination with other terms means a saturated cyclic group consisting of 3 to 8 ring atoms, respectively, whose 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the carbon, nitrogen, and sulfur heteroatoms may be optionally oxidized (i.e., C(=O), NO and S(=O) _p , p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spiro, fused and bridged rings. In addition, as for the "3-8 membered heterocycloalkyl", a heteroatom may occupy the attachment position of the heterocycloalkyl to the rest of the molecule. The 3-8 membered heterocycloalkyl includes 3-6, 3-5, 4-6, 5-6, 4, 5, 6, 7, 8-membered heterocycloalkyl, etc. . Examples of 3-8 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl Pyridyl or dioxepanyl, etc.

除非另有规定，术语“3-7元杂环烷基”本身或者与其他术语联合分别表示由3至7个环原子组成的饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，碳、氮和硫杂原子可任选被氧化(即C(＝O)、NO和S(＝O) _p，p是1或2)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。此外，就该“3-8元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。所述3-7元杂环烷基包括3-6元、3-5元、4-6元、5-6元、3元、4元、5元、6元、7元杂环烷基等。3-7元杂环烷基的实例包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基、高哌嗪基、高哌啶基或二氧杂环庚烷基等。 Unless otherwise specified, the term "3-7 membered heterocycloalkyl" by itself or in combination with other terms denotes a saturated cyclic group consisting of 3 to 7 ring atoms, respectively, whose 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the carbon, nitrogen, and sulfur heteroatoms may be optionally oxidized (i.e., C(=O), NO and S(=O) _p , p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spiro, fused and bridged rings. In addition, as for the "3-8 membered heterocycloalkyl", a heteroatom may occupy the attachment position of the heterocycloalkyl to the rest of the molecule. The 3-7 membered heterocycloalkyl includes 3-6, 3-5, 4-6, 5-6, 3, 4, 5, 6, 7-membered heterocycloalkyl, etc. . Examples of 3-7 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl Pyridyl or dioxepanyl, etc.

除非另有规定，术语“5-7元杂环烷基”本身或者与其他术语联合分别表示由5至7个环原子组成的饱和环状基团，其1、2、3或4个环原子为独立选自-O-、-NH-、-S-和-N-的杂原子或杂原子团，其余为碳原子，其中氮原子任选地被季铵化，碳、氮和硫杂原子可任选被氧化(即C(＝O)、NO和S(＝O) _p，p是1或2)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。此外，就该“5-7元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。所述5-7元杂环烷基包括5元、6元、7元、5-6元和6-7元杂环烷基。5-7元杂环烷基的实例包括但不限于吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基、高哌嗪基、高哌啶基、氮杂环庚烷、恶庚烷、噻庚烷、噁氮杂环庚烷或二氧杂环庚烷基等。 Unless otherwise specified, the term "5-7 membered heterocycloalkyl" by itself or in combination with other terms denotes a saturated cyclic group consisting of 5 to 7 ring atoms, respectively, whose 1, 2, 3 or 4 ring atoms is a heteroatom or heteroatom group independently selected from -O-, -NH-, -S-, and -N-, the rest being carbon atoms, wherein the nitrogen atom is optionally quaternized, and the carbon, nitrogen, and sulfur heteroatoms can be Optionally oxidized (ie C(=O), NO and S(=O) _p , where p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spiro, fused and bridged rings. In addition, with respect to the "5-7 membered heterocycloalkyl", a heteroatom may occupy the attachment position of the heterocycloalkyl to the rest of the molecule. The 5-7 membered heterocycloalkyl group includes 5-membered, 6-membered, 7-membered, 5-6-membered and 6-7-membered heterocycloalkyl groups. Examples of 5-7 membered heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.) , tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1 -piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazole Alkyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl, azepane, oxapane, thioheptane, oxane Azepane or dioxepanyl, etc.

除非另有规定，C _n-n+m或C _n-C _n+m包括n至n+m个碳的任何一种具体情况，例如C _1-12包括C ₁、C ₂、C ₃、C ₄、C ₅、C ₆、C ₇、C ₈、C ₉、C ₁₀、C ₁₁、和C ₁₂，也包括n至n+m中的任何一个范围，例如C _1-12包括C _1- ₃、C _1-6、C _1-9、C _3-6、C _3-9、C _3-12、C _6-9、C _6-12、和C _9-12等；同理，n元至n+m元表示环上原子数为n至n+m个，例如3-12元环包括3元环、4元环、5元环、6元环、7元环、8元环、9元环、10元环、11元环、和12元环，也包括n至n+m中的任何一个范围，例如3-12元环包括3-6元环、3-9元环、5-6元环、5-7元环、6-7元环、6-8元环、和6-10元环等。 Unless otherwise specified, C _n-n+m or C _n -C _n+m includes any specific instance of n to n+m carbons, for example C _1-12 includes C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , C ₁₀ , C ₁₁ , and C ₁₂ , also including any range from n to n+m, for example, C _1-12 includes C _1- ₃ , C _1-6 , C _1-9 , C _3-6 , C _3-9 , C _3-12 , C _6-9 , C _6-12 , and C _9-12 etc.; similarly, n to n +m means that the number of atoms on the ring is n to n+m, for example, a 3-12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, and a 9-membered ring , 10-membered rings, 11-membered rings, and 12-membered rings, also including any range from n to n+m, for example, 3-12-membered rings include 3-6-membered rings, 3-9-membered rings, 5-6-membered rings ring, 5-7-membered ring, 6-7-membered ring, 6-8-membered ring, and 6-10-membered ring, etc.

术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲核取代反应)所取代的官能团或原子。例如，代表性的离去基团包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。The term "leaving group" refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (eg, a nucleophilic substitution reaction). For example, representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, brosylate, tosylate esters, etc.; acyloxy groups such as acetoxy, trifluoroacetoxy, and the like.

术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)，2-(三甲基硅)乙氧基甲基(SEM)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、 9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。The term "protecting group" includes, but is not limited to, "amino protecting group", "hydroxyl protecting group" or "mercapto protecting group". The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the amino nitrogen position. Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc) ; arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS), 2-(trimethylsilyl)ethoxymethyl (SEM) and tert-butyldi Methylsilyl (TBS) and the like. The term "hydroxyl protecting group" refers to a protecting group suitable for preventing side reactions of the hydroxy group. Representative hydroxy protecting groups include, but are not limited to: alkyl groups such as methyl, ethyl, and tert-butyl; acyl groups such as alkanoyl (such as acetyl); arylmethyl groups such as benzyl (Bn), p-formyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.

本发明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发明的实施例。The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and the methods well known to those skilled in the art Equivalent alternatives, preferred embodiments include but are not limited to the examples of the present invention.

本发明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，如果本发明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 structure of the compounds of the present invention can be confirmed by conventional methods known to those skilled in the art. If the present invention involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, in single crystal X-ray diffraction (SXRD), the cultured single crystal is collected with a Bruker D8 venture diffractometer to collect diffraction intensity data, the light source is CuKα radiation, and the scanning method is:

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

本发明所使用的溶剂可经市售获得。The solvent used in the present invention is commercially available.

本发明采用下述缩略词：Alloc代表烯丙氧羰基；SEM代表三甲基硅烷基乙氧甲基；OTs代表4-甲苯磺酰基；Boc代表叔丁氧羰基；DCM代表二氯甲烷；DIEA代表N,N-二异丙基乙胺；MeI代表碘甲烷；PE代表石油醚；EA代表乙酸乙酯；THF代表四氢呋喃；EtOH代表乙醇；MeOH代表甲醇；Boc ₂O代表二碳酸二叔丁酯；NH ₄Cl代表氯化铵；T ₃P代表1-丙基磷酸三环酸酐；Pd/C代表钯/碳催化剂；TMSN ₃代表叠氮基三甲基硅烷；NCS代表N-氯代丁二酰亚胺；HBr代表氢溴酸；AcOH代表醋酸；HATU代表O-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐；DBU代表1,8-二氮杂二环十一碳-7-烯；FA代表甲酸；ACN代表乙腈；TLC代表薄层色谱；HPLC代表高效液相色谱；LCMS代表液质联用色谱；SFC代表超临界流体色谱法。DMSO代表二甲亚砜；DMSO-d ₆代表氘代二甲亚砜；CD ₃OD代表氘代甲醇；CDCl ₃代表氘代氯仿；D ₂O代表氘水。 The following abbreviations are used in the present invention: Alloc stands for allyloxycarbonyl; SEM stands for trimethylsilylethoxymethyl; OTs stands for 4-toluenesulfonyl; Boc stands for tert-butoxycarbonyl; DCM stands for dichloromethane; DIEA Represents N,N-diisopropylethylamine; MeI represents iodomethane; PE represents petroleum ether; EA represents ethyl acetate; THF represents tetrahydrofuran; EtOH represents ethanol; MeOH represents methanol; Boc ₂ O represents di-tert-butyl dicarbonate ; NH ₄ Cl stands for ammonium chloride; T ₃ P stands for 1-propylphosphoric tricyclic acid anhydride; Pd/C stands for palladium/carbon catalyst; TMSN ₃ stands for azidotrimethylsilane; NCS stands for N-chlorobutadiene Imide; HBr stands for hydrobromic acid; AcOH stands for acetic acid; HATU stands for O-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; DBU FA stands for formic acid; ACN stands for acetonitrile; TLC stands for thin layer chromatography; HPLC stands for high performance liquid chromatography; LCMS stands for liquid chromatography-mass chromatography; SFC stands for ultra Critical Fluid Chromatography. DMSO represents dimethyl sulfoxide; DMSO-d ₆ represents deuterated dimethyl sulfoxide; CD ₃ OD represents deuterated methanol; CDCl ₃ represents deuterated chloroform; D ₂ O represents deuterated water.

化合物依据本领域常规命名原则或者使用

软件命名，市售化合物采用供应商目录名称。 Compounds are named according to the conventional naming principles in this field or using

The software is named, and the commercially available compounds adopt the supplier catalog name.

具体实施方式detailed description

下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本发明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发明的实施例。对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。The present invention will be described in detail through examples below, but it does not imply any unfavorable limitation to the present invention. The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and the methods well known to those skilled in the art Equivalent alternatives, preferred embodiments include but are not limited to the examples of the present invention. Various changes and modifications to the specific embodiments of the invention will be apparent to those skilled in the art without departing from the spirit and scope of the invention.

中间体AIntermediate A

合成路线：synthetic route:

第一步first step

将溴二氟乙酸乙酯(3.37g,16.6mmol)溶于二甲亚砜(20mL)中,加入铜粉(1.06g,16.6mmol)。反应液在25℃搅拌反应1小时。然后在向反应液中加入化合物A-1(2.00g,6.65mmol),在70℃搅拌反应12小时。将反应液倒入20mL冰水中,加入乙酸乙酯(20mL),过滤,滤液用乙酸乙酯(20mL×3)萃取。有机相用饱和食盐水(20mL×3)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物经过硅胶柱层析法(石油醚/乙酸乙酯,1/0～20/1,V/V)分离纯化得到化合物A-3。 ¹H NMR(400MHz,CDCl ₃)δ7.75-7.68(m,1H),7.64-7.57(m,1H),7.16(t,J＝8.0Hz,1H),4.38(m,2H),1.34(t,J＝8.0Hz,3H)。 Ethyl bromodifluoroacetate (3.37g, 16.6mmol) was dissolved in dimethylsulfoxide (20mL), and copper powder (1.06g, 16.6mmol) was added. The reaction solution was stirred and reacted at 25° C. for 1 hour. Then compound A-1 (2.00 g, 6.65 mmol) was added to the reaction liquid, and the reaction was stirred at 70° C. for 12 hours. The reaction solution was poured into 20 mL of ice water, ethyl acetate (20 mL) was added, filtered, and the filtrate was extracted with ethyl acetate (20 mL×3). The organic phase was washed with saturated brine (20mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate, 1/0～20/1, V /V) separation and purification to obtain compound A-3. ¹ H NMR (400MHz, CDCl ₃ ) δ7.75-7.68(m, 1H), 7.64-7.57(m, 1H), 7.16(t, J=8.0Hz, 1H), 4.38(m, 2H), 1.34( t, J = 8.0 Hz, 3H).

第二步second step

在氮气保护下,将化合物A-3(677mg,1.82mmol)溶于甲苯(10mL)中,0℃下加入甲基溴化镁溶液(3M,2.43mL)。反应液在25℃搅拌反应2小时。加入饱和氯化铵溶液(10mL)淬灭,用乙酸乙酯(10mL×2)萃取。有机相用饱和食盐水(10mL×2)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物经过硅胶柱层析法(石油醚/乙酸乙酯,1/0～10/1,V/V)分离纯化得到化合物A-4。 ¹H NMR(400MHz,CDCl ₃)δ7.66(t,J＝6.4Hz,1H),7.51-7.34(m,1H),7.16-6.93(m,1H),2.01(s,1H),1.35(s,6H)。 Under nitrogen protection, compound A-3 (677mg, 1.82mmol) was dissolved in toluene (10mL), and methylmagnesium bromide solution (3M, 2.43mL) was added at 0°C. The reaction solution was stirred and reacted at 25° C. for 2 hours. Add saturated ammonium chloride solution (10 mL) to quench, and extract with ethyl acetate (10 mL×2). The organic phase was washed with saturated brine (10mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate, 1/0～10/1, V /V) separation and purification to obtain compound A-4. ¹ H NMR (400MHz, CDCl ₃ ) δ7.66(t, J=6.4Hz, 1H), 7.51-7.34(m, 1H), 7.16-6.93(m, 1H), 2.01(s, 1H), 1.35( s, 6H).

第三步third step

在氮气保护下,将化合物A-4(441mg,1.56mmol)溶于甲苯(5mL)中,加入化合物A-5(1.87g,5.19mmol)和双三苯基膦二氯化钯(109mg,0.16mmol),反应液在120℃搅拌反应12小时。降至室温后加入饱和氟化钾溶液(20mL)淬灭,用乙酸乙酯(15mL×2)萃取。过滤,减压浓缩得化合物A-6。Under nitrogen protection, compound A-4 (441 mg, 1.56 mmol) was dissolved in toluene (5 mL), compound A-5 (1.87 g, 5.19 mmol) and bistriphenylphosphine palladium dichloride (109 mg, 0.16 mmol), the reaction solution was stirred and reacted at 120°C for 12 hours. After cooling down to room temperature, it was quenched by adding saturated potassium fluoride solution (20 mL), and extracted with ethyl acetate (15 mL×2). Filter and concentrate under reduced pressure to obtain compound A-6.

第四步the fourth step

在氮气保护下,将化合物A-6(425mg,1.55mmol)溶于丙酮(10mL)中,0℃下逐滴加入盐酸溶液(12M,1.03mL),在25℃搅拌反应1小时。加入饱和碳酸氢钠溶液中和至pH＝8,用乙酸乙酯(10mL)萃取。有机相用饱和食盐水(10mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物经过硅胶柱层析法(石油醚/乙酸乙酯,20/1～4/1,V/V)分离纯化得到化合物A-7。MS-ESI计算值[M+H] ⁺247,实测值247。 Under nitrogen protection, compound A-6 (425mg, 1.55mmol) was dissolved in acetone (10mL), hydrochloric acid solution (12M, 1.03mL) was added dropwise at 0°C, and the reaction was stirred at 25°C for 1 hour. Add saturated sodium bicarbonate solution to neutralize to pH = 8, and extract with ethyl acetate (10 mL). The organic phase was washed with saturated brine (10 mL×1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate, 20/1～4/1, V /V) separation and purification to obtain compound A-7. MS-ESI calculated [M+H] ⁺ 247, found 247.

第五步the fifth step

在25℃下将化合物A-7(346mg,1.41mmol)溶于四氢呋喃(5mL)中,加入化合物A-8(511mg,4.22mmol)和四乙氧基钛(2.00g,7.03mmol)。反应液在80℃搅拌反应36小时。然后在-5℃下向反应液降中加入硼氢化钠(64.0mg,1.69mmol),在25℃搅拌反应1小时。将反应液倒入20mL冰水中,过滤,滤液用乙酸乙酯(5mL×2)萃取。有机相用饱和食盐水(5mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物经过硅胶柱层析法(石油醚/乙酸乙酯,2/1～0/1,V/V)分离纯化得到化合物A-9。MS-ESI计算值[M+H] ⁺352,实测值352。 Compound A-7 (346 mg, 1.41 mmol) was dissolved in tetrahydrofuran (5 mL) at 25°C, and compound A-8 (511 mg, 4.22 mmol) and tetraethoxytitanium (2.00 g, 7.03 mmol) were added. The reaction solution was stirred and reacted at 80° C. for 36 hours. Then sodium borohydride (64.0 mg, 1.69 mmol) was added to the reaction liquid at -5°C, and the reaction was stirred at 25°C for 1 hour. The reaction solution was poured into 20 mL of ice water, filtered, and the filtrate was extracted with ethyl acetate (5 mL×2). The organic phase was washed with saturated brine (5 mL×1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate, 2/1～0/1, V /V) separation and purification to obtain compound A-9. MS-ESI calculated [M+H] ⁺ 352, found 352.

第六步step six

将化合物A-9(366mg,1.04mmol)溶于二氧六环(2.5mL)中,加入氯化氢/二氧六环溶液(4M,1.15mL)。反应液在25℃搅拌反应6小时。反应液减压浓缩,剩余物经过硅胶柱层析法(二氯甲烷/甲醇,1/0～8/1,V/V)分离纯化得到中间体A的盐酸盐。MS-ESI计算值[M+H] ⁺248,实测值248。 Compound A-9 (366mg, 1.04mmol) was dissolved in dioxane (2.5mL), and hydrogen chloride/dioxane solution (4M, 1.15mL) was added. The reaction solution was stirred and reacted at 25° C. for 6 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (dichloromethane/methanol, 1/0-8/1, V/V) to obtain the hydrochloride of intermediate A. MS-ESI calculated value [M+H] ⁺ 248, found value 248.

中间体BIntermediate B

合成路线：synthetic route:

第一步first step

氮气保护下,将化合物B-1(3.00g,14.8mmol)溶于干燥二氯甲烷(30mL)中,0℃下滴加二乙氨基三氟化硫(3.57g,22.2mmol),反应液在25℃下搅拌12小时,向反应液中加入冰水(20mL),用二氯甲烷(20mL×1)萃取,有机相用饱和食盐水洗涤(20mL×1),无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱层析法(石油醚/乙酸乙酯,100/1～10/1,V/V)分离得到化合物B-2。 ¹H NMR(400MHz,CDCl ₃)δ7.72-7.67(m,1H),7.52-7.59(m,1H),7.16(t,J＝7.6Hz,1H),7.05-6.75(m,1H)。 Under nitrogen protection, compound B-1 (3.00g, 14.8mmol) was dissolved in dry dichloromethane (30mL), diethylaminosulfur trifluoride (3.57g, 22.2mmol) was added dropwise at 0°C, and the reaction solution was Stir at 25°C for 12 hours, add ice water (20 mL) to the reaction solution, extract with dichloromethane (20 mL×1), wash the organic phase with saturated brine (20 mL×1), dry over anhydrous sodium sulfate, filter, Concentrate under reduced pressure, and the residue is separated by silica gel column chromatography (petroleum ether/ethyl acetate, 100/1～10/1, V/V) to obtain compound B-2. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.72-7.67 (m, 1H), 7.52-7.59 (m, 1H), 7.16 (t, J=7.6 Hz, 1H), 7.05-6.75 (m, 1H).

第二步second step

氮气保护下,将化合物B-2(3.10g,13.8mmol)溶于干燥甲苯(50mL)中,加入三丁基(1-乙氧基乙烯)锡(9.95g,27.6mmol),再加入双三苯基膦二氯化钯(967mg,1.38mmol),反应液在110℃下搅拌12小时,降至室温后,向反应液中加入饱和氟化钾水溶液(200mL),用乙酸乙酯(200mL×1)萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩得到粗品化合物B-3,直接用于下一步。Under the protection of nitrogen, compound B-2 (3.10g, 13.8mmol) was dissolved in dry toluene (50mL), tributyl(1-ethoxyethylene)tin (9.95g, 27.6mmol) was added, and bistrimethyl Phenylphosphine palladium dichloride (967mg, 1.38mmol), the reaction solution was stirred at 110°C for 12 hours, and after cooling down to room temperature, saturated potassium fluoride aqueous solution (200mL) was added to the reaction solution, and ethyl acetate (200mL× 1) Extraction, the organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude compound B-3, which was directly used in the next step.

第三步third step

氮气保护下,将化合物B-3(2.98g,13.8mmol)溶于丙酮(90mL)中,0℃下滴加浓盐酸(12M,9.19mL),反应液在25℃下搅拌1小时,反应液用饱和碳酸氢钠水溶液碱化pH至8,用乙酸乙酯(200mL×2)萃取,饱和食盐水(200mL×1)洗涤有机相,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱层析法(石油醚/乙酸乙酯,100/1～10/1,V/V)分离得到化合物B-4。 ¹H NMR(400MHz,CDCl ₃)δ8.06-7.97(m,1H),7.84-7.76(m,1H),7.38-7.32(m,1H),7.10-6.80(m,1H),2.68(d,J＝4.8Hz,3H)。 Under nitrogen protection, compound B-3 (2.98g, 13.8mmol) was dissolved in acetone (90mL), and concentrated hydrochloric acid (12M, 9.19mL) was added dropwise at 0°C, and the reaction solution was stirred at 25°C for 1 hour, and the reaction solution Alkaline the pH to 8 with saturated aqueous sodium bicarbonate solution, extract with ethyl acetate (200mL×2), wash the organic phase with saturated brine (200mL×1), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and use Compound B-4 was isolated by silica gel column chromatography (petroleum ether/ethyl acetate, 100/1～10/1, V/V). ¹ H NMR (400MHz, CDCl ₃ )δ8.06-7.97(m,1H),7.84-7.76(m,1H),7.38-7.32(m,1H),7.10-6.80(m,1H),2.68(d , J=4.8Hz, 3H).

第四步the fourth step

氮气保护下,将化合物B-4(1.85g,9.83mmol)溶于干燥四氢呋喃(50mL)中,加入钛酸四乙酯(8.97g,39.3mmol)和(R)-(+)-叔丁基亚磺酰胺(2.38g,19.7mmol),反应液在72℃下搅拌36小时,降温至0℃滴加饱和氯化铵水溶液(20mL),再加入乙酸乙酯(20mL),过滤,滤饼用乙酸乙酯(10mL)洗涤,有机相用饱和食盐水(20mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱层析法(石油醚/乙酸乙酯,100/1～4/1,V/V)分离得到化合物B-5。MS-ESI计算值[M+H] ⁺292,实测值292。 Under nitrogen protection, compound B-4 (1.85g, 9.83mmol) was dissolved in dry tetrahydrofuran (50mL), and tetraethyl titanate (8.97g, 39.3mmol) and (R)-(+)-tert-butyl Sulfinamide (2.38g, 19.7mmol), the reaction solution was stirred at 72°C for 36 hours, cooled to 0°C, and saturated ammonium chloride aqueous solution (20mL) was added dropwise, then ethyl acetate (20mL) was added, filtered, and the filter cake was used Washed with ethyl acetate (10 mL), the organic phase was washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate, 100 /1～4/1, V/V) to obtain compound B-5. MS-ESI calculated value [M+H] ⁺ 292, found value 292.

第五步the fifth step

将化合物B-5(2.33g,8.00mmol)溶于无水四氢呋喃(20mL),加入硼氢化钠(303mg,8.00mmol),反应液在25℃下搅拌1小时,降温至0℃滴加饱和氯化铵水溶液(50mL),再加入乙酸乙酯(50mL),有机相用饱和食盐水(50mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩得到化合物B-6。MS-ESI计算值[M+H] ⁺294,实测值294。 Compound B-5 (2.33g, 8.00mmol) was dissolved in anhydrous tetrahydrofuran (20mL), sodium borohydride (303mg, 8.00mmol) was added, the reaction solution was stirred at 25°C for 1 hour, cooled to 0°C and saturated chlorine was added dropwise Ammonium chloride aqueous solution (50 mL), and ethyl acetate (50 mL) were added, the organic phase was washed with saturated brine (50 mL×1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound B-6. MS-ESI calculated value [M+H] ⁺ 294, found value 294.

第六步step six

将化合物B-6(200mg,0.682mmol)溶于乙酸乙酯(5mL)中,25℃下滴加氯化氢/乙酸乙酯溶液(4M,5.00mL),反应液于25℃搅拌2小时,将反应液减压浓缩得到粗品化合物B的盐酸盐,直接用于下一步。Compound B-6 (200mg, 0.682mmol) was dissolved in ethyl acetate (5mL), hydrogen chloride/ethyl acetate solution (4M, 5.00mL) was added dropwise at 25°C, the reaction solution was stirred at 25°C for 2 hours, and the reaction The solution was concentrated under reduced pressure to obtain the crude compound B hydrochloride, which was directly used in the next step.

中间体CIntermediate C

合成路线：synthetic route:

第一步first step

氮气保护下,将化合物C-1(6.00g,23.3mmol)溶于干燥甲苯(100mL)中,加入化合物A-5(12.6g,34.9mmol),再加入双三苯基膦二氯化钯(1.63g,2.33mmol),反应液在120℃下搅拌12小时,降至室温后,向反应液中加入饱和氟化钾水溶液(100mL),用乙酸乙酯(100mL×2)萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩得到粗品化合物C-2,直接用于下一步。Under nitrogen protection, compound C-1 (6.00 g, 23.3 mmol) was dissolved in dry toluene (100 mL), compound A-5 (12.6 g, 34.9 mmol) was added, and bistriphenylphosphine palladium dichloride ( 1.63g, 2.33mmol), the reaction solution was stirred at 120°C for 12 hours, and after cooling down to room temperature, saturated potassium fluoride aqueous solution (100mL) was added to the reaction solution, extracted with ethyl acetate (100mL×2), and the organic phase was used Dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain crude compound C-2, which is directly used in the next step.

第二步second step

将化合物C-2(5.83g,23.4mmol)溶于丙酮(80mL)中,0℃下滴加浓盐酸(12M,9.96mL),反应液在25℃下搅拌1小时,反应液用饱和碳酸氢钠水溶液碱化pH至8,用乙酸乙酯(50mL×3)萃取,饱和食盐水(50mL×1)洗涤有机相,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱层析法(石油醚/乙酸乙酯,100/1～4/1,V/V)分离得到化合物C-3。 ¹H NMR(400MHz,CDCl ₃)δ7.30-7.26(m,1H),7.08-7.00(m,1H),2.66-2.63(m,3H)。MS-ESI计算值[M+H] ⁺222,实测值222。 Compound C-2 (5.83g, 23.4mmol) was dissolved in acetone (80mL), concentrated hydrochloric acid (12M, 9.96mL) was added dropwise at 0°C, the reaction solution was stirred at 25°C for 1 hour, and the reaction solution was washed with saturated bicarbonate Sodium aqueous solution was basified to pH 8, extracted with ethyl acetate (50mL×3), the organic phase was washed with saturated brine (50mL×1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography Compound C-3 was isolated by the method (petroleum ether/ethyl acetate, 100/1～4/1, V/V). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.30-7.26 (m, 1H), 7.08-7.00 (m, 1H), 2.66-2.63 (m, 3H). MS-ESI calculated value [M+H] ⁺ 222, found value 222.

第三步third step

将化合物C-3(4.84g,16.7mmol)溶于干燥四氢呋喃(50mL)中,加入钛酸四乙酯(7.62g,33.4mmol)和化合物A-8(3.04g,25.1mmol),反应液在80℃下搅拌24小时,降温至0℃将水(50mL)倒入反应液中,再加入乙酸乙酯(50mL×1)洗涤,有机相用饱和食盐水(50mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱层析法(石油醚/乙酸乙酯,100/1～2/1,V/V)分离得到化合物C-4。MS-ESI计算值[M+H] ⁺325,实测值325。 Compound C-3 (4.84g, 16.7mmol) was dissolved in dry tetrahydrofuran (50mL), tetraethyl titanate (7.62g, 33.4mmol) and compound A-8 (3.04g, 25.1mmol) were added, and the reaction solution was Stir at 80°C for 24 hours, cool down to 0°C, pour water (50mL) into the reaction solution, add ethyl acetate (50mL×1) to wash, the organic phase is washed with saturated brine (50mL×1), anhydrous sulfuric acid It was dried over sodium, filtered, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 100/1～2/1, V/V) to obtain compound C-4. MS-ESI calculated [M+H] ⁺ 325, found 325.

第四步the fourth step

将化合物C-4(4.68g,11.8mmol)溶于无水四氢呋喃(60mL),在0℃加入硼氢化钠(535mg,14.2mmol),反应液在25℃下搅拌1小时,降温至0℃滴加水(100mL),再加入乙酸乙酯(100mL×1),有机相用饱和食盐水(200mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱层析法(石油醚/乙酸乙酯,1/1～1/2,V/V)分离得到化合物C-5。MS-ESI计算值[M+H] ⁺327,实测值327。 Compound C-4 (4.68g, 11.8mmol) was dissolved in anhydrous tetrahydrofuran (60mL), sodium borohydride (535mg, 14.2mmol) was added at 0°C, the reaction solution was stirred at 25°C for 1 hour, cooled to 0°C dropwise Add water (100 mL), then add ethyl acetate (100 mL×1), wash the organic phase with saturated brine (200 mL×1), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure, and the residue is subjected to silica gel column chromatography ( Petroleum ether/ethyl acetate, 1/1～1/2, V/V) to obtain compound C-5. MS-ESI calculated [M+H] ⁺ 327, found 327.

第五步the fifth step

将化合物C-5(2.16g,6.62mmol)溶于二氧六环(30mL)中,滴加氯化氢/二氧六环溶液(4M,16.6mL),反应液于20℃搅拌2小时,将反应液减压浓缩后在20℃加入二氯甲烷(5ml)搅拌10分钟,过滤,收集滤饼干燥得到中间体C的盐酸盐。MS-ESI计算值[M+H] ⁺223,实测值223。 Compound C-5 (2.16g, 6.62mmol) was dissolved in dioxane (30mL), hydrogen chloride/dioxane solution (4M, 16.6mL) was added dropwise, the reaction solution was stirred at 20°C for 2 hours, and the reaction After the solution was concentrated under reduced pressure, dichloromethane (5ml) was added at 20°C and stirred for 10 minutes, filtered, and the filter cake was collected and dried to obtain the hydrochloride of intermediate C. MS-ESI calculated value [M+H] ⁺ 223, found value 223.

中间体DIntermediate D

合成路线：synthetic route:

第一步first step

氮气保护下,将化合物D-1(5.00g,25.5mmol)溶于干燥甲苯(50mL)中,加入化合物A-5(10.2g,28.3mmol),再加入双三苯基膦二氯化钯(1.79g,2.55mmol),反应液在120℃下搅拌12小时,降至室温后,向反应液中加入饱和氟化钾水溶液(50mL),用乙酸乙酯(50mL×2)萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩得到粗品化合物D-2,直接用于下一步。Under nitrogen protection, compound D-1 (5.00 g, 25.5 mmol) was dissolved in dry toluene (50 mL), compound A-5 (10.2 g, 28.3 mmol) was added, and bistriphenylphosphine palladium dichloride ( 1.79g, 2.55mmol), the reaction solution was stirred at 120°C for 12 hours, and after cooling down to room temperature, saturated potassium fluoride aqueous solution (50mL) was added to the reaction solution, extracted with ethyl acetate (50mL×2), and the organic phase was washed with Dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain crude compound D-2, which is directly used in the next step.

第二步second step

将化合物D-2(5.00g,26.7mmol)溶于丙酮(80mL)中,0℃下滴加浓盐酸(12M,8.00mL),反应液在20℃下搅拌1小时,反应液用饱和碳酸氢钠水溶液碱化pH至8,用乙酸乙酯(20mL×3)萃取,饱和食盐水(20mL×1)洗涤有机相,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱层析法(石油醚/乙酸乙酯,100/1～5/1,V/V)分离得到化合物D-3。 ¹H NMR(400MHz,CDCl ₃)δ7.89-7.80(m,1H),7.80-7.68(m,1H),7.73(dd,J＝1.56,8.0Hz,1H),2.70(s,3H),2.63-2.58(m,3H)。MS-ESI计算值[M+H] ⁺160,实测值160。 Compound D-2 (5.00g, 26.7mmol) was dissolved in acetone (80mL), concentrated hydrochloric acid (12M, 8.00mL) was added dropwise at 0°C, the reaction solution was stirred at 20°C for 1 hour, and the reaction solution was washed with saturated bicarbonate Sodium aqueous solution was basified to pH 8, extracted with ethyl acetate (20mL×3), the organic phase was washed with saturated brine (20mL×1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography Compound D-3 was isolated by the method (petroleum ether/ethyl acetate, 100/1～5/1, V/V). ¹ H NMR (400MHz, CDCl ₃ )δ7.89-7.80(m,1H),7.80-7.68(m,1H),7.73(dd,J=1.56,8.0Hz,1H),2.70(s,3H), 2.63-2.58(m,3H). MS-ESI calculated value [M+H] ⁺ 160, found value 160.

第三步third step

将化合物D-3(3.53g,19.5mmol)溶于干燥四氢呋喃(40mL)中,加入钛酸四乙酯(8.89g,39.0mmol)和化合物A-8(3.54g,29.2mmol),反应液在80℃下搅拌24小时,降温至0℃将水(50mL)倒入反应液中,再加入乙酸乙酯(50mL×1)洗涤,有机相用饱和食盐水(50mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱层析法(石油醚/乙酸乙酯,10/1～1/1,V/V)分离得到化合物D-4。MS-ESI计算值[M+H] ⁺263,实测值263。 Compound D-3 (3.53g, 19.5mmol) was dissolved in dry tetrahydrofuran (40mL), and tetraethyl titanate (8.89g, 39.0mmol) and compound A-8 (3.54g, 29.2mmol) were added, and the reaction solution was Stir at 80°C for 24 hours, cool down to 0°C, pour water (50mL) into the reaction solution, add ethyl acetate (50mL×1) to wash, the organic phase is washed with saturated brine (50mL×1), anhydrous sulfuric acid Sodium-dried, filtered, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～1/1, V/V) to obtain compound D-4. MS-ESI calculated value [M+H] ⁺ 263, found value 263.

第四步the fourth step

将化合物D-4(5.37g,17.7mmol)溶于无水四氢呋喃(60mL),在0℃加入硼氢化钠(804mg,21.3mmol),反应液在20℃下搅拌1小时,降温至0℃滴加水(200mL),再加入乙酸乙酯(200mL×2),有机相用饱和食盐水(200mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱层析法(石油醚/乙酸乙酯,1/1～1/2,V/V)分离得到化合物D-5。MS-ESI计算值[M+H] ⁺265,实测值265。 Compound D-4 (5.37g, 17.7mmol) was dissolved in anhydrous tetrahydrofuran (60mL), sodium borohydride (804mg, 21.3mmol) was added at 0°C, the reaction solution was stirred at 20°C for 1 hour, cooled to 0°C dropwise Add water (200mL), then add ethyl acetate (200mL×2), wash the organic phase with saturated brine (200mL×1), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure, and the residue is subjected to silica gel column chromatography ( Petroleum ether/ethyl acetate, 1/1～1/2, V/V) to obtain compound D-5. MS-ESI calculated [M ⁺ H]+265, found 265.

第五步the fifth step

将化合物D-5(5.40g,20.4mmol)溶于二氧六环(30mL)中,滴加氯化氢/二氧六环溶液(4M,25.5mL),反应液于20℃搅拌2小时,将反应液减压浓缩后在20℃加入二氯甲烷(5ml)搅拌10分钟,过滤,收集滤饼,干燥得到中间体D的盐酸盐。MS-ESI计算值[M+H] ⁺161,实测值161。 Compound D-5 (5.40g, 20.4mmol) was dissolved in dioxane (30mL), hydrogen chloride/dioxane solution (4M, 25.5mL) was added dropwise, the reaction solution was stirred at 20°C for 2 hours, and the reaction After the solution was concentrated under reduced pressure, dichloromethane (5ml) was added at 20°C and stirred for 10 minutes, filtered, and the filter cake was collected and dried to obtain the hydrochloride of intermediate D. MS-ESI calculated value [M+H] ⁺ 161, found value 161.

中间体EIntermediate E

合成路线：synthetic route:

第一步first step

将化合物E-1(10.0g,42.5mmol)溶于二氯亚砜(30mL)中,加入N,N-二甲基甲酰胺(164μL,2.13mmol)。反应液在80℃搅拌反应3小时。向反应液中加入无水甲苯(100mL×2),减压浓缩后得到化合物E-2。Compound E-1 (10.0 g, 42.5 mmol) was dissolved in thionyl chloride (30 mL), and N,N-dimethylformamide (164 μL, 2.13 mmol) was added. The reaction solution was stirred and reacted at 80° C. for 3 hours. Anhydrous toluene (100 mL×2) was added to the reaction solution, and compound E-2 was obtained after concentration under reduced pressure.

第二步second step

氮气保护下,将化合物E-3(15.2g,89.5mmol)溶于乙腈(100mL)中,0℃下依次加入三乙胺(14.6g,144mmol)和氯化镁(9.33g,98.0mmol),15℃下搅拌反应2小时。冷却至0℃,逐滴加入化合物E-2(10.8g,42.6mmol)的乙腈(50mL)溶液,15℃下搅拌反应12小时。在0℃下向反应液中加入稀盐酸(4M,100mL),分液后浓缩除去乙腈,水相用乙酸乙酯(150mL×2)萃取,有机相用饱和碳酸氢钠水溶液(200mL)及饱和食盐水(200mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,得到化合物E-4。MS-ESI计算值为[M-H] ^-304,实测值304。 Under the protection of nitrogen, compound E-3 (15.2g, 89.5mmol) was dissolved in acetonitrile (100mL), and triethylamine (14.6g, 144mmol) and magnesium chloride (9.33g, 98.0mmol) were added successively at 0°C, The reaction was stirred for 2 hours. After cooling to 0°C, a solution of compound E-2 (10.8g, 42.6mmol) in acetonitrile (50mL) was added dropwise, and the reaction was stirred at 15°C for 12 hours. Dilute hydrochloric acid (4M, 100mL) was added to the reaction solution at 0°C, separated and concentrated to remove acetonitrile, the aqueous phase was extracted with ethyl acetate (150mL×2), and the organic phase was extracted with saturated aqueous sodium bicarbonate (200mL) and saturated Wash with brine (200 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain compound E-4. The MS-ESI calculated value was [MH] ^- 304, and the measured value was 304.

第三步third step

将化合物E-4(12.8g,41.9mmol)溶于乙酸(40mL)中,加入水(20mL)和浓硫酸(5mL),100℃下反应3小时。反应液浓缩除去乙酸,加入冰水(300mL),用乙酸乙酯(100mL×3)萃取,用饱和碳酸氢钠水溶液(100mL×2),氢氧化钠水溶液(2mol/L,100mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,粗产物经过硅胶柱色谱法分离纯化(石油醚/乙酸乙酯,10/1～2/1,V/V)分离得到化合物E-5。MS-ESI计算值为[M-H] ^-232,实测值232。 Compound E-4 (12.8g, 41.9mmol) was dissolved in acetic acid (40mL), water (20mL) and concentrated sulfuric acid (5mL) were added, and reacted at 100°C for 3 hours. The reaction solution was concentrated to remove acetic acid, added ice water (300mL), extracted with ethyl acetate (100mL×3), washed with saturated aqueous sodium bicarbonate (100mL×2), aqueous sodium hydroxide (2mol/L, 100mL×2) , dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～2/1, V/V) to obtain compound E-5. The MS-ESI calculated value was [MH] ^- 232, and the measured value was 232.

第四步the fourth step

将化合物E-5(8.00g,34.3mmol)溶于四氢呋喃(80mL)中,加入E-6(6.24g,51.5mmol)和钛酸四异丙酯(30.5g,85.8mmol,80％纯度),80℃下反应16小时。向反应液中加入水(300mL),过滤,滤液经无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱色谱法分离纯化(石油醚/乙酸乙酯,10/1～3/1,V/V)得到化合物E-7。MS-ESI计算值为[M+H] ⁺337,实测值337。 Compound E-5 (8.00g, 34.3mmol) was dissolved in tetrahydrofuran (80mL), E-6 (6.24g, 51.5mmol) and tetraisopropyl titanate (30.5g, 85.8mmol, 80% purity) were added, React at 80°C for 16 hours. Add water (300mL) to the reaction solution, filter, the filtrate is dried over anhydrous sodium sulfate, filter, and concentrate under reduced pressure, the residue is separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～3/1 , V/V) to obtain compound E-7. MS-ESI calculated value is [M ⁺ H]+337, found value is 337.

第五步the fifth step

于-78℃下,将化合物E-7(8.00g,23.8mmol)溶于四氢呋喃(100mL)和水(2mL)中,加入硼氢化钠(1.80g,47.5mmol),20℃下反应1小时。向反应液中加入水(300mL),用乙酸乙酯(100mL×3)萃取,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱色谱法分离纯化(石油醚/乙酸乙酯,5/1～2/1,V/V)得到化合物E-8。MS-ESI计算值为[M-H] ^-337,实测值337。 Compound E-7 (8.00g, 23.8mmol) was dissolved in tetrahydrofuran (100mL) and water (2mL) at -78°C, sodium borohydride (1.80g, 47.5mmol) was added, and reacted at 20°C for 1 hour. Water (300 mL) was added to the reaction solution, extracted with ethyl acetate (100 mL×3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1～2/1, V/V) to obtain compound E-8. MS-ESI calculated value is [MH] ^- 337, found value is 337.

第六步step six

将化合物E-8(5.50g,16.3mmol)溶于乙酸乙酯(10mL),加入氯化氢/乙酸乙酯溶液(4M,50.0mL)。15℃反应1小时。减压浓缩后,加入二氯甲烷(50mL)搅拌,过滤,真空干燥得到化合物E-9的盐酸盐。MS-ESI计算值为[M+H] ⁺235,实测值235。 Compound E-8 (5.50 g, 16.3 mmol) was dissolved in ethyl acetate (10 mL), and hydrogen chloride/ethyl acetate solution (4M, 50.0 mL) was added. React at 15°C for 1 hour. After concentration under reduced pressure, dichloromethane (50 mL) was added, stirred, filtered, and dried in vacuo to obtain the hydrochloride of compound E-9. The MS-ESI calculated value was [M ⁺ H]+235, and the measured value was 235.

第七步step seven

将化合物E-9的盐酸盐(3.50g,12.9mmol)溶于乙酸乙酯(70mL),加入钯碳(0.70g,10％纯度),15℃氢气(15Psi)气氛下反应2小时。硅藻土过滤滤除钯碳,减压浓缩得到中间体E的盐酸盐。MS-ESI计算值为[M+H] ⁺205,实测值205。 Compound E-9 hydrochloride (3.50g, 12.9mmol) was dissolved in ethyl acetate (70mL), palladium on carbon (0.70g, 10% purity) was added, and reacted at 15°C for 2 hours under hydrogen (15Psi) atmosphere. Celite was filtered to remove palladium carbon, and concentrated under reduced pressure to obtain the hydrochloride of intermediate E. The MS-ESI calculated value was [M ⁺ H]+205, and the measured value was 205.

中间体FIntermediate F

合成路线：synthetic route:

第一步first step

将化合物F-1(30.0g,333mmol)溶于甲醇(30mL)中,加入浓硫酸(500μL,9.38mmol),在60℃下搅拌反应2小时。向反应液中加入饱和碳酸氢钠溶液(20mL),用乙酸乙酯(30mL×3)萃取,有机相用饱和食盐水(50mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩得化合物F-2。 ¹H NMR(400MHz,CDCl ₃)δ4.55(s,2H),3.83(s,6H),3.44(s,2H)。 Compound F-1 (30.0 g, 333 mmol) was dissolved in methanol (30 mL), concentrated sulfuric acid (500 μL, 9.38 mmol) was added, and the reaction was stirred at 60°C for 2 hours. Add saturated sodium bicarbonate solution (20 mL) to the reaction solution, extract with ethyl acetate (30 mL×3), wash the organic phase with saturated brine (50 mL×1), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain Compound F-2. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.55 (s, 2H), 3.83 (s, 6H), 3.44 (s, 2H).

第二步second step

将化合物F-2(12.3g,69.0mmol)溶于氘代碘甲烷(100mL)中,加入氧化银(48.0g,207mmol),在45℃下搅拌反应12小时。将反应液过滤,将滤液减压浓缩,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,10/1～1/1,V/V)分离纯化得到化合物F-3。 ¹H NMR(400MHz,CDCl ₃)δ4.24(s,2H),3.81(s,6H)。 Compound F-2 (12.3g, 69.0mmol) was dissolved in deuteroiodomethane (100mL), silver oxide (48.0g, 207mmol) was added, and the reaction was stirred at 45°C for 12 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～1/1, V/V) to obtain compound F-3. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.24 (s, 2H), 3.81 (s, 6H).

第三步third step

将化合物F-3(7.00g,33.0mmol)溶于四氢呋喃(200mL)中,0℃下加入四氢锂铝(2.50g,66.0mmol), 在25℃下搅拌反应2小时。向反应液中缓慢加入水(200mL),用乙酸乙酯(200mL×1)萃取,有机相用饱和食盐水(200mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,10/1～1/1,V/V)分离纯化得到化合物F-4。 ¹H NMR(400MHz,CDCl ₃)δ3.82(d,J＝9.2Hz,2H),3.69(d,J＝10.8Hz,2H),3.55-3.42(m,2H),2.43(s,2H)。 Compound F-3 (7.00g, 33.0mmol) was dissolved in tetrahydrofuran (200mL), lithium aluminum tetrahydrogen (2.50g, 66.0mmol) was added at 0°C, and the reaction was stirred at 25°C for 2 hours. Water (200 mL) was slowly added to the reaction solution, extracted with ethyl acetate (200 mL×1), the organic phase was washed with saturated brine (200 mL×1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was washed with Compound F-4 was obtained by separation and purification by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～1/1, V/V). ¹ H NMR (400MHz, CDCl ₃ ) δ3.82(d, J=9.2Hz, 2H), 3.69(d, J=10.8Hz, 2H), 3.55-3.42(m, 2H), 2.43(s, 2H) .

第四步the fourth step

-78℃下将化合物F-4(7.20g,46.1mmol)溶于吡啶(100mL)中,加入对甲苯磺酰氯(35.2mg,184mmol),在25℃下搅拌反应12小时。向反应液中缓慢加入水(200mL),用乙酸乙酯(200mL×1)萃取,有机相用饱和食盐水(200mL×10)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,10/1～1/1,V/V)分离纯化得到中间体F。 ¹H NMR(400MHz,CDCl ₃)δ7.79(d,J＝8.4Hz,4H),7.37(d,J＝8.4Hz,4H),4.17-4.12(m,2H),4.08-4.00(m,2H),3.55-3.45(m,2H),2.46(s,6H)。 Compound F-4 (7.20 g, 46.1 mmol) was dissolved in pyridine (100 mL) at -78°C, p-toluenesulfonyl chloride (35.2 mg, 184 mmol) was added, and the reaction was stirred at 25°C for 12 hours. Water (200 mL) was slowly added to the reaction solution, extracted with ethyl acetate (200 mL×1), the organic phase was washed with saturated brine (200 mL×10), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was washed with Intermediate F was obtained by separation and purification by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～1/1, V/V). ¹ H NMR (400MHz, CDCl ₃ ) δ7.79(d, J=8.4Hz, 4H), 7.37(d, J=8.4Hz, 4H), 4.17-4.12(m, 2H), 4.08-4.00(m, 2H), 3.55-3.45(m, 2H), 2.46(s, 6H).

中间体GIntermediate G

合成路线：synthetic route:

第一步first step

将化合物G-1(2.00g,17.4mmol)溶于甲苯(20mL)中,加入二氯亚砜(2.52mL,34.7mmol),在70℃下搅拌反应3小时。将反应液减压浓缩得中间体G。 ¹H NMR(400MHz,DMSO-d ₆)δ4.14-4.09(m,1H),4.02-3.98(m,1H),3.73-3.67(m,1H),3.59-3.53(m,1H),3.13-3.05(m,1H),2.87(s,3H),2.27-2.22(m,1H),2.04-1.97(m,1H),1.93-1.87(m,1H),1.84-1.75(m,1H)。 Compound G-1 (2.00g, 17.4mmol) was dissolved in toluene (20mL), thionyl chloride (2.52mL, 34.7mmol) was added, and the reaction was stirred at 70°C for 3 hours. The reaction solution was concentrated under reduced pressure to obtain intermediate G. ¹ H NMR (400MHz,DMSO-d ₆ )δ4.14-4.09(m,1H),4.02-3.98(m,1H),3.73-3.67(m,1H),3.59-3.53(m,1H),3.13 -3.05(m,1H),2.87(s,3H),2.27-2.22(m,1H),2.04-1.97(m,1H),1.93-1.87(m,1H),1.84-1.75(m,1H) .

实施例1Example 1

合成路线：synthetic route:

第一步first step

将化合物1-1(10g,47.2mmol)溶于四氢呋喃(200mL)中,加入叔丁醇钾(26.5g,236mmol)和二甲基硫铜溴(1.94g,9.43mmol),在0℃下搅拌反应15分钟,向反应液中加入碘甲烷(13.39g,5.87mL),然后在25℃下搅拌反应12小时。向反应液中加入氯化铵溶液(200mL),用乙酸乙酯(150mL×3)萃取,过滤,减压浓缩,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,100/1～2/1,V/V)分离纯化得到化合物1-2。 ¹H NMR(400MHz,CDCl ₃)δ9.00(s,1H),7.20-7.16(m,1H),7.47(d,J＝4.0Hz,1H),7.05(d,J＝1.6Hz,1H),1.39(s,6H)。 Compound 1-1 (10g, 47.2mmol) was dissolved in tetrahydrofuran (200mL), potassium tert-butoxide (26.5g, 236mmol) and dimethylsulfide copper bromide (1.94g, 9.43mmol) were added, stirred at 0°C After reacting for 15 minutes, methyl iodide (13.39 g, 5.87 mL) was added to the reaction solution, and then the reaction was stirred at 25° C. for 12 hours. Ammonium chloride solution (200mL) was added to the reaction solution, extracted with ethyl acetate (150mL×3), filtered, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate, 100/1～2 /1, V/V) separation and purification to obtain compound 1-2. ¹ H NMR (400MHz, CDCl ₃ ) δ9.00(s, 1H), 7.20-7.16(m, 1H), 7.47(d, J=4.0Hz, 1H), 7.05(d, J=1.6Hz, 1H) ,1.39(s,6H).

第二步second step

将化合物1-2(9.50g,39.6mmol)溶于1,2-二氯乙烷(150mL)中,加入三氯化铝(19.0g,142mmol)和化合物1-3(6.61mL,83.1mmol),在0℃下搅拌反应20分钟,然后在50℃下搅拌反应12小时。降至室温后向反应液中加入水(200mL),用乙酸乙酯(150mL×3)萃取,过滤,减压浓缩,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,100/1～2/1,V/V)分离纯化得到化合物1-4。MS-ESI计算值[M+H] ⁺317和319,实测值317和319。 Compound 1-2 (9.50g, 39.6mmol) was dissolved in 1,2-dichloroethane (150mL), aluminum chloride (19.0g, 142mmol) and compound 1-3 (6.61mL, 83.1mmol) were added , the reaction was stirred at 0 °C for 20 min, then at 50 °C for 12 h. After cooling down to room temperature, water (200 mL) was added to the reaction liquid, extracted with ethyl acetate (150 mL×3), filtered, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate, 100/1～ 2/1, V/V) separation and purification to obtain compound 1-4. MS-ESI calculated [M+H] ⁺ 317 and 319, found 317 and 319.

第三步third step

将化合物1-4(3.70g,11.7mmol)溶于吡啶(27mL)中,在90℃下搅拌反应2.5小时,然后在50℃下搅拌反应12小时,过滤,滤饼用乙醇(18mL)洗涤。将滤饼溶于氢氧化钠溶液(2.5M,37mL),在80℃下搅拌反应12小时。降至室温后加入盐酸溶液(5.0M)中和至pH＝3,过滤,减压浓缩,干燥得到化合物1-5。 ¹H NMR(400MHz,DMSO-d ₆)δ10.70(s,1H),7.77(s,1H),7.11(s,1H),1.26(s,6H)。MS-ESI计算值[M+H] ⁺285和287,实测值285和287。 Compound 1-4 (3.70 g, 11.7 mmol) was dissolved in pyridine (27 mL), stirred at 90 °C for 2.5 hours, then stirred at 50 °C for 12 hours, filtered, and the filter cake was washed with ethanol (18 mL). The filter cake was dissolved in sodium hydroxide solution (2.5M, 37mL), and stirred at 80°C for 12 hours. After cooling down to room temperature, hydrochloric acid solution (5.0M) was added to neutralize to pH=3, filtered, concentrated under reduced pressure, and dried to obtain compound 1-5. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.70 (s, 1H), 7.77 (s, 1H), 7.11 (s, 1H), 1.26 (s, 6H). MS-ESI calculated [M+H] ⁺ 285 and 287, found 285 and 287.

第四步the fourth step

将化合物1-5(2.80g,9.86mmol)溶于甲醇(20mL)中,加入浓硫酸(525μL,142mmol),在60℃下搅拌反应24小时。降至室温后向反应液中加入饱和碳酸氢钠溶液(30mL),用乙酸乙酯(30mL×3)萃取,过滤,减压浓缩得化合物1-6。 ¹H NMR(400MHz,DMSO-d ₆)δ10.76(s,1H),7.78(s,1H),7.13(s,1H),3.82(s,3H),1.27(s,6H)。MS-ESI计算值[M+H] ⁺299和301,实测值299和301。 Compound 1-5 (2.80g, 9.86mmol) was dissolved in methanol (20mL), concentrated sulfuric acid (525μL, 142mmol) was added, and the reaction was stirred at 60°C for 24 hours. After cooling down to room temperature, saturated sodium bicarbonate solution (30 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL×3), filtered, and concentrated under reduced pressure to obtain compound 1-6. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.76 (s, 1H), 7.78 (s, 1H), 7.13 (s, 1H), 3.82 (s, 3H), 1.27 (s, 6H). MS-ESI calculated [M+H] ⁺ 299 and 301, found 299 and 301.

第五步the fifth step

将化合物1-6(2.20g,7.38mmol)溶于N,N-二甲基甲酰胺(20mL)中,加入碳酸钾(2.04g,14.8mmol)和碘甲烷(919μL,14.8mmol),在25℃下搅拌反应12小时。向反应液中加入水(20mL),用乙酸乙酯(30mL×3)萃取,过滤,减压浓缩,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,100/1～2/1,V/V)分离纯化得到化合物1-7。 ¹H NMR(400MHz,DMSO-d ₆)δ7.81(s,1H),7.43(s,1H),3.83(s,3H),3.16(s,3H),1.28(s,6H)。 Compound 1-6 (2.20g, 7.38mmol) was dissolved in N,N-dimethylformamide (20mL), potassium carbonate (2.04g, 14.8mmol) and iodomethane (919μL, 14.8mmol) were added, and the The reaction was stirred at °C for 12 hours. Water (20 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL×3), filtered, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate, 100/1～2/1, V/V) separation and purification to obtain compound 1-7. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.81 (s, 1H), 7.43 (s, 1H), 3.83 (s, 3H), 3.16 (s, 3H), 1.28 (s, 6H).

第六步step six

氮气保护下将化合物1-7(2.0g,6.41mmol)溶于甲苯(5mL)中,加入化合物A-5(3.47g,9.61mmol)和双三苯基膦二氯化钯(450mg,0.641mmol),反应液在120℃搅拌反应12小时。降至室温后加入饱和氟化钾溶液(50.0mL)淬灭,用乙酸乙酯(50mL×2)萃取。过滤,减压浓缩得化合物1-8。Compound 1-7 (2.0g, 6.41mmol) was dissolved in toluene (5mL) under nitrogen protection, compound A-5 (3.47g, 9.61mmol) and bistriphenylphosphine palladium dichloride (450mg, 0.641mmol ), the reaction solution was stirred and reacted at 120°C for 12 hours. After cooling down to room temperature, it was quenched by adding saturated potassium fluoride solution (50.0 mL), and extracted with ethyl acetate (50 mL×2). Filter and concentrate under reduced pressure to obtain compound 1-8.

第七步step seven

氮气保护下将化合物1-8(1.95g,6.43mmol)溶于丙酮(50mL)中,0℃下逐滴加入盐酸溶液(12M,11.7mL),在25℃搅拌反应1小时。加入饱和碳酸氢钠溶液碱化至pH＝8,用乙酸乙酯(60mL×2)萃取。有机相用饱和食盐水(100mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶色谱法(石油醚/乙酸乙酯,100/1～1/1,V/V)分离纯化得到化合物1-9。 ¹H NMR(400MHz,DMSO-d ₆)δ7.01(s,1H),6.34(s,1H),2.96(s,3H),2.35(s,3H),1.65(s,3H),0.47(s,6H)。MS-ESI计算值[M+H] ⁺276,实测值276。 Compound 1-8 (1.95g, 6.43mmol) was dissolved in acetone (50mL) under nitrogen protection, hydrochloric acid solution (12M, 11.7mL) was added dropwise at 0°C, and the reaction was stirred at 25°C for 1 hour. Add saturated sodium bicarbonate solution to basify to pH=8, and extract with ethyl acetate (60mL×2). The organic phase was washed with saturated brine (100mL×1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was chromatographed on silica gel (petroleum ether/ethyl acetate, 100/1～1/1, V/V ) separation and purification to obtain compound 1-9. ¹ H NMR (400MHz,DMSO-d ₆ )δ7.01(s,1H),6.34(s,1H),2.96(s,3H),2.35(s,3H),1.65(s,3H),0.47( s, 6H). MS-ESI calculated [M+H] ⁺ 276, found 276.

第八步eighth step

氮气保护下将化合物1-9(785mg,2.85mmol)溶于乙醇(20mL)中,加入水合肼(85％,489μL),在95℃搅拌反应0.5小时。降至室温后将反应液过滤,将滤饼干燥得到化合物1-10。 ¹H NMR(400MHz,DMSO-d ₆)δ12.34(s,1H),8.21(s,1H),7.36(s,1H),3.29(s,3H),2.54(s,3H),1.37(s,6H)。MS-ESI计算值[M+H] ⁺257,实测值257。 Compound 1-9 (785 mg, 2.85 mmol) was dissolved in ethanol (20 mL) under nitrogen protection, hydrazine hydrate (85%, 489 μL) was added, and the reaction was stirred at 95°C for 0.5 hours. After cooling down to room temperature, the reaction solution was filtered, and the filter cake was dried to obtain compound 1-10. ¹ H NMR (400MHz,DMSO-d ₆ )δ12.34(s,1H),8.21(s,1H),7.36(s,1H),3.29(s,3H),2.54(s,3H),1.37( s, 6H). MS-ESI calculated [M+H] ⁺ 257, found 257.

第九步Ninth step

将化合物1-10(570mg,2.22mmol)溶于氯苯(25mL)和三氯氧磷(0.6mL)中,加入N,N-二异丙基乙胺(1.16mL,6.65mmol),在90℃下搅拌反应5小时。将反应液倒入冰水中,用乙酸乙酯(40mL×3)萃取,过滤,减压浓缩,剩余物用硅胶柱色谱法(二氯甲烷/甲醇,100/1～10/1,V/V)分离纯化得到化合物1-11。 ¹H NMR(400MHz,DMSO-d ₆)δ8.23(s,1H),7.62(s,1H),3.34(s,3H),2.89(s,3H),1.43(s,6H)。MS-ESI计算值[M+H] ⁺276,实测值276。 Compound 1-10 (570mg, 2.22mmol) was dissolved in chlorobenzene (25mL) and phosphorus oxychloride (0.6mL), and N,N-diisopropylethylamine (1.16mL, 6.65mmol) was added, at 90 The reaction was stirred at °C for 5 hours. The reaction solution was poured into ice water, extracted with ethyl acetate (40mL×3), filtered, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (dichloromethane/methanol, 100/1～10/1, V/V ) separation and purification to obtain compound 1-11. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.23 (s, 1H), 7.62 (s, 1H), 3.34 (s, 3H), 2.89 (s, 3H), 1.43 (s, 6H). MS-ESI calculated [M+H] ⁺ 276, found 276.

第十步tenth step

将化合物1-11(100mg,363mmol)和中间体A的盐酸盐(135mg,544μmol)溶于1,4-二氧六环(15mL),加入双(二亚苄基丙酮)钯(20.9mg,36.3μmol),(±)-2,2-双(二苯膦基)-1,1-联萘(45.2mg,72.5μmol)和叔丁醇钾(40.7mg,363μmol),在100℃下搅拌反应12小时。降至室温后向反应液中加入水(20mL),用乙酸乙酯(30mL×3)萃取,过滤,减压浓缩后的剩余物经高效液相色谱分离纯化(色谱柱:Phenomenex C18 80mm×40mm×3μm；流动相:0.05％氨水-乙腈；梯度:乙腈47％-65％,8min)得化合物1。 ¹H NMR(400MHz,CD ₃OD)δ8.47(s,1H),7.52(t,J＝8.0Hz,1H),7.42(s,1H),7.33(t,J＝8.0Hz,1H),7.11(t,J＝8.0Hz,1H),5.77-5.69(m,1H),3.37(s,3H),2.72(s,3H),1.69(d,J＝8.0Hz,3H),1.50(s,6H),1.30(d,J＝4.0Hz,6H)。MS-ESI计算值[M+H] ⁺487,实测值487。 Compound 1-11 (100 mg, 363 mmol) and intermediate A hydrochloride (135 mg, 544 μmol) were dissolved in 1,4-dioxane (15 mL), bis(dibenzylideneacetone) palladium (20.9 mg , 36.3μmol), (±)-2,2-bis(diphenylphosphino)-1,1-binaphthyl (45.2mg, 72.5μmol) and potassium tert-butoxide (40.7mg, 363μmol), at 100℃ The reaction was stirred for 12 hours. After cooling down to room temperature, water (20 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL×3), filtered, and the residue after concentration under reduced pressure was separated and purified by high performance liquid chromatography (chromatographic column: Phenomenex C18 80 mm×40 mm ×3 μm; mobile phase: 0.05% ammonia water-acetonitrile; gradient: acetonitrile 47%-65%, 8min) to obtain compound 1. ¹ H NMR (400MHz, CD ₃ OD) δ8.47(s, 1H), 7.52(t, J=8.0Hz, 1H), 7.42(s, 1H), 7.33(t, J=8.0Hz, 1H), 7.11(t, J=8.0Hz, 1H), 5.77-5.69(m, 1H), 3.37(s, 3H), 2.72(s, 3H), 1.69(d, J=8.0Hz, 3H), 1.50(s , 6H), 1.30 (d, J=4.0Hz, 6H). MS-ESI calculated [M+H] ⁺ 487, found 487.

实施例2Example 2

合成路线：synthetic route:

第一步first step

将化合物2-1(9.00g,47.1mmol)溶于N,N-二甲基甲酰胺(100mL)中,在-10℃下加入碘甲烷(20.5ml,330mmol)和钠氢(7.53g,188mmol,60％纯度),在25℃下搅拌反应12小时后,向反应液中加入水(200mL),用乙酸乙酯(200mL×3)萃取,有机相用饱和食盐水(200mL×3)洗涤,无水硫酸钠干燥,过滤,减压浓缩。剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,10/1～2/1,V/V),分离纯化得到化合物2-2。 ¹H NMR(400MHz,CDCl ₃)δ7.81(dd,J＝7.6,1.2Hz,1H),7.51(d,J＝1.2Hz,1H),7.31-7.26(m,1H),3.95(s,3H),3.27(s,3H),1.40(s,6H)。MS-ESI计算值[M+H] ⁺234,实测值234。 Compound 2-1 (9.00g, 47.1mmol) was dissolved in N,N-dimethylformamide (100mL), and iodomethane (20.5ml, 330mmol) and sodium hydrogen (7.53g, 188mmol) were added at -10°C , 60% purity), stirred and reacted at 25°C for 12 hours, added water (200mL) to the reaction solution, extracted with ethyl acetate (200mL×3), washed the organic phase with saturated brine (200mL×3), Dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～2/1, V/V) to obtain compound 2-2. ¹ H NMR (400MHz, CDCl ₃ )δ7.81(dd, J=7.6,1.2Hz,1H),7.51(d,J=1.2Hz,1H),7.31-7.26(m,1H),3.95(s, 3H), 3.27(s,3H), 1.40(s,6H). MS-ESI calculated [M+H] ⁺ 234, found 234.

第二步second step

氮气保护下将化合物2-2(1.00g,3.54mmol)溶于N,N-二甲基甲酰胺(40mL)中,在0℃下加入N-溴代丁二酰亚胺(1.26g,7.09mmol),在25℃下搅拌反应1小时后在100℃下搅拌反应12小时。向反应液加入水(50mL),用乙酸乙酯(50mL×3)萃取,有机相用饱和食盐水(20mL×1)洗涤,无水硫酸钠干燥有机相,过滤,减压浓缩,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,10/1～2/1,V/V),分离纯化得到化合物2-3。 ¹H NMR(400MHz,CDCl ₃)δ7.45(s,1H),7.24(s,1H),3.95(s,3H),3.22(s,3H),1.38(s,6H)。MS-ESI计算值[M+H] ⁺312和314,实测值312和314。 Compound 2-2 (1.00g, 3.54mmol) was dissolved in N,N-dimethylformamide (40mL) under nitrogen protection, and N-bromosuccinimide (1.26g, 7.09 mmol), the reaction was stirred at 25°C for 1 hour and then stirred at 100°C for 12 hours. Add water (50mL) to the reaction solution, extract with ethyl acetate (50mL×3), wash the organic phase with saturated brine (20mL×1), dry the organic phase over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and use Silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～2/1, V/V), separation and purification to obtain compound 2-3. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.45 (s, 1H), 7.24 (s, 1H), 3.95 (s, 3H), 3.22 (s, 3H), 1.38 (s, 6H). MS-ESI calculated [M+H] ⁺ 312 and 314, found 312 and 314.

第三步third step

氮气保护下将化合物2-3(1.12g,3.59mmol)溶于甲苯(15mL)中,加入A-5(2.07g,5.74mmol)和双(三苯基膦)二氯化钯(252mg,359μmol),在120℃下搅拌反应12小时。降至室温后向反应液加入饱和氟化钾水溶液(200mL),用乙酸乙酯(100mL×2)萃取,无水硫酸钠干燥有机相,过滤浓缩得到化合物2-4。MS-ESI计算值[M+H] ⁺304,实测值304。 Compound 2-3 (1.12g, 3.59mmol) was dissolved in toluene (15mL) under nitrogen protection, and A-5 (2.07g, 5.74mmol) and bis(triphenylphosphine)palladium dichloride (252mg, 359μmol) were added ), and the reaction was stirred at 120°C for 12 hours. After cooling down to room temperature, saturated potassium fluoride aqueous solution (200 mL) was added to the reaction solution, extracted with ethyl acetate (100 mL×2), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 2-4. MS-ESI calculated [M+H] ⁺ 304, found 304.

第四步the fourth step

将化合物2-4(1.10g,3.63mmol)溶于丙酮(15mL)中,滴加盐酸溶液(12mol/L,1.50mL),在20℃下搅拌反应1小时。向反应液中加入饱和碳酸氢钠水溶液碱化pH至8,用乙酸乙酯(50mL×3)萃取,有机相用饱和食盐水(50mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物经过硅胶柱色谱法分离纯化(石油醚/乙酸乙酯,100/1～2/1,V/V),得到化合物2-5。MS-ESI计算值[M+H] ⁺276,实测值276。 Compound 2-4 (1.10g, 3.63mmol) was dissolved in acetone (15mL), hydrochloric acid solution (12mol/L, 1.50mL) was added dropwise, and the reaction was stirred at 20°C for 1 hour. Add saturated aqueous sodium bicarbonate solution to the reaction solution to alkalinize the pH to 8, extract with ethyl acetate (50mL×3), wash the organic phase with saturated brine (50mL×1), dry over anhydrous sodium sulfate, filter, and reduce pressure After concentration, the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 100/1～2/1, V/V) to obtain compound 2-5. MS-ESI calculated [M+H] ⁺ 276, found 276.

第五步the fifth step

将化合物2-5(898mg,3.26mmol)溶于乙醇(10mL)中,加入水合肼(9.79mmol,560μL,85％纯度),在95℃下搅拌反应1小时。降至室温后过滤,将滤饼干燥得到化合物2-6。MS-ESI计算值[M+H] ⁺258,实测值258。 Compound 2-5 (898mg, 3.26mmol) was dissolved in ethanol (10mL), hydrazine hydrate (9.79mmol, 560μL, 85% purity) was added, and the reaction was stirred at 95°C for 1 hour. After cooling down to room temperature, filter and dry the filter cake to obtain compound 2-6. MS-ESI calculated value [M+H] ⁺ 258, found value 258.

第六步step six

将化合物2-6(272mg,1.06mmol)溶于三氯氧磷(5mL)中,在90℃下搅拌反应12小时。降至室温后将反应液中倒入水(50mL),加入饱和碳酸氢钠溶液中和至pH为8,用乙酸乙酯(50mL×2)萃取,有机相用饱和食盐水(50mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物经过硅胶柱色谱法分离纯化(石油醚/乙酸乙酯,10/1～0/1,V/V),得到化合物2-7。MS-ESI计算值[M+H] ⁺276,实测值276。 Compound 2-6 (272mg, 1.06mmol) was dissolved in phosphorus oxychloride (5mL), and stirred at 90°C for 12 hours. After cooling down to room temperature, pour water (50mL) into the reaction solution, add saturated sodium bicarbonate solution to neutralize to pH 8, extract with ethyl acetate (50mL×2), and use saturated brine (50mL×1) for the organic phase Washed, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～0/1, V/V) to obtain compound 2-7. MS-ESI calculated [M+H] ⁺ 276, found 276.

第七步step seven

将化合物2-7(300mg,1.09mmol)溶于二氧六环(5mL)中,加入中间体A的盐酸盐(296mg,1.20mmol),4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(126mg,218μmol),碳酸钾(51mg,3.26mmol)和三(二亚苄基丙酮)二钯(100mg,109μmol),在100℃下搅拌反应3小时。降至室温后过滤,减压浓缩。剩余物经制备高效液相色谱分离纯化(色谱柱:Xtimate C18 150×40mm×5μm；流动相:0.05％盐酸水溶液-乙腈；梯度:乙腈15％-45％,10min),得到化合物2的盐酸盐。 ¹H NMR(400MHz,CD ₃OD)δ8.33(s,1H),8.27(s,1H),7.59(t,J＝6.8Hz,1H),7.46-7.32(m,1H),7.27-7.06(m,1H),5.65-5.54(m,1H),3.46(s,3H),2.89(s,3H),1.76(d,J＝6.8Hz,3H),1.56-1.47(m,6H),1.34-1.25(m,6H)。MS-ESI计算值[M+H] ⁺487,实测值487。 Compound 2-7 (300mg, 1.09mmol) was dissolved in dioxane (5mL), and the hydrochloride (296mg, 1.20mmol) of Intermediate A, 4,5-bis(diphenylphosphine)-9 , 9-dimethylxanthene (126mg, 218μmol), potassium carbonate (51mg, 3.26mmol) and tris(dibenzylideneacetone) dipalladium (100mg, 109μmol), stirred and reacted at 100°C for 3 hours. After cooling down to room temperature, it was filtered and concentrated under reduced pressure. The residue was separated and purified by preparative high performance liquid chromatography (column: Xtimate C18 150×40mm×5 μm; mobile phase: 0.05% aqueous hydrochloric acid-acetonitrile; gradient: acetonitrile 15%-45%, 10min), to obtain the hydrochloric acid of compound 2 Salt. ¹ H NMR (400MHz, CD ₃ OD) δ8.33(s, 1H), 8.27(s, 1H), 7.59(t, J=6.8Hz, 1H), 7.46-7.32(m, 1H), 7.27-7.06 (m,1H),5.65-5.54(m,1H),3.46(s,3H),2.89(s,3H),1.76(d,J=6.8Hz,3H),1.56-1.47(m,6H), 1.34-1.25(m,6H). MS-ESI calculated [M+H] ⁺ 487, found 487.

实施例3Example 3

合成路线：synthetic route:

将化合物1-11(60.0mg,218μmol)溶于二氧六环(2mL)中,加入中间体B的盐酸盐(61.7mg,326μmol),(±)-2,2-双(二苯膦基)-1,1-联萘(27.1mg,43.5μmol),叔丁醇钾(24.4mg,218μmol)和双(二亚苄基丙酮)钯(12.5mg,21.8μmol),在100℃下搅拌反应12小时。降至室温后,向反应液中加入水(20mL),用乙酸乙酯(10mL×3)萃取,有机相用饱和食盐水(20mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩。剩余物经制备高效液相色谱分离纯化(色谱柱:Xtimate C18 150×40mm×5μm；流动相:10mM碳酸氢胺水溶液-乙腈；梯度:乙腈35％-65％,10min),得到化合物3。 ¹H NMR(400MHz,CDCl ₃)δ7.71-7.61(m,2H),7.48-7.45(m,1H),7.02-7.61(m,1H),7.14(s,1H),7.05-6.78(m,1H),5.83-5.80(m,1H),4.75(s,1H),3.66 (s,3H),2.79(s,3H),1.76(d,J＝6.8Hz,3H),1.52(d,J＝1.2Hz,6H)。MS-ESI计算值[M+H] ⁺429,实测值429。 Compound 1-11 (60.0 mg, 218 μmol) was dissolved in dioxane (2 mL), and the hydrochloride (61.7 mg, 326 μmol) of intermediate B was added, (±)-2,2-bis(diphenylphosphine base)-1,1-binaphthyl (27.1mg, 43.5μmol), potassium tert-butoxide (24.4mg, 218μmol) and bis(dibenzylideneacetone)palladium (12.5mg, 21.8μmol), stirring at 100°C React for 12 hours. After cooling down to room temperature, water (20 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL×3), the organic phase was washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure . The residue was separated and purified by preparative high performance liquid chromatography (column: Xtimate C18 150×40mm×5 μm; mobile phase: 10 mM aqueous ammonium bicarbonate-acetonitrile; gradient: acetonitrile 35%-65%, 10 min) to obtain compound 3. ¹ H NMR (400MHz, CDCl ₃ )δ7.71-7.61(m,2H),7.48-7.45(m,1H),7.02-7.61(m,1H),7.14(s,1H),7.05-6.78(m ,1H),5.83-5.80(m,1H),4.75(s,1H),3.66(s,3H),2.79(s,3H),1.76(d,J=6.8Hz,3H),1.52(d, J=1.2Hz, 6H). MS-ESI calculated [M+H] ⁺ 429, found 429.

实施例4Example 4

合成路线：synthetic route:

第一步first step

将化合物2-1(5.00g,26.2mmol)溶于N,N-二甲基甲酰胺(100mL)中,在0℃下加入钠氢(2.62g,65.4mmol,60％纯度)和碘甲烷(3.34ml,53.6mmol),在25℃下搅拌反应4小时后,向反应液中加入水(200mL),用乙酸乙酯(200mL×3)萃取,有机相用饱和食盐水(200mL×3)洗涤,无水硫酸钠干燥,过滤,减压浓缩。剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,10/1～2/1,V/V),分离纯化,后再经制备高效液相色谱分离纯化(色谱柱:Xtimate C18 150mm×40mm×5μm；流动相:0.05％盐酸水溶液-乙腈；梯度:乙腈20％-50％,10min),得到化合物4-2。MS-ESI计算值[M+H] ⁺220,实测值220。 Compound 2-1 (5.00g, 26.2mmol) was dissolved in N,N-dimethylformamide (100mL), and sodium hydrogen (2.62g, 65.4mmol, 60% purity) and iodomethane ( 3.34ml, 53.6mmol), stirred and reacted at 25°C for 4 hours, added water (200mL) to the reaction solution, extracted with ethyl acetate (200mL×3), and washed the organic phase with saturated brine (200mL×3) , dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～2/1, V/V), and then separated and purified by preparative high performance liquid chromatography (chromatographic column: Xtimate C18 150mm×40mm ×5 μm; mobile phase: 0.05% hydrochloric acid aqueous solution-acetonitrile; gradient: acetonitrile 20%-50%, 10min), to obtain compound 4-2. MS-ESI calculated value [M+H] ⁺ 220, found value 220.

第二步second step

将化合物4-2(1.10g,5.02mmol)溶于N,N-二甲基甲酰胺(10mL)中,加入4-3(1.05g,7.53mmol)和碳酸钾(1.39g,10.0mmol),在25℃下搅拌反应12小时。向反应液加入水(100mL),用乙酸乙酯(100mL×3)萃取,有机相用饱和食盐水(100mL×3)洗涤,无水硫酸钠干燥有机相,过滤,减压浓缩,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,10/1～3/1,V/V),分离纯化得到化合物4-4。 ¹H NMR(400MHz,CDCl ₃)δ7.81-7.76(m,1H),7.61(d,J＝0.8Hz,1H),7.27-7.23(m,1H),3.98-3.94(m,2H),3.94(s,3H),3.65(t,J＝5.6Hz,2H),3.34(s,3H),1.39(s,6H)。MS-ESI计算值[M+H] ⁺278,实测值278。 Compound 4-2 (1.10g, 5.02mmol) was dissolved in N,N-dimethylformamide (10mL), 4-3 (1.05g, 7.53mmol) and potassium carbonate (1.39g, 10.0mmol) were added, The reaction was stirred at 25°C for 12 hours. Add water (100mL) to the reaction solution, extract with ethyl acetate (100mL×3), wash the organic phase with saturated brine (100mL×3), dry the organic phase over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and use Silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～3/1, V/V), separation and purification to obtain compound 4-4. ¹ H NMR (400MHz, CDCl ₃ ) δ7.81-7.76 (m, 1H), 7.61 (d, J=0.8Hz, 1H), 7.27-7.23 (m, 1H), 3.98-3.94 (m, 2H), 3.94(s, 3H), 3.65(t, J=5.6Hz, 2H), 3.34(s, 3H), 1.39(s, 6H). MS-ESI calculated value [M+H] ⁺ 278, found value 278.

第三步third step

氮气保护下将化合物4-4(1.35g,4.87mmol)溶于N,N-二甲基甲酰胺(10mL)中,在0℃下加入N-溴代丁二酰亚胺(1.73g,9.74mmol),在0℃下搅拌反应0.5小时,在25℃下搅拌反应1小时后在100℃下搅拌反应3小时。降至室温后向反应液加入水(50mL),用乙酸乙酯(50mL×3)萃取,有机相用饱和食盐水(20mL×1)洗涤,无水硫酸钠干燥有机相,过滤,减压浓缩,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,10/1～2/1,V/V),分离纯化得到化合物4-5。 ¹H NMR(400MHz,CDCl ₃)δ7.44(s,1H),7.39(s,1H),3.96(s,3H),3.90(t,J＝5.6Hz,2H),3.62(t,J＝5.6Hz,2H),3.33(s,3H),1.39(s,6H)。MS-ESI计算值[M+H] ⁺356和358,实测值356和358。 Compound 4-4 (1.35g, 4.87mmol) was dissolved in N,N-dimethylformamide (10mL) under nitrogen protection, and N-bromosuccinimide (1.73g, 9.74 mmol), the reaction was stirred at 0°C for 0.5 hours, at 25°C for 1 hour, and then at 100°C for 3 hours. After cooling down to room temperature, water (50 mL) was added to the reaction solution, extracted with ethyl acetate (50 mL×3), the organic phase was washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure , the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～2/1, V/V) to obtain compound 4-5. ¹ H NMR (400MHz, CDCl ₃ ) δ7.44(s, 1H), 7.39(s, 1H), 3.96(s, 3H), 3.90(t, J=5.6Hz, 2H), 3.62(t, J= 5.6Hz, 2H), 3.33(s, 3H), 1.39(s, 6H). MS-ESI calculated [M+H] ⁺ 356 and 358, found 356 and 358.

第四步the fourth step

氮气保护下将化合物4-5(1.30g,3.65mmol)溶于甲苯(10mL)中,加入A-5(2.11g,5.84mmol)和双(三苯基膦)二氯化钯(256mg,365μmol),在120℃下搅拌反应12小时。降至室温后向反应液加入饱和氟化钾水溶液(50mL),用乙酸乙酯(50mL×2)萃取,无水硫酸钠干燥有机相,过滤浓缩得到化合物4-6。Compound 4-5 (1.30g, 3.65mmol) was dissolved in toluene (10mL) under nitrogen protection, and A-5 (2.11g, 5.84mmol) and bis(triphenylphosphine)palladium dichloride (256mg, 365μmol) were added ), and the reaction was stirred at 120°C for 12 hours. After cooling down to room temperature, saturated potassium fluoride aqueous solution (50 mL) was added to the reaction solution, extracted with ethyl acetate (50 mL×2), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 4-6.

第五步the fifth step

将化合物4-6(1.27g,3.66mmol)溶于丙酮(15mL)中,滴加盐酸溶液(12mol/L,1.51mL),在25℃下搅拌反应0.5小时。向反应液中加入饱和碳酸氢钠水溶液碱化pH至8,用乙酸乙酯(50mL×3)萃取,有机相用饱和食盐水(50mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物经过硅胶柱色谱法分离纯化(石油醚/乙酸乙酯,100/1～1/1,V/V),得到化合物4-7。MS-ESI计算值[M+H] ⁺320,实测值320。 Compound 4-6 (1.27g, 3.66mmol) was dissolved in acetone (15mL), hydrochloric acid solution (12mol/L, 1.51mL) was added dropwise, and the reaction was stirred at 25°C for 0.5 hours. Add saturated aqueous sodium bicarbonate solution to the reaction solution to alkalinize the pH to 8, extract with ethyl acetate (50mL×3), wash the organic phase with saturated brine (50mL×1), dry over anhydrous sodium sulfate, filter, and reduce pressure After concentration, the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 100/1～1/1, V/V) to obtain compound 4-7. MS-ESI calculated value [M+H] ⁺ 320, found value 320.

第六步step six

将化合物4-7(1.02g,3.19mmol)溶于乙醇(10mL)中,加入水合肼(9.58mmol,548μL,85％纯度),在95℃下搅拌反应1小时。降至室温后过滤,将滤饼干燥得到化合物4-8。MS-ESI计算值[M+H] ⁺302,实测值302。 Compound 4-7 (1.02 g, 3.19 mmol) was dissolved in ethanol (10 mL), hydrazine hydrate (9.58 mmol, 548 μL, 85% purity) was added, and the reaction was stirred at 95°C for 1 hour. After cooling down to room temperature, filter, and dry the filter cake to obtain compound 4-8. MS-ESI calculated value [M+H] ⁺ 302, found value 302.

第七步step seven

将化合物4-8(200mg,664μmol)溶于三氯氧磷(3mL)中,在90℃下搅拌反应12小时。降至室温后将水(50mL)倒入反应液中,加入饱和碳酸氢钠溶液中和至pH为8,用乙酸乙酯(50mL×2)萃取,有机相用饱和食盐水(50mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物经过硅胶柱色谱法分离纯化(石油醚/乙酸乙酯,10/1～0/1,V/V),得到化合物4-9。MS-ESI计算值[M+H] ⁺320,实测值320。 Compound 4-8 (200mg, 664μmol) was dissolved in phosphorus oxychloride (3mL), and stirred at 90°C for 12 hours. After cooling down to room temperature, pour water (50mL) into the reaction solution, add saturated sodium bicarbonate solution to neutralize to pH 8, extract with ethyl acetate (50mL×2), and use saturated brine (50mL×1) for the organic phase Washed, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～0/1, V/V) to obtain compound 4-9. MS-ESI calculated value [M+H] ⁺ 320, found value 320.

第八步eighth step

将化合物4-9(177mg,554μmol)溶于二氧六环(5mL)中,加入中间体A的盐酸盐(164mg,664mmol),4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(50.7mg,55.4μmol),碳酸铯(541mg,1.66mmol)和三(二亚苄基丙酮)二钯(64.1mg,111μmol),在100℃下搅拌反应12小时。过滤,减压浓缩。剩余物经制备高效液相色谱分离纯化(色谱柱:Xtimate C18 150mm×40mm×5μm；流动相:0.05％盐酸水溶液-乙腈；梯度:乙腈14％-44％,10min),得到化合物4的盐酸盐。 ¹H NMR(400MHz,CD ₃OD)δ8.40-8.24(m,2H),7.57(t,J＝6.4Hz,1H),7.39(t,J＝6.4Hz,1H),7.25-7.11(m,1H),5.63-5.54(m,1H),4.25-4.07(m,2H),3.78(t,J＝5.0Hz,2H),3.34(s,3H), 2.89(s,3H),1.76(d,J＝6.4Hz,3H),1.55-1.43(m,6H),1.33-1.26(m,6H)。MS-ESI计算值[M+H] ⁺531,实测值531。 Compound 4-9 (177 mg, 554 μmol) was dissolved in dioxane (5 mL), and the hydrochloride (164 mg, 664 mmol) of Intermediate A, 4,5-bis(diphenylphosphine)-9,9 -Dimethylxanthene (50.7mg, 55.4μmol), cesium carbonate (541mg, 1.66mmol) and tris(dibenzylideneacetone) dipalladium (64.1mg, 111μmol), stirred at 100°C for 12 hours. Filter and concentrate under reduced pressure. The residue was separated and purified by preparative high performance liquid chromatography (chromatographic column: Xtimate C18 150mm×40mm×5μm; mobile phase: 0.05% aqueous hydrochloric acid-acetonitrile; gradient: acetonitrile 14%-44%, 10min), to obtain the hydrochloric acid of compound 4 Salt. ¹ H NMR (400MHz, CD ₃ OD) δ8.40-8.24(m, 2H), 7.57(t, J=6.4Hz, 1H), 7.39(t, J=6.4Hz, 1H), 7.25-7.11(m ,1H),5.63-5.54(m,1H),4.25-4.07(m,2H),3.78(t,J＝5.0Hz,2H),3.34(s,3H), 2.89(s,3H),1.76( d, J=6.4Hz, 3H), 1.55-1.43(m, 6H), 1.33-1.26(m, 6H). MS-ESI calculated value [M+H] ⁺ 531, found value 531.

实施例5Example 5

合成路线：synthetic route:

将化合物2-7(250mg,0.907mmol)溶于二氧六环(5mL)中,加入中间体B的盐酸盐(206mg,1.09mmol),1,1’-联萘-2,2’-二苯膦(113mg,181μmol),叔丁醇钾(203mg,1.81mmol)和二(二亚苄基丙酮)钯(52.1mg,90.7μmol),在100℃下搅拌反应12小时。降至室温后,过滤,将滤液减压浓缩。剩余物经制备高效液相色谱分离纯化(色谱柱:Xtimate C18 150mm×40mm×5μm；流动相:0.05％盐酸水溶液-乙腈；梯度:乙腈15％-45％,10min),得到化合物5的盐酸盐。 ¹H NMR(400MHz,CD ₃OD)δ8.33(s,1H),8.25(s,1H),7.64(t,J＝7.2Hz,1H),7.50(t,J＝7.2Hz,1H),7.24(t,J＝7.2Hz,1H),7.00(t,J＝109.2Hz,1H),5.60-5.56(m,1H),3.46(s,3H),2.89(s,3H),1.77(d,J＝6.8Hz,3H),1.50(d,J＝4.0Hz,6H)。MS-ESI计算值[M+H] ⁺429,实测值429。 Compound 2-7 (250mg, 0.907mmol) was dissolved in dioxane (5mL), and the hydrochloride (206mg, 1.09mmol) of Intermediate B, 1,1'-binaphthyl-2,2'- Diphenylphosphine (113mg, 181μmol), potassium tert-butoxide (203mg, 1.81mmol) and bis(dibenzylideneacetone)palladium (52.1mg, 90.7μmol) were stirred at 100°C for 12 hours. After cooling down to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by preparative high performance liquid chromatography (chromatographic column: Xtimate C18 150mm×40mm×5μm; mobile phase: 0.05% aqueous hydrochloric acid-acetonitrile; gradient: acetonitrile 15%-45%, 10min), to obtain the hydrochloric acid of compound 5 Salt. ¹ H NMR (400MHz, CD ₃ OD) δ8.33(s, 1H), 8.25(s, 1H), 7.64(t, J=7.2Hz, 1H), 7.50(t, J=7.2Hz, 1H), 7.24(t, J=7.2Hz, 1H), 7.00(t, J=109.2Hz, 1H), 5.60-5.56(m, 1H), 3.46(s, 3H), 2.89(s, 3H), 1.77(d , J=6.8Hz, 3H), 1.50(d, J=4.0Hz, 6H). MS-ESI calculated [M+H] ⁺ 429, found 429.

实施例6Example 6

合成路线：synthetic route:

将化合物2-7(100mg,363μmol)溶于二氧六环(6mL)中,加入中间体C的盐酸盐(88.6mg,399μmol), 4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(42.0mg,72.5μmol),碳酸钾(150mg,1.09mmol)和三(二亚苄基丙酮)二钯(33.2mg,36.3μmol),在100℃下搅拌反应12小时。向反应液中加入水(50mL),用乙酸乙酯(50mL×2)萃取,有机相用饱和食盐水(50mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩。剩余物经制备高效液相色谱分离纯化(色谱柱:Xtimate C18 150mm×40mm×5μm；流动相:0.05％盐酸水溶液-乙腈；梯度:乙腈：5％-35％,10min),得到化合物6的盐酸盐。 ¹H NMR(400MHz,CD ₃OD)δ8.47(s,1H),8.42-8.30(m,3H),4.81-4.64(m,1H),3.50(s,3H),3.05(s,3H),1.77(d,J＝6.8Hz,3H),1.54(s,6H)。MS-ESI计算值[M+H] ⁺462,实测值462。 Compound 2-7 (100 mg, 363 μmol) was dissolved in dioxane (6 mL), and the hydrochloride (88.6 mg, 399 μmol) of Intermediate C, 4,5-bis(diphenylphosphine)-9, 9-Dimethylxanthene (42.0 mg, 72.5 μmol), potassium carbonate (150 mg, 1.09 mmol) and tris(dibenzylideneacetone) dipalladium (33.2 mg, 36.3 μmol) were stirred at 100°C for reaction 12 Hour. Water (50 mL) was added to the reaction solution, extracted with ethyl acetate (50 mL×2), the organic phase was washed with saturated brine (50 mL×1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by preparative high-performance liquid chromatography (chromatographic column: Xtimate C18 150mm×40mm×5μm; mobile phase: 0.05% aqueous hydrochloric acid-acetonitrile; gradient: acetonitrile: 5%-35%, 10min), and the salt of compound 6 was obtained salt. ¹ H NMR(400MHz,CD ₃ OD)δ8.47(s,1H),8.42-8.30(m,3H),4.81-4.64(m,1H),3.50(s,3H),3.05(s,3H) , 1.77 (d, J=6.8Hz, 3H), 1.54 (s, 6H). MS-ESI calculated [M+H] ⁺ 462, found 462.

实施例7Example 7

合成路线：synthetic route:

将化合物2-7(100mg,363μmol)溶于二氧六环(6mL)中,加入中间体D的盐酸盐(69.7mg,435μmol),双(二亚苄基丙酮)钯(20.9mg,36.3μmol),叔丁醇钾(81.4mg,725μmol)和2,2-二(二苯基膦基)-1,1-联萘(45.2mg,72.5μmol),在100℃下搅拌反应4小时。过滤,减压浓缩。剩余物经制备高效液相色谱分离纯化(色谱柱:Phenomenex C18 80mm×40mm×3μm；流动相:0.05％氨水溶液-乙腈；梯度:乙腈：39％-69％,8min),得到化合物7。 ¹H NMR(400MHz,CD ₃OD)δ7.97(s,1H),7.94(s,1H),7.74(d,J＝8.0Hz,1H),7.48(d,J＝7.6Hz,1H),7.23(t,J＝7.6Hz,1H),5.59-5.56(m,1H),3.38(s,3H),2.74(s,3H),2.70(s,3H),1.64(d,J＝6.8Hz,3H),1.51-1.42(m,6H)。MS-ESI计算值[M+H] ⁺400,实测值400。 Compound 2-7 (100 mg, 363 μmol) was dissolved in dioxane (6 mL), and intermediate D hydrochloride (69.7 mg, 435 μmol), bis(dibenzylideneacetone) palladium (20.9 mg, 36.3 μmol), potassium tert-butoxide (81.4mg, 725μmol) and 2,2-bis(diphenylphosphino)-1,1-binaphthyl (45.2mg, 72.5μmol), stirred and reacted at 100°C for 4 hours. Filter and concentrate under reduced pressure. The residue was separated and purified by preparative high performance liquid chromatography (column: Phenomenex C18 80mm×40mm×3μm; mobile phase: 0.05% ammonia solution-acetonitrile; gradient: acetonitrile: 39%-69%, 8min) to obtain compound 7. ¹ H NMR (400MHz, CD ₃ OD) δ7.97(s, 1H), 7.94(s, 1H), 7.74(d, J=8.0Hz, 1H), 7.48(d, J=7.6Hz, 1H), 7.23(t, J=7.6Hz, 1H), 5.59-5.56(m, 1H), 3.38(s, 3H), 2.74(s, 3H), 2.70(s, 3H), 1.64(d, J=6.8Hz ,3H), 1.51-1.42(m,6H). MS-ESI calculated value [M+H] ⁺ 400, measured value 400.

实施例8Example 8

合成路线：synthetic route:

第一步first step

将化合物8-1(10.0g,44.2mmol)溶于乙腈(150mL)中,加入碳酸钾(24.5g,177mmol)和碘甲烷(12.6g,88.5mmol),反应液在60℃下搅拌反应12小时。降至室温后,向反应液加入水(150mL),用二氯甲烷(150mL×5)萃取,无水硫酸钠干燥有机相,过滤浓缩得到化合物8-2。Compound 8-1 (10.0g, 44.2mmol) was dissolved in acetonitrile (150mL), potassium carbonate (24.5g, 177mmol) and methyl iodide (12.6g, 88.5mmol) were added, and the reaction solution was stirred at 60°C for 12 hours . After cooling down to room temperature, water (150 mL) was added to the reaction solution, extracted with dichloromethane (150 mL×5), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 8-2.

第二步second step

将化合物8-2(10.2g,42.5mmol)溶于甲醇(60mL),N,N-二甲基甲酰胺(20mL)和三乙胺(20mL)中,加入1,1-双(二苯基膦)二茂铁氯化钯(3.11g,4.25mmol),在一氧化碳(45psi),80℃下搅拌反应12小时。降至室温后,向反应液加入水(100mL),用乙酸乙酯(50mL×5)萃取,有机相用饱和食盐水(100mL×2)洗涤,无水硫酸钠干燥有机相,过滤,减压浓缩,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,100/1～2/1,V/V),分离纯化得到化合物8-3。 ¹H NMR(400MHz,CDCl ₃)δ7.84-7.82(m,1H),7.68(d,J＝7.6Hz,1H),7.55(s,1H),3.99(s,3H),3.32(s,3H)。MS-ESI计算值[M+H] ⁺220,实测值220。 Compound 8-2 (10.2g, 42.5mmol) was dissolved in methanol (60mL), N,N-dimethylformamide (20mL) and triethylamine (20mL), and 1,1-bis(diphenyl Phosphine) ferrocenepalladium chloride (3.11g, 4.25mmol), stirred and reacted under carbon monoxide (45psi) at 80°C for 12 hours. After cooling down to room temperature, water (100 mL) was added to the reaction solution, extracted with ethyl acetate (50 mL×5), the organic phase was washed with saturated brine (100 mL×2), the organic phase was dried over anhydrous sodium sulfate, filtered, and reduced pressure After concentration, the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 100/1～2/1, V/V) to obtain compound 8-3. ¹ H NMR (400MHz, CDCl ₃ )δ7.84-7.82(m,1H),7.68(d,J=7.6Hz,1H),7.55(s,1H),3.99(s,3H),3.32(s, 3H). MS-ESI calculated value [M+H] ⁺ 220, found value 220.

第三步third step

将化合物8-3(500mg,2.28mmol)溶于二氯甲烷(5mL)中,在20℃下加入二甲基锌的甲苯溶液(1M,13.7mL),在25℃下搅拌反应12小时。向反应液中加入饱和氯化铵水溶液(20mL)淬灭,用乙酸乙酯(20mL×5)萃取,有机相用饱和食盐水(30mL×2)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物经过硅胶柱色谱法分离纯化(石油醚/乙酸乙酯,20/1～5/1,V/V),得到化合物8-4。MS-ESI计算值[M+H-18] ⁺218,实测值218。 Compound 8-3 (500mg, 2.28mmol) was dissolved in dichloromethane (5mL), a toluene solution of dimethyl zinc (1M, 13.7mL) was added at 20°C, and the reaction was stirred at 25°C for 12 hours. Add saturated ammonium chloride aqueous solution (20mL) to the reaction solution to quench, extract with ethyl acetate (20mL×5), wash the organic phase with saturated brine (30mL×2), dry over anhydrous sodium sulfate, filter, and reduce pressure After concentration, the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 20/1～5/1, V/V) to obtain compound 8-4. MS-ESI calculated value [M+H-18] ⁺ 218, found value 218.

第四步the fourth step

将化合物8-4(110mg,467μmol)溶于四氢呋喃(5mL)中,在0℃下加入氢氧化钠(37.4mg,935μmol)和碘甲烷(133mg,935μmol),在25℃下搅拌反应12小时。向反应液加入水(50mL),用乙酸乙酯(40mL×5)萃取,有机相用饱和食盐水(100mL×2)洗涤,无水硫酸钠干燥有机相,过滤,减压浓缩,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,5/1～5/1,V/V),分离纯化得到化合物8-5。 ¹H NMR(400MHz,CDCl ₃)δ7.86-7.84(m,1H),7.51(d,J＝1.2Hz,1H),7.40(d,J＝7.6Hz,1H),3.96(s,3H),3.28(s,3H),3.03(s,3H),1.57(s,3H)。MS-ESI计算值[M+H-32] ⁺218,实测值218。 Compound 8-4 (110 mg, 467 μmol) was dissolved in tetrahydrofuran (5 mL), sodium hydroxide (37.4 mg, 935 μmol) and methyl iodide (133 mg, 935 μmol) were added at 0°C, and the reaction was stirred at 25°C for 12 hours. Add water (50mL) to the reaction solution, extract with ethyl acetate (40mL×5), wash the organic phase with saturated brine (100mL×2), dry the organic phase over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and use Silica gel column chromatography (petroleum ether/ethyl acetate, 5/1～5/1, V/V), separation and purification to obtain compound 8-5. ¹ H NMR (400MHz, CDCl ₃ ) δ7.86-7.84 (m, 1H), 7.51 (d, J = 1.2Hz, 1H), 7.40 (d, J = 7.6Hz, 1H), 3.96 (s, 3H) ,3.28(s,3H),3.03(s,3H),1.57(s,3H). MS-ESI calculated value [M+H-32] ⁺ 218, found value 218.

第五步the fifth step

氮气保护下将化合物8-5(110mg,441μmol)溶于N,N-二甲基甲酰胺(2mL)中,在0℃下加入N-溴代丁二酰亚胺(157mmol,882μmol),在0℃下搅拌反应0.5小时,25℃下搅拌反应1小时,100℃下搅拌反应3小时。降至室温后,向反应液加入水(20mL),用乙酸乙酯(15mL×3)萃取,有机相用饱和食盐水(20 mL×1)洗涤,无水硫酸钠干燥有机相,过滤,减压浓缩,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,10/1～2/1,V/V),分离纯化得到化合物8-6。 ¹H NMR(400MHz,CDCl ₃)δ7.57(s,1H),7.22(s,1H),3.96(s,3H),3.23(s,3H),3.03(s,3H),1.80(s,3H)。MS-ESI计算值[M+H-32] ⁺298,实测值298。 Compound 8-5 (110mg, 441μmol) was dissolved in N,N-dimethylformamide (2mL) under nitrogen protection, and N-bromosuccinimide (157mmol, 882μmol) was added at 0°C. The reaction was stirred at 0°C for 0.5 hours, at 25°C for 1 hour, and at 100°C for 3 hours. After cooling down to room temperature, water (20 mL) was added to the reaction solution, extracted with ethyl acetate (15 mL×3), the organic phase was washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate, filtered, and reduced Concentrate under reduced pressure, and the residue is separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～2/1, V/V) to obtain compound 8-6. ¹ H NMR (400MHz, CDCl ₃ )δ7.57(s,1H),7.22(s,1H),3.96(s,3H),3.23(s,3H),3.03(s,3H),1.80(s, 3H). MS-ESI calculated value [M+H-32] ⁺ 298, found value 298.

第六步step six

氮气保护下将化合物8-6(144mg,438μmol)溶于甲苯(2mL)中,加入中间体A-5(211mg,584μmol)和双(三苯基膦)二氯化钯(30.8mg,43.9μmol),在120℃下搅拌反应12小时。降至室温后,向反应液加入饱和氟化钾水溶液(12mL),用乙酸乙酯(20mL×2)萃取,无水硫酸钠干燥有机相,过滤浓缩得到化合物8-7。MS-ESI计算值[M+H-32] ⁺288,实测值288。 Compound 8-6 (144 mg, 438 μmol) was dissolved in toluene (2 mL) under nitrogen protection, and intermediate A-5 (211 mg, 584 μmol) and bis(triphenylphosphine) palladium dichloride (30.8 mg, 43.9 μmol) were added ), and the reaction was stirred at 120°C for 12 hours. After cooling down to room temperature, saturated potassium fluoride aqueous solution (12 mL) was added to the reaction solution, extracted with ethyl acetate (20 mL×2), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 8-7. MS-ESI calculated value [M+H-32] ⁺ 288, found value 288.

第七步step seven

将化合物8-7(140mg,438μmol)溶于丙酮(128mL)中,在0℃下滴加盐酸溶液(12M,292μL),在25℃下搅拌反应1小时。向反应液中加入饱和碳酸氢钠水溶液碱化pH至8,用乙酸乙酯(500mL×3)萃取,有机相用饱和食盐水(250mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物经过硅胶柱色谱法分离纯化(石油醚/乙酸乙酯,20/1～5/1,V/V),得到化合物8-8。 ¹H NMR(400MHz,CD ₃OD)δ7.53(s,1H),7.19(s,1H),3.26(s,3H),2.97(s,3H),2.57(s,3H),1.90(s,3H)。MS-ESI计算值[M+H-32] ⁺260,实测值260。 Compound 8-7 (140mg, 438μmol) was dissolved in acetone (128mL), hydrochloric acid solution (12M, 292μL) was added dropwise at 0°C, and the reaction was stirred at 25°C for 1 hour. Add saturated aqueous sodium bicarbonate solution to the reaction solution to alkalinize the pH to 8, extract with ethyl acetate (500mL×3), wash the organic phase with saturated brine (250mL×1), dry over anhydrous sodium sulfate, filter, and reduce pressure After concentration, the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 20/1～5/1, V/V) to obtain compound 8-8. ¹ H NMR (400MHz, CD ₃ OD) δ7.53(s,1H),7.19(s,1H),3.26(s,3H),2.97(s,3H),2.57(s,3H),1.90(s ,3H). MS-ESI calculated value [M+H-32] ⁺ 260, measured value 260.

第八步eighth step

将化合物8-8(128mg,436μmol)溶于乙醇(5mL)中,加入水合肼(74.9μL,1.31mmol,85％纯度),在95℃下搅拌反应1小时。降至室温后,过滤,将滤饼干燥得到化合物8-9。 ¹H NMR(400MHz,CDCl ₃)δ7.84(s,1H),7.74(s,1H),3.36(s,3H),3.09(s,3H),2.62(s,3H),1.66(s,3H)。MS-ESI计算值[M+H] ⁺274,实测值274。 Compound 8-8 (128 mg, 436 μmol) was dissolved in ethanol (5 mL), hydrazine hydrate (74.9 μL, 1.31 mmol, 85% purity) was added, and the reaction was stirred at 95°C for 1 hour. After cooling down to room temperature, filter and dry the filter cake to obtain compound 8-9. ¹ H NMR (400MHz, CDCl ₃ )δ7.84(s,1H),7.74(s,1H),3.36(s,3H),3.09(s,3H),2.62(s,3H),1.66(s, 3H). MS-ESI calculated [M+H] ⁺ 274, found 274.

第九步Ninth step

将化合物8-9(70mg,256μmol)溶于三氯氧磷(2mL)中,在90℃下搅拌反应12小时。降至室温后,向反应液中倒入冰水(10mL),用乙酸乙酯(40mL×3)萃取,有机相用饱和食盐水(100mL×2)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物经过硅胶柱色谱法分离纯化(二氯甲烷/甲醇,1/0～0/1,V/V),得到化合物8-10。 ¹H NMR(400MHz,CDCl ₃)δ8.00(s,1H),7.52(s,1H),3.43(s,3H),3.11(s,3H),3.01(s,3H),1.68(s,3H)。MS-ESI计算值[M+H] ⁺292,实测值292。 Compound 8-9 (70mg, 256μmol) was dissolved in phosphorus oxychloride (2mL), and stirred at 90°C for 12 hours. After cooling down to room temperature, pour ice water (10 mL) into the reaction solution, extract with ethyl acetate (40 mL×3), wash the organic phase with saturated brine (100 mL×2), dry over anhydrous sodium sulfate, filter, and reduce Concentrate under reduced pressure, and the residue is separated and purified by silica gel column chromatography (dichloromethane/methanol, 1/0～0/1, V/V) to obtain compound 8-10. ¹ H NMR (400MHz, CDCl ₃ )δ8.00(s,1H),7.52(s,1H),3.43(s,3H),3.11(s,3H),3.01(s,3H),1.68(s, 3H). MS-ESI calculated value [M+H] ⁺ 292, found value 292.

第十步tenth step

氮气保护下将化合物8-10(68mg,233μmol)溶于二氧六环(2mL)中,加入中间体B的盐酸盐(66.1mg,350μmol),(±)-2,2-双(二苯膦基)-1,1-联萘(29.0mg,46.6μmol),碳酸钾(26.2mg,233μmol)和双(二亚苄基丙酮)钯(13.4mg,23.3μmol),在100℃下搅拌反应12小时。降至室温后,向反应液加入水(20mL),用乙酸乙酯(10mL×3)萃取,有机相用饱和食盐水(20mL×1)洗涤,无水硫酸钠干燥有机相,过滤,减压浓缩。剩余物经制备高效液相色谱分离纯化(色谱柱:Phenomenex C18 150mm×40mm×5μm；流动相:0.05％盐酸水溶液-乙腈；梯度:乙腈：18％-48％,10min),得到化合物8的盐酸盐。 ¹H NMR(400MHz,CD ₃OD)δ8.36(s,1H),8.29(s,1H),7.65(t,J＝7.2Hz,1H),7.50(t,J＝6.4Hz,1H),7.25(t,J＝7.6Hz,1H),7.13-6.86(m,1H),5.62-5.56(m,1H),3.47(s,3H),3.05(d,J＝8.0Hz,3H),2.90(s,3H),1.77(d,J＝6.8Hz,3H),1.64(d,J＝4.4Hz,3H)。MS-ESI计算值[M+H] ⁺445,实测值445。 Compound 8-10 (68 mg, 233 μmol) was dissolved in dioxane (2 mL) under nitrogen protection, and the hydrochloride (66.1 mg, 350 μmol) of intermediate B was added, (±)-2,2-bis(di Phenylphosphino)-1,1-binaphthyl (29.0 mg, 46.6 μmol), potassium carbonate (26.2 mg, 233 μmol) and bis(dibenzylideneacetone) palladium (13.4 mg, 23.3 μmol), stirred at 100 ° C React for 12 hours. After cooling down to room temperature, water (20 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL×3), the organic phase was washed with saturated brine (20 mL×1), the organic phase was dried over anhydrous sodium sulfate, filtered, and reduced pressure concentrate. The residue was separated and purified by preparative high performance liquid chromatography (chromatographic column: Phenomenex C18 150mm×40mm×5μm; mobile phase: 0.05% hydrochloric acid aqueous solution-acetonitrile; gradient: acetonitrile: 18%-48%, 10min), and the salt of compound 8 was obtained salt. ¹ H NMR (400MHz, CD ₃ OD) δ8.36(s, 1H), 8.29(s, 1H), 7.65(t, J=7.2Hz, 1H), 7.50(t, J=6.4Hz, 1H), 7.25(t, J=7.6Hz, 1H), 7.13-6.86(m, 1H), 5.62-5.56(m, 1H), 3.47(s, 3H), 3.05(d, J=8.0Hz, 3H), 2.90 (s, 3H), 1.77 (d, J=6.8Hz, 3H), 1.64 (d, J=4.4Hz, 3H). MS-ESI calculated [M+H] ⁺ 445, found 445.

实施例9Example 9

合成路线：synthetic route:

第一步first step

将化合物9-1(1.00g,5.10mmol)溶于乙酸(8mL)中,在0℃下加入液溴(2.44g,15.3mmol),在0℃下搅拌反应1.5小时后,在25℃下搅拌反应10小时。向反应液加入水(100mL),并加入亚硫酸钠(2g)淬灭反应,用二氯甲烷(100mL×1)萃取,有机相用饱和食盐水(20mL×1)洗涤,无水硫酸钠干燥有机相,过滤,减压浓缩,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,10/1～3/1,V/V),分离纯化得到化合物9-2。 ¹H NMR(400MHz,CDCl ₃)δ7.41(s,1H),7.10(s,1H),3.94-3.88(m,9H)。MS-ESI计算值[M+H] ⁺275和277,实测值275和277。 Compound 9-1 (1.00g, 5.10mmol) was dissolved in acetic acid (8mL), liquid bromine (2.44g, 15.3mmol) was added at 0°C, stirred at 0°C for 1.5 hours, then stirred at 25°C React for 10 hours. Add water (100mL) to the reaction solution, and add sodium sulfite (2g) to quench the reaction, extract with dichloromethane (100mL×1), wash the organic phase with saturated brine (20mL×1), and dry the organic phase over anhydrous sodium sulfate , filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～3/1, V/V) to obtain compound 9-2. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.41 (s, 1H), 7.10 (s, 1H), 3.94-3.88 (m, 9H). MS-ESI calculated [M+H] ⁺ 275 and 277, found 275 and 277.

第二步second step

氮气保护下将化合物9-2(969mg,2.98mmol)溶于甲苯(15mL)中,加入A-5(1.61g,4.47mmol)和双(三苯基膦)二氯化钯(209mg,298μmol),在120℃下搅拌反应12小时。降至室温后向反应液加入饱和氟化钾水溶液(100mL),用乙酸乙酯(100mL×2)萃取,无水硫酸钠干燥有机相,过滤浓缩得到化合物9-3。MS-ESI计算值[M+H] ⁺267,实测值267。 Compound 9-2 (969mg, 2.98mmol) was dissolved in toluene (15mL) under nitrogen protection, and A-5 (1.61g, 4.47mmol) and bis(triphenylphosphine)palladium dichloride (209mg, 298μmol) were added , The reaction was stirred at 120°C for 12 hours. After cooling down to room temperature, saturated potassium fluoride aqueous solution (100 mL) was added to the reaction solution, extracted with ethyl acetate (100 mL×2), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 9-3. MS-ESI calculated [M ⁺ H]+267, found 267.

第三步third step

将化合物9-3(793mg,2.98mmol)溶于丙酮(15mL)中,滴加盐酸溶液(12mol/L,1.50mL),在25℃下搅拌反应1小时。向反应液中加入饱和碳酸氢钠水溶液碱化pH至8,用乙酸乙酯(50mL×3)萃取,有机相用饱和食盐水(50mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物经过硅胶柱色谱法分离纯化(石油醚/乙酸乙酯,10/1～2/1,V/V),得到化合物9-4。MS-ESI计算值[M+H] ⁺239,实测值239。 Compound 9-3 (793mg, 2.98mmol) was dissolved in acetone (15mL), hydrochloric acid solution (12mol/L, 1.50mL) was added dropwise, and the reaction was stirred at 25°C for 1 hour. Add saturated aqueous sodium bicarbonate solution to the reaction solution to alkalinize the pH to 8, extract with ethyl acetate (50mL×3), wash the organic phase with saturated brine (50mL×1), dry over anhydrous sodium sulfate, filter, and reduce pressure After concentration, the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～2/1, V/V) to obtain compound 9-4. MS-ESI calculated [M+H] ⁺ 239, found 239.

第四步the fourth step

将化合物9-4(606mg,2.28mmol)溶于乙醇(10mL)中,加入水合肼(391μL,6.83mmol,85％纯度),在95℃下搅拌反应1小时。过滤,将滤饼干燥得到化合物9-5。MS-ESI计算值[M+H] ⁺221,实测值221。 Compound 9-4 (606mg, 2.28mmol) was dissolved in ethanol (10mL), hydrazine hydrate (391μL, 6.83mmol, 85% purity) was added, and the reaction was stirred at 95°C for 1 hour. Filter and dry the filter cake to obtain compound 9-5. MS-ESI calculated value [M+H] ⁺ 221, found value 221.

第五步the fifth step

将化合物9-5(500mg,2.27mmol)溶于氢溴酸(10mL,48％纯度)中,在120℃下搅拌反应48小时。降至室温,减压浓缩,向反应液中加入水(20mL),过滤,将滤饼干燥得到化合物9-6。 ¹H NMR(400MHz,CDCl ₃)δ7.51(s,1H),7.10(s,1H),2.37(s,3H)。MS-ESI计算值[M+H] ⁺193,实测值193。 Compound 9-5 (500mg, 2.27mmol) was dissolved in hydrobromic acid (10mL, 48% purity), and the reaction was stirred at 120°C for 48 hours. Cool down to room temperature, concentrate under reduced pressure, add water (20 mL) to the reaction solution, filter, and dry the filter cake to obtain compound 9-6. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.51 (s, 1H), 7.10 (s, 1H), 2.37 (s, 3H). MS-ESI calculated value [M+H] ⁺ 193, found value 193.

第六步step six

将化合物9-6(440mg,2.29mmol)和中间体F(1.06g,2.29mmol)溶于N,N-二甲基甲酰胺(10mL)中,加入碳酸钾(1.27g,9.16mmol),在80℃下搅拌反应12小时。降至室温后向反应液加入水(50mL),用乙酸乙酯(50mL×5)萃取,有机相用饱和食盐水(50mL×3)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,10/1～1/3,V/V)分离纯化得化合物9-7。 ¹H NMR(400MHz,CDCl ₃)δ8.03(s,1H),7.35(s,1H),4.60-4.53(m,1H),4.43-4.35(m,2H),4.33-4.27(m,1H),3.58-3.52(m,2H),2.49(s,3H)。产率：42％。MS-ESI计算值[M+H] ⁺313,实测值313。 Compound 9-6 (440mg, 2.29mmol) and intermediate F (1.06g, 2.29mmol) were dissolved in N,N-dimethylformamide (10mL), potassium carbonate (1.27g, 9.16mmol) was added, and The reaction was stirred at 80°C for 12 hours. After cooling down to room temperature, water (50 mL) was added to the reaction solution, extracted with ethyl acetate (50 mL×5), the organic phase was washed with saturated brine (50 mL×3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the remaining The product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～1/3, V/V) to obtain compound 9-7. ¹ H NMR (400MHz, CDCl ₃ )δ8.03(s,1H),7.35(s,1H),4.60-4.53(m,1H),4.43-4.35(m,2H),4.33-4.27(m,1H ), 3.58-3.52(m,2H), 2.49(s,3H). Yield: 42%. MS-ESI calculated [M+H] ⁺ 313, found 313.

第七步step seven

将化合物9-7(200mg,640μmol)溶于三氯氧磷(5mL)中,在90℃下搅拌反应12小时。降至室温后将水(10mL)倒入反应液中,加入饱和碳酸氢钠溶液中和至pH为8,用乙酸乙酯(10mL×2)萃取,有机相用饱和食盐水(10mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物经过硅胶柱色谱法分离纯化(石油醚/乙酸乙酯,10/1～0/1,V/V),得到化合物9-8。MS-ESI计算值[M+H] ⁺331,实测值331。 Compound 9-7 (200mg, 640μmol) was dissolved in phosphorus oxychloride (5mL), and stirred at 90°C for 12 hours. After cooling down to room temperature, pour water (10 mL) into the reaction solution, add saturated sodium bicarbonate solution to neutralize to pH 8, extract with ethyl acetate (10 mL×2), and use saturated brine (10 mL×1) for the organic phase Washed, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～0/1, V/V) to obtain compound 9-8. MS-ESI calculated [M+H] ⁺ 331, found 331.

第八步eighth step

将化合物9-8(194mg,586μmol)溶于二氧六环(5mL)中,加入中间体A的盐酸盐(160mg,645mmol),4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(67.9mg,117μmol),碳酸铯(573mg,1.76mmol)和三(二亚苄基丙酮)二钯(53.7mg,58.7μmol),在100℃下搅拌反应3小时。降至室温后过滤,将滤液减压浓缩。剩余物经制备高效液相色谱分离纯化(色谱柱:Xtimate C18 150mm×40mm×5μm；流动相:0.05％盐酸水溶液-乙腈；梯度:乙腈:15％-45％,10min),得到化合物9(9a和9b的混合物)的盐酸盐。 ¹H NMR(400MHz,CD ₃OD)δ8.34(s,1H),7.94(s,1H),7.60-7.49(m,1H),7.44-7.34(m,1H),7.25-7.13(m,1H),5.59-5.49(m,1H),4.74-4.34(m,4H),3.66-3.56(m,2H),2.78(s,3H),1.72(d,J＝6.8Hz,3H),1.33-1.26(m,6H)。MS-ESI计算值[M+H] ⁺542,实测值542。 Compound 9-8 (194 mg, 586 μmol) was dissolved in dioxane (5 mL), and the hydrochloride (160 mg, 645 mmol) of Intermediate A, 4,5-bis(diphenylphosphine)-9,9 -Dimethylxanthene (67.9mg, 117μmol), cesium carbonate (573mg, 1.76mmol) and tris(dibenzylideneacetone) dipalladium (53.7mg, 58.7μmol), stirred and reacted at 100°C for 3 hours. After cooling down to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by preparative high-performance liquid chromatography (column: Xtimate C18 150mm×40mm×5μm; mobile phase: 0.05% aqueous hydrochloric acid-acetonitrile; gradient: acetonitrile: 15%-45%, 10min), to obtain compound 9 (9a and 9b) hydrochloride. ¹ H NMR (400MHz, CD ₃ OD) δ8.34(s,1H),7.94(s,1H),7.60-7.49(m,1H),7.44-7.34(m,1H),7.25-7.13(m, 1H),5.59-5.49(m,1H),4.74-4.34(m,4H),3.66-3.56(m,2H),2.78(s,3H),1.72(d,J＝6.8Hz,3H),1.33 -1.26(m,6H). MS-ESI calculated value [M+H] ⁺ 542, found value 542.

实施例10Example 10

合成路线：synthetic route:

将化合物2-7(350mg,1.27mmol)溶于二氧六环(15mL)中,加入中间体E的盐酸盐(311mg,1.53mmol),4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(147mg,253μmol),碳酸钾(526mg,3.81mmol)和三(二亚苄基丙酮)二钯(116mg,127μmol),在100℃下搅拌反应12小时。降至室温后,过滤,将滤液减压浓缩。剩余物用甲醇(10mL)溶解,过滤,将滤液减压浓缩,剩余物经制备高效液相色谱分离纯化(色谱柱:Xtimate C18 150mm×40mm×5μm；流动相:10mM碳酸氢铵水溶液-乙腈；梯度:乙腈30％-60％,10min),得到化合物10。 ¹H NMR(400MHz,CD ₃OD)δ8.20(s,1H),8.08(s,2H),7.95(s,1H),7.36(s,1H),4.15(q,J＝6.8Hz,1H),3.40(s,3H),2.83(s,3H),1.49(s,6H),1.47(d,J＝6.8Hz,3H)。MS-ESI计算值[M+H] ⁺444,实测值444。 Compound 2-7 (350mg, 1.27mmol) was dissolved in dioxane (15mL), and the hydrochloride (311mg, 1.53mmol) of Intermediate E, 4,5-bis(diphenylphosphine)-9 , 9-dimethylxanthene (147mg, 253μmol), potassium carbonate (526mg, 3.81mmol) and tris(dibenzylideneacetone) dipalladium (116mg, 127μmol), stirred and reacted at 100°C for 12 hours. After cooling down to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (10 mL), filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by preparative high performance liquid chromatography (chromatographic column: Xtimate C18 150mm×40mm×5μm; mobile phase: 10mM aqueous ammonium bicarbonate-acetonitrile; Gradient: acetonitrile 30%-60%, 10min), to obtain compound 10. ¹ H NMR (400MHz, CD ₃ OD) δ8.20(s, 1H), 8.08(s, 2H), 7.95(s, 1H), 7.36(s, 1H), 4.15(q, J=6.8Hz, 1H ), 3.40 (s, 3H), 2.83 (s, 3H), 1.49 (s, 6H), 1.47 (d, J=6.8Hz, 3H). MS-ESI calculated [M+H] ⁺ 444, found 444.

实施例11Example 11

合成路线：synthetic route:

第一步first step

将化合物11-1(1.00g,4.83mmol)溶于N,N-二甲基甲酰胺(10mL)中,加入碳酸钾(867mg,6.27mmol)和碘甲烷(1.03g,7.24mmol),反应液在25℃下搅拌反应12小时。向反应液加入水(500mL),用乙酸乙酯(200mL×3)萃取,有机相用饱和食盐水(250mL×1)洗涤,无水硫酸钠干燥有机相,过滤减压浓缩,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,20/1～5/1,V/V),分离纯化得到化合物11-2。 ¹H NMR(400MHz,CDCl ₃)δ7.75-7.72(m,1H),7.68(d,J＝2.0Hz,1H),7.01(d,J＝8.4Hz,1H),4.70(s,2H),3.93(s,3H),3.42(s,3H)。MS-ESI计算值[M+H] ⁺222,实测值222。 Compound 11-1 (1.00g, 4.83mmol) was dissolved in N,N-dimethylformamide (10mL), potassium carbonate (867mg, 6.27mmol) and methyl iodide (1.03g, 7.24mmol) were added, and the reaction solution The reaction was stirred at 25°C for 12 hours. Add water (500mL) to the reaction solution, extract with ethyl acetate (200mL×3), wash the organic phase with saturated brine (250mL×1), dry the organic phase over anhydrous sodium sulfate, filter and concentrate under reduced pressure, and the residue is washed with silica gel Column chromatography (petroleum ether/ethyl acetate, 20/1～5/1, V/V), separation and purification to obtain compound 11-2. ¹ H NMR (400MHz, CDCl ₃ ) δ7.75-7.72 (m, 1H), 7.68 (d, J = 2.0Hz, 1H), 7.01 (d, J = 8.4Hz, 1H), 4.70 (s, 2H) ,3.93(s,3H),3.42(s,3H). MS-ESI calculated value [M+H] ⁺ 222, found value 222.

第二步second step

氮气保护下将化合物11-2(1.00g,4.52mmol)溶于N,N-二甲基甲酰胺(5mL)中,在0℃下加入N-溴代丁二酰亚胺(1.61g,9.04mmol),在0℃下搅拌反应0.5小时,25℃下搅拌反应1小时,100℃下搅拌反应3小时。降至室温后,向反应液加入水(20mL),用乙酸乙酯(15mL×3)萃取,有机相用饱和食盐水(20mL×1)洗涤,无水硫酸钠干燥有机相,过滤,减压浓缩,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,10/1～2/1,V/V),分离纯化得到化合物11-3。 ¹H NMR(400MHz,CDCl ₃)δ7.51(s,1H),7.28(d,J＝5.6Hz,1H),4.70(s,2H),3.94(s,3H),3.39(s,3H)。MS-ESI计算值[M+H] ⁺300和302实测值300和302。 Compound 11-2 (1.00g, 4.52mmol) was dissolved in N,N-dimethylformamide (5mL) under nitrogen protection, and N-bromosuccinimide (1.61g, 9.04 mmol), the reaction was stirred at 0°C for 0.5 hours, at 25°C for 1 hour, and at 100°C for 3 hours. After cooling down to room temperature, water (20 mL) was added to the reaction solution, extracted with ethyl acetate (15 mL×3), the organic phase was washed with saturated brine (20 mL×1), the organic phase was dried over anhydrous sodium sulfate, filtered, and reduced pressure After concentration, the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～2/1, V/V) to obtain compound 11-3. ¹ H NMR (400MHz, CDCl ₃ )δ7.51(s,1H),7.28(d,J=5.6Hz,1H),4.70(s,2H),3.94(s,3H),3.39(s,3H) . MS-ESI calculated [M+H] ⁺ 300 and 302 found 300 and 302.

第三步third step

氮气保护下将化合物11-3(646mg,2.15mmol)溶于甲苯(5mL)中,加入A-5(1.03g,2.86mmol)和双(三苯基膦)二氯化钯(151mg,215μmol),在120℃下搅拌反应7小时。降至室温后,向反应液加入饱和氟化钾水溶液(100mL),用乙酸乙酯(30mL×2)萃取,无水硫酸钠干燥有机相,过滤浓缩得到化合物11-4。MS-ESI计算值[M+H] ⁺292,实测值292。 Compound 11-3 (646mg, 2.15mmol) was dissolved in toluene (5mL) under nitrogen protection, and A-5 (1.03g, 2.86mmol) and bis(triphenylphosphine)palladium dichloride (151mg, 215μmol) were added , The reaction was stirred at 120°C for 7 hours. After cooling down to room temperature, saturated potassium fluoride aqueous solution (100 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL×2), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 11-4. MS-ESI calculated value [M+H] ⁺ 292, found value 292.

第四步the fourth step

将化合物11-4(627mg,2.15mmol)溶于丙酮(6.2mL)中,在0℃下滴加盐酸溶液(12M,1.43mL),在25℃下搅拌反应1小时。向反应液中加入饱和碳酸氢钠水溶液碱化pH至8,用乙酸乙酯(500mL×3)萃取,有机相用饱和食盐水(250mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物经过硅胶柱色谱法分离纯化(石油醚/乙酸乙酯,20/1～5/1,V/V),得到化合物11-5。 ¹H NMR(400MHz,CDCl ₃)δ7.47(s,1H),7.01(s,1H),4.71(s,2H),3.91(s,3H),3.42(s,3H),2.52(s,3H)。MS-ESI计算值[M+H] ⁺264,实测值264。 Compound 11-4 (627mg, 2.15mmol) was dissolved in acetone (6.2mL), hydrochloric acid solution (12M, 1.43mL) was added dropwise at 0°C, and the reaction was stirred at 25°C for 1 hour. Add saturated aqueous sodium bicarbonate solution to the reaction solution to alkalinize the pH to 8, extract with ethyl acetate (500mL×3), wash the organic phase with saturated brine (250mL×1), dry over anhydrous sodium sulfate, filter, and reduce pressure After concentration, the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 20/1～5/1, V/V) to obtain compound 11-5. ¹ H NMR (400MHz, CDCl ₃ )δ7.47(s,1H),7.01(s,1H),4.71(s,2H),3.91(s,3H),3.42(s,3H),2.52(s, 3H). MS-ESI calculated [M+H] ⁺ 264, found 264.

第五步the fifth step

将化合物11-5(439mg,1.67mmol)溶于乙醇(5mL)中,加入水合肼(286μL,5.00mmol,85％纯度),在95℃下搅拌反应1小时。降至室温后,过滤,将滤饼干燥得到化合物11-6。 ¹H NMR(400MHz,CDCl ₃)δ9.75(s,1H),7.98(s,1H),7.31(s,1H),4.80(s,2H),3.51(s,3H),2.54(s,3H)。MS-ESI计算值[M+H] ⁺246,实测值246。 Compound 11-5 (439mg, 1.67mmol) was dissolved in ethanol (5mL), hydrazine hydrate (286μL, 5.00mmol, 85% purity) was added, and the reaction was stirred at 95°C for 1 hour. After cooling down to room temperature, filter and dry the filter cake to obtain compound 11-6. ¹ H NMR (400MHz, CDCl ₃ )δ9.75(s,1H),7.98(s,1H),7.31(s,1H),4.80(s,2H),3.51(s,3H),2.54(s, 3H). MS-ESI calculated [M+H] ⁺ 246, found 246.

第六步step six

将化合物11-6(380mg,1.55mmol)溶于三氯氧磷(5mL)中,在90℃下搅拌反应12小时。降至室温后,向反应液中倒入氯化铵水溶液(20mL),用乙酸乙酯(20mL×5)萃取,有机相用饱和食盐水(30mL×2)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物经过硅胶柱色谱法分离纯化(石油醚/乙酸乙酯,20/1～5/1,V/V),得到化合物11-7。 ¹H NMR(400MHz,CDCl ₃)δ7.69(s,1H),7.54(s,1H),4.85(s,2H),3.57(s,3H),2.90(s,3H)。MS-ESI计算值[M+H] ⁺264,实测值264。 Compound 11-6 (380mg, 1.55mmol) was dissolved in phosphorus oxychloride (5mL), and stirred at 90°C for 12 hours. After cooling down to room temperature, pour ammonium chloride aqueous solution (20mL) into the reaction solution, extract with ethyl acetate (20mL×5), wash the organic phase with saturated brine (30mL×2), dry over anhydrous sodium sulfate, and filter , concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 20/1～5/1, V/V) to obtain compound 11-7. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.69 (s, 1H), 7.54 (s, 1H), 4.85 (s, 2H), 3.57 (s, 3H), 2.90 (s, 3H). MS-ESI calculated [M+H] ⁺ 264, found 264.

第七步step seven

氮气保护下将化合物11-7(100mg,379μmol)溶于二氧六环(2mL)中,加入中间体B的盐酸盐(108mg,569μmol),(±)-2,2-双(二苯膦基)-1,1-联萘(47.2mg,75.8μmol),叔丁醇钾(42.6mg,379μmol)和双(二亚苄基丙酮)钯(21.8mg,37.9μmol),在100℃下搅拌反应12小时。降至室温后,向反应液加入水(20mL), 用乙酸乙酯(10mL×3)萃取,有机相用饱和食盐水(20mL×1)洗涤,无水硫酸钠干燥有机相,过滤,减压浓缩。剩余物经制备高效液相色谱分离纯化(色谱柱:Welch Ultimate XB-NH2 250mm×50mm×10μm；流动相:0.05％盐酸水溶液-乙腈；梯度:乙腈12％-42％,10min),得到化合物11的盐酸盐。 ¹H NMR(400MHz,CD ₃OD)δ8.35(s,1H),7.84(s,1H),7.68(t,J＝7.6Hz,1H),7.50(t,J＝7.2Hz,1H),7.25(t,J＝7.6Hz,1H),7.13-6.86(m,1H),5.62-5.56(m,1H),4.94(s,2H),3.63(s,3H),2.78(s,3H),1.77(d,J＝6.8Hz,3H)。MS-ESI计算值[M+H] ⁺417,实测值417。 Compound 11-7 (100 mg, 379 μmol) was dissolved in dioxane (2 mL) under nitrogen protection, and the hydrochloride (108 mg, 569 μmol) of intermediate B was added, (±)-2,2-bis(diphenyl Phosphino)-1,1-binaphthyl (47.2 mg, 75.8 μmol), potassium tert-butoxide (42.6 mg, 379 μmol) and bis(dibenzylideneacetone) palladium (21.8 mg, 37.9 μmol), at 100 ° C The reaction was stirred for 12 hours. After cooling down to room temperature, water (20 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL×3), the organic phase was washed with saturated brine (20 mL×1), the organic phase was dried over anhydrous sodium sulfate, filtered, and reduced pressure concentrate. The residue was separated and purified by preparative high performance liquid chromatography (chromatographic column: Welch Ultimate XB-NH2 250mm×50mm×10μm; mobile phase: 0.05% hydrochloric acid aqueous solution-acetonitrile; gradient: acetonitrile 12%-42%, 10min), to obtain compound 11 hydrochloride. ¹ H NMR (400MHz, CD ₃ OD) δ8.35(s, 1H), 7.84(s, 1H), 7.68(t, J=7.6Hz, 1H), 7.50(t, J=7.2Hz, 1H), 7.25(t, J=7.6Hz, 1H), 7.13-6.86(m, 1H), 5.62-5.56(m, 1H), 4.94(s, 2H), 3.63(s, 3H), 2.78(s, 3H) , 1.77 (d, J=6.8Hz, 3H). MS-ESI calculated [M+H] ⁺ 417, found 417.

实施例12Example 12

合成路线：synthetic route:

第一步first step

将化合物4-2(2.00g,9.12mmol)和化合物12-1(3.05g,11.0mmol)溶于N,N-二甲基甲酰胺(10mL)中,加入碳酸铯(8.92g,27.4mmol),反应液在25℃下搅拌反应12小时。过滤,滤饼用乙酸乙酯(80mL×3)洗涤。滤液分别用水(50mL×3)和饱和食盐水(50mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,5/1～3/1,V/V),分离纯化得到化合物12-2。MS-ESI计算值[M+H-56] ⁺361,实测值361。 Compound 4-2 (2.00g, 9.12mmol) and compound 12-1 (3.05g, 11.0mmol) were dissolved in N,N-dimethylformamide (10mL), cesium carbonate (8.92g, 27.4mmol) was added , The reaction solution was stirred and reacted at 25° C. for 12 hours. Filter and wash the filter cake with ethyl acetate (80mL×3). The filtrate was washed with water (50mL×3) and saturated brine (50mL×1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate, 5/1～ 3/1, V/V), isolated and purified to obtain compound 12-2. MS-ESI calculated value [M+H-56] ⁺ 361, found value 361.

第二步second step

氮气保护下将化合物12-2(3.60g,8.64mmol)溶于甲醇(40mL)中,加入氯化氢/甲醇溶液(4M,8.64mL),在25℃下搅拌反应1小时。反应液减压浓缩,向剩余物中加入甲基叔丁基醚(50mL),在25℃下搅拌反应1小时,过滤,滤饼干燥,得到化合物12-3的盐酸盐。 ¹H NMR(400MHz,CDCl ₃)δ7.83-7.76(m,1H),7.48-7.40(m,1H),7.30-7.27(m,1H),3.94(s,3H),3.69(d,J＝7.2Hz,2H),3.60-3.49(m,2H),2.98-2.77(m,2H),2.19-2.04(m,1H),1.96-1.72(m,4H),1.38(s,6H)。MS-ESI计算值[M+H] ⁺317实测值317。 Compound 12-2 (3.60g, 8.64mmol) was dissolved in methanol (40mL) under nitrogen protection, hydrogen chloride/methanol solution (4M, 8.64mL) was added, and the reaction was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure, methyl tert-butyl ether (50 mL) was added to the residue, the reaction was stirred at 25°C for 1 hour, filtered, and the filter cake was dried to obtain the hydrochloride of compound 12-3. ¹ H NMR (400MHz, CDCl ₃ )δ7.83-7.76(m,1H),7.48-7.40(m,1H),7.30-7.27(m,1H),3.94(s,3H),3.69(d,J =7.2Hz, 2H), 3.60-3.49(m, 2H), 2.98-2.77(m, 2H), 2.19-2.04(m, 1H), 1.96-1.72(m, 4H), 1.38(s, 6H). MS-ESI calcd [M+H] ⁺ 317 found 317.

第三步third step

化合物12-3的盐酸盐(1.00g,2.83mmol)溶于甲醇(20mL)中,加入醋酸(851mg,14.2mmol)和甲醛水溶液(690mg,8.50mmol,37％纯度),在25℃下搅拌反应1小时,然后加入氰基硼氢化钠(534mg,8.50mmol),在25℃下搅拌反应1小时。反应液减压浓缩,向剩余物中加入饱和碳酸氢钠水溶液(100mL)，25℃下搅拌反应2小时,用乙酸乙酯(50mL×3)萃取,有机相用饱和食盐水(100mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩得到化合物12-4。 ¹H NMR(400MHz,CDCl ₃)δ7.75-7.69(m,1H),7.42-7.39(m,1H),7.22-7.19(m,1H),3.86(s,3H),3.58(d,J＝7.2Hz,2H),3.11-2.67(m,4H),2.26(s,3H),1.97-1.90(m,2H),1.86-1.74(m,1H),1.49-1.37(m,2H),1.32(s,6H)。MS-ESI计算值[M+H] ⁺331,实测值331。 Compound 12-3 hydrochloride (1.00g, 2.83mmol) was dissolved in methanol (20mL), added acetic acid (851mg, 14.2mmol) and aqueous formaldehyde (690mg, 8.50mmol, 37% purity), stirred at 25°C After reacting for 1 hour, sodium cyanoborohydride (534 mg, 8.50 mmol) was added, and the reaction was stirred at 25° C. for 1 hour. The reaction solution was concentrated under reduced pressure, and saturated aqueous sodium bicarbonate solution (100 mL) was added to the residue, stirred and reacted at 25°C for 2 hours, extracted with ethyl acetate (50 mL×3), and the organic phase was washed with saturated brine (100 mL×1) Wash, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain compound 12-4. ¹ H NMR (400MHz, CDCl ₃ )δ7.75-7.69(m,1H),7.42-7.39(m,1H),7.22-7.19(m,1H),3.86(s,3H),3.58(d,J =7.2Hz,2H),3.11-2.67(m,4H),2.26(s,3H),1.97-1.90(m,2H),1.86-1.74(m,1H),1.49-1.37(m,2H), 1.32(s,6H). MS-ESI calculated [M+H] ⁺ 331, found 331.

第四步the fourth step

将化合物12-4(1.60g,4.84mmol)溶于醋酸(10mL)中,加入液溴(2.32g,14.5mmol),在50℃下搅拌反应2小时。降至室温后,减压浓缩反应液,向剩余物中加入甲基叔丁基醚(30mL),在25℃下搅拌反应2小时,过滤,滤饼用水(20mL×3)洗涤,干燥,得到化合物12-5。 ¹H NMR(400MHz,CD ₃OD)δ7.67(s,1H),7.43(s,1H),3.92(s,3H),3.76-3.68(m,2H),3.57-3.47(m,2H),3.00-2.93(m,2H),2.84(s,3H),2.20-2.09(m,1H),2.00-1.90(m,2H),1.68-1.52(m,2H),1.39(s,6H)。MS-ESI计算值[M+H] ⁺409和411实测值409和411。 Compound 12-4 (1.60g, 4.84mmol) was dissolved in acetic acid (10mL), liquid bromine (2.32g, 14.5mmol) was added, and the reaction was stirred at 50°C for 2 hours. After cooling down to room temperature, the reaction solution was concentrated under reduced pressure, methyl tert-butyl ether (30 mL) was added to the residue, stirred and reacted at 25°C for 2 hours, filtered, the filter cake was washed with water (20 mL×3), dried to obtain Compound 12-5. ¹ H NMR (400MHz, CD ₃ OD) δ7.67(s,1H),7.43(s,1H),3.92(s,3H),3.76-3.68(m,2H),3.57-3.47(m,2H) ,3.00-2.93(m,2H),2.84(s,3H),2.20-2.09(m,1H),2.00-1.90(m,2H),1.68-1.52(m,2H),1.39(s,6H) . MS-ESI calculated [M+H] ⁺ 409 and 411 found 409 and 411.

第五步the fifth step

将化合物12-5(2.00g,4.89mmol)溶于甲苯(40mL)中,加入化合物A-5(3.25g,9.00mmol)和双(三苯基膦)二氯化钯(343mg,489μmol),在氮气保护和120℃下搅拌反应12小时。降至室温后,向反应液加入水(100mL),用乙酸乙酯(50mL×3)萃取,有机相用饱和食盐水(80mL×1)洗涤,无水硫酸钠干燥,过滤,浓缩得到化合物12-6。MS-ESI计算值[M+H] ⁺401,实测值401。 Compound 12-5 (2.00g, 4.89mmol) was dissolved in toluene (40mL), compound A-5 (3.25g, 9.00mmol) and bis(triphenylphosphine)palladium dichloride (343mg, 489μmol) were added, The reaction was stirred under nitrogen protection at 120°C for 12 hours. After cooling down to room temperature, water (100 mL) was added to the reaction solution, extracted with ethyl acetate (50 mL×3), the organic phase was washed with saturated brine (80 mL×1), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 12 -6. MS-ESI calculated value [M+H] ⁺ 401, found value 401.

第六步step six

将化合物12-6(4.10g,10.2mmol)溶于丙酮(40mL)中,在0℃下滴加盐酸溶液(6M,5.12mL),在25℃下搅拌反应0.5小时。反应液减压浓缩,向剩余物中加入水(100mL),用甲基叔丁基醚(30mL×3)洗涤,加入碳酸氢钠碱化pH至8,用二氯甲烷/甲醇混合溶液(10:1,50mL×5)萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩得到化合物12-7。MS-ESI计算值[M+H] ⁺373,实测值373。 Compound 12-6 (4.10g, 10.2mmol) was dissolved in acetone (40mL), hydrochloric acid solution (6M, 5.12mL) was added dropwise at 0°C, and the reaction was stirred at 25°C for 0.5 hours. The reaction solution was concentrated under reduced pressure, water (100 mL) was added to the residue, washed with methyl tert-butyl ether (30 mL×3), and the pH was basified to 8 by adding sodium bicarbonate, and mixed with dichloromethane/methanol (10 : 1,50mL×5) extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 12-7. MS-ESI calculated [M+H] ⁺ 373, found 373.

第七步step seven

将化合物12-7(800mg,2.15mmol)溶于乙醇(10mL)中,加入水合肼(1.30mL,22.8mmol,85％纯度),在90℃下搅拌反应1小时。降至室温后,减压浓缩，向剩余物中加入甲基叔丁基醚/乙酸乙酯混合溶液(1:1,20mL),在25℃下搅拌2小时,过滤,干燥滤饼，得到化合物12-8。 ¹H NMR(400MHz,CD ₃OD)δ7.94(s,1H),7.83(s,1H),3.80(d,J＝7.2Hz,2H),3.35–3.32(m,2H),2.99-2.84(m,2H),2.62(s,3H),2.29(s,3H),2.12 -2.02(m,2H),2.00-1.93(m,1H),1.79-1.69(m,2H),1.48(s,6H)。MS-ESI计算值[M+H] ⁺355,实测值355。 Compound 12-7 (800mg, 2.15mmol) was dissolved in ethanol (10mL), hydrazine hydrate (1.30mL, 22.8mmol, 85% purity) was added, and the reaction was stirred at 90°C for 1 hour. After cooling down to room temperature, concentrate under reduced pressure, add methyl tert-butyl ether/ethyl acetate mixed solution (1:1, 20mL) to the residue, stir at 25°C for 2 hours, filter, and dry the filter cake to obtain compound 12-8. ¹ H NMR (400MHz, CD ₃ OD) δ7.94(s,1H),7.83(s,1H),3.80(d,J=7.2Hz,2H),3.35–3.32(m,2H),2.99-2.84 (m,2H),2.62(s,3H),2.29(s,3H),2.12-2.02(m,2H),2.00-1.93(m,1H),1.79-1.69(m,2H),1.48(s ,6H). MS-ESI calculated [M+H] ⁺ 355, found 355.

第八步eighth step

将化合物12-8(400mg,1.13mmol)溶于三氯氧磷(8mL)中,在90℃下搅拌反应15小时。降至室温后,减压浓缩，向剩余物中加入饱和碳酸氢钠水溶液(40mL),25℃下搅拌30分钟,减压浓缩。剩余物加二氯甲烷(100mL)稀释,过滤，滤液减压浓缩。剩余物经过硅胶薄层层析色谱法分离纯化(二氯甲烷/甲醇,6/1～6/1,V/V),得到化合物12-9。MS-ESI计算值[M+H] ⁺373,实测值373。 Compound 12-8 (400mg, 1.13mmol) was dissolved in phosphorus oxychloride (8mL), and stirred at 90°C for 15 hours. After cooling down to room temperature, it was concentrated under reduced pressure, and saturated aqueous sodium bicarbonate solution (40 mL) was added to the residue, stirred at 25°C for 30 minutes, and then concentrated under reduced pressure. The residue was diluted with dichloromethane (100 mL), filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel thin-layer chromatography (dichloromethane/methanol, 6/1～6/1, V/V) to obtain compound 12-9. MS-ESI calculated [M+H] ⁺ 373, found 373.

第九步Ninth step

将化合物12-9(100mg,268μmol)溶于二氧六环(1mL)中,加入中间体B的盐酸盐(60.9mg,322μmol),碳酸钾(111mg,805μmol),4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(31.0mg,53.6μmol)和三(二亚苄基丙酮)二钯(24.6mg,26.8μmol)，反应液在氮气保护及90℃下搅拌反应12小时。反应液降至室温后,减压浓缩,加入水(20mL),用乙酸乙酯(10mL×3)萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩。剩余物经制备高效液相色谱分离纯化(色谱柱:Phenomenex Luna C18 75mm×30mm×3μm；流动相:0.05％盐酸水溶液-乙腈；梯度:乙腈16％-36％,10min),得到化合物12的盐酸盐。 ¹H NMR(400MHz,CD3OD)δ8.53(br s,1H),8.36(s,1H),7.86-7.73(m,1H),7.53-7.45(m,1H),7.32-7.21(m,1H),7.16-6.84(m,1H),5.69-5.57(m,1H),4.04-3.92(m,2H),3.60-3.51(m,2H),3.10-2.99(m,2H),2.89-2.87(m,3H),2.47-2.30(m,1H),2.09-2.01(m,5H),1.87-1.66(m,5H),1.53(s,3H),1.52(s,3H)。MS-ESI计算值[M+H] ⁺526,实测值526。 Compound 12-9 (100 mg, 268 μmol) was dissolved in dioxane (1 mL), and intermediate B hydrochloride (60.9 mg, 322 μmol), potassium carbonate (111 mg, 805 μmol), 4,5-bis( Diphenylphosphine)-9,9-dimethylxanthene (31.0mg, 53.6μmol) and tris(dibenzylideneacetone)dipalladium (24.6mg, 26.8μmol), the reaction solution was protected under nitrogen at 90°C The reaction was stirred for 12 hours. After the reaction solution was lowered to room temperature, it was concentrated under reduced pressure, water (20 mL) was added, extracted with ethyl acetate (10 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by preparative high performance liquid chromatography (chromatographic column: Phenomenex Luna C18 75mm×30mm×3μm; mobile phase: 0.05% aqueous hydrochloric acid-acetonitrile; gradient: acetonitrile 16%-36%, 10min) to obtain the salt of compound 12 salt. ¹ H NMR(400MHz,CD3OD)δ8.53(br s,1H),8.36(s,1H),7.86-7.73(m,1H),7.53-7.45(m,1H),7.32-7.21(m,1H ),7.16-6.84(m,1H),5.69-5.57(m,1H),4.04-3.92(m,2H),3.60-3.51(m,2H),3.10-2.99(m,2H),2.89-2.87 (m,3H), 2.47-2.30(m,1H), 2.09-2.01(m,5H), 1.87-1.66(m,5H), 1.53(s,3H), 1.52(s,3H). MS-ESI calculated value [M+H] ⁺ 526, found value 526.

实施例13Example 13

合成路线：synthetic route:

第一步first step

将化合物4-2(2.00g,8.33mmol)溶于N,N-二甲基甲酰胺(20mL)中,加入碳酸钾(2.30g,16.7mmol)和溴甲基环丙烷(2.25g,16.7mmol),在25℃下搅拌反应12小时。向反应液加入水(200mL),用乙酸乙酯(80mL)萃取,有机相用水(50mL×3)洗涤,无水硫酸钠干燥,过滤,减压浓缩。剩余物经过硅胶柱色谱法分离纯化(石油醚/二氯甲烷,5/1～1/1,V/V)得到化合物13-1。MS-ESI计算值[M+H] ⁺274,实测值274。 Compound 4-2 (2.00g, 8.33mmol) was dissolved in N,N-dimethylformamide (20mL), potassium carbonate (2.30g, 16.7mmol) and bromomethylcyclopropane (2.25g, 16.7mmol) were added ), and the reaction was stirred at 25°C for 12 hours. Water (200 mL) was added to the reaction solution, extracted with ethyl acetate (80 mL), the organic phase was washed with water (50 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether/dichloromethane, 5/1～1/1, V/V) to obtain compound 13-1. MS-ESI calculated [M+H] ⁺ 274, found 274.

第二步second step

将化合物13-1(850mg,3.11mmol)溶于N,N-二甲基甲酰胺(8mL)中,加入N-溴代丁二酰亚胺(996mg,5.60mmol),反应液在80℃下搅拌反应2小时。降至室温后,向反应液加入水(80mL),用乙酸乙酯(30mL)萃取,有机相用饱和食盐水(20mL×2)洗涤,无水硫酸钠干燥,过滤,减压浓缩。剩余物经薄层色谱(石油醚/乙酸乙酯,6/1,V/V)分离纯化得化合物13-2。 ¹H NMR(400MHz,CDCl ₃)δ7.46(s,1H),7.33(s,1H),3.97(s,3H),3.61(d,J＝6.8Hz,2H),1.39(s,6H),1.19-1.15(m,1H),0.56-0.52(m,2H),0.41-0.37(m,2H)。MS-ESI计算值[M+H] ⁺352,实测值352。 Compound 13-1 (850mg, 3.11mmol) was dissolved in N,N-dimethylformamide (8mL), N-bromosuccinimide (996mg, 5.60mmol) was added, and the reaction solution was heated at 80°C The reaction was stirred for 2 hours. After cooling down to room temperature, water (80 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL), the organic phase was washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by thin layer chromatography (petroleum ether/ethyl acetate, 6/1, V/V) to obtain compound 13-2. ¹ H NMR (400MHz, CDCl ₃ )δ7.46(s,1H),7.33(s,1H),3.97(s,3H),3.61(d,J＝6.8Hz,2H),1.39(s,6H) ,1.19-1.15(m,1H),0.56-0.52(m,2H),0.41-0.37(m,2H). MS-ESI calculated [M+H] ⁺ 352, found 352.

第三步third step

将化合物13-2(800mg,2.24mmol)溶于甲苯(2mL)中,加入双(三苯基膦)二氯化钯(157mg,224μmol)和化合物A-5(1.36g,3.77mmol),在氮气氛围90℃下搅拌反应12小时。向反应液中加入饱和氟化钾溶液(15mL),搅拌30分钟,用乙酸乙酯(2mL×20)萃取,无水硫酸钠干燥,过滤浓缩得到化合物13-3。MS-ESI计算值[M+H] ⁺344,实测值344。 Compound 13-2 (800mg, 2.24mmol) was dissolved in toluene (2mL), bis(triphenylphosphine) palladium dichloride (157mg, 224μmol) and compound A-5 (1.36g, 3.77mmol) were added, and The reaction was stirred at 90° C. for 12 hours under a nitrogen atmosphere. Saturated potassium fluoride solution (15 mL) was added to the reaction solution, stirred for 30 minutes, extracted with ethyl acetate (2 mL×20), dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 13-3. MS-ESI calculated [M+H] ⁺ 344, found 344.

第四步the fourth step

将化合物13-3(770mg,2.24mmol)溶于丙酮(7mL)中,加入盐酸水溶液(12M,934μL),在25℃下搅拌反应1小时。将反应液减压浓缩,剩余物经制备薄层色谱法(石油醚/乙酸乙酯,3/1,V/V)分离纯化得化合物13-4。 ¹H NMR(400MHz,CDCl ₃)δ7.38(s,1H),7.26(s,1H),3.94(s,3H),3.64(d,J＝6.8Hz,2H),2.56(s,3H),1.41(s,6H),1.22-1.15(m,1H),0.57-0.52(m,2H),0.42-0.39(m,2H)。MS-ESI计算值[M+H] ⁺316,实测值316。 Compound 13-3 (770mg, 2.24mmol) was dissolved in acetone (7mL), and aqueous hydrochloric acid (12M, 934μL) was added, and the reaction was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by preparative thin-layer chromatography (petroleum ether/ethyl acetate, 3/1, V/V) to obtain compound 13-4. ¹ H NMR (400MHz, CDCl ₃ )δ7.38(s,1H),7.26(s,1H),3.94(s,3H),3.64(d,J＝6.8Hz,2H),2.56(s,3H) ,1.41(s,6H),1.22-1.15(m,1H),0.57-0.52(m,2H),0.42-0.39(m,2H). MS-ESI calculated [M+H] ⁺ 316, found 316.

第五步the fifth step

将化合物13-4(360mg,1.12mmol)溶于乙醇(4mL)中,加入水合肼(182mg,3.45mmol,85％纯度),在95℃下搅拌反应1小时。向反应液中加水(15mL),过滤,将滤饼干燥得到化合物13-5。 ¹H NMR(400MHz,CDCl ₃)δ10.13(s,1H),7.91(s,1H),7.57(s,1H),3.73(d,J＝7.2Hz,2H),2.61(s,3H),1.49(s,6H),1.30-1.24(m,1H),0.57-0.52(m,2H),0.45-0.41(m,2H)。MS-ESI计算值[M+H] ⁺298,实测298。 Compound 13-4 (360mg, 1.12mmol) was dissolved in ethanol (4mL), hydrazine hydrate (182mg, 3.45mmol, 85% purity) was added, and the reaction was stirred at 95°C for 1 hour. Add water (15 mL) to the reaction solution, filter, and dry the filter cake to obtain compound 13-5. ¹ H NMR (400MHz, CDCl ₃ )δ10.13(s,1H),7.91(s,1H),7.57(s,1H),3.73(d,J=7.2Hz,2H),2.61(s,3H) ,1.49(s,6H),1.30-1.24(m,1H),0.57-0.52(m,2H),0.45-0.41(m,2H). MS-ESI calculated value [M+H] ⁺ 298, measured 298.

第六步step six

将化合物13-5(252mg,844μmol)和二异丙基乙胺(441mg,2.53mmol)溶于氯苯(2mL)中,加入三氯氧磷(388mg,2.53mmol),反应液在95℃下搅拌反应12小时。反应液用水(3mL×2)洗涤,向有机相中加入正庚烷(20mL),过滤,真空干燥得化合物13-6。 ¹H NMR(400MHz,CDCl ₃)δ7.82(s,1H),7.61(s,1H),3.79(d,J＝7.2Hz,2H),2.99(s,3H),1.52(s,6H),1.30-1.25(m,1H),0.64-0.59(m,2H),0.50-0.46(m,2H)。MS-ESI计算值[M+H] ⁺316,实测316。 Compound 13-5 (252mg, 844μmol) and diisopropylethylamine (441mg, 2.53mmol) were dissolved in chlorobenzene (2mL), phosphorus oxychloride (388mg, 2.53mmol) was added, and the reaction solution was heated at 95°C The reaction was stirred for 12 hours. The reaction solution was washed with water (3 mL×2), and n-heptane (20 mL) was added to the organic phase, filtered, and dried in vacuo to obtain compound 13-6. ¹ H NMR (400MHz, CDCl ₃ )δ7.82(s,1H),7.61(s,1H),3.79(d,J=7.2Hz,2H),2.99(s,3H),1.52(s,6H) ,1.30-1.25(m,1H),0.64-0.59(m,2H),0.50-0.46(m,2H). MS-ESI calculated value [M+H] ⁺ 316, measured 316.

第七步step seven

将化合物13-6(230mg,728μmol)和中间体B的盐酸盐(413mg,2.18mmol)溶于二氧六环(3mL), 加入4,5-双二苯基膦-9,9-二甲基氧杂蒽(84.3mg,146μmol),碳酸铯(712mg,2.18mmol),双(二亚苄基丙酮)钯(41.9mg,72.8μmol),在氮气氛围95℃下搅拌反应12小时。向反应液中加入水(5mL),用乙酸乙酯(2mL×5)萃取,无水硫酸钠干燥,过滤,减压浓缩。剩余物经制备高效液相色谱法(色谱柱:Phenomenex Luna C18 150mm×25mm×3μm；流动相:0.05％盐酸水溶液-乙腈；梯度:乙腈33％-53％，6min)分离纯化得化合物13的盐酸盐。 ¹H NMR(400MHz,CD ₃OD)δ8.33(s,1H),8.30(s,1H),7.64-7.60(m,1H),7.51-7.47(m,1H),7.26-7.21(m,1H),7.00(t,J＝54.4Hz,1H),5.62-5.56(m,1H),3.86(d,J＝7.2Hz,2H),2.88(s,3H),1.77(d,J＝7.2Hz,3H),1.51(s,3H),1.50(s,3H),1.35-1.31(m,1H),0.62-0.57(m,2H),0.51-0.47(m,2H)。MS-ESI计算值[M+H] ⁺469,实测值469。 Compound 13-6 (230 mg, 728 μmol) and intermediate B hydrochloride (413 mg, 2.18 mmol) were dissolved in dioxane (3 mL), and 4,5-bisdiphenylphosphine-9,9-bis Methylxanthene (84.3 mg, 146 μmol), cesium carbonate (712 mg, 2.18 mmol), bis(dibenzylideneacetone) palladium (41.9 mg, 72.8 μmol), stirred and reacted at 95° C. under nitrogen atmosphere for 12 hours. Water (5 mL) was added to the reaction solution, extracted with ethyl acetate (2 mL×5), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by preparative high performance liquid chromatography (chromatographic column: Phenomenex Luna C18 150mm×25mm×3μm; mobile phase: 0.05% aqueous hydrochloric acid-acetonitrile; gradient: acetonitrile 33%-53%, 6min) to obtain the salt of compound 13 salt. ¹ H NMR (400MHz, CD ₃ OD) δ8.33(s,1H),8.30(s,1H),7.64-7.60(m,1H),7.51-7.47(m,1H),7.26-7.21(m, 1H), 7.00(t, J=54.4Hz, 1H), 5.62-5.56(m, 1H), 3.86(d, J=7.2Hz, 2H), 2.88(s, 3H), 1.77(d, J=7.2 Hz, 3H), 1.51(s, 3H), 1.50(s, 3H), 1.35-1.31(m, 1H), 0.62-0.57(m, 2H), 0.51-0.47(m, 2H). MS-ESI calculated [M+H] ⁺ 469, found 469.

实施例14Example 14

合成路线：synthetic route:

第一步first step

将化合物4-2(5.00g,22.8mmol)溶于N,N-二甲基甲酰胺(60mL)中,加入碳酸钾(9.46g,68.4mmol)和溴代异丙烷(3.37g,27.4mmol),在100℃搅拌反应12小时。降至室温后,向反应液中加入水(100mL),用乙酸乙酯(100mL×3)萃取,有机相用饱和食盐水(100mL×3)洗涤,无水硫酸钠干燥,过滤,减压浓缩。剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,100/1～3/1,V/V)分离纯化得到化合物14-1。MS-ESI计算值[M+H] ⁺262,实测262。 Compound 4-2 (5.00g, 22.8mmol) was dissolved in N,N-dimethylformamide (60mL), potassium carbonate (9.46g, 68.4mmol) and bromoisopropane (3.37g, 27.4mmol) were added , The reaction was stirred at 100°C for 12 hours. After cooling down to room temperature, water (100 mL) was added to the reaction solution, extracted with ethyl acetate (100 mL×3), the organic phase was washed with saturated brine (100 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure . The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 100/1～3/1, V/V) to obtain compound 14-1. MS-ESI calculated value [M+H] ⁺ 262, measured 262.

第二步second step

将化合物14-1(3.86g,10.8mmol)溶于N,N-二甲基甲酰胺(50mL)中,加入溴代丁二酰亚胺(3.86g,21.7mmol),在25℃下搅拌反应1小时,100℃搅拌反应12小时。降至室温后,向反应液中加入水(100mL),用乙酸乙酯(100mL×3)萃取,有机相用饱和食盐水(100mL×3)洗涤,无水硫酸钠干燥,过滤,减压浓缩。剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,100/1～4/1,V/V)分离纯化得到化合物14-2。MS-ESI计算值[M+H] ⁺340和342,实测340和342。 Compound 14-1 (3.86g, 10.8mmol) was dissolved in N,N-dimethylformamide (50mL), bromosuccinimide (3.86g, 21.7mmol) was added, and the reaction was stirred at 25°C 1 hour, 100 ° C stirring reaction for 12 hours. After cooling down to room temperature, water (100 mL) was added to the reaction solution, extracted with ethyl acetate (100 mL×3), the organic phase was washed with saturated brine (100 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure . The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 100/1～4/1, V/V) to obtain compound 14-2. MS-ESI calculated [M+H] ⁺ 340 and 342, found 340 and 342.

第三步third step

在氮气保护下,将化合物14-2(2.05g,6.03mmol)溶于甲苯(30mL)中,加入双三苯基膦二氯化钯(423mg,603μmol)和化合物A-5(2.61g,7.23mmol),在120℃搅拌反应12小时。降至室温后,向反应液中加入饱和氟化钾溶液(50mL),过滤,滤液用乙酸乙酯(50mL×2)萃取,无水硫酸钠干燥,过滤浓缩得到化合物14-3。Under nitrogen protection, compound 14-2 (2.05g, 6.03mmol) was dissolved in toluene (30mL), bistriphenylphosphine palladium dichloride (423mg, 603μmol) and compound A-5 (2.61g, 7.23 mmol), stirred and reacted at 120°C for 12 hours. After cooling down to room temperature, saturated potassium fluoride solution (50 mL) was added to the reaction solution, filtered, and the filtrate was extracted with ethyl acetate (50 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 14-3.

第四步the fourth step

0℃下,将化合物14-3(2.6g,7.85mmol)溶于丙酮(30mL)中,加入浓盐酸(3mL,12M),25℃下搅拌反应1小时。向反应液中加入饱和碳酸氢钠水溶液(150mL),用乙酸乙酯(100mL×3)萃取,有机相用饱和食盐水(100mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩。剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,9/1～0/1,V/V),分离纯化得到化合物14-4。MS-ESI计算值[M+H] ⁺304,实测304。 Compound 14-3 (2.6g, 7.85mmol) was dissolved in acetone (30mL) at 0°C, concentrated hydrochloric acid (3mL, 12M) was added, and the reaction was stirred at 25°C for 1 hour. Saturated aqueous sodium bicarbonate solution (150 mL) was added to the reaction solution, extracted with ethyl acetate (100 mL×3), the organic phase was washed with saturated brine (100 mL×1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 9/1～0/1, V/V) to obtain compound 14-4. MS-ESI calculated value [M+H] ⁺ 304, measured 304.

第五步the fifth step

将化合物14-4(1.38g,4.55mmol)溶于乙醇(15mL)中,加入水合肼(910μL,15.9mmol,85％纯度),在90℃下搅拌反应1小时。降至室温后,过滤,滤饼用石油醚(100mL×1)洗涤,将滤饼干燥得到化合物14-5。MS-ESI计算值[M+H] ⁺286,实测286。 Compound 14-4 (1.38g, 4.55mmol) was dissolved in ethanol (15mL), hydrazine hydrate (910μL, 15.9mmol, 85% purity) was added, and the reaction was stirred at 90°C for 1 hour. After cooling down to room temperature, it was filtered, the filter cake was washed with petroleum ether (100 mL×1), and the filter cake was dried to obtain compound 14-5. MS-ESI calculated value [M+H] ⁺ 286, measured 286.

第六步step six

将化合物14-5(830mg,2.91mmol)溶于三氯氧磷(6mL)中,在90℃下搅拌反应12小时。降至室温后,向反应液中倒入水(50mL),加入饱和碳酸氢钠溶液中和至pH为8,用乙酸乙酯(50mL×2)萃取,有机相用饱和食盐水(50mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物经过硅胶柱色谱法分离纯化(石油醚/乙酸乙酯,10/1～0/1,V/V),得到化合物14-6。 ¹H NMR(400MHz,CDCl ₃)δ7.80(s,1H),7.66(s,1H),4.81-4.69(m,1H),2.97(s,3H),1.60(d,J＝7.2Hz,6H),1.49(s,6H)。MS-ESI计算值[M+H] ⁺304,实测值304。 Compound 14-5 (830mg, 2.91mmol) was dissolved in phosphorus oxychloride (6mL), and stirred at 90°C for 12 hours. After cooling down to room temperature, pour water (50mL) into the reaction solution, add saturated sodium bicarbonate solution to neutralize to pH 8, extract with ethyl acetate (50mL×2), and use saturated brine (50mL×1 ), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～0/1, V/V) to obtain compound 14-6 . ¹ H NMR (400MHz, CDCl ₃ )δ7.80(s,1H),7.66(s,1H),4.81-4.69(m,1H),2.97(s,3H),1.60(d,J=7.2Hz, 6H), 1.49(s, 6H). MS-ESI calculated [M+H] ⁺ 304, found 304.

第七步step seven

将化合物14-6(200mg,658μmol)溶于二氧六环(20mL)中,加入A(195mg,790μmol),甲烷磺酸(2-二环己基膦-3,6-二甲氧基-2,4,6-三异丙基-1,1-联苯)(2-氨基-1,1-联苯-2-基)钯(II)(59.7mg,65.8μmol)和叔丁醇钾(148mg,1.32mmol),在100℃下搅拌反应12小时。降至室温后,过滤,将滤液减压浓缩。剩余物用甲醇(10mL)溶解,过滤,将滤液减压浓缩,剩余物经制备高效液相色谱分离纯化(色谱柱:Phenomenex C18 150mm×40mm×5μm；流动相:0.05％盐酸水溶液-乙腈；梯度:乙腈24％-54％,10min),得到化合物14的盐酸盐。 ¹H NMR(400MHz,CD ₃OD)δ8.32(s,1H),8.28(s,1H),7.60(s,1H),7.39(s,1H),7.17(s,1H),5.68-5.49(m,1H),2.88(s,3H),1.84-1.71(m,3H),1.69-1.59(m,6H),1.47(s,6H),1.29(s,6H)。MS-ESI计算值[M+H] ⁺515,实测值515。 Compound 14-6 (200 mg, 658 μmol) was dissolved in dioxane (20 mL), A (195 mg, 790 μmol), methanesulfonic acid (2-dicyclohexylphosphine-3,6-dimethoxy-2 , 4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (59.7mg, 65.8μmol) and potassium tert-butoxide ( 148mg, 1.32mmol), stirred and reacted at 100°C for 12 hours. After cooling down to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (10mL), filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by preparative high performance liquid chromatography (chromatographic column: Phenomenex C18 150mm×40mm×5μm; mobile phase: 0.05% aqueous hydrochloric acid-acetonitrile; gradient : acetonitrile 24%-54%, 10min), to obtain the hydrochloride of compound 14. ¹ H NMR (400MHz, CD ₃ OD) δ8.32(s,1H),8.28(s,1H),7.60(s,1H),7.39(s,1H),7.17(s,1H),5.68-5.49 (m,1H), 2.88(s,3H), 1.84-1.71(m,3H), 1.69-1.59(m,6H), 1.47(s,6H), 1.29(s,6H). MS-ESI calculated [M+H] ⁺ 515, found 515.

实施例15Example 15

合成路线：synthetic route:

将化合物14-6(240mg,790μmol)溶于二氧六环(20mL)中,加入B(179mg,948μmol),1,1’-联萘-2,2’-二苯膦(98.4mg,158μmol),叔丁醇钾(177mg,1.58mmol)和二(二亚苄基丙酮)钯(45.4mg,79.0μmol),在100℃下搅拌反应12小时。降至室温后,过滤,减压浓缩。剩余物用甲醇(10mL)溶解,过滤,将滤液减压浓缩,剩余物经制备高效液相色谱分离纯化(色谱柱:Phenomenex C18 80mm×40mm×3μm；流动相:氨水溶液-乙腈；梯度:乙腈47％-77％,8min),得到化合物15。 ¹H NMR(400MHz,CD ₃OD)δ8.15-7.95(m,2H),8.00(s,1H),7.58(s,1H),7.22-6.75(m,2H),5.85-5.65(m,1H),4.75-4.61(m,1H),2.68(s,3H),1.69(d,J＝6.0Hz,3H),1.69(d,J＝5.6Hz,6H),1.44(s,6H)。MS-ESI计算值[M+H] ⁺457,实测值457。 Dissolve compound 14-6 (240mg, 790μmol) in dioxane (20mL), add B (179mg, 948μmol), 1,1'-binaphthyl-2,2'-diphenylphosphine (98.4mg, 158μmol ), potassium tert-butoxide (177mg, 1.58mmol) and bis(dibenzylideneacetone)palladium (45.4mg, 79.0μmol), the reaction was stirred at 100°C for 12 hours. After cooling down to room temperature, it was filtered and concentrated under reduced pressure. The residue was dissolved in methanol (10mL), filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by preparative high performance liquid chromatography (column: Phenomenex C18 80mm×40mm×3μm; mobile phase: ammonia solution-acetonitrile; gradient: acetonitrile 47%-77%, 8min), to obtain compound 15. ¹ H NMR (400MHz, CD ₃ OD) δ8.15-7.95 (m, 2H), 8.00 (s, 1H), 7.58 (s, 1H), 7.22-6.75 (m, 2H), 5.85-5.65 (m, 1H), 4.75-4.61(m, 1H), 2.68(s, 3H), 1.69(d, J=6.0Hz, 3H), 1.69(d, J=5.6Hz, 6H), 1.44(s, 6H). MS-ESI calculated [M+H] ⁺ 457, found 457.

实施例16Example 16

合成路线：synthetic route:

第一步first step

将化合物4-2(12.0g,54.9mmol)溶于N,N-二甲基甲酰胺(120mL),加入N-溴代丁二酰亚胺(10.7g,60.4mmol),在60℃下搅拌反应3小时。降至室温后,向反应液中加入水(400mL),过滤,滤饼在石油醚/二氯甲烷(80mL/20mL)中搅拌2小时,过滤,干燥得化合物16-1。MS-ESI计算值[M+H] ⁺298和300,实测值 298和300。 Compound 4-2 (12.0g, 54.9mmol) was dissolved in N,N-dimethylformamide (120mL), N-bromosuccinimide (10.7g, 60.4mmol) was added, stirred at 60°C React for 3 hours. After cooling down to room temperature, water (400 mL) was added to the reaction liquid, filtered, and the filter cake was stirred in petroleum ether/dichloromethane (80 mL/20 mL) for 2 hours, filtered, and dried to obtain compound 16-1. MS-ESI calculated [M+H] ⁺ 298 and 300, found 298 and 300.

第二步second step

将化合物16-1(800mg,2.68mmol)溶于N,N-二甲基甲酰胺(20mL)中,加入碳酸铯(8.74g,26.8mmol)和中间体G(2.74g,16.1mmol),反应液在25℃下搅拌反应12小时。将反应液过滤,滤液倒入乙酸乙酯(40mL),用水(80mL,20mL,10mL)分别洗涤一次,有机相用无水硫酸钠干燥,过滤,减压浓缩得化合物16-2。 ¹H NMR(400MHz,CDCl ₃)δ7.78(s,1H),7.40(s,1H),3.86(s,3H),3.76-3.71(m,1H),3.65-3.60(m,1H),2.94-2.84(m,3H),2.29(s,3H),2.03-1.99(m,4H),1.29(s,6H)。MS-ESI计算值[M+H] ⁺395和397,实测值395和397。 Compound 16-1 (800mg, 2.68mmol) was dissolved in N,N-dimethylformamide (20mL), cesium carbonate (8.74g, 26.8mmol) and intermediate G (2.74g, 16.1mmol) were added, and the reaction The solution was stirred and reacted at 25°C for 12 hours. The reaction solution was filtered, the filtrate was poured into ethyl acetate (40 mL), washed once with water (80 mL, 20 mL, 10 mL) respectively, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 16-2. ¹ H NMR (400MHz, CDCl ₃ )δ7.78(s,1H),7.40(s,1H),3.86(s,3H),3.76-3.71(m,1H),3.65-3.60(m,1H), 2.94-2.84 (m, 3H), 2.29 (s, 3H), 2.03-1.99 (m, 4H), 1.29 (s, 6H). MS-ESI calculated [M+H] ⁺ 395 and 397, found 395 and 397.

第三步third step

将化合物16-2(1.12g,2.13mmol)溶于甲苯(10mL)中,加入双(三苯基膦)二氯化钯(149mg,213μmol)和三丁基(1-乙氧基乙烯)锡(2.98g,8.24mmol),在氮气氛围90℃下搅拌反应12小时。降至室温后,向反应液中加入饱和氟化钾溶液(15mL),搅拌30分钟,用乙酸乙酯(10mL×2)萃取,无水硫酸钠干燥,过滤浓缩得到化合物16-3。MS-ESI计算值[M+H] ⁺387,实测值387。 Compound 16-2 (1.12g, 2.13mmol) was dissolved in toluene (10mL), and bis(triphenylphosphine)palladium dichloride (149mg, 213μmol) and tributyl(1-ethoxyethylene)tin were added (2.98g, 8.24mmol), stirred and reacted under nitrogen atmosphere at 90°C for 12 hours. After cooling down to room temperature, saturated potassium fluoride solution (15 mL) was added to the reaction solution, stirred for 30 minutes, extracted with ethyl acetate (10 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 16-3. MS-ESI calculated [M+H] ⁺ 387, found 387.

第四步the fourth step

将化合物16-3(820mg,2.12mmol)溶于乙酸乙酯(5mL)中,加入氯化氢/乙酸乙酯溶液(4M,2.12mL),在25℃下搅拌反应0.5小时。将反应液减压浓缩得化合物16-4的盐酸盐。MS-ESI计算值[M+H] ⁺359,实测值359。 Compound 16-3 (820mg, 2.12mmol) was dissolved in ethyl acetate (5mL), hydrogen chloride/ethyl acetate solution (4M, 2.12mL) was added, and the reaction was stirred at 25°C for 0.5 hours. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride of compound 16-4. MS-ESI calculated [M+H] ⁺ 359, found 359.

第五步the fifth step

将化合物16-4(760mg,2.12mmol)溶于乙醇(12mL)中,加入水合肼(1.2g,20.4mmol,85％纯度),在95℃下搅拌反应1小时。降至室温后,将反应液减压浓缩得化合物16-5。MS-ESI计算值[M+H] ⁺341,实测值341。 Compound 16-4 (760mg, 2.12mmol) was dissolved in ethanol (12mL), hydrazine hydrate (1.2g, 20.4mmol, 85% purity) was added, and the reaction was stirred at 95°C for 1 hour. After cooling down to room temperature, the reaction solution was concentrated under reduced pressure to obtain compound 16-5. MS-ESI calculated [M+H] ⁺ 341, found 341.

第六步step six

将化合物16-5(720mg,2.12mmol)溶于三氯氧磷(7mL)中,反应液在95℃下搅拌反应12小时。降至室温后,将反应液减压浓缩,剩余物溶于水(8mL)中,用碳酸钠将pH调到8,乙酸乙酯(8mL×2)萃取,无水硫酸钠干燥,过滤浓缩。剩余物经制备薄层色谱法(石油醚/乙酸乙酯,2/1,V/V)纯化得化合物16-6。MS-ESI计算值[M+H] ⁺359,实测359。 Compound 16-5 (720mg, 2.12mmol) was dissolved in phosphorus oxychloride (7mL), and the reaction solution was stirred at 95°C for 12 hours. After cooling down to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was dissolved in water (8 mL), adjusted to pH 8 with sodium carbonate, extracted with ethyl acetate (8 mL×2), dried over anhydrous sodium sulfate, and concentrated by filtration. The residue was purified by preparative thin-layer chromatography (petroleum ether/ethyl acetate, 2/1, V/V) to obtain compound 16-6. MS-ESI calculated value [M+H] ⁺ 359, measured 359.

第七步step seven

将化合物16-6(200mg,557μmol)和中间体B的盐酸盐(211mg,1.11mmol)溶于二氧六环(3mL),加入4,5-双二苯基膦-9,9-二甲基氧杂蒽(64.5mg,111μmol),碳酸铯(635mg,1.95mmol)和双(二亚苄基丙酮)钯(32.1mg,55.7μmol),在氮气氛围95℃下搅拌反应12小时。降至室温后,将反应液倒入水(10mL),用乙酸乙酯(10mL×2)萃取,无水硫酸钠干燥,过滤,减压浓缩。剩余物经制备高效液相色谱法(色谱柱:Waters Xbridge 150mm×25mm×3μm；流动相:0.05％氨水溶液-乙腈；梯度:乙腈38％-68％,8min)分离纯化得化合物16。 ¹H NMR(400MHz,CDCl ₃)δ7.68(s,1H),7.61(t,J＝7.2Hz,1H),7.45(t,J＝7.2Hz,1H),7.34(d,J＝7.6Hz,1H),7.17(t,J＝7.6Hz,1H),6.89(t,J＝54.2Hz,1H),5.85-5.80(m,1H),5.30-5.29(m,1H),4.01-3.83(m,2H),3.12-3.09(m,1H),2.84-2.79(m,4H),2.49(d,J＝4.4Hz,3H),2.35-2.28(m,1H),1.94-1.90(m,1H),1.77-1.72(m,5H),1.49-1.46(m,6H)。MS-ESI计算值[M+H] ⁺512实测值512。 Compound 16-6 (200 mg, 557 μmol) and intermediate B hydrochloride (211 mg, 1.11 mmol) were dissolved in dioxane (3 mL), and 4,5-bisdiphenylphosphine-9,9-bis Methylxanthene (64.5 mg, 111 μmol), cesium carbonate (635 mg, 1.95 mmol) and bis(dibenzylideneacetone) palladium (32.1 mg, 55.7 μmol) were stirred and reacted at 95° C. under a nitrogen atmosphere for 12 hours. After cooling down to room temperature, the reaction solution was poured into water (10 mL), extracted with ethyl acetate (10 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by preparative high performance liquid chromatography (column: Waters Xbridge 150mm×25mm×3μm; mobile phase: 0.05% ammonia solution-acetonitrile; gradient: acetonitrile 38%-68%, 8min) to obtain compound 16. ¹ H NMR (400MHz, CDCl ₃ ) δ7.68(s, 1H), 7.61(t, J=7.2Hz, 1H), 7.45(t, J=7.2Hz, 1H), 7.34(d, J=7.6Hz ,1H),7.17(t,J=7.6Hz,1H),6.89(t,J=54.2Hz,1H),5.85-5.80(m,1H),5.30-5.29(m,1H),4.01-3.83( m,2H),3.12-3.09(m,1H),2.84-2.79(m,4H),2.49(d,J＝4.4Hz,3H),2.35-2.28(m,1H),1.94-1.90(m, 1H), 1.77-1.72(m, 5H), 1.49-1.46(m, 6H). MS-ESI calculated [M+H] ⁺ 512 found 512.

实施例17Example 17

合成路线：synthetic route:

将化合物12-9(20.0mg,53.6μmol)溶于二氧六环(0.5mL)中,加入中间体A的盐酸盐(15.9mg,64.4μmol),碳酸钾(22.2mg,161μmol),4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(6.21mg,10.7μmol)和三(二亚苄基丙酮)二钯(4.91mg,5.36μmol)，反应液在氮气保护及110℃下搅拌反应12小时。反应液降至室温后,加入水(20mL),用乙酸乙酯(10mL×3)萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩。剩余物经制备高效液相色谱分离纯化(色谱柱:Waters Xbridge 150mm×25mm×5μm；流动相:10mM碳酸氢铵水溶液-乙腈；梯度:乙腈35％-65％,10min),得到化合物17。 ¹H NMR(400MHz,CD ₃OD)δ8.25-8.04(m,2H),7.66-7.53(m,1H),7.42-7.30(m,1H),7.21-7.07(m,1H),5.79-5.68(m,1H),4.03-3.89(m,2H),3.54-3.45(m,2H),3.05-2.87(m,2H),2.82(s,3H),2.77(s,3H),2.42-2.26(m,1H),2.08-1.94(m,2H),1.76(d,J＝6.8Hz,3H),1.72-1.59(m,2H),1.52(d,J＝4.2Hz,6H),1.32(br s,6H)。MS-ESI计算值[M+H] ⁺584,实测值584。 Compound 12-9 (20.0mg, 53.6μmol) was dissolved in dioxane (0.5mL), and the hydrochloride (15.9mg, 64.4μmol) of Intermediate A, potassium carbonate (22.2mg, 161μmol), 4 , 5-bis(diphenylphosphine)-9,9-dimethylxanthene (6.21mg, 10.7μmol) and tris(dibenzylideneacetone)dipalladium (4.91mg, 5.36μmol), the reaction solution was in Nitrogen protection and stirring reaction at 110° C. for 12 hours. After the reaction solution was cooled to room temperature, water (20 mL) was added, extracted with ethyl acetate (10 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by preparative high performance liquid chromatography (column: Waters Xbridge 150mm×25mm×5μm; mobile phase: 10mM ammonium bicarbonate aqueous solution-acetonitrile; gradient: acetonitrile 35%-65%, 10min) to obtain compound 17. ¹ H NMR (400MHz, CD ₃ OD) δ8.25-8.04 (m, 2H), 7.66-7.53 (m, 1H), 7.42-7.30 (m, 1H), 7.21-7.07 (m, 1H), 5.79- 5.68(m,1H),4.03-3.89(m,2H),3.54-3.45(m,2H),3.05-2.87(m,2H),2.82(s,3H),2.77(s,3H),2.42- 2.26(m,1H),2.08-1.94(m,2H),1.76(d,J=6.8Hz,3H),1.72-1.59(m,2H),1.52(d,J=4.2Hz,6H),1.32 (br s, 6H). MS-ESI calculated [M+H] ⁺ 584, found 584.

实施例18Example 18

合成路线：synthetic route:

第一步first step

将化合物18-1(8.00g,42.6mmol)溶解在四氢呋喃(50mL)中,加入羰基二咪唑(8.28g,51.1mmol),在80℃反应1小时。降至室温后,反应液加入水(250mL),过滤,水(250mL)洗涤滤饼,将滤饼干燥得到化合物18-2。MS-ESI计算值[M+H] ⁺214和216,实测值214和216。 Compound 18-1 (8.00g, 42.6mmol) was dissolved in tetrahydrofuran (50mL), carbonyldiimidazole (8.28g, 51.1mmol) was added, and reacted at 80°C for 1 hour. After cooling down to room temperature, the reaction solution was added with water (250 mL), filtered, and the filter cake was washed with water (250 mL), and the filter cake was dried to obtain compound 18-2. MS-ESI calculated [M+H] ⁺ 214 and 216, found 214 and 216.

第二步second step

将化合物18-2(6.53g,30.5mmol)和碳酸铯(19.9g,61.0mmol)加入N,N-二甲基甲酰胺(70mL)中。在25℃搅拌30分钟后加入碘甲烷(5.20g,36.6mmol),继续在25℃反应12小时。向反应液中加入水(500mL),过滤,收集滤饼,干燥,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,10/1～1/1,V/V)分离纯化得到化合物18-3。MS-ESI计算值[M+H] ⁺228和230,实测值228和230。 Compound 18-2 (6.53 g, 30.5 mmol) and cesium carbonate (19.9 g, 61.0 mmol) were added to N,N-dimethylformamide (70 mL). After stirring at 25°C for 30 minutes, iodomethane (5.20 g, 36.6 mmol) was added, and the reaction was continued at 25°C for 12 hours. Add water (500mL) to the reaction solution, filter, collect the filter cake, dry, and the residue is separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～1/1, V/V) to obtain compound 18 -3. MS-ESI calculated [M+H] ⁺ 228 and 230, found 228 and 230.

第三步third step

一氧化碳气体保护下将化合物18-3(5.20g,22.8mmol)溶于甲醇(60mL),N,N-二甲基甲酰胺(20mL)和三乙胺(20mL)中,加入1,1-双(二苯基膦)二茂铁氯化钯(1.67g,2.28mmol),在80℃下搅拌反应72小时。降至室温后,过滤,将滤液减压浓缩,向反应液加入水(200mL),用乙酸乙酯(200mL×3)萃取,有机相用饱和食盐水(200mL×3)洗涤,无水硫酸钠干燥有机相,过滤,减压浓缩,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,10/1～2/1,V/V),分离纯化得到化合物18-4。MS-ESI计算值[M+H] ⁺208,实测值208。 Under the protection of carbon monoxide gas, compound 18-3 (5.20g, 22.8mmol) was dissolved in methanol (60mL), N,N-dimethylformamide (20mL) and triethylamine (20mL), and 1,1-bis (Diphenylphosphine)ferrocenepalladium chloride (1.67g, 2.28mmol), stirred and reacted at 80°C for 72 hours. After cooling down to room temperature, filter, concentrate the filtrate under reduced pressure, add water (200mL) to the reaction solution, extract with ethyl acetate (200mL×3), wash the organic phase with saturated brine (200mL×3), and anhydrous sodium sulfate The organic phase was dried, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～2/1, V/V) to obtain compound 18-4. MS-ESI calculated value [M+H] ⁺ 208, found value 208.

第四步the fourth step

氮气保护下将化合物18-4(3.00g,12.1mmol)溶于三氟乙酸(30mL)中,在0℃下加入N-溴代丁二酰亚胺(2.37g,13.3mmol),在0℃下加入硫酸(3mL),在25℃下搅拌反应1小时。向反应液中加入饱和碳酸氢钠水溶液碱化pH至8,用二氯甲烷(200mL×2)萃取,有机相用饱和食盐水(200mL×1)洗涤,无水硫酸钠干燥有机相,过滤,减压浓缩,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,10/1～2/1,V/V),分离纯化得到化合物18-5。 ¹H NMR(400MHz,CDCl ₃)δ7.49(s,1H),7.44(s,1H),3.95(s,3H),3.42(s,3H)。 Compound 18-4 (3.00g, 12.1mmol) was dissolved in trifluoroacetic acid (30mL) under nitrogen protection, N-bromosuccinimide (2.37g, 13.3mmol) was added at 0°C, and Sulfuric acid (3 mL) was added under low temperature, and the reaction was stirred at 25°C for 1 hour. Add saturated aqueous sodium bicarbonate solution to the reaction solution to alkalinize the pH to 8, extract with dichloromethane (200mL×2), wash the organic phase with saturated brine (200mL×1), dry the organic phase over anhydrous sodium sulfate, filter, Concentrate under reduced pressure, and the residue is separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～2/1, V/V) to obtain compound 18-5. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.49 (s, 1H), 7.44 (s, 1H), 3.95 (s, 3H), 3.42 (s, 3H).

第五步the fifth step

氮气保护下将化合物18-5(3.35g,8.96mmol)溶于甲苯(30mL)中,加入A-5(5.50g,15.2mmol)和双(三苯基膦)二氯化钯(629mg,896μmol),在120℃下搅拌反应12小时。降至室温后向反应液加入饱和氟化钾水溶液(200mL),用乙酸乙酯(200mL×2)萃取,无水硫酸钠干燥有机相,过滤浓缩得到化合物18-6。MS-ESI计算值[M+H] ⁺278,实测值278。 Compound 18-5 (3.35g, 8.96mmol) was dissolved in toluene (30mL) under nitrogen protection, and A-5 (5.50g, 15.2mmol) and bis(triphenylphosphine)palladium dichloride (629mg, 896μmol) were added ), and the reaction was stirred at 120°C for 12 hours. After cooling down to room temperature, saturated potassium fluoride aqueous solution (200 mL) was added to the reaction solution, extracted with ethyl acetate (200 mL×2), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 18-6. MS-ESI calculated value [M+H] ⁺ 278, found value 278.

第六步step six

将化合物18-6(2.50g,9.02mmol)溶于丙酮(30mL)中,滴加盐酸溶液(12mol/L,3.00mL),在25℃下搅拌反应0.5小时。向反应液中加入饱和碳酸氢钠水溶液碱化pH至8,用乙酸乙酯(50mL×3)萃取,有机相用饱和食盐水(50mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物经过硅胶柱色谱法分离纯化(石油醚/乙酸乙酯,10/1～1/1,V/V),得到化合物18-7。MS-ESI计算值[M+H] ⁺250,实测值250。 Compound 18-6 (2.50g, 9.02mmol) was dissolved in acetone (30mL), hydrochloric acid solution (12mol/L, 3.00mL) was added dropwise, and the reaction was stirred at 25°C for 0.5 hours. Add saturated aqueous sodium bicarbonate solution to the reaction solution to alkalinize the pH to 8, extract with ethyl acetate (50mL×3), wash the organic phase with saturated brine (50mL×1), dry over anhydrous sodium sulfate, filter, and reduce pressure After concentration, the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～1/1, V/V) to obtain compound 18-7. MS-ESI calculated value [M+H] ⁺ 250, found value 250.

第七步step seven

将化合物18-7(2.48g,9.95mmol)溶于乙醇(25mL)中,加入水合肼(30.0mmol,1.49mL,85％纯度),在95℃下搅拌反应1小时。降至室温后过滤,将滤饼干燥得到化合物18-8。MS-ESI计算值[M+H] ⁺232,实测值232。 Compound 18-7 (2.48g, 9.95mmol) was dissolved in ethanol (25mL), hydrazine hydrate (30.0mmol, 1.49mL, 85% purity) was added, and the reaction was stirred at 95°C for 1 hour. After cooling down to room temperature, it was filtered, and the filter cake was dried to obtain compound 18-8. MS-ESI calculated [M+H] ⁺ 232, found 232.

第八步eighth step

将化合物18-8(2.06g,8.91mmol)溶于三氯氧磷(10mL)中,在90℃下搅拌反应12小时。降至室温后加入饱和碳酸氢钠溶液中和至pH为8,将水(100mL)倒入反应液中,用二氯甲烷(100mL×1)萃取,有机相用饱和食盐水(100mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物经过硅胶柱色谱法分离纯化(二氯甲烷/甲醇,100/1～10/1,V/V),得到化合物18-9。MS-ESI计算值[M+H] ⁺250,实测值250。 Compound 18-8 (2.06g, 8.91mmol) was dissolved in phosphorus oxychloride (10mL), and stirred at 90°C for 12 hours. After cooling down to room temperature, add saturated sodium bicarbonate solution to neutralize to pH 8, pour water (100mL) into the reaction solution, extract with dichloromethane (100mL×1), and use saturated brine (100mL×1) for the organic phase Washed, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (dichloromethane/methanol, 100/1～10/1, V/V) to obtain compound 18-9. MS-ESI calculated value [M+H] ⁺ 250, found value 250.

第九步Ninth step

将化合物18-9(400mg,1.60mmol)溶于二氧六环(2mL)中,加入中间体B的盐酸盐(364mg,1.92mmol),4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(185mg,320μmol),碳酸钾(664mg,4.81mmol)和三(二亚苄基丙酮)二钯(147mg,160μmol),在100℃下搅拌反应12小时。降至室温后将水(100mL)倒入反应液中,用二氯甲烷(100mL×3)萃取,有机相用饱和食盐水(100mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物经过硅胶柱色谱法分离纯化(二氯甲烷/甲醇,100/1～10/1,V/V),剩余物经制备高效液相色谱分离纯化(色谱柱:Xtimate C18 150mm×40mm×5μm；流动相:0.05％盐酸水溶液-乙腈；梯度:乙腈16％-46％,10min),得到化合物18的盐酸盐。 ¹H NMR(400MHz,CD ₃OD)δ8.52(s,1H),8.23(s,1H),7.70-7.59(m,1H),7.57-7.44(m,1H),7.35-7.20(m,1H),7.16-6.83(m,1H),5.67-5.53(m,1H),3.63(s,3H),2.88(s,3H),1.78(d,J＝6.8Hz,3H)。MS-ESI计算值[M+H] ⁺403,实测值403。 Compound 18-9 (400mg, 1.60mmol) was dissolved in dioxane (2mL), and the hydrochloride (364mg, 1.92mmol) of Intermediate B, 4,5-bis(diphenylphosphine)-9 , 9-dimethylxanthene (185 mg, 320 μmol), potassium carbonate (664 mg, 4.81 mmol) and tris(dibenzylideneacetone) dipalladium (147 mg, 160 μmol), and stirred at 100° C. for 12 hours. After cooling down to room temperature, pour water (100 mL) into the reaction solution, extract with dichloromethane (100 mL×3), wash the organic phase with saturated brine (100 mL×1), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure , the residue was separated and purified by silica gel column chromatography (dichloromethane/methanol, 100/1～10/1, V/V), and the residue was separated and purified by preparative high performance liquid chromatography (column: Xtimate C18 150mm×40mm× 5 μm; mobile phase: 0.05% hydrochloric acid aqueous solution-acetonitrile; gradient: acetonitrile 16%-46%, 10min), to obtain the hydrochloride of compound 18. ¹ H NMR (400MHz, CD ₃ OD) δ8.52(s,1H),8.23(s,1H),7.70-7.59(m,1H),7.57-7.44(m,1H),7.35-7.20(m, 1H), 7.16-6.83 (m, 1H), 5.67-5.53 (m, 1H), 3.63 (s, 3H), 2.88 (s, 3H), 1.78 (d, J=6.8Hz, 3H). MS-ESI calculated [M+H] ⁺ 403, found 403.

实施例19Example 19

合成路线：synthetic route:

第一步first step

将化合物4-2(1.80g,8.21mmol)溶于四氢呋喃(36mL)中,加入19-1的氢溴酸盐(3.83g,16.4mmol)和碳酸铯(8.03g,24.6mmol),在80℃下搅拌反应12小时。降至室温后,过滤,减压浓缩,剩余物用硅胶柱色谱法(二氯甲烷/甲醇,100/1～10/1,V/V),分离纯化得到化合物19-2。MS-ESI计算值[M+H] ⁺291,实测值291。 Compound 4-2 (1.80g, 8.21mmol) was dissolved in tetrahydrofuran (36mL), and hydrobromide (3.83g, 16.4mmol) and cesium carbonate (8.03g, 24.6mmol) of 19-1 were added, at 80°C The reaction was stirred for 12 hours. After cooling down to room temperature, it was filtered and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (dichloromethane/methanol, 100/1～10/1, V/V) to obtain compound 19-2. MS-ESI calculated value [M+H] ⁺ 291, found value 291.

第二步second step

氮气保护下将化合物19-2(1.54g,5.30mmol)溶于三氟乙酸(15mL)中,加入液溴(2.54g,15.9mmol),在55℃下搅拌反应24小时。向反应液中加入饱和亚硫酸钠水溶液(100mL),用二氯甲烷(100mL×3)萃取,有机相用饱和食盐水(100mL×1)洗涤,无水硫酸钠干燥有机相,过滤,减压浓缩,剩余物用硅胶柱色谱法(二氯甲烷/甲醇,100/1～10/1,V/V),分离纯化得到化合物19-3。MS-ESI计算值[M+H] ⁺369和371,实测值369和371。 Compound 19-2 (1.54g, 5.30mmol) was dissolved in trifluoroacetic acid (15mL) under nitrogen protection, liquid bromine (2.54g, 15.9mmol) was added, and the reaction was stirred at 55°C for 24 hours. Add saturated aqueous sodium sulfite solution (100 mL) to the reaction solution, extract with dichloromethane (100 mL×3), wash the organic phase with saturated brine (100 mL×1), dry the organic phase over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue was separated and purified by silica gel column chromatography (dichloromethane/methanol, 100/1～10/1, V/V) to obtain compound 19-3. MS-ESI calculated [M+H] ⁺ 369 and 371, found 369 and 371.

第三步third step

氮气保护下将化合物19-3(1.40g,3.79mmol)溶于甲苯(5mL)中,加入A-5(2.19g,6.07mmol)和双(三苯基膦)二氯化钯(266mg,379μmol),在120℃下搅拌反应12小时。降至室温后向反应液加入饱和氟化钾水溶液(100mL),用乙酸乙酯(100mL×3)萃取,有机相用饱和食盐水(50mL×1)洗涤,无水硫酸钠干燥有机相,过滤浓缩得到化合物19-4。MS-ESI计算值[M+H] ⁺361,实测值361。 Compound 19-3 (1.40g, 3.79mmol) was dissolved in toluene (5mL) under nitrogen protection, and A-5 (2.19g, 6.07mmol) and bis(triphenylphosphine)palladium dichloride (266mg, 379μmol) were added ), and the reaction was stirred at 120°C for 12 hours. After cooling down to room temperature, saturated potassium fluoride aqueous solution (100 mL) was added to the reaction solution, extracted with ethyl acetate (100 mL×3), the organic phase was washed with saturated brine (50 mL×1), dried over anhydrous sodium sulfate, and filtered Concentration afforded compound 19-4. MS-ESI calculated [M+H] ⁺ 361, found 361.

第四步the fourth step

将化合物19-4(1.37g,3.80mmol)溶于丙酮(20mL)中,滴加盐酸溶液(12mol/L,2.00mL),在25℃下搅拌反应0.5小时。向反应液中加入饱和碳酸氢钠水溶液碱化pH至8,用乙酸乙酯(100mL×3)萃取,有机相用饱和食盐水(100mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物经过硅胶柱色谱法分离纯化(二氯甲烷/甲醇,100/1～10/1,V/V),得到化合物19-5。 ¹H NMR(400MHz,CDCl ₃)δ7.35(s,1H),7.22(s,1H),3.93(s,3H),3.85(t,J＝6.8Hz,2H),2.59-2.53(m,5H),2.30(s,6H),1.40(s,6H)。MS-ESI计算值[M+H] ⁺333,实测值333。 Compound 19-4 (1.37g, 3.80mmol) was dissolved in acetone (20mL), hydrochloric acid solution (12mol/L, 2.00mL) was added dropwise, and the reaction was stirred at 25°C for 0.5 hours. Add saturated aqueous sodium bicarbonate solution to the reaction solution to alkalinize the pH to 8, extract with ethyl acetate (100mL×3), wash the organic phase with saturated brine (100mL×1), dry over anhydrous sodium sulfate, filter, and reduce pressure After concentration, the residue was separated and purified by silica gel column chromatography (dichloromethane/methanol, 100/1-10/1, V/V) to obtain compound 19-5. ¹ H NMR (400MHz, CDCl ₃ ) δ7.35(s, 1H), 7.22(s, 1H), 3.93(s, 3H), 3.85(t, J=6.8Hz, 2H), 2.59-2.53(m, 5H), 2.30(s,6H), 1.40(s,6H). MS-ESI calculated [M+H] ⁺ 333, found 333.

第五步the fifth step

将化合物19-5(880mg,2.65mmol)溶于乙醇(10mL)中,加入水合肼(7.94mmol,386μL),在95℃下搅拌反应1小时。降至室温后过滤,将滤液减压浓缩,剩余物经过硅胶柱色谱法分离纯化(二氯甲烷/甲醇,100/1～10/1,V/V),得到化合物19-6。MS-ESI计算值[M+H] ⁺315,实测值315。 Compound 19-5 (880mg, 2.65mmol) was dissolved in ethanol (10mL), hydrazine hydrate (7.94mmol, 386μL) was added, and the reaction was stirred at 95°C for 1 hour. After cooling down to room temperature, it was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (dichloromethane/methanol, 100/1-10/1, V/V) to obtain compound 19-6. MS-ESI calculated [M+H] ⁺ 315, found 315.

第六步step six

将化合物19-6(700mg,2.23mmol)溶于三氯氧磷(3mL)中,在90℃下搅拌反应12小时。降至室温后将水(10mL)倒入反应液中,加入饱和碳酸氢钠溶液中和至pH为8,用二氯甲烷(100mL×2)萃取,有机相用饱和食盐水(100mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物经过硅胶柱色谱法分离纯化(二氯甲烷/甲醇,100/1～10/1,V/V),得到化合物19-7。MS-ESI计算值[M+H] ⁺333,实测值333。 Compound 19-6 (700mg, 2.23mmol) was dissolved in phosphorus oxychloride (3mL), and stirred at 90°C for 12 hours. After cooling down to room temperature, pour water (10 mL) into the reaction solution, add saturated sodium bicarbonate solution to neutralize to pH 8, extract with dichloromethane (100 mL×2), and use saturated brine (100 mL×1) for the organic phase Washed, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (dichloromethane/methanol, 100/1～10/1, V/V) to obtain compound 19-7. MS-ESI calculated [M+H] ⁺ 333, found 333.

第七步step seven

将化合物19-7(200mg,601μmol)溶于二氧六环(2mL)中,加入中间体B的盐酸盐(136mg,721mmol),4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(70.0mg,120μmol),碳酸钾(249mg,1.80mmol)和三(二亚苄基丙酮)二钯(55.0mg,60.1μmol),在100℃下搅拌反应12小时。降至室温后将水(100mL)倒入反应液中,用二氯甲烷(100mL×3)萃取,有机相用饱和食盐水(100mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物经过硅胶柱色谱法分离纯化(二氯甲烷/甲醇,100/1～10/1,V/V),剩余物经制备高效液相色谱分离纯化(色谱柱:Xtimate C18 150mm×40mm×5μm；流动相:0.05％盐酸水溶液-乙腈；梯度:乙腈5％-35％,10min),得到化合物19的盐酸盐。 ¹H NMR(400MHz,CD ₃OD)δ8.74(s,1H),8.36(s,1H),7.86-7.73(m,1H),7.58-7.41(m,1H),7.31-7.17(m,1H),7.15-6.84(m,1H),5.68-5.58(m,1H),4.54-4.36(m,2H),3.75-3.60(m,2H),3.08(s,6H),2.89(s,3H),1.82(d,J＝6.4Hz,3H),1.58-1.52(m,6H)。MS-ESI计算值[M+H] ⁺486,实测值486。 Compound 19-7 (200 mg, 601 μmol) was dissolved in dioxane (2 mL), and the hydrochloride (136 mg, 721 mmol) of Intermediate B, 4,5-bis(diphenylphosphine)-9,9 -Dimethylxanthene (70.0 mg, 120 μmol), potassium carbonate (249 mg, 1.80 mmol) and tris(dibenzylideneacetone) dipalladium (55.0 mg, 60.1 μmol), stirred and reacted at 100° C. for 12 hours. After cooling down to room temperature, pour water (100 mL) into the reaction solution, extract with dichloromethane (100 mL×3), wash the organic phase with saturated brine (100 mL×1), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure , the residue was separated and purified by silica gel column chromatography (dichloromethane/methanol, 100/1～10/1, V/V), and the residue was separated and purified by preparative high performance liquid chromatography (column: Xtimate C18 150mm×40mm× 5 μm; mobile phase: 0.05% hydrochloric acid aqueous solution-acetonitrile; gradient: acetonitrile 5%-35%, 10min), to obtain the hydrochloride of compound 19. ¹ H NMR (400MHz, CD ₃ OD) δ8.74(s,1H),8.36(s,1H),7.86-7.73(m,1H),7.58-7.41(m,1H),7.31-7.17(m, 1H),7.15-6.84(m,1H),5.68-5.58(m,1H),4.54-4.36(m,2H),3.75-3.60(m,2H),3.08(s,6H),2.89(s, 3H), 1.82 (d, J=6.4Hz, 3H), 1.58-1.52 (m, 6H). MS-ESI calculated [M+H] ⁺ 486, found 486.

实施例20Example 20

合成路线：synthetic route:

将化合物4-9(100mg,313μmol)溶于二氧六环(2mL)中,加入中间体B的盐酸盐(71.0mg,375μmol),4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(36.2mg,62.5μmol),碳酸钾(130mg,938μmol)和三(二亚苄基丙酮)二钯(28.6mg,31.3μmol),在100℃下搅拌反应12小时。降至室温后,过滤,将滤液减压浓缩。剩余物用甲醇(10mL)溶解,过滤,减压浓缩,剩余物经制备高效液相色谱分离纯化(色谱柱:Phenomenex C18 150mm×40mm×5um；流动相:0.05％盐酸水溶液-乙腈；梯度:乙腈15％-45％,10min),得到化合物20的盐酸盐。 ¹H NMR(400MHz,CD ₃OD)δ8.41-8.31(m,2H),7.65(m,1H),7.49(m,1H),7.24(t,J＝7.2Hz,1H),6.99(t,J＝54.8Hz,1H),5.59(q,J＝6.8Hz,1H),4.18(s,2H),3.84-3.74(m,2H),3.34(s,3H),2.89(s,3H),1.77(d,J＝6.4Hz,3H),1.51(d,J＝4.4Hz,6H)。MS-ESI计算值[M+H] ⁺473,实测值473。 Compound 4-9 (100 mg, 313 μmol) was dissolved in dioxane (2 mL), and the hydrochloride (71.0 mg, 375 μmol) of Intermediate B, 4,5-bis(diphenylphosphine)-9, 9-Dimethylxanthene (36.2 mg, 62.5 μmol), potassium carbonate (130 mg, 938 μmol) and tris(dibenzylideneacetone) dipalladium (28.6 mg, 31.3 μmol), stirred at 100°C for 12 hours . After cooling down to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (10mL), filtered, concentrated under reduced pressure, and the residue was separated and purified by preparative high performance liquid chromatography (chromatographic column: Phenomenex C18 150mm×40mm×5um; mobile phase: 0.05% aqueous hydrochloric acid-acetonitrile; gradient: acetonitrile 15%-45%, 10min), the hydrochloride of compound 20 was obtained. ¹ H NMR (400MHz, CD ₃ OD) δ8.41-8.31(m, 2H), 7.65(m, 1H), 7.49(m, 1H), 7.24(t, J=7.2Hz, 1H), 6.99(t ,J=54.8Hz,1H),5.59(q,J=6.8Hz,1H),4.18(s,2H),3.84-3.74(m,2H),3.34(s,3H),2.89(s,3H) , 1.77 (d, J=6.4Hz, 3H), 1.51 (d, J=4.4Hz, 6H). MS-ESI calculated [M+H] ⁺ 473, found 473.

实施例21Example 21

合成路线：synthetic route:

第一步first step

将化合物2-1(2.00g,10.5mmol)溶于四氢呋喃(30mL)中,加入N-氟代双苯磺酰胺(8.25g,26.1mmol)和氢氧化钠(1.26g,31.4mmol),反应液在0℃下搅拌反应1小时。用乙酸乙酯(50mL×3)萃取,有机相用饱和食盐水(50mL×1)洗涤,无水硫酸钠干燥有机相,过滤减压浓缩,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,1/0～5/1,V/V),分离纯化得到化合物21-1。 ¹H NMR(400MHz,CDCl ₃)δ8.19-8.06(m,1H),7.90-7.88(d,J＝8.0Hz,1H),7.66-7.63(m,2H),4.70(s,3H)。MS-ESI计算值[M+H] ⁺228,实测值228。 Dissolve compound 2-1 (2.00g, 10.5mmol) in tetrahydrofuran (30mL), add N-fluorobisbenzenesulfonamide (8.25g, 26.1mmol) and sodium hydroxide (1.26g, 31.4mmol), and the reaction solution The reaction was stirred at 0 °C for 1 hour. Extracted with ethyl acetate (50mL×3), the organic phase was washed with saturated brine (50mL×1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate Esters, 1/0～5/1, V/V), separated and purified to obtain compound 21-1. ¹ H NMR (400MHz, CDCl ₃ ) δ8.19-8.06 (m, 1H), 7.90-7.88 (d, J=8.0Hz, 1H), 7.66-7.63 (m, 2H), 4.70 (s, 3H). MS-ESI calculated value [M+H] ⁺ 228, found value 228.

第二步second step

将化合物21-1(1.35g,5.94mmol)溶于N,N-二甲基甲酰胺(10mL)中,加入碳酸钾(1.07g,7.73mmol)和碘甲烷(1.27g,8.91mmol),反应液在25℃下搅拌反应12小时。向反应液加入水(100mL),用乙酸乙酯(20mL×3)萃取,有机相用饱和食盐水(25mL×1)洗涤,无水硫酸钠干燥有机相,过滤减压浓缩,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,20/1～5/1,V/V),分离纯化得到化合物21-2。 ¹H NMR(400MHz,CDCl ₃)δ7.91-7.89(d,J＝8.0Hz,1H),7.64-7.63(m,1H),7.55(s,1H),3.98(s,3H),3.28(s,3H)。MS-ESI计算值[M+H] ⁺242,实测值242。 Compound 21-1 (1.35g, 5.94mmol) was dissolved in N,N-dimethylformamide (10mL), potassium carbonate (1.07g, 7.73mmol) and iodomethane (1.27g, 8.91mmol) were added, and the reaction The solution was stirred and reacted at 25°C for 12 hours. Add water (100mL) to the reaction solution, extract with ethyl acetate (20mL×3), wash the organic phase with saturated brine (25mL×1), dry the organic phase over anhydrous sodium sulfate, filter and concentrate under reduced pressure, and wash the residue with silica gel Column chromatography (petroleum ether/ethyl acetate, 20/1～5/1, V/V), separation and purification to obtain compound 21-2. ¹ H NMR (400MHz, CDCl ₃ ) δ7.91-7.89 (d, J=8.0Hz, 1H), 7.64-7.63 (m, 1H), 7.55 (s, 1H), 3.98 (s, 3H), 3.28 ( s, 3H). MS-ESI calculated value [M+H] ⁺ 242, found value 242.

第三步third step

氮气保护下将化合物21-2(1.12g,4.64mmol)溶于三氟甲酸(5mL)和硫酸(0.5mL)中,在25℃下加入N-溴代丁二酰亚胺(909mg,5.11mmol),在25℃下搅拌反应1小时。向反应液加入水(50mL),用乙酸乙酯(20mL×3)萃取,有机相用饱和食盐水(25mL×1)洗涤,无水硫酸钠干燥有机相,过滤,减压浓缩,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,20/1～5/1,V/V),分离纯化得到化合物21-3。 ¹H NMR(400MHz,CDCl ₃)δ7.83-7.82(m,1H),7.26(s,1H),3.99(s,3H),3.25(s,3H)。MS-ESI计算值[M+H] ⁺320和322实测值320和322。 Compound 21-2 (1.12g, 4.64mmol) was dissolved in trifluoroformic acid (5mL) and sulfuric acid (0.5mL) under nitrogen protection, and N-bromosuccinimide (909mg, 5.11mmol) was added at 25°C ), and the reaction was stirred at 25°C for 1 hour. Add water (50 mL) to the reaction solution, extract with ethyl acetate (20 mL×3), wash the organic phase with saturated brine (25 mL×1), dry the organic phase over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and use Silica gel column chromatography (petroleum ether/ethyl acetate, 20/1～5/1, V/V), separation and purification to obtain compound 21-3. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.83-7.82 (m, 1H), 7.26 (s, 1H), 3.99 (s, 3H), 3.25 (s, 3H). MS-ESI calculated [M+H] ⁺ 320 and 322 found 320 and 322.

第四步the fourth step

氮气保护下将化合物21-3(1.12g,3.50mmol)溶于甲苯(10mL)中,加入A-5(1.68g,4.65mmol)和双(三苯基膦)二氯化钯(246mg,350μmol),在120℃下搅拌反应7小时。降至室温后,向反应液加入饱和氟化钾水溶液(100mL),用乙酸乙酯(30mL×2)萃取,无水硫酸钠干燥有机相,过滤浓缩得到化合物21-4。MS-ESI计算值[M+H] ⁺312,实测值312。 Compound 21-3 (1.12g, 3.50mmol) was dissolved in toluene (10mL) under nitrogen protection, and A-5 (1.68g, 4.65mmol) and bis(triphenylphosphine)palladium dichloride (246mg, 350μmol) were added ), stirred and reacted at 120°C for 7 hours. After cooling down to room temperature, saturated potassium fluoride aqueous solution (100 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL×2), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 21-4. MS-ESI calculated [M+H] ⁺ 312, found 312.

第五步the fifth step

将化合物21-4(1.09g,3.50mmol)溶于丙酮(26mL)中,在0℃下滴加盐酸溶液(12M,2.33mL),在25℃下搅拌反应1小时。向反应液中加入饱和碳酸氢钠水溶液碱化pH至8,用乙酸乙酯(100mL×3)萃取,有机相用饱和食盐水(250mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物经过硅胶柱色谱法分离纯化(石油醚/乙酸乙酯,20/1～5/1,V/V),得到化合物21-5。 ¹H NMR(400MHz,CDCl ₃)δ7.79(s,1H),7.20(s,1H),3.95(s,3H),3.28(s,3H),2.58(s,3H)。MS-ESI计算值[M+H] ⁺284,实测值284。 Compound 21-4 (1.09g, 3.50mmol) was dissolved in acetone (26mL), hydrochloric acid solution (12M, 2.33mL) was added dropwise at 0°C, and the reaction was stirred at 25°C for 1 hour. Add saturated aqueous sodium bicarbonate solution to the reaction solution to alkalinize the pH to 8, extract with ethyl acetate (100mL×3), wash the organic phase with saturated brine (250mL×1), dry over anhydrous sodium sulfate, filter, and reduce pressure After concentration, the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 20/1～5/1, V/V) to obtain compound 21-5. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.79 (s, 1H), 7.20 (s, 1H), 3.95 (s, 3H), 3.28 (s, 3H), 2.58 (s, 3H). MS-ESI calculated value [M+H] ⁺ 284, found value 284.

第六步step six

将化合物21-5(830mg,2.93mmol)溶于乙醇(5mL)中,加入水合肼(503μL,8.79mmol,85％纯度),在95℃下搅拌反应0.5小时。降至室温后,过滤,将固体减压浓缩得到化合物21-6。 ¹H NMR(400MHz,CDCl ₃)δ12.6(s,1H),8.37(s,1H),7.85(s,1H),3.32(s,3H),2.55(s,3H)。MS-ESI计算值[M+H] ⁺266,实测值266。 Compound 21-5 (830 mg, 2.93 mmol) was dissolved in ethanol (5 mL), hydrazine hydrate (503 μL, 8.79 mmol, 85% purity) was added, and the reaction was stirred at 95°C for 0.5 hours. After cooling down to room temperature, it was filtered, and the solid was concentrated under reduced pressure to obtain compound 21-6. ¹ H NMR (400 MHz, CDCl ₃ ) δ 12.6 (s, 1H), 8.37 (s, 1H), 7.85 (s, 1H), 3.32 (s, 3H), 2.55 (s, 3H). MS-ESI calculated [M+H] ⁺ 266, found 266.

第七步step seven

将化合物21-6(479mg,1.81mmol)溶于三氯氧磷(3mL)中,在90℃下搅拌反应12小时。降至室温后,向反应液中倒入氯化铵水溶液(20mL),用乙酸乙酯(20mL×5)萃取,有机相用饱和食盐水(30mL×2)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物经过硅胶柱色谱法分离纯化(石油醚/乙酸乙酯,20/1～5/1,V/V),得到化合物21-7。 ¹H NMR(400MHz,CDCl ₃)δ8.78(s,1H),7.73(s,1H),3.37(s,3H),2.95(s,3H)。MS-ESI计算值[M+H] ⁺284,实测值284。 Compound 21-6 (479mg, 1.81mmol) was dissolved in phosphorus oxychloride (3mL), and stirred at 90°C for 12 hours. After cooling down to room temperature, pour ammonium chloride aqueous solution (20mL) into the reaction solution, extract with ethyl acetate (20mL×5), wash the organic phase with saturated brine (30mL×2), dry over anhydrous sodium sulfate, and filter , concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 20/1～5/1, V/V) to obtain compound 21-7. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.78 (s, 1H), 7.73 (s, 1H), 3.37 (s, 3H), 2.95 (s, 3H). MS-ESI calculated value [M+H] ⁺ 284, found value 284.

第八步eighth step

氮气保护下将化合物21-7(100mg,352μmol)溶于二氧六环(2mL)中,加入中间体B的盐酸盐(100mg,529μmol),(±)-2,2-双(二苯膦基)-1,1-联萘(40.8mg,70.5μmol),碳酸钾(146mg,1.06mmol)和双(二亚苄基丙酮)钯(32.2mg,35.2μmol),在100℃下搅拌反应12小时。降至室温后,向反应液加入水(20mL),用乙酸乙酯(10mL×3)萃取,有机相用饱和食盐水(20mL×1)洗涤,无水硫酸钠干燥有机相,过滤,减压浓缩。剩余物经制备高效液相色谱分离纯化(色谱柱:Welch Ultimate Xtimate C18 150mm×40mm×5μm；流动相:0.05％盐酸水溶液-乙腈；梯度:乙腈15％-45％,10min),得到化合物21的盐酸盐。 ¹H NMR(400MHz,CD ₃OD)δ8.72(s,1H),8.38(s,1H),7.68(t,J＝7.0Hz,1H),7.50(t,J＝6.4Hz,1H),7.26(t,J＝7.6Hz,1H),7.13-6.86(m,1H),5.60-5.58(m,1H),3.45(s,3H),2.90(s,3H),1.77(d,J＝7.2Hz,3H)。MS-ESI计算值[M+H] ⁺437,实测值437。 Compound 21-7 (100 mg, 352 μmol) was dissolved in dioxane (2 mL) under nitrogen protection, and the hydrochloride (100 mg, 529 μmol) of intermediate B was added, (±)-2,2-bis(diphenyl Phosphino)-1,1-binaphthyl (40.8 mg, 70.5 μmol), potassium carbonate (146 mg, 1.06 mmol) and bis(dibenzylideneacetone) palladium (32.2 mg, 35.2 μmol), stirred at 100 ° C 12 hours. After cooling down to room temperature, water (20 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL×3), the organic phase was washed with saturated brine (20 mL×1), the organic phase was dried over anhydrous sodium sulfate, filtered, and reduced pressure concentrate. The residue was separated and purified by preparative high-performance liquid chromatography (column: Welch Ultimate Xtimate C18 150mm×40mm×5μm; mobile phase: 0.05% aqueous hydrochloric acid-acetonitrile; gradient: acetonitrile 15%-45%, 10min), to obtain compound 21 Hydrochloride. ¹ H NMR (400MHz, CD ₃ OD) δ8.72(s, 1H), 8.38(s, 1H), 7.68(t, J=7.0Hz, 1H), 7.50(t, J=6.4Hz, 1H), 7.26(t,J=7.6Hz,1H),7.13-6.86(m,1H),5.60-5.58(m,1H),3.45(s,3H),2.90(s,3H),1.77(d,J= 7.2Hz, 3H). MS-ESI calculated [M+H] ⁺ 437, found 437.

实施例22Example 22

合成路线：synthetic route:

第一步first step

将化合物2-1(20.0g,105mmol)溶于四氢呋喃(200mL)中,加入二碳酸二叔丁酯(25.1g,115mmol)和碳酸钠(22.2g,209mmol),在70℃下搅拌反应12小时后,反应液减压浓缩。剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,10/1～5/1,V/V),分离纯化得到化合物22-1。 ¹H NMR(400MHz,CDCl ₃)δ8.48(s,1H),7.92-7.86(m,1H),7.34(d,J＝8.0Hz,1H),3.95(s,3H),3.71(s,2H),1.68(s,9H)。 Compound 2-1 (20.0g, 105mmol) was dissolved in tetrahydrofuran (200mL), di-tert-butyl dicarbonate (25.1g, 115mmol) and sodium carbonate (22.2g, 209mmol) were added, and the reaction was stirred at 70°C for 12 hours Afterwards, the reaction solution was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～5/1, V/V) to obtain compound 22-1. ¹ H NMR (400MHz, CDCl ₃ ) δ8.48(s, 1H), 7.92-7.86(m, 1H), 7.34(d, J=8.0Hz, 1H), 3.95(s, 3H), 3.71(s, 2H), 1.68(s, 9H).

第二步second step

将化合物22-1(13.0g,44.6mmol)溶于二甲基亚砜(200mL)中,加入碳酸铯(17.5g,53.6mmol)和1,2-二溴乙烷(9.22g,49.1mmol),在25℃下搅拌反应12小时,然后补加碳酸铯(7.27g,22.3mmol),在25℃下搅拌反应4小时。过滤,滤饼用乙酸乙酯(150mL×3)洗涤。减压浓缩滤液,剩余物加乙酸乙酯(600mL),用水(200mL×3)萃取,有机相用饱和食盐水(300mL×1)洗涤,无水硫酸钠干燥有机相,过滤,减压浓缩,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,10/1～5/1,V/V),分离纯化得到化合物22-2。 ¹H NMR(400MHz,CDCl ₃)δ8.63-8.54(m,1H),7.91-7.82(m,1H),6.88(d,J＝8.0Hz,1H),3.94(s,3H),1.94-1.89(m,2H),1.68(s,9H),1.65-1.60(m,2H)。MS-ESI计算值[M+H-100] ⁺218,实测值218。 Compound 22-1 (13.0g, 44.6mmol) was dissolved in dimethylsulfoxide (200mL), cesium carbonate (17.5g, 53.6mmol) and 1,2-dibromoethane (9.22g, 49.1mmol) were added , the reaction was stirred at 25°C for 12 hours, then cesium carbonate (7.27g, 22.3mmol) was added, and the reaction was stirred at 25°C for 4 hours. Filter and wash the filter cake with ethyl acetate (150mL×3). Concentrate the filtrate under reduced pressure, add ethyl acetate (600 mL) to the residue, extract with water (200 mL×3), wash the organic phase with saturated brine (300 mL×1), dry the organic phase over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～5/1, V/V) to obtain compound 22-2. ¹ H NMR (400MHz, CDCl ₃ ) δ8.63-8.54 (m, 1H), 7.91-7.82 (m, 1H), 6.88 (d, J=8.0Hz, 1H), 3.94 (s, 3H), 1.94- 1.89(m,2H),1.68(s,9H),1.65-1.60(m,2H). MS-ESI calculated value [M+H-100] ⁺ 218, measured value 218.

第三步third step

将化合物22-2(5.00g,14.1mmol)溶于二氯甲烷(100mL)中,加入三氟乙酸(25.0mL,338mmol),在20℃下搅拌反应1小时。反应液减压浓缩,向剩余物中加入甲基叔丁基醚(50mL),在25℃下搅拌反应30分钟,过滤,滤饼干燥,得到化合物22-3。 ¹H NMR(400MHz,CDCl ₃)δ8.77(br s,1H),7.79-7.73(m,1H),7.65(s,1H),6.89(d,J＝7.2Hz,1H),3.93(s,3H),1.96-1.79(m,2H),1.73-1.53(m,2H)。MS-ESI计算值[M+H] ⁺218实测值218。 Compound 22-2 (5.00g, 14.1mmol) was dissolved in dichloromethane (100mL), trifluoroacetic acid (25.0mL, 338mmol) was added, and the reaction was stirred at 20°C for 1 hour. The reaction solution was concentrated under reduced pressure, methyl tert-butyl ether (50 mL) was added to the residue, the reaction was stirred at 25°C for 30 minutes, filtered, and the filter cake was dried to obtain compound 22-3. ¹ H NMR (400MHz, CDCl ₃ )δ8.77(br s, 1H), 7.79-7.73(m, 1H), 7.65(s, 1H), 6.89(d, J=7.2Hz, 1H), 3.93(s ,3H), 1.96-1.79(m,2H), 1.73-1.53(m,2H). MS-ESI calculated [M+H] ⁺ 218 found 218.

第四步the fourth step

将化合物22-3(2.90g,13.4mmol)溶于N,N-二甲基甲酰胺(30mL)中,加入碳酸铯(13.1g,40.1mmol)和碘甲烷(1.66mL,26.7mmol),在25℃下搅拌反应12小时。反应液减压浓缩,加入二氯甲烷(150mL),过滤,滤液减压浓缩,向剩余物中加入甲基叔丁基醚(30mL),在25℃下搅拌反应2小时,过滤,滤饼干燥, 得到化合物22-4。 ¹H NMR(400MHz,CDCl ₃)δ7.78-7.74(m,1H),7.56(d,J＝1.2Hz,1H),6.89(d,J＝7.6Hz,1H),3.94(s,3H),3.34(s,3H),1.87-1.79(m,2H),1.63-1.58(m,2H)。MS-ESI计算值[M+H] ⁺232实测值232。 Compound 22-3 (2.90g, 13.4mmol) was dissolved in N,N-dimethylformamide (30mL), cesium carbonate (13.1g, 40.1mmol) and methyl iodide (1.66mL, 26.7mmol) were added, and The reaction was stirred at 25°C for 12 hours. The reaction solution was concentrated under reduced pressure, dichloromethane (150 mL) was added, filtered, the filtrate was concentrated under reduced pressure, methyl tert-butyl ether (30 mL) was added to the residue, stirred and reacted at 25°C for 2 hours, filtered, and the filter cake was dried , to obtain compound 22-4. ¹ H NMR (400MHz, CDCl ₃ ) δ7.78-7.74 (m, 1H), 7.56 (d, J = 1.2Hz, 1H), 6.89 (d, J = 7.6Hz, 1H), 3.94 (s, 3H) , 3.34 (s, 3H), 1.87-1.79 (m, 2H), 1.63-1.58 (m, 2H). MS-ESI calculated [M+H] ⁺ 232 found 232.

第五步the fifth step

将化合物22-4(2.90g,12.5mmol)溶于N,N-二甲基甲酰胺(30mL)中,在0℃下加入N-溴代丁二酰亚胺(2.46g,13.8mmol),在0℃下搅拌反应0.5小时,在20℃下搅拌反应14小时。反应液减压浓缩,加入乙酸乙酯(200mL),用水(100mL×3)洗涤,饱和食盐水(100mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,向剩余物中加入甲基叔丁基醚(30mL),在25℃下搅拌反应2小时,过滤,滤饼干燥,得到化合物22-5。 ¹H NMR(400MHz,CDCl ₃)δ7.33(s,1H),7.09(s,1H),3.96(s,3H),3.31(s,3H),1.84(q,J＝4.2Hz,2H),1.63-1.59(m,2H)。MS-ESI计算值[M+H] ⁺310和312,实测值310和312。 Compound 22-4 (2.90g, 12.5mmol) was dissolved in N,N-dimethylformamide (30mL), and N-bromosuccinimide (2.46g, 13.8mmol) was added at 0°C, The reaction was stirred at 0 °C for 0.5 h and at 20 °C for 14 h. The reaction solution was concentrated under reduced pressure, ethyl acetate (200 mL) was added, washed with water (100 mL×3), washed with saturated brine (100 mL×1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and added formazan to the residue. tert-butyl ether (30 mL), stirred at 25°C for 2 hours, filtered, and the filter cake was dried to obtain compound 22-5. ¹ H NMR (400MHz, CDCl ₃ )δ7.33(s,1H),7.09(s,1H),3.96(s,3H),3.31(s,3H),1.84(q,J=4.2Hz,2H) ,1.63-1.59(m,2H). MS-ESI calculated [M+H] ⁺ 310 and 312, found 310 and 312.

第六步step six

将化合物22-5(1.00g,3.22mmol)和22-6(1.61g,16.1mmol)溶于N,N-二甲基甲酰胺(10mL)和水(10mL)中,加入碳酸钾(534mg,3.86mmol),醋酸钯(72.3mg,322μmol)和1,3-双(二苯基膦)丙烷(266mg,644μmol),反应液在100℃及氮气保护下搅拌反应12小时。降至室温后向反应液加入2M盐酸溶液(12.9mL),在25℃下搅拌0.5小时,反应液减压浓缩,加水(100mL),用乙酸乙酯(50mL×3)萃取,饱和食盐水(80mL×1)洗涤,无水硫酸钠干燥有机相,过滤浓缩,剩余物经过硅胶柱色谱法分离纯化(石油醚/乙酸乙酯,4/1～2/1,V/V),得到化合物22-7。 ¹H NMR(400MHz,CDCl ₃)δ7.28(s,1H),6.94(s,1H),3.93(s,3H),3.35(s,3H),2.51(s,3H),1.92-1.83(m,2H),1.69-1.62(m,2H)。MS-ESI计算值[M+H] ⁺274,实测值274。 Compound 22-5 (1.00g, 3.22mmol) and 22-6 (1.61g, 16.1mmol) were dissolved in N,N-dimethylformamide (10mL) and water (10mL), potassium carbonate (534mg, 3.86mmol), palladium acetate (72.3mg, 322μmol) and 1,3-bis(diphenylphosphine)propane (266mg, 644μmol), and the reaction solution was stirred at 100°C for 12 hours under nitrogen protection. After cooling down to room temperature, 2M hydrochloric acid solution (12.9mL) was added to the reaction solution, stirred at 25°C for 0.5 hours, the reaction solution was concentrated under reduced pressure, water (100mL) was added, extracted with ethyl acetate (50mL×3), saturated brine ( 80mL×1) was washed, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 4/1～2/1, V/V) to obtain compound 22 -7. ¹ H NMR (400MHz, CDCl ₃ ) δ7.28(s,1H),6.94(s,1H),3.93(s,3H),3.35(s,3H),2.51(s,3H),1.92-1.83( m,2H), 1.69-1.62(m,2H). MS-ESI calculated [M+H] ⁺ 274, found 274.

第七步step seven

将化合物22-7(520mg,1.90mmol)溶于乙醇(10mL)中,加入水合肼(12.8mmol,729μL,85％纯度),在90℃下搅拌反应2小时。降至室温后过滤,滤饼用水(5mL×3)洗涤,干燥得到化合物22-8。 ¹H NMR(400MHz,CDCl ₃)δ9.67(br s,1H),7.88(s,1H),7.16(s,1H),3.43(s,3H),2.57(s,3H),1.96(s,2H),1.79-1.72(m,2H)。MS-ESI计算值[M+H] ⁺256,实测值256。 Compound 22-7 (520 mg, 1.90 mmol) was dissolved in ethanol (10 mL), hydrazine hydrate (12.8 mmol, 729 μL, 85% purity) was added, and the reaction was stirred at 90°C for 2 hours. After cooling down to room temperature, it was filtered, the filter cake was washed with water (5 mL×3), and dried to obtain compound 22-8. ¹ H NMR (400MHz, CDCl ₃ )δ9.67(br s,1H),7.88(s,1H),7.16(s,1H),3.43(s,3H),2.57(s,3H),1.96(s ,2H), 1.79-1.72(m,2H). MS-ESI calculated [M+H] ⁺ 256, found 256.

第八步eighth step

将化合物22-8(390mg,1.53mol)溶于三氯氧磷(4mL)中,在90℃下搅拌反应2小时。降至室温后,减压浓缩,加入饱和碳酸氢钠溶液(30mL),在25℃下搅拌反应30分钟,用二氯甲烷/甲醇的混合溶液(10:1,20mL×3)萃取,有机相用饱和食盐水(20mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物经过硅胶柱色谱法分离纯化(二氯甲烷/甲醇,40/1～20/1,V/V),得到化合物22-9。MS-ESI计算值[M+H] ⁺274实测值274。 Compound 22-8 (390mg, 1.53mol) was dissolved in phosphorus oxychloride (4mL), and stirred at 90°C for 2 hours. After cooling down to room temperature, concentrate under reduced pressure, add saturated sodium bicarbonate solution (30mL), stir and react at 25°C for 30 minutes, extract with a mixed solution of dichloromethane/methanol (10:1, 20mL×3), and the organic phase Wash with saturated brine (20mL×1), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and the residue is separated and purified by silica gel column chromatography (dichloromethane/methanol, 40/1～20/1, V/V ), to obtain compound 22-9. MS-ESI calcd [M+H] ⁺ 274 found 274.

第九步Ninth step

将化合物22-9(120mg,438μmol)和中间体B的盐酸盐(99.5mg,526μmol)溶于二氧六环(2mL)中,加入碳酸钾(182mg,1.32mmol),4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(50.7mg,87.7μmol)和三(二亚苄基丙酮)二钯(40.2mg,43.8μmol),在100℃下搅拌反应12小时。降至室温后,减压浓缩,加水(30mL),用乙酸乙酯(15mL×3)萃取,无水硫酸钠干燥,过滤,浓缩,剩余物经制备高效液相色谱分离纯化(色谱柱:Waters Xbridge 150mm×25mm×5μm；流动相:10mM碳酸氢铵-乙腈；梯度:乙腈38％-68％,10min),得到化合物22。 ¹H NMR(400MHz,CD ₃OD)δ8.03(s,1H),7.65(s,1H),7.63-7.57(m,1H),7.48-7.43(m,1H),7.18(t,J＝7.6Hz,1H),7.16-6.87(m,1H),5.85-5.66(m,1H),3.51(s,3H),2.68(s,3H),1.94-1.89(m,2H),1.87-1.83(m,2H),1.73(d,J＝7.2Hz,3H)。MS-ESI计算值[M+H] ⁺427,实测值427。 Compound 22-9 (120 mg, 438 μmol) and intermediate B hydrochloride (99.5 mg, 526 μmol) were dissolved in dioxane (2 mL), potassium carbonate (182 mg, 1.32 mmol), 4,5-bis (Diphenylphosphine)-9,9-dimethylxanthene (50.7 mg, 87.7 μmol) and tris(dibenzylideneacetone) dipalladium (40.2 mg, 43.8 μmol) were stirred at 100° C. for 12 Hour. After cooling down to room temperature, concentrate under reduced pressure, add water (30mL), extract with ethyl acetate (15mL×3), dry over anhydrous sodium sulfate, filter, concentrate, and the residue is separated and purified by preparative high performance liquid chromatography (column: Waters Xbridge 150mm×25mm×5μm; mobile phase: 10mM ammonium bicarbonate-acetonitrile; gradient: acetonitrile 38%-68%, 10min), to obtain compound 22. ¹ H NMR (400MHz, CD ₃ OD) δ8.03(s, 1H), 7.65(s, 1H), 7.63-7.57(m, 1H), 7.48-7.43(m, 1H), 7.18(t, J= 7.6Hz,1H),7.16-6.87(m,1H),5.85-5.66(m,1H),3.51(s,3H),2.68(s,3H),1.94-1.89(m,2H),1.87-1.83 (m, 2H), 1.73 (d, J=7.2Hz, 3H). MS-ESI calculated [M+H] ⁺ 427, found 427.

实施例23Example 23

合成路线：synthetic route:

第一步first step

将化合物2-1(15.0g,78.5mmol)和化合物23-1(20.0g,86.3mmol)溶于N,N-二甲基甲酰胺(600mL)中,加入碳酸铯(38.4g,118mmol),在25℃下搅拌反应48小时。过滤,滤饼用乙酸乙酯(100mL×3)洗涤。减压浓缩滤液,剩余物加乙酸乙酯(600mL),用水(200mL×3)洗涤,饱和食盐水(300mL×1)洗涤,无水硫酸钠干燥有机相,过滤,减压浓缩,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,5/1～3/1,V/V),分离纯化得到化合物23-2。MS-ESI计算值[M+H] ⁺262,实测值262。 Compound 2-1 (15.0g, 78.5mmol) and compound 23-1 (20.0g, 86.3mmol) were dissolved in N,N-dimethylformamide (600mL), cesium carbonate (38.4g, 118mmol) was added, The reaction was stirred at 25°C for 48 hours. Filter and wash the filter cake with ethyl acetate (100mL×3). Concentrate the filtrate under reduced pressure, add ethyl acetate (600mL) to the residue, wash with water (200mL×3), wash with saturated brine (300mL×1), dry the organic phase over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and wash the residue with Silica gel column chromatography (petroleum ether/ethyl acetate, 5/1～3/1, V/V), separation and purification to obtain compound 23-2. MS-ESI calculated value [M+H] ⁺ 262, found value 262.

第二步second step

将化合物23-2(6.20g,23.7mmol)溶于N,N-二甲基甲酰胺(60mL)中,加入碳酸铯(23.2g,71.2mmol)和碘甲烷(2.95mL,47.5mmol),在25℃下搅拌反应12小时。反应液减压浓缩,加入二氯甲烷(200mL),过滤,滤液减压浓缩,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,5/1～3/1,V/V),分离纯化得到化合物23-3。 ¹H NMR(400MHz,CDCl ₃)δ7.84-7.79(m,1H),7.52-7.48(m,1H),7.43(d,J＝7.8Hz,1H),4.32-4.25(m,2H),3.95(s,3H),3.94-3.89(m,2H),3.26(s,3H),1.91-1.84(m,4H)。MS-ESI计算值[M+H] ⁺276实测值276。 Compound 23-2 (6.20g, 23.7mmol) was dissolved in N,N-dimethylformamide (60mL), cesium carbonate (23.2g, 71.2mmol) and iodomethane (2.95mL, 47.5mmol) were added, and the The reaction was stirred at 25°C for 12 hours. The reaction solution was concentrated under reduced pressure, dichloromethane (200 mL) was added, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1～3/1, V/V). Purification afforded compound 23-3. ¹ H NMR (400MHz, CDCl ₃ ) δ7.84-7.79 (m, 1H), 7.52-7.48 (m, 1H), 7.43 (d, J=7.8Hz, 1H), 4.32-4.25 (m, 2H), 3.95 (s, 3H), 3.94-3.89 (m, 2H), 3.26 (s, 3H), 1.91-1.84 (m, 4H). MS-ESI calculated [M+H] ⁺ 276 found 276.

第三步third step

将化合物23-3(4.00g,14.5mmol)溶于醋酸(40mL)中,在0℃下加入液溴(3.48g,21.8mmol),在25℃下搅拌反应1小时,补加液溴(1.16g,7.26mmol),在25℃下搅拌反应12小时。减压浓缩反应液,向剩余物中加入甲基叔丁基醚(30mL),在25℃下搅拌反应2小时,过滤,干燥得到化合物23-4。 ¹H NMR(400MHz,CDCl ₃)δ7.61(s,1H),7.25(s,1H),4.30-4.21(m,2H),3.96(s,3H),3.94-3.85(m,2H),3.22(s,3H),1.89-1.82(m,4H)。MS-ESI计算值[M+H] ⁺354和356实测值354和356。 Compound 23-3 (4.00g, 14.5mmol) was dissolved in acetic acid (40mL), liquid bromine (3.48g, 21.8mmol) was added at 0°C, the reaction was stirred at 25°C for 1 hour, and liquid bromine (1.16 g, 7.26mmol), stirred and reacted at 25°C for 12 hours. The reaction solution was concentrated under reduced pressure, methyl tert-butyl ether (30 mL) was added to the residue, the reaction was stirred at 25 °C for 2 hours, filtered, and dried to obtain compound 23-4. ¹ H NMR (400MHz, CDCl ₃ )δ7.61(s,1H),7.25(s,1H),4.30-4.21(m,2H),3.96(s,3H),3.94-3.85(m,2H), 3.22(s,3H),1.89-1.82(m,4H). MS-ESI calculated [M+H] ⁺ 354 and 356 found 354 and 356.

第四步the fourth step

将化合物23-4(1.00g,2.82mmol)和22-6(1.41g,14.1mmol)溶于N,N-二甲基甲酰胺(10mL)和水(1mL)中,加入碳酸钾(468mg,3.38mmol),醋酸钯(63.3mg,282μmol)和1,3-双(二苯基膦)丙烷(291mg,705μmol),反应液在100℃及氮气保护下搅拌反应12小时。降至室温后向反应液加入2M盐酸溶液(11.3mL),在25℃下搅拌0.5小时,反应液减压浓缩,加水(100mL),用乙酸乙酯(50mL×3)萃取,饱和食盐水(80mL×1)洗涤,无水硫酸钠干燥有机相,过滤浓缩,剩余物经过硅胶柱色谱法分离纯化(石油醚/乙酸乙酯,4/1～2/1,V/V),得到化合物23-5。 ¹H NMR(400MHz,CDCl ₃)δ7.50(s,1H),7.18(s,1H),4.34-4.22(m,2H),3.96-3.89(m,5H),3.25(s,3H),2.55(s,3H),1.99-1.76(m,4H)。MS-ESI计算值[M+H] ⁺318,实测值318。 Compound 23-4 (1.00g, 2.82mmol) and 22-6 (1.41g, 14.1mmol) were dissolved in N,N-dimethylformamide (10mL) and water (1mL), potassium carbonate (468mg, 3.38mmol), palladium acetate (63.3mg, 282μmol) and 1,3-bis(diphenylphosphine)propane (291mg, 705μmol), and the reaction solution was stirred at 100°C for 12 hours under nitrogen protection. After cooling down to room temperature, 2M hydrochloric acid solution (11.3mL) was added to the reaction solution, stirred at 25°C for 0.5 hours, the reaction solution was concentrated under reduced pressure, water (100mL) was added, extracted with ethyl acetate (50mL×3), saturated brine ( 80mL×1) was washed, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 4/1～2/1, V/V) to obtain compound 23 -5. ¹ H NMR (400MHz, CDCl ₃ )δ7.50(s,1H),7.18(s,1H),4.34-4.22(m,2H),3.96-3.89(m,5H),3.25(s,3H), 2.55(s,3H),1.99-1.76(m,4H). MS-ESI calculated [M+H] ⁺ 318, found 318.

第五步the fifth step

将化合物23-5(590mg,1.86mmol)溶于乙醇(10mL)中,加入水合肼(9.30mmol,532μL,85％纯度),在90℃下搅拌反应1小时。降至室温后过滤,滤饼用水(5mL×3)洗涤,干燥得到化合物23-6。 ¹H NMR(400MHz,CDCl ₃)δ9.91(br s,1H),7.84(s,1H),7.70(s,1H),4.45-4.29(m,2H),4.10-3.90(m,2H),3.36(s,3H),2.63(s,3H),2.13-2.00(m,2H),1.94-1.85(m,2H)。MS-ESI计算值[M+H] ⁺300,实测值300。 Compound 23-5 (590 mg, 1.86 mmol) was dissolved in ethanol (10 mL), hydrazine hydrate (9.30 mmol, 532 μL, 85% purity) was added, and the reaction was stirred at 90°C for 1 hour. After cooling down to room temperature, it was filtered, the filter cake was washed with water (5 mL×3), and dried to obtain compound 23-6. ¹ H NMR (400MHz, CDCl ₃ )δ9.91(br s,1H),7.84(s,1H),7.70(s,1H),4.45-4.29(m,2H),4.10-3.90(m,2H) ,3.36(s,3H),2.63(s,3H),2.13-2.00(m,2H),1.94-1.85(m,2H). MS-ESI calculated value [M+H] ⁺ 300, measured value 300.

第六步step six

将化合物23-6(400mg,1.34mol)溶于三氯氧磷(4mL)中,在90℃下搅拌反应2小时。降至室温后,减压浓缩,加入饱和碳酸氢钠溶液(30mL),在25℃下搅拌反应30分钟,用二氯甲烷/甲醇的混合溶液(10:1,20mL×3)萃取,有机相用饱和食盐水(20mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩得到化合物23-7。MS-ESI计算值[M+H] ⁺318实测值318。 Compound 23-6 (400mg, 1.34mol) was dissolved in phosphorus oxychloride (4mL), and stirred at 90°C for 2 hours. After cooling down to room temperature, concentrate under reduced pressure, add saturated sodium bicarbonate solution (30mL), stir and react at 25°C for 30 minutes, extract with a mixed solution of dichloromethane/methanol (10:1, 20mL×3), and the organic phase Wash with saturated brine (20 mL×1), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain compound 23-7. MS-ESI calculated [M+H] ⁺ 318 found 318.

第七步step seven

将化合物23-7(100mg,315μmol)和中间体B的盐酸盐(71.4mg,378μmol)溶于二氧六环(2mL)中,加入碳酸钾(130mg,944μmol),4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(36.4mg,62.9μmol)和三(二亚苄基丙酮)二钯(28.8mg,31.5μmol),在90℃和氮气保护下搅拌反应12小时。减压浓缩,加水(50mL),用乙酸乙酯(30mL×3)萃取,无水硫酸钠干燥,过滤,浓缩,剩余物经制备高效液相色谱分离纯化(色谱柱:Phenomenex Luna C18 75mm×30mm×3μm；流动相:0.05％盐酸水溶液-乙腈；梯度:乙腈20％-40％,7min),得到化合物23的盐酸盐。 ¹H NMR(400MHz,CD ₃OD)δ8.36(s,1H),8.23(s,1H),7.69-7.60(m,1H),7.56-7.44(m,1H),7.31-7.21(m,1H),7.18-6.80(m,1H),5.67-5.52(m,1H),4.45-4.20(m,2H),4.04-3.89(m,2H),3.44(s,3H),2.90(s,3H),2.24-2.12(m,2H),1.85-1.85(m,1H),1.91-1.81(m,1H),1.77(d,J＝7.0Hz,3H)。MS-ESI计算值[M+H] ⁺471,实测值471。 Compound 23-7 (100 mg, 315 μmol) and intermediate B hydrochloride (71.4 mg, 378 μmol) were dissolved in dioxane (2 mL), potassium carbonate (130 mg, 944 μmol), 4,5-bis( Diphenylphosphine)-9,9-dimethylxanthene (36.4mg, 62.9μmol) and tris(dibenzylideneacetone)dipalladium (28.8mg, 31.5μmol), stirring at 90°C under nitrogen protection React for 12 hours. Concentrate under reduced pressure, add water (50mL), extract with ethyl acetate (30mL×3), dry over anhydrous sodium sulfate, filter, concentrate, and the residue is separated and purified by preparative high performance liquid chromatography (column: Phenomenex Luna C18 75mm×30mm ×3 μm; mobile phase: 0.05% hydrochloric acid aqueous solution-acetonitrile; gradient: acetonitrile 20%-40%, 7min), to obtain the hydrochloride of compound 23. ¹ H NMR (400MHz, CD ₃ OD) δ8.36(s,1H),8.23(s,1H),7.69-7.60(m,1H),7.56-7.44(m,1H),7.31-7.21(m, 1H),7.18-6.80(m,1H),5.67-5.52(m,1H),4.45-4.20(m,2H),4.04-3.89(m,2H),3.44(s,3H),2.90(s, 3H), 2.24-2.12 (m, 2H), 1.85-1.85 (m, 1H), 1.91-1.81 (m, 1H), 1.77 (d, J=7.0Hz, 3H). MS-ESI calculated [M+H] ⁺ 471, found 471.

实施例24Example 24

合成路线：synthetic route:

第一步first step

将化合物24-1(3.20g,14.7mmol)溶于二氯甲烷(35mL)中,加入三乙胺(4.10mL,29.5mmol)和对甲苯磺酰氯(2.95g,15.5mmol),在25℃下搅拌反应8小时。反应液用饱和碳酸氢钠溶液(20mL×2)洗涤,无水硫酸钠干燥,过滤,减压浓缩。剩余物经柱层析(石油醚/二氯甲烷,4/1～0/1,V/V)纯化得化合物24-2。 ¹H NMR(400MHz,CDCl ₃)δ7.81(d,J＝8.0Hz,2H),7.36(d,J＝8.0Hz,2H),4.08-3.99(m,2H),3.93-3.81(m,3H),3.62-3.59(m,1H),3.51-3.43(m,1H),2.94-2.86(m,1H),2.73-2.62(m,1H),2.64(s,3H),1.47(s,9H)。 Compound 24-1 (3.20g, 14.7mmol) was dissolved in dichloromethane (35mL), triethylamine (4.10mL, 29.5mmol) and p-toluenesulfonyl chloride (2.95g, 15.5mmol) were added, at 25°C The reaction was stirred for 8 hours. The reaction solution was washed with saturated sodium bicarbonate solution (20 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/dichloromethane, 4/1～0/1, V/V) to obtain compound 24-2. ¹ H NMR (400MHz, CDCl ₃ ) δ7.81(d, J=8.0Hz, 2H), 7.36(d, J=8.0Hz, 2H), 4.08-3.99(m, 2H), 3.93-3.81(m, 3H),3.62-3.59(m,1H),3.51-3.43(m,1H),2.94-2.86(m,1H),2.73-2.62(m,1H),2.64(s,3H),1.47(s, 9H).

第二步second step

将化合物24-2(2.17g,5.83mmol)和化合物16-1(1.50g,5.03mmol)溶于N,N-二甲基甲酰胺(20mL),加入碳酸铯(8.74g,26.8mmol),反应液在50℃下搅拌反应3小时。降至室温后,将反应液过滤,滤液倒入乙酸乙酯(40mL),分别用50mL,20mL,10mL用水洗涤,有机相用无水硫酸钠干燥,过滤,减压浓缩得化合物24-3。 ¹H NMR(400MHz,CDCl ₃)δ7.45(s,1H),7.39(s,1H),3.97(s,3H),3.88-3.80(m,4H),3.72-3.66(m,2H),3.49-3.42(m,1H),2.95-2.90(m,1H),2.72-2.66(m,1H),1.45(s,9H),1.40(s,3H),1.39(s,3H)。MS-ESI计算值[M+H-100] ⁺397和399,实测值397和399。 Compound 24-2 (2.17g, 5.83mmol) and compound 16-1 (1.50g, 5.03mmol) were dissolved in N,N-dimethylformamide (20mL), cesium carbonate (8.74g, 26.8mmol) was added, The reaction solution was stirred and reacted at 50° C. for 3 hours. After cooling down to room temperature, the reaction liquid was filtered, the filtrate was poured into ethyl acetate (40 mL), washed with 50 mL, 20 mL, and 10 mL of water respectively, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 24-3. ¹ H NMR (400MHz, CDCl ₃ )δ7.45(s,1H),7.39(s,1H),3.97(s,3H),3.88-3.80(m,4H),3.72-3.66(m,2H), 3.49-3.42 (m, 1H), 2.95-2.90 (m, 1H), 2.72-2.66 (m, 1H), 1.45 (s, 9H), 1.40 (s, 3H), 1.39 (s, 3H). MS-ESI calculated [M+H-100] ⁺ 397 and 399, found 397 and 399.

第三步third step

将化合物24-3(2.40g,4.83mmol)溶于乙酸乙酯(0.5mL)中,加入氯化氢/乙酸乙酯溶液(4M,4.83mL)中,在25℃下搅拌反应2小时。用碳酸氢钠将反应液的pH调至7～8,无水硫酸钠干燥,过滤,浓缩。剩余物经经柱层析(石油醚/二氯甲烷:1/1～二氯甲烷/甲醇:20/1,V/V)纯化得化合物24-4。 ¹H NMR(400MHz,CDCl ₃)δ7.44(s,1H),7.40(s,1H),3.96(s,3H),3.88-3.86(m,1H),3.85-3.82(m,1H),3.78-3.77(m,2H),3.67-3.60(m,1H),3.50(s,1H),3.06-3.02(m,1H),2.89-2.86(m,2H),2.68-2.66(m,1H),1.39(s,3H),1.38(s,3H)。MS-ESI计算值[M+H] ⁺397和399,实测值397和399。 Compound 24-3 (2.40g, 4.83mmol) was dissolved in ethyl acetate (0.5mL), added into hydrogen chloride/ethyl acetate solution (4M, 4.83mL), and stirred at 25°C for 2 hours. The pH of the reaction solution was adjusted to 7-8 with sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether/dichloromethane: 1/1 to dichloromethane/methanol: 20/1, V/V) to obtain compound 24-4. ¹ H NMR (400MHz, CDCl ₃ )δ7.44(s,1H),7.40(s,1H),3.96(s,3H),3.88-3.86(m,1H),3.85-3.82(m,1H), 3.78-3.77(m,2H),3.67-3.60(m,1H),3.50(s,1H),3.06-3.02(m,1H),2.89-2.86(m,2H),2.68-2.66(m,1H ), 1.39(s,3H), 1.38(s,3H). MS-ESI calculated [M+H] ⁺ 397 and 399, found 397 and 399.

第四步the fourth step

将化合物24-4(2.00g,5.03mmol)溶于甲醇(20mL)中,加甲醛(1.12mL,15.1mmol,37％纯度)和醋酸(1.15mL,20.1mmol),25℃下搅拌反应2小时,再加入氰基硼氢化钠(949mg,15.1mmol),25℃下搅拌反应1小时。加入水(60mL),用碳酸氢钠将pH调至7,用二氯甲烷(60mL和30mL)萃取,无水硫酸钠干燥,过滤,浓缩。剩余物经柱层析(二氯甲烷/甲醇,1/0～20/1)纯化得化合物24-5。 ¹H NMR(400MHz,CDCl ₃)δ7.44(s,1H),7.41(s,1H),3.96(s,3H),3.88-3.74(m,4H),3.66-3.60(m,1H),2.78(d,J＝11.2Hz,1H),2.64(d,J＝11.2Hz,1H),2.30(m,3H),2.17-2.10(m,1H),1.92(t,J＝10.8Hz,1H),1.39(s,6H)。MS-ESI计算值[M+H] ⁺411和413,实测值411和413。 Dissolve compound 24-4 (2.00g, 5.03mmol) in methanol (20mL), add formaldehyde (1.12mL, 15.1mmol, 37% purity) and acetic acid (1.15mL, 20.1mmol), and stir at 25°C for 2 hours , and sodium cyanoborohydride (949 mg, 15.1 mmol) was added, and the reaction was stirred at 25° C. for 1 hour. Add water (60 mL), adjust the pH to 7 with sodium bicarbonate, extract with dichloromethane (60 mL and 30 mL), dry over anhydrous sodium sulfate, filter, and concentrate. The residue was purified by column chromatography (dichloromethane/methanol, 1/0～20/1) to obtain compound 24-5. ¹ H NMR (400MHz, CDCl ₃ )δ7.44(s,1H),7.41(s,1H),3.96(s,3H),3.88-3.74(m,4H),3.66-3.60(m,1H), 2.78(d, J=11.2Hz, 1H), 2.64(d, J=11.2Hz, 1H), 2.30(m, 3H), 2.17-2.10(m, 1H), 1.92(t, J=10.8Hz, 1H ), 1.39(s,6H). MS-ESI calculated [M+H] ⁺ 411 and 413, found 411 and 413.

第五步the fifth step

将化合物24-5(2.00g,4.86mmol),1-乙烯基丁基醚(2.44g,24.3mmol),醋酸钯(109mg,486μmol),碳酸钾(806mg,5.84mmol)和1,3-双(二苯基膦)丙烷(501mg,1.22mmol)溶于N,N-二甲基甲酰胺(30mL)和水(3mL)中,在氮气氛围100℃下搅拌反应6小时。降至室温后,向反应液中加入乙酸乙酯(60mL),用水(60mL×3)洗涤,无水硫酸钠干燥,经硅胶过滤,滤液浓缩得到化合物24-6。 ¹H NMR(400MHz,CDCl ₃)δ7.28-7.26(m,2H),4.33(d,J＝2.4Hz,1H),4.25(d,J＝2.4Hz,1H),3.87(s,3H),3.85-3.74(m,6H),3.63-3.56(m,1H),2.75-2.72(m,1H),2.61-2.59(m,1H),2.27(s,3H),2.13-2.10(m,1H),1.92-1.87(m,1H),1.73-1.66(m,2H),1.46-1.41(m,2H),1.38(s,6H),0.95(t,J＝7.6Hz,3H)。MS-ESI计算值[M+H] ⁺431,实测值431。 Compound 24-5 (2.00g, 4.86mmol), 1-vinylbutyl ether (2.44g, 24.3mmol), palladium acetate (109mg, 486μmol), potassium carbonate (806mg, 5.84mmol) and 1,3-bis (Diphenylphosphine)propane (501mg, 1.22mmol) was dissolved in N,N-dimethylformamide (30mL) and water (3mL), and the reaction was stirred under nitrogen atmosphere at 100°C for 6 hours. After cooling down to room temperature, ethyl acetate (60 mL) was added to the reaction solution, washed with water (60 mL×3), dried over anhydrous sodium sulfate, filtered through silica gel, and the filtrate was concentrated to obtain compound 24-6. ¹ H NMR (400MHz, CDCl ₃ ) δ7.28-7.26(m, 2H), 4.33(d, J=2.4Hz, 1H), 4.25(d, J=2.4Hz, 1H), 3.87(s, 3H) ,3.85-3.74(m,6H),3.63-3.56(m,1H),2.75-2.72(m,1H),2.61-2.59(m,1H),2.27(s,3H),2.13-2.10(m, 1H), 1.92-1.87(m, 1H), 1.73-1.66(m, 2H), 1.46-1.41(m, 2H), 1.38(s, 6H), 0.95(t, J=7.6Hz, 3H). MS-ESI calculated [M+H] ⁺ 431, found 431.

第六步step six

将化合物24-6(1.80g,4.18mmol)溶于丙酮(18mL)中,加入盐酸/水溶液(12M,1.05mL),在25℃下搅拌反应0.5小时。用碳酸氢钠将pH调至7,用二氯甲烷(40mL)稀释,无水硫酸钠干燥,过滤,浓缩得化合物24-7。 ¹H NMR(400MHz,CD ₃OD)δ7.68(s,1H),7.40(s,1H),3.91-3.82(m,7H),3.58-3.51(m,1H),2.84-2.80(m,1H),2.64-2.60(m,1H),2.55(s,3H),2.29(s,3H),2.15-2.08(m,1H),1.95-1.90(m,1H),1.40(s,6H)。MS-ESI计算值[M+H] ⁺375,实测值375。 Compound 24-6 (1.80g, 4.18mmol) was dissolved in acetone (18mL), hydrochloric acid/water solution (12M, 1.05mL) was added, and the reaction was stirred at 25°C for 0.5 hours. Adjust the pH to 7 with sodium bicarbonate, dilute with dichloromethane (40 mL), dry over anhydrous sodium sulfate, filter, and concentrate to obtain compound 24-7. ¹ H NMR (400MHz, CD ₃ OD) δ7.68(s,1H),7.40(s,1H),3.91-3.82(m,7H),3.58-3.51(m,1H),2.84-2.80(m, 1H),2.64-2.60(m,1H),2.55(s,3H),2.29(s,3H),2.15-2.08(m,1H),1.95-1.90(m,1H),1.40(s,6H) . MS-ESI calculated [M+H] ⁺ 375, found 375.

第七步step seven

将化合物24-7(1.55g,4.14mmol)溶于乙醇(30mL)中,加入水合肼(1.29g,21.9mmol,85％纯度),在95℃下搅拌反应1小时。降至室温后,加水(15mL),过滤得化合物24-8。 ¹H NMR(400MHz,CD ₃OD)δ7.95(s,1H),7.92(s,1H),3.97-3.82(m,4H),3.58-3.52(m,1H),2.88-2.83(m,1H),2.66-2.63(m,1H),2.61(s,3H),2.29(s,3H),2.15-2.09(m,1H),1.99-1.94(m,1H),1.47(s,6H)。MS-ESI计算值[M+H] ⁺357,实测值357。 Compound 24-7 (1.55g, 4.14mmol) was dissolved in ethanol (30mL), hydrazine hydrate (1.29g, 21.9mmol, 85% purity) was added, and the reaction was stirred at 95°C for 1 hour. After cooling down to room temperature, water (15 mL) was added, and compound 24-8 was obtained by filtration. ¹ H NMR (400MHz, CD ₃ OD) δ7.95(s,1H),7.92(s,1H),3.97-3.82(m,4H),3.58-3.52(m,1H),2.88-2.83(m, 1H),2.66-2.63(m,1H),2.61(s,3H),2.29(s,3H),2.15-2.09(m,1H),1.99-1.94(m,1H),1.47(s,6H) . MS-ESI calculated [M+H] ⁺ 357, found 357.

第八步eighth step

将化合物24-8(700mg,1.96mmol)溶于三氯氧磷(7mL)中,反应液在95℃下搅拌反应12小时。降至室温后,将反应液减压浓缩,剩余物溶于水(8mL)中,用碳酸钠将pH调到8,乙酸乙酯(8mL×2)萃取,无水硫酸钠干燥,过滤浓缩得化合物24-9。 ¹H NMR(400MHz,CD ₃OD)δ8.24(s,1H),7.86(s,1H),4.08-3.98(m,2H),3.95-3.90(m,1H),3.87-3.84(m,1H),3.60-3.54(m,1H),3.97(s,3H),2.90-2.87(m,1H),2.68-2.64(m,1H),2.30(s,3H),2.16-2.09(m,1H),2.01-1.95(m,1H),1.52(s,6H)。MS-ESI计算值[M+H] ⁺375,实测375。 Compound 24-8 (700mg, 1.96mmol) was dissolved in phosphorus oxychloride (7mL), and the reaction solution was stirred at 95°C for 12 hours. After cooling down to room temperature, the reaction solution was concentrated under reduced pressure, the residue was dissolved in water (8 mL), the pH was adjusted to 8 with sodium carbonate, extracted with ethyl acetate (8 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain Compound 24-9. ¹ H NMR (400MHz, CD ₃ OD) δ8.24(s,1H),7.86(s,1H),4.08-3.98(m,2H),3.95-3.90(m,1H),3.87-3.84(m, 1H),3.60-3.54(m,1H),3.97(s,3H),2.90-2.87(m,1H),2.68-2.64(m,1H),2.30(s,3H),2.16-2.09(m, 1H), 2.01-1.95(m, 1H), 1.52(s, 6H). MS-ESI calculated value [M+H] ⁺ 375, found 375.

第九步Ninth step

将化合物24-9(200mg,533μmol)和中间体B的盐酸盐(131mg,694μmol)溶于二氧六环(3mL),加入4,5-双二苯基膦-9,9-二甲基氧杂蒽(61.7mg,106μmol),碳酸铯(608mg,1.87mmol)和双(二亚苄基丙酮)钯(30.7mg,53.4μmol),在氮气氛围95℃下搅拌反应12小时。降至室温后,将反应液倒入水(10mL),用乙酸乙酯(10mL×2)萃取,无水硫酸钠干燥,过滤,减压浓缩。剩余物经制备高效液相色谱法(色谱柱:3_Phenomenex Luna C18 75mm×30mm×3μm；流动相:0.05％盐酸水溶液-乙腈；梯度:乙腈8％-28％,8min)分离纯化得化合物24的盐酸盐。 ¹H NMR(400MHz,CDCl ₃)δ8.56(d,J＝9.2Hz,1H),8.36(s,1H),7.78-7.72(m,1H),7.50-7.47(m,1H),7.26-7.22(m,1H),7.00(t,J＝54.4Hz,1H),5.64-5.59(m,1H),4.38-4.32(m,1H),4.30-4.23(m,1H),4.12-4.07(m,2H),3.85-3.74(m,2H),3.48-3.45(m,1H),3.22-3.14(m,1H),3.12-3.05(m,1H),2.98(s,3H),2.89(s,3H),1.81(d,J＝6.8Hz,3H),1.54-1.52(m,6H)。MS-ESI计算值[M+H] ⁺528实测值528。 Compound 24-9 (200 mg, 533 μmol) and intermediate B hydrochloride (131 mg, 694 μmol) were dissolved in dioxane (3 mL), and 4,5-bisdiphenylphosphine-9,9-dimethyl Xanthene (61.7 mg, 106 μmol), cesium carbonate (608 mg, 1.87 mmol) and bis(dibenzylideneacetone) palladium (30.7 mg, 53.4 μmol) were stirred at 95°C for 12 hours under a nitrogen atmosphere. After cooling down to room temperature, the reaction solution was poured into water (10 mL), extracted with ethyl acetate (10 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by preparative high-performance liquid chromatography (column: 3-Phenomenex Luna C18 75mm×30mm×3μm; mobile phase: 0.05% aqueous hydrochloric acid-acetonitrile; gradient: acetonitrile 8%-28%, 8min) to obtain the salt of compound 24 salt. ¹ H NMR (400MHz, CDCl ₃ ) δ8.56(d, J=9.2Hz, 1H), 8.36(s, 1H), 7.78-7.72(m, 1H), 7.50-7.47(m, 1H), 7.26- 7.22(m,1H),7.00(t,J＝54.4Hz,1H),5.64-5.59(m,1H),4.38-4.32(m,1H),4.30-4.23(m,1H),4.12-4.07( m,2H),3.85-3.74(m,2H),3.48-3.45(m,1H),3.22-3.14(m,1H),3.12-3.05(m,1H),2.98(s,3H),2.89( s, 3H), 1.81 (d, J=6.8Hz, 3H), 1.54-1.52 (m, 6H). MS-ESI calculated [M+H] ⁺ 528 found 528.

实施例25Example 25

合成路线：synthetic route:

第一步first step

氮气保护下将化合物2-3(1.00g,3.20mmol)溶于二甲亚砜(15mL)中,加入25-1(1.29g,9.61mmol),碳酸钾(1.33g,9.61mmol),在20℃下搅拌反应0.5小时后加入1,1-双(二苯基膦)二茂铁氯化钯(234mg,320μmol),在100℃下搅拌反应12小时。降至室温后向反应液加入水(50mL),用乙酸乙酯(50mL×3)萃取,有机相用饱和食盐水(50mL×5)洗涤,无水硫酸钠干燥有机相,剩余物经过硅胶柱色谱法分离纯化(石油醚/乙酸乙酯,100/1～2/1,V/V),得到化合物25-2。 ¹H NMR(400MHz,CDCl ₃)δ7.50-7.43(m,1H),7.43-7.39(m,1H),7.31(s,1H),5.67-5.57(m,1H),5.36-5.28(m,1H),3.93(s,3H),3.25(s,3H),1.40(s,6H)。 MS-ESI计算值[M+H] ⁺260,实测值260。 Under nitrogen protection, compound 2-3 (1.00g, 3.20mmol) was dissolved in dimethyl sulfoxide (15mL), and 25-1 (1.29g, 9.61mmol), potassium carbonate (1.33g, 9.61mmol) were added, and the After the reaction was stirred at ℃ for 0.5 hours, 1,1-bis(diphenylphosphine)ferrocenepalladium chloride (234mg, 320μmol) was added, and the reaction was stirred at 100℃ for 12 hours. After cooling down to room temperature, water (50 mL) was added to the reaction solution, extracted with ethyl acetate (50 mL×3), the organic phase was washed with saturated brine (50 mL×5), the organic phase was dried over anhydrous sodium sulfate, and the residue was passed through a silica gel column. Separation and purification by chromatography (petroleum ether/ethyl acetate, 100/1～2/1, V/V) gave compound 25-2. ¹ H NMR (400MHz, CDCl ₃ )δ7.50-7.43(m,1H),7.43-7.39(m,1H),7.31(s,1H),5.67-5.57(m,1H),5.36-5.28(m ,1H), 3.93(s,3H), 3.25(s,3H), 1.40(s,6H). MS-ESI calculated value [M+H] ⁺ 260, found value 260.

第二步second step

将化合物25-2(0.71g,2.74mmol)溶于二氯甲烷(10mL)中,在-78℃下通入臭氧0.5小时,加入三苯基磷(862mg,3.29mmol),氮气保护下在20℃反应1.5小时,向反应液中加入水(50mL),用二氯甲烷(50mL×3)萃取,有机相用饱和食盐水(50mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物经过硅胶柱色谱法分离纯化(石油醚/乙酸乙酯,100/1～1/1,V/V),得到化合物25-3。 ¹H NMR(400MHz,CDCl ₃)δ10.54(s,1H),7.88(s,1H),7.36(s,1H),4.01(s,3H),3.30(s,3H),1.41(s,6H)。MS-ESI计算值[M+H] ⁺262,实测值262。 Compound 25-2 (0.71g, 2.74mmol) was dissolved in dichloromethane (10mL), ozone was passed through at -78°C for 0.5 hours, triphenylphosphine (862mg, 3.29mmol) was added, and under nitrogen protection, the mixture was heated at 20 React at ℃ for 1.5 hours, add water (50mL) to the reaction solution, extract with dichloromethane (50mL×3), wash the organic phase with saturated brine (50mL×1), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure , and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 100/1～1/1, V/V) to obtain compound 25-3. ¹ H NMR (400MHz, CDCl ₃ )δ10.54(s,1H),7.88(s,1H),7.36(s,1H),4.01(s,3H),3.30(s,3H),1.41(s, 6H). MS-ESI calculated value [M+H] ⁺ 262, found value 262.

第三步third step

将化合物25-3(552mg,2.11mmol)溶于乙醇(6mL)中,加入水合肼(6.34mmol,308μL,100％纯度),在95℃下搅拌反应1小时。降至室温后过滤,将滤饼干燥得到化合物25-4。MS-ESI计算值[M+H] ⁺244,实测值244。 Compound 25-3 (552mg, 2.11mmol) was dissolved in ethanol (6mL), hydrazine hydrate (6.34mmol, 308μL, 100% purity) was added, and the reaction was stirred at 95°C for 1 hour. After cooling down to room temperature, filter and dry the filter cake to obtain compound 25-4. MS-ESI calculated value [M+H] ⁺ 244, found value 244.

第四步the fourth step

将化合物25-4(400mg,1.64mmol)溶于乙腈(5mL)中,加入N,N-二异丙基乙胺(286μL,1.64mmol)和***(764μl,8.22mmol),在80℃下搅拌反应12小时。降至室温后向反应液中加入饱和碳酸氢钠溶液中和至pH为8,用二氯甲烷(100mL×1)萃取,有机相用饱和食盐水(100mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物经过硅胶柱色谱法分离纯化(二氯甲烷/甲醇,100/1～10/1,V/V),得到化合物25-5。MS-ESI计算值[M+H] ⁺262,实测值262。 Compound 25-4 (400mg, 1.64mmol) was dissolved in acetonitrile (5mL), and N,N-diisopropylethylamine (286μL, 1.64mmol) and phosphorus oxychloride (764μl, 8.22mmol) were added, at 80 The reaction was stirred at °C for 12 hours. After cooling down to room temperature, add saturated sodium bicarbonate solution to the reaction solution to neutralize to pH 8, extract with dichloromethane (100mL×1), wash the organic phase with saturated brine (100mL×1), and dry over anhydrous sodium sulfate , filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (dichloromethane/methanol, 100/1～10/1, V/V) to obtain compound 25-5. MS-ESI calculated value [M+H] ⁺ 262, found value 262.

第五步the fifth step

将化合物25-5(420mg,1.36mmol)溶于二氧六环(2mL)中,加入B(284mg,1.50mmol),4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(158mg,273μmol),碳酸钾(565mg,4.09mmol)和三(二亚苄基丙酮)二钯(125mg,136μmol),在100℃下搅拌反应12小时。降至室温后,向反应液中加入水(100mL),用二氯甲烷(100mL×3)萃取,有机相用饱和食盐水(100mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩。剩余物经制备高效液相色谱分离纯化(色谱柱:Phenomenex C18 80mm×40mm×3μm；流动相:0.05％氨水溶液-乙腈；梯度:乙腈37％-67％,8min),得到化合物25。 ¹H NMR(400MHz,CD ₃OD)δ8.81(s,1H),8.03(s,1H),7.93(s,1H),7.66-7.55(m,1H),7.50-7.38(m,1H),7.24-7.15(m,1H),7.15-6.82(m,1H),5.82-5.67(m,1H),3.42(s,3H),1.74(d,J＝6.8Hz,3H),1.51-1.43(m,6H)。MS-ESI计算值[M+H] ⁺415,实测值415。 Compound 25-5 (420mg, 1.36mmol) was dissolved in dioxane (2mL), and B (284mg, 1.50mmol), 4,5-bis(diphenylphosphine)-9,9-dimethyl Xanthene (158mg, 273μmol), potassium carbonate (565mg, 4.09mmol) and tris(dibenzylideneacetone) dipalladium (125mg, 136μmol) were stirred at 100°C for 12 hours. After cooling down to room temperature, water (100 mL) was added to the reaction solution, extracted with dichloromethane (100 mL×3), the organic phase was washed with saturated brine (100 mL×1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure . The residue was separated and purified by preparative high performance liquid chromatography (column: Phenomenex C18 80mm×40mm×3μm; mobile phase: 0.05% ammonia solution-acetonitrile; gradient: acetonitrile 37%-67%, 8min) to obtain compound 25. ¹ H NMR (400MHz, CD ₃ OD) δ8.81(s,1H),8.03(s,1H),7.93(s,1H),7.66-7.55(m,1H),7.50-7.38(m,1H) ,7.24-7.15(m,1H),7.15-6.82(m,1H),5.82-5.67(m,1H),3.42(s,3H),1.74(d,J＝6.8Hz,3H),1.51-1.43 (m,6H). MS-ESI calculated [M+H] ⁺ 415, found 415.

实施例26Example 26

合成路线：synthetic route:

第一步first step

将化合物26-1(95.0g,408mmol)溶于硫酸(500mL)中,冷却至0℃,分批慢慢加入硝酸钾(46.2g,457mmol),在0℃下搅拌反应3小时。反应液慢慢加入到冰水(4000mL),搅拌30分钟,过滤,滤饼用水(500mL×4)洗涤,干燥,得到化合物26-2。 ¹H NMR(400MHz,CDCl ₃)δ8.63(d,J＝8.0Hz,1H),7.68(d,J＝10.0Hz,1H),3.99(s,3H)。 Compound 26-1 (95.0g, 408mmol) was dissolved in sulfuric acid (500mL), cooled to 0°C, potassium nitrate (46.2g, 457mmol) was slowly added in batches, and the reaction was stirred at 0°C for 3 hours. The reaction solution was slowly added to ice water (4000 mL), stirred for 30 minutes, filtered, and the filter cake was washed with water (500 mL×4) and dried to obtain compound 26-2. ¹ H NMR (400MHz, CDCl ₃ ) δ8.63 (d, J=8.0Hz, 1H), 7.68 (d, J=10.0Hz, 1H), 3.99 (s, 3H).

第二步second step

将化合物26-2(100g,360mmol)溶于四氢呋喃(1000mL)中,加入碳酸钾(249g,1.80mol)和甲胺盐酸盐(97.1g,1.44mol),在25℃下搅拌反应12小时。反应液加入水(100mL)中,用乙酸乙酯(800mL×4)萃取,饱和食盐水(1000mL×1)洗涤,无水硫酸钠干燥有机相,过滤浓缩,得到化合物26-3。 ¹H NMR(400MHz,DMSO-d ₆)δ8.59(s,1H),8.55(d,J＝4.8Hz,1H),7.27(s,1H),3.82(s,3H),2.99(d,J＝4.8Hz,3H)。 Compound 26-2 (100g, 360mmol) was dissolved in tetrahydrofuran (1000mL), potassium carbonate (249g, 1.80mol) and methylamine hydrochloride (97.1g, 1.44mol) were added, and the reaction was stirred at 25°C for 12 hours. The reaction solution was added to water (100 mL), extracted with ethyl acetate (800 mL×4), washed with saturated brine (1000 mL×1), dried the organic phase over anhydrous sodium sulfate, filtered and concentrated to obtain compound 26-3. ¹ H NMR (400MHz, DMSO-d ₆ )δ8.59(s, 1H), 8.55(d, J=4.8Hz, 1H), 7.27(s, 1H), 3.82(s, 3H), 2.99(d, J=4.8Hz, 3H).

第三步third step

将化合物26-3(50.0g,173mmol)溶于乙醇(400mL)和水(80mL)的混合溶液中,加入铁粉(29.0g,519mmol)和氯化铵(27.8g,519mmol),在80℃下搅拌反应2小时。反应液冷却至20℃,反应液通过硅藻土过滤,滤饼用甲醇(100mL×5)洗涤,减压浓缩滤液。向剩余物中加入水(800mL),用碳酸氢钠将水相pH调至8～9,用乙酸乙酯(500mL×3)萃取,饱和食盐水(500mL×1)洗涤,无水硫酸钠干燥有机相,过滤,滤液减压浓缩。向剩余物中加入甲基叔丁基醚(200mL),在25℃下搅拌反应1小时,过滤,干燥得到化合物26-4。 ¹H NMR(400MHz,DMSO-d ₆)δ7.14(s,1H),6.51(s,1H),5.70-5.50(m,1H),4.84(s,2H),3.73(s,3H),2.76(d,J＝5.0Hz,3H)。MS-ESI计算值[M+H] ⁺259和261,实测值259和261。 Compound 26-3 (50.0g, 173mmol) was dissolved in a mixed solution of ethanol (400mL) and water (80mL), iron powder (29.0g, 519mmol) and ammonium chloride (27.8g, 519mmol) were added, at 80°C The reaction was stirred for 2 hours. The reaction solution was cooled to 20°C, the reaction solution was filtered through diatomaceous earth, the filter cake was washed with methanol (100mL×5), and the filtrate was concentrated under reduced pressure. Add water (800mL) to the residue, adjust the pH of the aqueous phase to 8-9 with sodium bicarbonate, extract with ethyl acetate (500mL×3), wash with saturated brine (500mL×1), and dry over anhydrous sodium sulfate The organic phase was filtered, and the filtrate was concentrated under reduced pressure. Methyl tert-butyl ether (200 mL) was added to the residue, the reaction was stirred at 25 °C for 1 hour, filtered, and dried to obtain compound 26-4. ¹ H NMR (400MHz,DMSO-d ₆ )δ7.14(s,1H),6.51(s,1H),5.70-5.50(m,1H),4.84(s,2H),3.73(s,3H), 2.76 (d, J=5.0Hz, 3H). MS-ESI calculated [M+H] ⁺ 259 and 261, found 259 and 261.

第四步the fourth step

将化合物26-4(15.0g,57.9mmol)溶解在N,N-二甲基甲酰胺(150mL)中,加入羰基二咪唑(12.2g,75.3mmol),在60℃反应1小时。降至室温后,反应液加入水(500mL),搅拌30分钟,过滤,用水(200mL x 3)洗涤滤饼,将滤饼加入到甲基叔丁基醚(100mL)中,在25℃下搅拌反应1小时,过滤,干燥得到化合物26-5。 ¹H NMR(400MHz,DMSO-d ₆)δ11.22(br s,1H),7.50(s,1H),7.39(s,1H),3.82(s,3H),3.30(s, Compound 26-4 (15.0 g, 57.9 mmol) was dissolved in N,N-dimethylformamide (150 mL), carbonyldiimidazole (12.2 g, 75.3 mmol) was added, and reacted at 60° C. for 1 hour. After cooling down to room temperature, add water (500mL) to the reaction solution, stir for 30 minutes, filter, wash the filter cake with water (200mL x 3), add the filter cake to methyl tert-butyl ether (100mL), and stir at 25°C React for 1 hour, filter and dry to obtain compound 26-5. ¹ H NMR (400MHz,DMSO-d ₆ )δ11.22(br s,1H),7.50(s,1H),7.39(s,1H),3.82(s,3H),3.30(s,

3H)。MS-ESI计算值[M+H] ⁺285和287,实测值285和287。 3H). MS-ESI calculated [M+H] ⁺ 285 and 287, found 285 and 287.

第五步the fifth step

将化合物26-5(15.0g,52.6mmol)溶于N,N-二甲基甲酰胺(100mL)中,加入碳酸铯(34.3g,105mmol)和碘甲烷(6.55mL,150mmol),在25℃下搅拌反应12小时。将反应液中加入到冰水(400mL),搅拌30分钟,过滤,用水(30mL x 3)洗涤滤饼,将滤饼加入到甲基叔丁基醚(200mL)中,在20℃下搅拌反应1小时,过滤,干燥得到化合物26-6。 ¹H NMR(400MHz,DMSO-d ₆)δ7.59(s,1H),7.57(s,1H),3.85(s,3H),3.35(s,6H)。MS-ESI计算值[M+H] ⁺299和301,实测值299和301。 Compound 26-5 (15.0g, 52.6mmol) was dissolved in N,N-dimethylformamide (100mL), cesium carbonate (34.3g, 105mmol) and iodomethane (6.55mL, 150mmol) were added, at 25°C The reaction was stirred for 12 hours. Add the reaction solution to ice water (400mL), stir for 30 minutes, filter, wash the filter cake with water (30mL x 3), add the filter cake to methyl tert-butyl ether (200mL), and stir the reaction at 20°C 1 hour, filtered and dried to obtain compound 26-6. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.59 (s, 1H), 7.57 (s, 1H), 3.85 (s, 3H), 3.35 (s, 6H). MS-ESI calculated [M+H] ⁺ 299 and 301, found 299 and 301.

第六步step six

将化合物26-6(14.0g,46.8mmol)和乙烯基正丁醚(23.4g,234mmol)溶于N,N-二甲基甲酰胺(140mL)和水(14mL)中,加入碳酸钾(7.76g,56.2mmol),醋酸钯(1.05g,4.68mmol)和1,3-双(二苯基膦)丙烷(3.86g,9.36mmol),反应液在100℃及氮气保护下搅拌反应12小时。降至室温后向反应液加入2M盐酸溶液(46.8mL),在25℃下搅拌15分钟,反应液加水(700mL),用乙酸乙酯(300mL×4)萃取,饱和食盐水(500mL×1)洗涤,无水硫酸钠干燥有机相,过滤浓缩,剩余物经过硅胶柱色谱法分离纯化(石油醚/乙酸乙酯/二氯甲烷,4/1/0～2/1/1,V/V/V),得到化合物26-7。 ¹H NMR(400MHz,CDCl ₃)δ7.47(s,1H),6.96(s,1H),3.91(s,3H),3.46(s,3H),3.45(s,3H),2.53(s,3H)。MS-ESI计算值[M+H] ⁺263实测值263。 Compound 26-6 (14.0g, 46.8mmol) and vinyl n-butyl ether (23.4g, 234mmol) were dissolved in N,N-dimethylformamide (140mL) and water (14mL), and potassium carbonate (7.76 g, 56.2mmol), palladium acetate (1.05g, 4.68mmol) and 1,3-bis(diphenylphosphine)propane (3.86g, 9.36mmol), the reaction solution was stirred and reacted at 100°C under nitrogen protection for 12 hours. After cooling down to room temperature, 2M hydrochloric acid solution (46.8mL) was added to the reaction solution, stirred at 25°C for 15 minutes, water (700mL) was added to the reaction solution, extracted with ethyl acetate (300mL×4), saturated brine (500mL×1) Wash, dry the organic phase with anhydrous sodium sulfate, filter and concentrate, and the residue is separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate/dichloromethane, 4/1/0～2/1/1, V/V/ V), obtain compound 26-7. ¹ H NMR (400MHz, CDCl ₃ )δ7.47(s,1H),6.96(s,1H),3.91(s,3H),3.46(s,3H),3.45(s,3H),2.53(s, 3H). MS-ESI calculated [M+H] ⁺ 263 found 263.

第七步step seven

将化合物26-7(12.0g,45.8mmol)溶于乙醇(250mL)中,加入水合肼(14.1mL,246mmol,85％纯度),在90℃下搅拌反应3小时。降至室温后过滤,滤饼用水(50mL×3)洗涤,乙醇(50mL×2)洗涤,滤饼干燥。将滤饼加入到甲基叔丁基醚(100mL)中,在20℃下搅拌1小时,过滤,干燥得到化合物26-8。 ¹H NMR(400MHz,DMSO-d ₆)δ12.24(br s,1H),7.90(s,1H),7.60(s,1H),3.48(s,3H),3.46(s,3H),3.29(s,3H)。MS-ESI计算值[M+H] ⁺245,实测值245。 Compound 26-7 (12.0 g, 45.8 mmol) was dissolved in ethanol (250 mL), hydrazine hydrate (14.1 mL, 246 mmol, 85% purity) was added, and the reaction was stirred at 90°C for 3 hours. After cooling down to room temperature, filter, wash the filter cake with water (50mL×3), wash with ethanol (50mL×2), and dry the filter cake. The filter cake was added into methyl tert-butyl ether (100 mL), stirred at 20 °C for 1 hour, filtered, and dried to obtain compound 26-8. ¹ H NMR (400MHz,DMSO-d ₆ )δ12.24(br s,1H),7.90(s,1H),7.60(s,1H),3.48(s,3H),3.46(s,3H),3.29 (s,3H). MS-ESI calculated [M+H] ⁺ 245, found 245.

第八步eighth step

将化合物26-8(5.00g,20.5mmol)溶于三氯氧磷(100mL)中,在90℃下搅拌反应48小时。降至室温后,减压浓缩,加入饱和碳酸氢钠水溶液(200mL),在20℃下搅拌1小时,过滤,滤饼用水(50mL×3)洗涤,滤饼干燥。将滤饼加入到甲基叔丁基醚(100mL)中,在20℃下搅拌1小时,过滤,干燥得到化合物26-9。 ¹H NMR(400MHz,DMSO-d ₆)δ7.87(s,1H),7.78(s,1H),3.52(s,3H),3.51(s,3H),2.90(s,3H)。MS-ESI计算值[M+H] ⁺263实测值263。 Compound 26-8 (5.00g, 20.5mmol) was dissolved in phosphorus oxychloride (100mL), and stirred at 90°C for 48 hours. After cooling down to room temperature, concentrate under reduced pressure, add saturated aqueous sodium bicarbonate (200 mL), stir at 20°C for 1 hour, filter, wash the filter cake with water (50 mL×3), and dry the filter cake. The filter cake was added to methyl tert-butyl ether (100 mL), stirred at 20 °C for 1 hour, filtered, and dried to obtain compound 26-9. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.87 (s, 1H), 7.78 (s, 1H), 3.52 (s, 3H), 3.51 (s, 3H), 2.90 (s, 3H). MS-ESI calculated [M+H] ⁺ 263 found 263.

第九步Ninth step

将化合物26-9(1.90g,7.23mmol)和中间体B(1.78g,9.40mmol)溶于二氧六环(100mL)中,加入碳酸钾(3.00g,21.7mmol),4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(837mg,1.45mmol)和三(二亚苄基丙酮)二钯(662mg,723μmol),在120℃和氮气保护下搅拌反应12小时。减压浓缩,加水(100mL),用10:1二氯甲烷/甲醇混合溶液(50mL×3)萃取,无水硫酸钠干燥有机相,过滤,浓缩,剩余物经制备高效液相色谱分离纯化(色谱柱:Kromasil Eternity XT 250mm×80mm×10μm；流动相:0.05％碳酸氢铵水溶液-乙腈；梯度:乙腈30％-60％,20min),得到化合物26。 ¹H NMR(400MHz,CD ₃OD)δ8.15(s,1H),7.64(s,1H),7.62-7.55(m,1H),7.46-7.40(m,1H),7.24-6.76(m,2H),5.81-5.70(m,1H),3.60(s,3H),3.56(s,3H),2.73(s,3H),1.71(d,J＝7.2Hz,3H)。MS-ESI计算值[M+H] ⁺416,实测值416。 Compound 26-9 (1.90g, 7.23mmol) and Intermediate B (1.78g, 9.40mmol) were dissolved in dioxane (100mL), potassium carbonate (3.00g, 21.7mmol), 4,5-bis (Diphenylphosphine)-9,9-dimethylxanthene (837mg, 1.45mmol) and tris(dibenzylideneacetone)dipalladium (662mg, 723μmol) were stirred at 120°C under nitrogen protection for 12 Hour. Concentrate under reduced pressure, add water (100mL), extract with 10:1 dichloromethane/methanol mixed solution (50mL×3), dry the organic phase with anhydrous sodium sulfate, filter, concentrate, and the residue is separated and purified by preparative high performance liquid chromatography ( Chromatographic column: Kromasil Eternity XT 250mm×80mm×10μm; mobile phase: 0.05% aqueous ammonium bicarbonate-acetonitrile; gradient: acetonitrile 30%-60%, 20min), to obtain compound 26. ¹ H NMR (400MHz, CD ₃ OD) δ8.15(s,1H),7.64(s,1H),7.62-7.55(m,1H),7.46-7.40(m,1H),7.24-6.76(m, 2H), 5.81-5.70 (m, 1H), 3.60 (s, 3H), 3.56 (s, 3H), 2.73 (s, 3H), 1.71 (d, J=7.2Hz, 3H). MS-ESI calculated [M+H] ⁺ 416, found 416.

实施例27Example 27

合成路线：synthetic route:

第一步first step

将化合物22-5(1.5g,4.84mmo),乙烯基三氟硼酸钾(1.94g,14.5mmol)和碳酸钾(2.01g,14.5mmol)溶于二甲基亚砜(25mL)中,在20℃氮气氛围中搅拌反应0.5小时,再加入1,1-双(二苯基膦)二茂铁氯化钯(354mg,484μmol),在80℃氮气氛围中搅拌反应12小时。将反应液倒入乙酸乙酯(60mL)中,用水(70+30+10mL)依次洗涤,无水硫酸钠干燥,过滤,减压浓缩。剩余物经硅胶柱色谱法(二氯甲烷/甲醇,1/0～30/1,V/V)纯化得化合物27-1。MS-ESI计算值[M+H] ⁺258,实测值258。 Compound 22-5 (1.5g, 4.84mmo), potassium vinyltrifluoroborate (1.94g, 14.5mmol) and potassium carbonate (2.01g, 14.5mmol) were dissolved in dimethyl sulfoxide (25mL) at 20 The reaction was stirred and reacted in a nitrogen atmosphere at ℃ for 0.5 hours, then 1,1-bis(diphenylphosphine)ferrocenepalladium chloride (354 mg, 484 μmol) was added, and the reaction was stirred and reacted in a nitrogen atmosphere at 80°C for 12 hours. The reaction solution was poured into ethyl acetate (60 mL), washed with water (70+30+10 mL) successively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol, 1/0～30/1, V/V) to obtain compound 27-1. MS-ESI calculated value [M+H] ⁺ 258, found value 258.

第二步second step

将化合物27-1(1.21g,4.70mmol)溶于二氯甲烷(20mL)中,在-78℃下通臭氧(压力:15psi)0.5小时,然后加入三苯基磷(2.47g,9.41mmol),反应液在20℃下搅拌反应1.5小时。将反应液减压浓缩,剩余物经硅胶柱色谱法(二氯甲烷/甲醇,1/0～40/1,V/V)纯化得化合物27-2。 ¹H NMR(400MHz,CDCl ₃)δ10.57(s,1H),7.52(s,1H),7.44(s,1H),4.02(s,3H),3.39(s,3H),1.88-1.86(m,2H),1.73-1.71(m,2H)。MS-ESI计算值[M+H] ⁺260,实测值260。 Compound 27-1 (1.21g, 4.70mmol) was dissolved in dichloromethane (20mL), and ozone (pressure: 15psi) was passed through at -78°C for 0.5 hours, then triphenylphosphine (2.47g, 9.41mmol) was added , the reaction solution was stirred and reacted at 20° C. for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol, 1/0-40/1, V/V) to obtain compound 27-2. ¹ H NMR (400MHz, CDCl ₃ ) δ10.57(s,1H),7.52(s,1H),7.44(s,1H),4.02(s,3H),3.39(s,3H),1.88-1.86( m,2H), 1.73-1.71(m,2H). MS-ESI calculated value [M+H] ⁺ 260, found value 260.

第三步third step

将化合物27-2(800mg,3.09mmol)溶于乙醇(0.5mL)中,加入水合肼(940mg,16.0mmol,85％纯度),在95℃下搅拌反应1小时。冷却后过滤,真空干燥得化合物27-3。MS-ESI计算值[M+H] ⁺242,实测值242。 Compound 27-2 (800mg, 3.09mmol) was dissolved in ethanol (0.5mL), hydrazine hydrate (940mg, 16.0mmol, 85% purity) was added, and the reaction was stirred at 95°C for 1 hour. After cooling, it was filtered and dried in vacuo to obtain compound 27-3. MS-ESI calculated value [M+H] ⁺ 242, found value 242.

第四步the fourth step

将化合物27-3(700mg,2.90mmol)溶于三氯氧磷(10mL)中,95℃下搅拌反应20分钟。浓缩后向剩余物中加入饱和碳酸氢钠(40mL)溶液,用二氯甲烷/甲醇(9/1,40mL×2)萃取,无水硫酸钠干燥,过滤,浓缩得化合物27-4。MS-ESI计算值[M+H] ⁺260,实测值260。 Compound 27-3 (700mg, 2.90mmol) was dissolved in phosphorus oxychloride (10mL), and stirred at 95°C for 20 minutes. After concentration, saturated sodium bicarbonate (40 mL) solution was added to the residue, extracted with dichloromethane/methanol (9/1, 40 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 27-4. MS-ESI calculated value [M+H] ⁺ 260, found value 260.

第五步the fifth step

将化合物27-4(650mg,2.50mmol)和化合物B(616mg,3.25mmol)溶于二氧六环(12mL)中,加入4,5-双二苯基膦-9,9-二甲基氧杂蒽(290mg,500μmol),碳酸铯(2.85g,8.76mmol)和双(二亚苄基丙酮)钯(144mg,250μmol),在氮气氛围95℃下搅拌反应12小时。将反应液倒入水(15mL),用乙酸乙酯(15mL×2)萃取,无水硫酸钠干燥,过滤,减压浓缩。剩余物经制备薄层色谱法(二氯甲烷/甲醇,30/1,V/V)分离纯化得化合物27。 ¹H NMR(400MHz,CD ₃OD)δ8.69(s,1H),8.02(s,1H),7.62-7.59(m,1H),7.52(s,1H),7.47-7.43(m,1H),7.18(t,J＝7.6Hz,1H),7.00(t,J＝54.8Hz,1H),5.81-5.76(m,1H),3.49(s,3H),1.84-1.83(m,4H),1.73(d,J＝6.8Hz,3H)。MS-ESI计算值[M+H] ⁺413实测值413。 Compound 27-4 (650mg, 2.50mmol) and compound B (616mg, 3.25mmol) were dissolved in dioxane (12mL), and 4,5-bisdiphenylphosphine-9,9-dimethyloxy Xanthene (290 mg, 500 μmol), cesium carbonate (2.85 g, 8.76 mmol) and bis(dibenzylideneacetone) palladium (144 mg, 250 μmol) were stirred and reacted at 95° C. under a nitrogen atmosphere for 12 hours. The reaction solution was poured into water (15 mL), extracted with ethyl acetate (15 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by preparative thin-layer chromatography (dichloromethane/methanol, 30/1, V/V) to obtain compound 27. ¹ H NMR (400MHz, CD ₃ OD) δ8.69(s,1H),8.02(s,1H),7.62-7.59(m,1H),7.52(s,1H),7.47-7.43(m,1H) ,7.18(t,J=7.6Hz,1H),7.00(t,J=54.8Hz,1H),5.81-5.76(m,1H),3.49(s,3H),1.84-1.83(m,4H), 1.73 (d, J=6.8Hz, 3H). MS-ESI calculated [M+H] ⁺ 413 found 413.

实施例28Example 28

合成路线：synthetic route:

第一步first step

将化合物18-2(8.84g,41.3mmol)溶于N,N-二甲基甲酰胺(10mL)中,加入2-溴代丙烷(6.10g,49.6mmol)和碳酸钾(17.1g,124mmol),反应液在100℃下搅拌反应12小时。降至室温后,用乙酸乙酯(500mL×3)萃取,有机相用饱和食盐水(250mL×1)洗涤,无水硫酸钠干燥有机相,过滤,减压浓缩,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,20/1～5/1,V/V),分离纯化得到化合物28-1。 ¹H NMR(400MHz,CDCl ₃)δ7.25-7.22(m,2H),7.09-7.07(m,1H),4.56-4.49(m,1H),1.55-1.54(d,J＝6.4Hz,6H)。MS-ESI计算值[M+H] ⁺256和258,实测值256和258。 Compound 18-2 (8.84g, 41.3mmol) was dissolved in N,N-dimethylformamide (10mL), and 2-bromopropane (6.10g, 49.6mmol) and potassium carbonate (17.1g, 124mmol) were added , The reaction solution was stirred and reacted at 100° C. for 12 hours. After cooling down to room temperature, extract with ethyl acetate (500mL×3), wash the organic phase with saturated brine (250mL×1), dry the organic phase over anhydrous sodium sulfate, filter and concentrate under reduced pressure, and the residue is subjected to silica gel column chromatography (Petroleum ether/ethyl acetate, 20/1～5/1, V/V), separated and purified to obtain compound 28-1. ¹ H NMR (400MHz, CDCl ₃ ) δ7.25-7.22(m, 2H), 7.09-7.07(m, 1H), 4.56-4.49(m, 1H), 1.55-1.54(d, J=6.4Hz, 6H ). MS-ESI calculated [M+H] ⁺ 256 and 258, found 256 and 258.

第二步second step

将化合物28-1(21.8g,85.1mmol)溶于甲醇(120mL),N,N-二甲基甲酰胺(40mL)和三乙胺(40mL)中,加入1,1-双(二苯基磷)二茂铁氯化钯(6.22g,8.50mmol),反应液在80℃,一氧化碳(45psi)氛围下搅拌反应60小时。降至室温后,用乙酸乙酯(100mL×5)萃取,有机相用饱和食盐水(100mL×2)洗涤,无水硫酸钠干燥有机相,过滤减压浓缩,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,100/1～2/1,V/V),分离纯化得到化合物28-2。 ¹H NMR(400MHz,CDCl ₃)δ7.90-7.87(m,1H),7.78-7.77(d,J＝1.2Hz,1H),7.26-7.23 (d,J＝8.8Hz,1H),4.62-4.5(m,1H),3.95(s,3H),1.59-1.58(d,J＝6.8Hz,6H)。MS-ESI计算值[M+H] ⁺236,实测值236。 Compound 28-1 (21.8g, 85.1mmol) was dissolved in methanol (120mL), N,N-dimethylformamide (40mL) and triethylamine (40mL), and 1,1-bis(diphenyl Phosphorus) ferrocenepalladium chloride (6.22g, 8.50mmol), the reaction solution was stirred and reacted at 80°C under a carbon monoxide (45psi) atmosphere for 60 hours. After cooling down to room temperature, it was extracted with ethyl acetate (100 mL×5), the organic phase was washed with saturated brine (100 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography ( Petroleum ether/ethyl acetate, 100/1～2/1, V/V), separated and purified to obtain compound 28-2. ¹ H NMR (400MHz, CDCl ₃ ) δ7.90-7.87 (m, 1H), 7.78-7.77 (d, J=1.2Hz, 1H), 7.26-7.23 (d, J=8.8Hz, 1H), 4.62- 4.5 (m, 1H), 3.95 (s, 3H), 1.59-1.58 (d, J=6.8Hz, 6H). MS-ESI calculated [M+H] ⁺ 236, found 236.

第三步third step

氮气保护下将化合物28-2(12.5g,53.2mmol)溶于三氟乙酸(100mL)和硫酸(10mL)中,加入N-溴代丁二酰亚胺(11.4g,63.8mmol),在25℃下搅拌反应12小时。向反应液加入水(200mL),用乙酸乙酯(150mL×3)萃取,有机相用饱和食盐水(200mL×1)洗涤,无水硫酸钠干燥有机相,过滤,减压浓缩,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,20/1～5/1,V/V),分离纯化得到化合物28-3。 ¹H NMR(400MHz,CDCl ₃)δ7.57(s,1H),7.52(s,1H),4.58-4.51(m,1H),3.94(s,3H),1.58-1.56(d,J＝6.8Hz,6H)。MS-ESI计算值[M+H] ⁺314和316实测值314和316。 Under nitrogen protection, compound 28-2 (12.5g, 53.2mmol) was dissolved in trifluoroacetic acid (100mL) and sulfuric acid (10mL), and N-bromosuccinimide (11.4g, 63.8mmol) was added, and at 25 The reaction was stirred at °C for 12 hours. Add water (200mL) to the reaction solution, extract with ethyl acetate (150mL×3), wash the organic phase with saturated brine (200mL×1), dry the organic phase over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and use Silica gel column chromatography (petroleum ether/ethyl acetate, 20/1～5/1, V/V), separation and purification to obtain compound 28-3. ¹ H NMR (400MHz, CDCl ₃ ) δ7.57(s, 1H), 7.52(s, 1H), 4.58-4.51(m, 1H), 3.94(s, 3H), 1.58-1.56(d, J=6.8 Hz, 6H). MS-ESI calculated [M+H] ⁺ 314 and 316 found 314 and 316.

第四步the fourth step

氮气保护下将化合物28-3(13.8g,43.9mmol)溶于甲苯(100mL)中,加入A-5(21.1g,58.4mmol)和双(三苯基膦)二氯化钯(3.08g,4.39mmol),在120℃下搅拌反应12小时。降至室温后,向反应液加入饱和氟化钾水溶液(300mL),用乙酸乙酯(100mL×3)萃取,无水硫酸钠干燥有机相,过滤浓缩得到化合物28-4。MS-ESI计算值[M+H] ⁺306,实测值306。 Under nitrogen protection, compound 28-3 (13.8g, 43.9mmol) was dissolved in toluene (100mL), and A-5 (21.1g, 58.4mmol) and bis(triphenylphosphine)palladium dichloride (3.08g, 4.39mmol), stirred and reacted at 120°C for 12 hours. After cooling down to room temperature, saturated potassium fluoride aqueous solution (300 mL) was added to the reaction solution, extracted with ethyl acetate (100 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 28-4. MS-ESI calculated value [M+H] ⁺ 306, found value 306.

第五步the fifth step

将化合物28-4(13.4g,43.9mmol)溶于丙酮(300mL)中,在0℃下滴加盐酸溶液(12M,29.3mL),在25℃下搅拌反应1小时。向反应液中加入饱和碳酸氢钠水溶液碱化pH至8,用乙酸乙酯(100mL×3)萃取,有机相用饱和食盐水(250mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物经过硅胶柱色谱法分离纯化(石油醚/乙酸乙酯,20/1～5/1,V/V),得到化合物28-5。 ¹H NMR(400MHz,CDCl ₃)δ7.52(s,1H),7.30(s,1H),4.61-4.54(m,1H),3.93(s,3H),2.55(s,3H),1.59-1.57(d,J＝6.8Hz,6H)。MS-ESI计算值[M+H] ⁺278,实测值278。 Compound 28-4 (13.4g, 43.9mmol) was dissolved in acetone (300mL), hydrochloric acid solution (12M, 29.3mL) was added dropwise at 0°C, and the reaction was stirred at 25°C for 1 hour. Add saturated aqueous sodium bicarbonate solution to the reaction solution to alkalinize the pH to 8, extract with ethyl acetate (100mL×3), wash the organic phase with saturated brine (250mL×1), dry over anhydrous sodium sulfate, filter, and reduce pressure After concentration, the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 20/1～5/1, V/V) to obtain compound 28-5. ¹ H NMR (400MHz, CDCl ₃ )δ7.52(s,1H),7.30(s,1H),4.61-4.54(m,1H),3.93(s,3H),2.55(s,3H),1.59- 1.57 (d, J=6.8Hz, 6H). MS-ESI calculated value [M+H] ⁺ 278, found value 278.

第六步step six

将化合物28-5(9.05g,32.6mmol)溶于乙醇(100mL)中,加入水合肼(4.76mL,97.9mmol,85％纯度),在95℃下搅拌反应0.5小时。降至室温后,过滤,将固体减压浓缩得到化合物28-6。 ¹H NMR(400MHz,CDCl ₃)δ8.12(s,1H),4.70-4.66(m,1H),3.60(s,3H),1.62-1.61(d,J＝6.8Hz,6H)。MS-ESI计算值[M+H] ⁺260,实测值260。 Compound 28-5 (9.05g, 32.6mmol) was dissolved in ethanol (100mL), hydrazine hydrate (4.76mL, 97.9mmol, 85% purity) was added, and the reaction was stirred at 95°C for 0.5 hours. After cooling down to room temperature, it was filtered, and the solid was concentrated under reduced pressure to obtain compound 28-6. ¹ H NMR (400MHz, CDCl ₃ ) δ8.12 (s, 1H), 4.70-4.66 (m, 1H), 3.60 (s, 3H), 1.62-1.61 (d, J=6.8Hz, 6H). MS-ESI calculated value [M+H] ⁺ 260, found value 260.

第七步step seven

将化合物28-6(3.00g,11.6mmol)溶于三氯氧磷(40mL)中,在90℃下搅拌反应10分钟。降至室温后,向反应液中倒入氯化铵水溶液(200mL),用乙酸乙酯(200mL×5)萃取,有机相用饱和食盐水(60mL×2)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物经过硅胶柱色谱法分离纯化(石油醚/乙酸乙酯,20/1～5/1,V/V),得到化合物28-7。 ¹H NMR(400MHz,CD ₃OD)δ8.12(s,1H),8.01(s,1H),4.78-4.75(m,1H),2.97(s,3H),1.67-1.65(d,J＝6.8Hz,6H)。MS-ESI计算值[M+H] ⁺278,实测值278。 Compound 28-6 (3.00g, 11.6mmol) was dissolved in phosphorus oxychloride (40mL), and stirred at 90°C for 10 minutes. After cooling down to room temperature, pour ammonium chloride aqueous solution (200mL) into the reaction solution, extract with ethyl acetate (200mL×5), wash the organic phase with saturated brine (60mL×2), dry over anhydrous sodium sulfate, and filter , concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 20/1～5/1, V/V) to obtain compound 28-7. ¹ H NMR (400MHz, CD ₃ OD) δ8.12(s, 1H), 8.01(s, 1H), 4.78-4.75(m, 1H), 2.97(s, 3H), 1.67-1.65(d, J= 6.8Hz, 6H). MS-ESI calculated value [M+H] ⁺ 278, found value 278.

第八步eighth step

氮气保护下将化合物28-7(0.40g,1.44mmol)溶于二氧六环(10mL)中,加入中间体B(327mg,1.73mmol),(±)-2,2-双(二苯膦基)-1,1-联萘(167mg,288μmol),碳酸钾(597mg,4.32mmol)和双(二亚苄基丙酮) 钯(132mg,144μmol),在100℃下搅拌反应12小时。降至室温后,向反应液加入水(100mL),用二氯甲烷(20mL×5)萃取,有机相用饱和食盐水(20mL×1)洗涤,无水硫酸钠干燥有机相,过滤,减压浓缩。剩余物经制备高效液相色谱分离纯化(色谱柱:Welch Ultimate Xtimate C18 150mm×40mm×5μm；流动相:0.05％盐酸水溶液-乙腈；梯度:乙腈15％-45％,10min),得到化合物28的盐酸盐。 ¹H NMR(400MHz,CD ₃OD)δ8.32(s,1H),7.92(s,1H),7.59(t,J＝6.8Hz,1H),7.44(t,J＝6.6Hz,1H),7.12(t,J＝7.8Hz,1H),7.13-6.86(m,1H),5.74-5.68(m,1H),4.75-4.68(m,1H),2.71(s,3H),1.73-1.71(d,J＝6.8Hz,3H),1.69-1.67(d,J＝6.8Hz,6H)。MS-ESI计算值[M+H] ⁺431,实测值431。 Compound 28-7 (0.40g, 1.44mmol) was dissolved in dioxane (10mL) under nitrogen protection, and intermediate B (327mg, 1.73mmol), (±)-2,2-bis(diphenylphosphine base)-1,1-binaphthyl (167 mg, 288 μmol), potassium carbonate (597 mg, 4.32 mmol) and bis(dibenzylideneacetone) palladium (132 mg, 144 μmol), and stirred at 100° C. for 12 hours. After cooling down to room temperature, add water (100mL) to the reaction solution, extract with dichloromethane (20mL×5), wash the organic phase with saturated brine (20mL×1), dry the organic phase over anhydrous sodium sulfate, filter, and depressurize concentrate. The residue was separated and purified by preparative high performance liquid chromatography (chromatographic column: Welch Ultimate Xtimate C18 150mm×40mm×5μm; mobile phase: 0.05% aqueous hydrochloric acid-acetonitrile; gradient: acetonitrile 15%-45%, 10min), to obtain compound 28 Hydrochloride. ¹ H NMR (400MHz, CD ₃ OD) δ8.32(s, 1H), 7.92(s, 1H), 7.59(t, J=6.8Hz, 1H), 7.44(t, J=6.6Hz, 1H), 7.12(t, J=7.8Hz, 1H), 7.13-6.86(m, 1H), 5.74-5.68(m, 1H), 4.75-4.68(m, 1H), 2.71(s, 3H), 1.73-1.71( d, J=6.8Hz, 3H), 1.69-1.67 (d, J=6.8Hz, 6H). MS-ESI calculated [M+H] ⁺ 431, found 431.

实施例29Example 29

合成路线：synthetic route:

第一步first step

将化合物29-1(2.00g,19.8mmol)溶于二氯甲烷(20mL)中,冷却至0℃,加入吡啶(3.91g,49.4mmol)和对甲苯磺酰氯(5.65g,29.7mmol),在20℃下搅拌反应14小时。反应液减压浓缩,剩余物加二氯甲烷(200mL),用水(50mL×2)洗涤,无水硫酸钠干燥有机相,过滤,减压浓缩得到化合物29-2。 ¹H NMR(400MHz,CDCl ₃)δ7.79(d,J＝8.0Hz,2H),7.36(d,J＝8.0Hz,2H),5.14-4.97(m,1H),3.18-2.98(m,1H),2.89-2.80(m,2H),2.79-2.65(m,1H),2.50(s,3H),2.46(s,3H),2.31-2.02(m,2H)。 Compound 29-1 (2.00g, 19.8mmol) was dissolved in dichloromethane (20mL), cooled to 0°C, added pyridine (3.91g, 49.4mmol) and p-toluenesulfonyl chloride (5.65g, 29.7mmol), in The reaction was stirred at 20°C for 14 hours. The reaction solution was concentrated under reduced pressure, dichloromethane (200 mL) was added to the residue, washed with water (50 mL×2), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 29-2. ¹ H NMR (400MHz, CDCl ₃ ) δ7.79(d, J=8.0Hz, 2H), 7.36(d, J=8.0Hz, 2H), 5.14-4.97(m, 1H), 3.18-2.98(m, 1H), 2.89-2.80(m, 2H), 2.79-2.65(m, 1H), 2.50(s, 3H), 2.46(s, 3H), 2.31-2.02(m, 2H).

第二步second step

将化合物25-5(4.00g,14.0mmol)溶于N,N-二甲基甲酰胺(40mL)中,加入碳酸铯(9.14g,28.1mmol)和29-2(4.30g,16.8mmol),在25℃下搅拌反应12小时,在60℃下搅拌反应12小时。反应液加水(300 mL),用乙酸乙酯(100mL×3)萃取,饱和食盐水(100mL×1)洗涤,有机相用无水硫酸钠干燥,减压浓缩,剩余物用硅胶柱色谱法(二氯甲烷/甲醇,40/1～20/1,V/V),分离纯化得到化合物29-3。 ¹H NMR(400MHz,CDCl ₃)δ8.29(s,1H),7.23(s,1H),5.26-5.05(m,1H),3.94(s,3H),3.40(s,3H),3.15-3.07(m,1H),3.04-2.95(m,1H),2.67-2.54(m,1H),2.43(s,3H),2.39-2.24(m,2H),2.15-2.01(m,1H)。MS-ESI计算值[M+H] ⁺368和370,实测值368和370。 Compound 25-5 (4.00g, 14.0mmol) was dissolved in N,N-dimethylformamide (40mL), cesium carbonate (9.14g, 28.1mmol) and 29-2 (4.30g, 16.8mmol) were added, The reaction was stirred at 25°C for 12 hours and at 60°C for 12 hours. The reaction solution was added with water (300 mL), extracted with ethyl acetate (100 mL×3), washed with saturated brine (100 mL×1), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography ( Dichloromethane/methanol, 40/1～20/1, V/V), separated and purified to obtain compound 29-3. ¹ H NMR (400MHz, CDCl ₃ )δ8.29(s,1H),7.23(s,1H),5.26-5.05(m,1H),3.94(s,3H),3.40(s,3H),3.15- 3.07 (m, 1H), 3.04-2.95 (m, 1H), 2.67-2.54 (m, 1H), 2.43 (s, 3H), 2.39-2.24 (m, 2H), 2.15-2.01 (m, 1H). MS-ESI calculated [M+H] ⁺ 368 and 370, found 368 and 370.

第三步third step

将化合物29-3(2.00g,5.43mmol)和乙烯基正丁醚(2.72g,27.2mmol)溶于N,N-二甲基甲酰胺(20mL)和水(2mL)中,加入碳酸钾(901mg,6.52mmol),醋酸钯(122mg,543μmol)和1,3-双(二苯基膦)丙烷(448mg,1.09mmol),反应液在100℃及氮气保护下搅拌反应12小时。降至室温后向反应液加入2M盐酸溶液(5.4mL),在25℃下搅拌15分钟,反应液加水(100mL),用10:1二氯甲烷/甲醇(50mL×4)萃取,无水硫酸钠干燥有机相,过滤浓缩,剩余物经过硅胶柱色谱法分离纯化(二氯甲烷/甲醇,40/1～20/1,V/V),得到化合物29-4。MS-ESI计算值[M+H] ⁺332,实测值332。 Compound 29-3 (2.00g, 5.43mmol) and vinyl n-butyl ether (2.72g, 27.2mmol) were dissolved in N,N-dimethylformamide (20mL) and water (2mL), and potassium carbonate ( 901mg, 6.52mmol), palladium acetate (122mg, 543μmol) and 1,3-bis(diphenylphosphine)propane (448mg, 1.09mmol), the reaction solution was stirred at 100°C under nitrogen protection for 12 hours. After cooling down to room temperature, 2M hydrochloric acid solution (5.4mL) was added to the reaction solution, stirred at 25°C for 15 minutes, the reaction solution was added with water (100mL), extracted with 10:1 dichloromethane/methanol (50mL×4), anhydrous sulfuric acid The organic phase was dried over sodium, concentrated by filtration, and the residue was separated and purified by silica gel column chromatography (dichloromethane/methanol, 40/1-20/1, V/V) to obtain compound 29-4. MS-ESI calculated [M+H] ⁺ 332, found 332.

第四步the fourth step

将化合物29-4(1.50g,4.53mmol)溶于乙醇(20mL)中,加入水合肼(2.1mL,37.2mmol,85％纯度),在90℃下搅拌反应2小时。降至室温后过滤,滤饼用水(5mL×2)洗涤,干燥得到化合物29-5。 ¹H NMR(400MHz,DMSO-d ₆)δ12.23(s,1H),8.40(s,1H),7.58(s,1H),5.24-5.04(m,1H),3.46(s,3H),3.10-2.94(m,2H),2.72-2.57(m,2H),2.54(s,3H),2.36(s,3H),2.28-2.15(m,1H),2.12-1.99(m,1H)。MS-ESI计算值[M+H] ⁺314,实测值314。 Compound 29-4 (1.50g, 4.53mmol) was dissolved in ethanol (20mL), hydrazine hydrate (2.1mL, 37.2mmol, 85% purity) was added, and the reaction was stirred at 90°C for 2 hours. After cooling down to room temperature, it was filtered, the filter cake was washed with water (5 mL×2), and dried to obtain compound 29-5. ¹ H NMR (400MHz,DMSO-d ₆ )δ12.23(s,1H),8.40(s,1H),7.58(s,1H),5.24-5.04(m,1H),3.46(s,3H), 3.10-2.94 (m, 2H), 2.72-2.57 (m, 2H), 2.54 (s, 3H), 2.36 (s, 3H), 2.28-2.15 (m, 1H), 2.12-1.99 (m, 1H). MS-ESI calculated [M+H] ⁺ 314, found 314.

第五步the fifth step

将化合物29-5(500mg,1.60mol)溶于三氯氧磷(5mL)中,在100℃下搅拌反应2小时。降至室温后,减压浓缩,加入饱和碳酸氢钠溶液(50mL),在25℃下搅拌30分钟,用10:1二氯甲烷/甲醇的混合溶液(30mL×4)萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩得到化合物29-6。MS-ESI计算值[M+H] ⁺332,实测值332。 Compound 29-5 (500mg, 1.60mol) was dissolved in phosphorus oxychloride (5mL), and stirred at 100°C for 2 hours. After cooling down to room temperature, concentrate under reduced pressure, add saturated sodium bicarbonate solution (50mL), stir at 25°C for 30 minutes, extract with a 10:1 mixed solution of dichloromethane/methanol (30mL×4), the organic phase was washed with Dry over sodium sulfate, filter, and concentrate under reduced pressure to obtain compound 29-6. MS-ESI calculated [M+H] ⁺ 332, found 332.

第六步step six

将化合物29-6(500mg,1.51mol)和中间体B(371mg,1.96mmol)溶于二氧六环(10mL)中,加入碳酸钾(625mg,452mol),4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(174mg,301μmol)和三(二亚苄基丙酮)二钯(138mg,151μmol),在120℃和氮气保护下搅拌反应12小时。反应液冷却至室温,加10:1二氯甲烷/甲醇混合溶液(150mL),过滤,浓缩,剩余物经制备高效液相色谱分离纯化(色谱柱:3_Phenomenex Luna C1875mm×30mm×3μm；流动相:0.05％盐酸水溶液-乙腈；梯度:乙腈8％-28％,8min),得到化合物29的盐酸盐。 ¹H NMR(400MHz,CD ₃OD)δ8.91(s,1H),8.10-8.00(m,1H),7.82-7.71(m,1H),7.53-7.45(m,1H),7.23(t,J＝8.0Hz,1H),7.15-6.82(m,1H),5.72-5.50(m,2H),4.33-3.68(m,3H),3.62(s,3H),3.53-3.35(m,1H),3.20-3.09(m,3H),2.92(s,3H),2.85-2.51(m,2H),1.82(br d,J＝6.4Hz,3H)。MS-ESI计算值[M+H] ⁺485,实测值485。 Compound 29-6 (500mg, 1.51mol) and Intermediate B (371mg, 1.96mmol) were dissolved in dioxane (10mL), potassium carbonate (625mg, 452mol), 4,5-bis(diphenyl Phosphine)-9,9-dimethylxanthene (174 mg, 301 μmol) and tris(dibenzylideneacetone) dipalladium (138 mg, 151 μmol), stirred and reacted at 120° C. for 12 hours under nitrogen protection. The reaction solution was cooled to room temperature, added 10:1 dichloromethane/methanol mixed solution (150mL), filtered, concentrated, and the residue was separated and purified by preparative high performance liquid chromatography (chromatographic column: 3_Phenomenex Luna C18 75mm×30mm×3μm; mobile phase: 0.05% hydrochloric acid aqueous solution-acetonitrile; gradient: acetonitrile 8%-28%, 8min), to obtain the hydrochloride of compound 29. ¹ H NMR (400MHz, CD ₃ OD) δ8.91(s, 1H), 8.10-8.00(m, 1H), 7.82-7.71(m, 1H), 7.53-7.45(m, 1H), 7.23(t, J＝8.0Hz,1H),7.15-6.82(m,1H),5.72-5.50(m,2H),4.33-3.68(m,3H),3.62(s,3H),3.53-3.35(m,1H) , 3.20-3.09 (m, 3H), 2.92 (s, 3H), 2.85-2.51 (m, 2H), 1.82 (br d, J = 6.4Hz, 3H). MS-ESI calculated [M+H] ⁺ 485, found 485.

实施例30Example 30

合成路线：synthetic route:

第一步first step

将化合物30-1(20.0g,100mmol)溶于四氢呋喃(250mL)中,加入碳酸钾(69.4g,502mmol)和甲胺盐酸盐(27.1g,402mmol),在25℃下搅拌反应12小时。反应液加入水(3000mL)中,搅拌5分钟,抽滤,将滤饼干燥得到化合物30-2。MS-ESI计算值[M+H] ⁺211,实测值211。 Compound 30-1 (20.0g, 100mmol) was dissolved in tetrahydrofuran (250mL), potassium carbonate (69.4g, 502mmol) and methylamine hydrochloride (27.1g, 402mmol) were added, and the reaction was stirred at 25°C for 12 hours. The reaction solution was added into water (3000 mL), stirred for 5 minutes, filtered with suction, and the filter cake was dried to obtain compound 30-2. MS-ESI calculated value [M+H] ⁺ 211, found value 211.

第二步second step

将化合物30-2(24.0g,114mmol)溶于乙醇(200mL)和水(40mL)的混合溶液中,加入铁粉(19.1g,343mmol)和氯化铵(18.3g,343mmol),在80℃下搅拌反应2小时。反应液冷却至20℃,反应液通过硅藻土过滤,用乙酸乙酯(500mL×3)萃取,饱和食盐水(500mL×1)洗涤,无水硫酸钠干燥有机相,过滤,滤液减压浓缩,得到化合物30-3。MS-ESI计算值[M+H] ⁺181,实测值181。 Compound 30-2 (24.0g, 114mmol) was dissolved in a mixed solution of ethanol (200mL) and water (40mL), iron powder (19.1g, 343mmol) and ammonium chloride (18.3g, 343mmol) were added, at 80°C The reaction was stirred for 2 hours. The reaction solution was cooled to 20°C, the reaction solution was filtered through diatomaceous earth, extracted with ethyl acetate (500mL×3), washed with saturated brine (500mL×1), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure , to obtain compound 30-3. MS-ESI calculated value [M+H] ⁺ 181, found value 181.

第三步third step

将化合物30-3(20.1g,112mmol)溶解在四氢呋喃(200mL)中,加入羰基二咪唑(21.7g,134mmol),在80℃反应12小时。降至室温后,将反应液浓缩,剩余物经过硅胶柱色谱法分离纯化(二氯甲烷/乙酸乙酯,10/1～2/1,V/V),得到化合物30-4。MS-ESI计算值[M+H] ⁺207,实测值207。 Compound 30-3 (20.1 g, 112 mmol) was dissolved in tetrahydrofuran (200 mL), carbonyldiimidazole (21.7 g, 134 mmol) was added, and reacted at 80° C. for 12 hours. After cooling down to room temperature, the reaction solution was concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane/ethyl acetate, 10/1～2/1, V/V) to obtain compound 30-4. MS-ESI calculated [M+H] ⁺ 207, found 207.

第四步the fourth step

将化合物30-4(5.60g,23.0mmol)溶于N,N-二甲基甲酰胺(50mL)中,加入N-溴代丁二酰亚胺(4.30g,24.2mmol),在80℃下搅拌反应12小时。向反应液中加入水(200mL),搅拌30分钟后过滤,滤饼用水(50mL×3)洗涤,干燥得到化合物30-5。MS-ESI计算值[M+H] ⁺285和287,实测值285和287。 Compound 30-4 (5.60g, 23.0mmol) was dissolved in N,N-dimethylformamide (50mL), N-bromosuccinimide (4.30g, 24.2mmol) was added, and at 80°C The reaction was stirred for 12 hours. Water (200 mL) was added to the reaction liquid, stirred for 30 minutes and filtered, the filter cake was washed with water (50 mL×3), and dried to obtain compound 30-5. MS-ESI calculated [M+H] ⁺ 285 and 287, found 285 and 287.

第五步the fifth step

将化合物30-5(6.20g,21.8mmol)溶于N,N-二甲基甲酰胺(50mL)中,加入碳酸铯(21.3g,65.2mmol)和碘甲烷(2.71mL,43.5mmol),在25℃下搅拌反应12小时。向反应液中加入水(200mL),25℃下搅拌20分钟后过滤,滤饼用水(20mL×3)洗涤,干燥得到化合物30-6。MS-ESI计算值[M+H] ⁺299和301,实测值299和301。 Compound 30-5 (6.20g, 21.8mmol) was dissolved in N,N-dimethylformamide (50mL), cesium carbonate (21.3g, 65.2mmol) and iodomethane (2.71mL, 43.5mmol) were added, and the The reaction was stirred at 25°C for 12 hours. Water (200 mL) was added to the reaction solution, stirred at 25 °C for 20 minutes and filtered, the filter cake was washed with water (20 mL×3), and dried to obtain compound 30-6. MS-ESI calculated [M+H] ⁺ 299 and 301, found 299 and 301.

第六步step six

将化合物30-6(4.60g,15.4mmol)和22-6(7.70g,76.9mmol)溶于N,N-二甲基甲酰胺(50mL)和水(5mL)中,加入碳酸钾(2.55g,18.5mmol),醋酸钯(345mg,1.54mmol)和1,3-双(二苯基膦)丙烷(1.27g,3.08mmol),反应液在100℃及氮气保护下搅拌反应12小时。降至室温后向反应液加入1M盐酸溶液(30.8mL),在25℃下搅拌0.25小时,反应液减压浓缩,加水(300mL),用10:1二氯甲烷/甲醇的混合溶液(150mL×3)萃取,无水硫酸钠干燥有机相,过滤浓缩,剩余物经过硅胶柱色谱法分离纯化(石油醚/乙酸乙酯,5/1～1/1,V/V),得到化合物30-7。MS-ESI计算值[M+H] ⁺263,实测值263。 Compound 30-6 (4.60g, 15.4mmol) and 22-6 (7.70g, 76.9mmol) were dissolved in N,N-dimethylformamide (50mL) and water (5mL), potassium carbonate (2.55g , 18.5mmol), palladium acetate (345mg, 1.54mmol) and 1,3-bis(diphenylphosphine)propane (1.27g, 3.08mmol), the reaction solution was stirred at 100°C for 12 hours under nitrogen protection. After cooling down to room temperature, 1M hydrochloric acid solution (30.8mL) was added to the reaction solution, stirred at 25°C for 0.25 hours, the reaction solution was concentrated under reduced pressure, water (300mL) was added, and a mixed solution of 10:1 dichloromethane/methanol (150mL× 3) Extraction, dry the organic phase with anhydrous sodium sulfate, filter and concentrate, and the residue is separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1～1/1, V/V) to obtain compound 30-7 . MS-ESI calculated value [M+H] ⁺ 263, found value 263.

第七步step seven

将化合物30-7(3.80g,14.5mmol)溶于乙醇(50mL)中,加入水合肼(5.04mL,88.1mmol,85％纯度),在90℃下搅拌反应12小时。降至室温后过滤,滤饼用水(5mL×3)洗涤,将滤饼加入二氯甲烷(50mL)中,25℃下搅拌15分钟后过滤,干燥滤饼,得到化合物30-8。 ¹H NMR(400MHz,DMSO-d ₆)δ12.20(s,1H),7.74(d,J＝8.4Hz,1H),7.62(d,J＝8.4Hz,1H),3.83(s,3H),3.44(s,3H),2.49(br s,3H)。MS-ESI计算值[M+H] ⁺245,实测值245。 Compound 30-7 (3.80g, 14.5mmol) was dissolved in ethanol (50mL), hydrazine hydrate (5.04mL, 88.1mmol, 85% purity) was added, and the reaction was stirred at 90°C for 12 hours. After cooling down to room temperature, filter, wash the filter cake with water (5mL×3), add the filter cake to dichloromethane (50mL), stir at 25°C for 15 minutes, filter and dry the filter cake to obtain compound 30-8. ¹ H NMR (400MHz,DMSO-d ₆ )δ12.20(s,1H),7.74(d,J=8.4Hz,1H),7.62(d,J=8.4Hz,1H),3.83(s,3H) , 3.44(s,3H), 2.49(br s,3H). MS-ESI calculated [M+H] ⁺ 245, found 245.

第八步eighth step

将化合物30-8(1.00g,4.09mmol)溶于三氯氧磷(20mL)中,在90℃下搅拌反应12小时。降至室温后,减压浓缩,加入饱和碳酸氢钠溶液(20mL),在25℃下搅拌反应30分钟,用10:1二氯甲烷/甲醇的混合溶液(10mL×3)萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩得到化合物30-9。 ¹H NMR(400MHz,DMSO-d ₆)δ8.05(s,2H),3.74(s,3H),3.52(s,3H),2.87(s,3H)。MS-ESI计算值[M+H] ⁺263,实测值263。 Compound 30-8 (1.00g, 4.09mmol) was dissolved in phosphorus oxychloride (20mL), and stirred at 90°C for 12 hours. After cooling down to room temperature, concentrate under reduced pressure, add saturated sodium bicarbonate solution (20mL), stir and react at 25°C for 30 minutes, extract with 10:1 dichloromethane/methanol mixed solution (10mL×3), and use Dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain compound 30-9. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.05 (s, 2H), 3.74 (s, 3H), 3.52 (s, 3H), 2.87 (s, 3H). MS-ESI calculated value [M+H] ⁺ 263, found value 263.

第九步Ninth step

将化合物30-9(200mg,761μmol)和中间体B(187mg,990μmol)溶于二氧六环(4mL)中,加入碳酸钾(316mg,2.28mmol),4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(88.1mg,152μmol)和三(二亚苄基丙酮)二钯(69.7mg,76.1μmol),在105℃和氮气保护下搅拌反应12小时。减压浓缩,加入二氯甲烷(100mL)后过滤,滤饼用二氯甲烷(20mL×3)洗涤,剩余物经制备高效液相色谱分离纯化(色谱柱:Phenomenex Luna C18 75mm×30mm×3μm；流动相:0.05％盐酸水溶液-乙腈；梯度:乙腈16％-36％,8min),得到化合物30的盐酸盐。 ¹H NMR(400MHz,CD ₃OD)δ8.21(br d,J＝8.6Hz,1H),8.03(d,J＝8.4Hz,1H),7.58(br t,J＝7.6Hz,1H),7.54-7.47(m,1H),7.26-7.20(m,1H),7.17-6.87(m,1H),5.65-5.54(m,1H),3.77(s,3H),3.65(s,3H),2.88(s,3H),1.74(d,J＝7.0Hz,3H)。MS-ESI计算值[M+H] ⁺416,实测值416。 Compound 30-9 (200 mg, 761 μmol) and intermediate B (187 mg, 990 μmol) were dissolved in dioxane (4 mL), potassium carbonate (316 mg, 2.28 mmol), 4,5-bis(diphenylphosphine )-9,9-dimethylxanthene (88.1 mg, 152 μmol) and tris(dibenzylideneacetone) dipalladium (69.7 mg, 76.1 μmol), stirred and reacted at 105°C for 12 hours under nitrogen protection. Concentrate under reduced pressure, add dichloromethane (100mL) and filter, the filter cake is washed with dichloromethane (20mL×3), and the residue is separated and purified by preparative high performance liquid chromatography (column: Phenomenex Luna C18 75mm×30mm×3 μm; Mobile phase: 0.05% hydrochloric acid aqueous solution-acetonitrile; gradient: acetonitrile 16%-36%, 8min), to obtain the hydrochloride of compound 30. ¹ H NMR (400MHz, CD ₃ OD) δ8.21 (br d, J = 8.6Hz, 1H), 8.03 (d, J = 8.4Hz, 1H), 7.58 (br t, J = 7.6Hz, 1H), 7.54-7.47(m,1H),7.26-7.20(m,1H),7.17-6.87(m,1H),5.65-5.54(m,1H),3.77(s,3H),3.65(s,3H), 2.88 (s, 3H), 1.74 (d, J=7.0Hz, 3H). MS-ESI calculated [M+H] ⁺ 416, found 416.

实施例31Example 31

合成路线：synthetic route:

将化合物29-6(150mg,452μmol)和中间体A的盐酸盐(145mg,588μmol)溶于二氧六环(3mL)中,加入碳酸钾(187mg,1.36mmol),4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(52.3mg,90.4μmol)和三(二亚苄基丙酮)二钯(41.4mg,45.2μmol),在120℃和氮气保护下搅拌反应12小时。反应液冷却至室温,反应液通过硅藻土过滤,滤饼用10:1二氯甲烷/甲醇混合溶液(10mL×3)洗涤,滤液减压浓缩,剩余物经快速硅胶色谱法(色谱柱:

40g

预填球形C18硅胶闪蒸柱；0.05％甲酸水溶液/乙腈,45～55％,V/V,45mL/min)分离纯化,得到化合物31的甲酸盐。 ¹H NMR(400MHz,CD ₃OD)δ8.52-8.33(m,3H),7.88(s,1H),7.66-7.53(m,1H),7.44-7.33(m,1H),7.24-7.09(m,1H),5.77-5.62(m,1H),5.52-5.33(m,1H),3.92-3.83(m,1H),3.81-3.71(m,1H),3.61(s,3H),3.60-3.54(m,1H),3.31-3.24(m,1H),2.95(s,3H),2.85(s,3H),2.75-2.64(m,1H),2.62-2.48(m,1H),1.76(d,J＝7.2Hz,3H),1.32(s,3H),1.31(s,3H)。MS-ESI计算值[M+H] ⁺543,实测值543。 Compound 29-6 (150 mg, 452 μmol) and intermediate A hydrochloride (145 mg, 588 μmol) were dissolved in dioxane (3 mL), potassium carbonate (187 mg, 1.36 mmol), 4,5-bis( Diphenylphosphine)-9,9-dimethylxanthene (52.3mg, 90.4μmol) and tris(dibenzylideneacetone)dipalladium (41.4mg, 45.2μmol), stirring at 120°C under nitrogen protection React for 12 hours. The reaction solution was cooled to room temperature, the reaction solution was filtered through diatomaceous earth, the filter cake was washed with a 10:1 dichloromethane/methanol mixed solution (10mL×3), the filtrate was concentrated under reduced pressure, and the residue was subjected to flash silica gel chromatography (column:

40g

Prepacked spherical C18 silica gel flash column; 0.05% aqueous formic acid/acetonitrile, 45-55%, V/V, 45mL/min) was separated and purified to obtain the formate salt of compound 31. ¹ H NMR (400MHz, CD ₃ OD) δ8.52-8.33 (m, 3H), 7.88 (s, 1H), 7.66-7.53 (m, 1H), 7.44-7.33 (m, 1H), 7.24-7.09 ( m,1H),5.77-5.62(m,1H),5.52-5.33(m,1H),3.92-3.83(m,1H),3.81-3.71(m,1H),3.61(s,3H),3.60- 3.54(m,1H),3.31-3.24(m,1H),2.95(s,3H),2.85(s,3H),2.75-2.64(m,1H),2.62-2.48(m,1H),1.76( d, J=7.2Hz, 3H), 1.32(s, 3H), 1.31(s, 3H). MS-ESI calculated value [M+H] ⁺ 543, found value 543.

生物学评价：Biological Evaluation:

实验例1：KRAS(G12C)和SOS1结合实验Experimental example 1: KRAS (G12C) and SOS1 binding experiment

实验原理：Experimental principle:

小分子化合物结合在SOS1的催化位点而抑制SOS1与KRAS(G12C)的结合,当荧光标记的SOS1蛋白与荧光标记的KRAS(G12C)蛋白的结合被抑制时,发出的荧光发生改变。通过检测荧光改变,可以测试小分子阻止SOS1与KRAS(G12C)结合的能力。采用均相时间分辨荧光(HTRF)结合试验来检测本发明的化合物抑制SOS1与KRAS(G12C)相互结合的能力。The small molecular compound binds to the catalytic site of SOS1 to inhibit the combination of SOS1 and KRAS(G12C). When the combination of fluorescently labeled SOS1 protein and fluorescently labeled KRAS(G12C) protein is inhibited, the emitted fluorescence changes. The ability of small molecules to prevent the binding of SOS1 to KRAS(G12C) can be tested by detecting changes in fluorescence. A homogeneous time-resolved fluorescence (HTRF) binding assay was used to detect the ability of the compounds of the present invention to inhibit the interaction between SOS1 and KRAS (G12C).

实验材料：Experimental Materials:

KRAS(G12C)蛋白由武汉普健生物科技有限公司表达纯化,SOS1 exchange domin(564-1049)protein(Hμman recombinant)购自Cytoskeleton,Mab Anti 6HIS-XL665和Mab Anti GST-Eμcryptate购自Cisbio。多功能酶标仪Nivo5购自于PerkinElmer。KRAS (G12C) protein was expressed and purified by Wuhan Pujian Biotechnology Co., Ltd., SOS1 exchange domin (564-1049) protein (Hμman recombinant) was purchased from Cytoskeleton, Mab Anti 6HIS-XL665 and Mab Anti GST-Eμcryptate were purchased from Cisbio. Multifunctional microplate reader Nivo5 was purchased from PerkinElmer.

实验方法：experimental method:

1X buffer配制(现配现用):Hepes:5mM；NaCl:150mM；EDTA:10mM；Igepal:0.0025％；KF:100mM； DTT:1mM；BSA:005％；1X buffer preparation (ready to use): Hepes: 5mM; NaCl: 150mM; EDTA: 10mM; Igepal: 0.0025%; KF: 100mM; DTT: 1mM; BSA: 005%;

用DMSO将待测化合物用排枪进行5倍稀释至第8个浓度,即从1mM稀释至0.064μM。Use DMSO to dilute the compound to be tested 5 times to the eighth concentration, that is, from 1mM to 0.064μM.

用1X buffer将待测化合物各梯度稀释成DMSO为2％的工作液,5μL/孔加到对应孔中,对应浓度梯度为20μM至0.00128nM,置双复孔实验。1000转,离心1分钟。Use 1X buffer to dilute each compound to be tested into a working solution of 2% DMSO, add 5 μL/well to the corresponding well, the corresponding concentration gradient is 20 μM to 0.00128nM, and set up a double well experiment. Centrifuge at 1000 rpm for 1 min.

用1X buffer配制KRAS(G12C)(200nM)和Mab Anti GST-Eμcryptate(1ng/μL)的混和工作液,将该混合工作液放置25℃中孵育5分钟,2.5μL/孔加入到对应孔。Prepare a mixed working solution of KRAS (G12C) (200nM) and Mab Anti GST-Eμcryptate (1ng/μL) with 1X buffer, place the mixed working solution at 25°C for 5 minutes, and add 2.5μL/well to the corresponding well.

用1X buffer配制SOS1(80nM)和Mab Anti 6HIS-XL665(8g/μL)的混和工作液,2.5μL/孔加入到对应孔中,Blank孔中加入2.5μL Mab Anti 6HIS-XL665(8g/μL)稀释液,此时化合物终浓度梯度为10μM稀释至0.64nM,KRAS(G12C)(500nM),MAb Anti GST-Eu cryptate(0.25ng/μL),SOS1(20nM),Mab Anti 6HIS-XL665(2g/μL),反应体系置于25℃反应60分钟。反应结束后采用多标记分析仪读取HTRF。Prepare a mixed working solution of SOS1 (80nM) and Mab Anti 6HIS-XL665 (8g/μL) with 1X buffer, add 2.5μL/well to the corresponding well, add 2.5μL Mab Anti 6HIS-XL665 (8g/μL) to the Blank well Diluent, at this time the compound concentration gradient is 10μM diluted to 0.64nM, KRAS (G12C) (500nM), MAb Anti GST-Eu cryptate (0.25ng/μL), SOS1 (20nM), Mab Anti 6HIS-XL665 (2g/ μL), and the reaction system was placed at 25°C for 60 minutes. After the reaction, the HTRF was 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)。实验结果见表1： Use the equation (Sample-Min)/(Max-Min)×100% to convert the original data into inhibition rate, and the value of IC ₅₀ can be obtained by curve fitting with four parameters (log(inhibitor)vs.response in GraphPad Prism --Variable slope mode derived). The experimental results are shown in Table 1:

表1本发明化合物对KRAS(G12C)和SOS1结合的抑制活性的IC ₅₀值 Table 1 The compounds of the present invention are combined with the IC ₅₀ value of the inhibitory activity of KRAS (G12C) and SOS1

受试化合物test compound	IC ₅₀(nM) IC ₅₀ (nM)
化合物1Compound 1	40.5040.50
化合物2的盐酸盐Compound 2 hydrochloride	15.3715.37
化合物3Compound 3	45.9745.97
化合物4的盐酸盐Hydrochloride of compound 4	17.0117.01
化合物5的盐酸盐Compound 5 hydrochloride	16.9316.93
化合物23的盐酸盐Hydrochloride of compound 23	28.4228.42
化合物29的盐酸盐Hydrochloride of compound 29	20.5320.53

实验结论：本发明化合物对KRAS(G12C)和SOS1结合有显著的抑制效果。Experimental conclusion: the compound of the present invention has a significant inhibitory effect on the combination of KRAS (G12C) and SOS1.

实验例2：DLD-1细胞p-ERK增殖抑制活性测试Experimental example 2: DLD-1 cell p-ERK proliferation inhibitory activity test

实验材料：Experimental Materials:

DLD-1细胞购自南京科佰；1640培养基购自Biological Industries；胎牛血清购自Biosera；Advanced Phospho-ERK1/2(THR202/TYR204)KIT购自Cisbio；Advanced Phospho-ERK1/2(THR202/TYR204)KIT成分表见表2。DLD-1 cells were purchased from Nanjing Kebai; 1640 medium was purchased from Biological Industries; fetal bovine serum was purchased from Biosera; Advanced Phospho-ERK1/2 (THR202/TYR204) KIT was purchased from Cisbio; Advanced Phospho-ERK1/2 (THR202/ TYR204)KIT composition list is shown in Table 2.

表2 Advanced Phospho-ERK1/2(THR202/TYR204)KIT成分表Table 2 Composition list of Advanced Phospho-ERK1/2(THR202/TYR204)KIT

成分名称ingredient name	储存温度Storage temperature
Advanced PhosphoERK1/2 Eu Cryptate antibodyAdvanced PhosphoERK1/2 Eu Cryptate antibody	≤--16℃≤--16℃
Advanced PhosphoERK1/2 d2 antibodyAdvanced PhosphoERK1/2 d2 antibody	≤--16℃≤--16℃

Blocking reagent(stock solution 100X)Blocking reagent(stock solution 100X)	≤--16℃≤--16℃
Lysis buffer#1(stock solution 4X)Lysis buffer#1(stock solution 4X)	≤--16℃≤--16℃
Detection buffer(ready-to-use)Detection buffer (ready-to-use)	≤--16℃≤--16℃

实验方法：experimental method:

DLD-1细胞种于透明96孔细胞培养板中，80μL细胞悬液每孔，每孔包含8000个DLD-1细胞，细胞板放入二氧化碳培养箱，37℃过夜孵育；DLD-1 cells were planted in a transparent 96-well cell culture plate, 80 μL of cell suspension per well, each well contained 8000 DLD-1 cells, the cell plate was placed in a carbon dioxide incubator, and incubated overnight at 37 °C;

将待测化合物用100％DMSO稀释到2mM作为第一个浓度，然后再用移液器进行5倍稀释至第8个浓度，即从2mM稀释至0.026μM。取2μL化合物加入78μL细胞饥饿培养基，混匀后，取20μL化合物溶液加入到对应细胞板孔中，细胞板放回二氧化碳培养箱继续孵育1小时，此时化合物浓度为10μM至0.128nM，DMSO浓度为0.5％；The compound to be tested was diluted to 2mM with 100% DMSO as the first concentration, and then diluted 5 times to the eighth concentration with a pipette, that is, diluted from 2mM to 0.026μM. Take 2 μL of the compound and add 78 μL of cell starvation medium, mix well, take 20 μL of the compound solution and add it to the corresponding well of the cell plate, put the cell plate back into the carbon dioxide incubator and continue to incubate for 1 hour. 0.5%;

结束孵育后，弃掉细胞上清加入50μL细胞裂解液每孔，室温摇晃孵育30分钟；After the incubation, discard the cell supernatant and add 50 μL of cell lysate to each well, shake and incubate at room temperature for 30 minutes;

使用Detection buffer将Phospho-ERK1/2 Eu Cryptate antibody和Phospho-ERK1/2 d2 antibody稀释20倍；Use Detection buffer to dilute Phospho-ERK1/2 Eu Cryptate antibody and Phospho-ERK1/2 d2 antibody 20 times;

取16μL细胞裂解物上清每孔到新的384白色微孔板中，再加入2μL Phospho-ERK1/2 Eu Cryptate antibody稀释液和2μL Phospho-ERK1/2 d2 antibody稀释液，常温孵育4小时；Take 16 μL cell lysate supernatant per well into a new 384 white microwell plate, then add 2 μL Phospho-ERK1/2 Eu Cryptate antibody dilution and 2 μL Phospho-ERK1/2 d2 antibody dilution, incubate at room temperature for 4 hours;

孵育结束后使用多标记分析仪读取HTRF excitation:320nm,emission:615nm，665nm。After incubation, use a multi-label analyzer to read HTRF excitation: 320nm, emission: 615nm, 665nm.

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)。 Use the equation (Sample-Min)/(Max-Min)*100% to convert the original data into an inhibition rate, and the value of IC ₅₀ can be obtained by curve fitting with four parameters (log(inhibitor)vs.response in GraphPad Prism --Variable slope mode derived).

Max孔:阳性对照孔读值为1X裂解液Max well: positive control well reading is 1X lysate

Min孔：阴性对照孔读值为0.5％DMSO细胞孔细胞裂解液Min well: Negative control well reading is 0.5% DMSO cell well cell lysate

本发明的化合物对DLD-1细胞p-ERK的抑制活性测试结果见表3。See Table 3 for the test results of the inhibitory activity of the compounds of the present invention on p-ERK in DLD-1 cells.

表3本发明化合物对DLD-1细胞p-ERK增殖的IC ₅₀值测试结果 Table 3 The compound of the present invention is to the _IC50 value test result of DLD-1 cell p-ERK proliferation

受试化合物test compound	IC ₅₀(nM) IC ₅₀ (nM)
化合物2的盐酸盐Compound 2 hydrochloride	153.3153.3
化合物5的盐酸盐Compound 5 hydrochloride	40.8840.88
化合物14的盐酸盐Hydrochloride of compound 14	130.5130.5
化合物15Compound 15	84.5284.52
化合物20的盐酸盐Hydrochloride of compound 20	126.4126.4
化合物22Compound 22	55.3855.38
化合物23的盐酸盐Hydrochloride of compound 23	65.7465.74
化合物26Compound 26	56.2956.29
化合物29的盐酸盐Hydrochloride of compound 29	9.59.5

化合物31的甲酸盐Formate salt of compound 31

30.330.3

实验结论：本发明化合物对DLD-1细胞p-ERK增殖有显著的抑制效果。Experimental conclusion: the compound of the present invention has a significant inhibitory effect on the proliferation of p-ERK in DLD-1 cells.

实验例3：化合物药代动力学评价Experimental Example 3: Pharmacokinetic Evaluation of Compounds

实验材料：Experimental Materials:

Balb/c小鼠(雄性,北京维通利华实验动物技术有限公司)Balb/c mice (male, Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.)

实验操作：Experimental operation:

以标准方案测试化合物静脉注射及口服给药后的啮齿类动物药代特征,实验中候选化合物配成澄清溶液,给予小鼠单次静脉注射及口服给药。静注及口服溶媒为5％二甲基亚砜、5％solutol与90％水配成的混合溶媒。该项目使用四只雄性Balb/c小鼠,两只小鼠进行静脉注射给药,给药剂量为10mg/kg,收集给药后0.083,0.25,0.5,1,2,4,8,24h的血浆样品；另外两只小鼠口服灌胃给药,给药剂量为50mg/kg,收集给药后0.25、0.5,1,2,4,6,8,12,24h的血浆样品,血液样本采集后置于冰上，并于1小时之内离心分离血浆(离心条件：6000g，3分钟，2-8℃)。血浆样本在分析前存放时则放于-80℃冰箱内。以LC-MS/MS分析方法定量分析血药浓度,并计算药代参数,如达峰浓度(C _max),清除率(CL),半衰期(T _1/2),组织分布(Vdss),药时曲线下面积(AUC _0-last),生物利用度(F)等。 The pharmacokinetic characteristics of compounds in rodents after intravenous injection and oral administration were tested by standard protocols. In the experiment, candidate compounds were made into clear solutions and given to mice for single intravenous injection and oral administration. The vehicle for intravenous injection and oral administration is a mixed vehicle composed of 5% dimethyl sulfoxide, 5% solutol and 90% water. The project used four male Balb/c mice, two mice were administered intravenously, and the dose was 10 mg/kg, and the blood samples of 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration were collected. Plasma samples; the other two mice were orally orally administered with a dosage of 50 mg/kg, plasma samples were collected at 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours after administration, and blood samples were collected Then put it on ice, and centrifuge the plasma within 1 hour (centrifugation conditions: 6000g, 3 minutes, 2-8°C). Plasma samples were stored in a -80°C freezer until analysis. Quantitatively analyze blood drug concentration by LC-MS/MS analysis method, and calculate pharmacokinetic parameters, such as peak concentration (C _max ), clearance rate (CL), half-life (T _1/2 ), tissue distribution (Vdss), drug Area under the time curve (AUC _0-last ), bioavailability (F) and so on.

实验结果如表4所示：The experimental results are shown in Table 4:

表4本发明化合物的药代动力学测试结果The pharmacokinetic test result of the compound of the present invention in table 4

实验结论：本发明化合物具有良好的药代动力学性质,包括良好的口服生物利用度,口服暴露量,半衰期和清除率等。Experimental conclusion: the compound of the present invention has good pharmacokinetic properties, including good oral bioavailability, oral exposure, half-life and clearance rate.

实验例4：化合物在Miapaca2裸鼠移植瘤模型的体内药效评价Experimental Example 4: In vivo drug efficacy evaluation of compounds in the Miapaca2 nude mouse xenograft model

细胞培养：Cell culture:

人胰腺癌细胞(Miapaca2),体外贴壁单层培养,培养条件为DMEM培养基中加10％胎牛血清,37℃,5％CO ₂孵箱培养。一周两到三次用胰酶–EDTA进行常规消化处理传代。当细胞饱和度为80％–90％,数量到达要求时,收取细胞,计数,接种。 Human pancreatic cancer cells (Miapaca2) were cultured in vitro in an adherent monolayer. The culture conditions were 10% fetal bovine serum in DMEM medium, and cultured in a 37°C, 5% CO ₂ incubator. Passage with routine digestion with trypsin-EDTA two to three times a week. When the cell saturation was 80%-90%, and the number reached the requirement, the cells were collected, counted, and inoculated.

实验动物：Experimental animals:

Balb/c裸小鼠,雌性,6-7周,购自上海西普尔-必凯实验动物有限公司。Balb/c nude mice, female, 6-7 weeks old, were purchased from Shanghai Xipuer-Bikay Experimental Animal Co., Ltd.

模型制备：Model preparation:

将0.2mL(5×10 ⁶个)Miapaca2细胞(加基质胶，体积比为1:1)皮下接种于每只小鼠的右后背,肿瘤平均体积达到118mm ³时开始分组给药。 0.2 mL (5×10 ⁶ cells) of Miapaca2 cells (plus matrigel, volume ratio 1:1) were subcutaneously inoculated on the right back of each mouse, and the administration began when the average tumor volume reached 118 mm ³ .

给药方案见表5。The dosing regimen is shown in Table 5.

表5实验动物分组及给药方案Table 5 Experimental Animal Grouping and Dosing Scheme

肿瘤测量和实验指标：Tumor measurements and experimental indicators:

每周两次用游标卡尺测量肿瘤直径,肿瘤体积以立方毫米计量,通过以下的公式计算:V＝0.5a×b ²,其中a和b分别是肿瘤的长径和短径。受试化合物的抑瘤疗效通过使用TGI(％)来评价。TGI(％),反映肿瘤生长抑制率。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％。 The tumor diameter was measured twice a week with a vernier caliper. The tumor volume was measured in cubic millimeters and calculated by the following formula: V=0.5a×b ² , where a and b are the long and short diameters of the tumor, respectively. The antitumor efficacy of the test compound was evaluated by using TGI (%). TGI (%), reflecting the rate of tumor growth inhibition. 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 of the solvent control group-Average tumor volume at the beginning of treatment of the solvent control group Tumor volume)]×100%.

实验结果见表6。The experimental results are shown in Table 6.

表6本发明化合物在Miapaca2裸鼠移植瘤模型中的抑瘤药效评价Table 6 Evaluation of antitumor efficacy of compounds of the present invention in Miapaca2 nude mouse xenograft model

(基于给药后第28天肿瘤体积计算得出)(calculated based on tumor volume on day 28 after administration)

实验结论：本发明的化合物与AMG-510联用在Miapaca2裸鼠移植瘤模型中展现出优异的抑瘤效果。Experimental conclusion: the combination of the compound of the present invention and AMG-510 exhibits excellent tumor-inhibiting effect in the Miapaca2 nude mouse xenograft tumor model.

Claims

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

其中，in,

R ₁₁、R ₁₂与它们相连的碳原子一起形成环A，其中环A选自

R ₁₁ , R ₁₂ form ring A together with the carbon atoms they are connected to, wherein ring A is selected from

E选自-(CH ₂CH ₂O) _m-； E is selected from -(CH ₂ CH ₂ O) _m -;

E ₁选自-(CR ₈R ₉) _n-； E ₁ is selected from -(CR ₈ R ₉ ) _n -;

E ₂选自-(CH ₂CH ₂O) _t-； E ₂ is selected from -(CH ₂ CH ₂ O) _t -;

R ₁选自H、F、Cl、Br、I、-OH、-NH ₂和-CN； R ₁ is selected from H, F, Cl, Br, I, -OH, -NH ₂ and -CN;

R ₂选自H、F、Cl、Br、I、-OH、-NH ₂、-CN和C _1-4烷基，其中所述C _1-4烷基任选被1、2或3个R _a取代； R ₂ is selected from H, F, Cl, Br, I, -OH, -NH ₂ , -CN and C _1-4 alkyl, wherein the C _1-4 alkyl is optionally replaced by 1, 2 or 3 R _a replaces;

R ₃选自H、F、Cl、Br、I、-OH、-NH ₂、-CN和C _1-4烷基，其中所述C _1-4烷基任选被1、2或3个R _b取代； R ₃ is selected from H, F, Cl, Br, I, -OH, -NH ₂ , -CN and C _1-4 alkyl, wherein the C _1-4 alkyl is optionally replaced by 1, 2 or 3 R _b replaces;

R ₄选自H和CH ₃； R ₄ is selected from H and CH ₃ ;

R ₅和R ₆分别独立地选自H、F、Cl、Br、I和-CN； R ₅ and R ₆ are independently selected from H, F, Cl, Br, I and -CN;

R ₇选自H、C _1-4烷基、C _3-8环烷基、3-8元杂环烷基、-CH ₂-C _3-8环烷基和-CH ₂-3-8元杂环烷基，其中所述C _1- ₄烷基、C _3-8环烷基、3-8元杂环烷基、-CH ₂-C _3-8环烷基和-CH ₂-3-8元杂环烷基分别独立地任选被1、2、3或4个R _c取代； R ₇ is selected from H, C _1-4 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocycloalkyl, -CH ₂ -C _3-8 cycloalkyl and -CH ₂ -3-8 membered Heterocycloalkyl, wherein the C _1-4 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocycloalkyl, -CH ₂ _-C _3-8 cycloalkyl and -CH ₂ -3- The 8-membered heterocycloalkyl group is independently optionally substituted by 1, 2, 3 or 4 R _c ;

各R ₈和R ₉分别独立地选自H、F、Cl、Br、I、-OH、-NH ₂、-CN、C _1-4烷基、C _1-4烷氧基、C _1-4烷氨基和-C(＝O)NR _fR _g，其中所述C _1-4烷基、C _1-4烷氧基和C _1-4烷氨基分别独立地任选被1、2或3个R _d取代； Each R ₈ and R ₉ are independently selected from H, F, Cl, Br, I, -OH, -NH ₂ , -CN, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 Alkylamino and -C(=O)NR _f R _g , wherein the C _1-4 alkyl, C _1-4 alkoxy and C _1-4 alkylamino are independently optionally replaced by 1, 2 or 3 _Rd replaces;

或者，R ₈、R ₉和与它们相连的碳原子一起形成
C _3-6环烷基或3-7元杂环烷基，其中所述C _3-6环烷基和3-7元杂环烷基分别独立地任选被1、2、3或4个R _e取代； Alternatively, R ₈ , R ₉ and the carbon atom to which they are attached together form
C _3-6 cycloalkyl or 3-7 membered heterocycloalkyl, wherein said C _3-6 cycloalkyl and 3-7 membered heterocycloalkyl are independently optionally replaced by 1, 2, 3 or 4 R _e replaces;

或者，R ₆、R ₁₁与它们相连的碳原子一起形成环B，其中环B选自
Or, R ₆ , R ₁₁ together with the carbon atoms they are attached to form ring B, wherein ring B is selected from

各R ₁₃分别独立地选自H、F、Cl、Br、I、-OH、-NH ₂、-CN、C _1-4烷基、C _1-4烷氧基和C _1-4烷氨基，其中所述C _1-4烷基、C _1-4烷氧基和C _1-4烷氨基分别独立地任选被1、2或3个R _h取代； Each R ₁₃ is independently selected from H, F, Cl, Br, I, -OH, -NH ₂ , -CN, C _1-4 alkyl, C _1-4 alkoxy and C _1-4 alkylamino, Wherein said C _1-4 alkyl, C _1-4 alkoxy and C _1-4 alkylamino are independently optionally substituted by 1, 2 or 3 _Rh ;

各R _a分别独立地选自F、Cl、Br、I、-OH、-NH ₂和-CN； Each _Ra is independently selected from F, Cl, Br, I, -OH, -NH ₂ and -CN;

各R _b分别独立地选自F、Cl、Br、I、-OH、-NH ₂和-CN； Each R _b is independently selected from F, Cl, Br, I, -OH, -NH ₂ and -CN;

各R _c分别独立地选自F、Cl、Br、I、-OH、-NH ₂、-CN、-OCH ₃、-N(CH ₃) ₂和C _1-4烷基； Each R _c is independently selected from F, Cl, Br, I, -OH, -NH ₂ , -CN, -OCH ₃ , -N(CH ₃ ) ₂ and C _1-4 alkyl;

各R _d分别独立地选自D、F、Cl、Br、I、-OH、-NH ₂、-CN、-CH ₃和-OCH ₃； Each R _d is independently selected from D, F, Cl, Br, I, -OH, -NH ₂ , -CN, -CH ₃ and -OCH ₃ ;

各R _e分别独立地选自F、Cl、Br、I、-OH、-NH ₂、-CN、-CH ₃和-OCH ₃； Each _Re is independently selected from F, Cl, Br, I, -OH, -NH ₂ , -CN, -CH ₃ and -OCH ₃ ;

R _f和R _g分别独立地选自H、C _1-4烷基和5-7元杂环烷基，其中C _1-4烷基和5-7元杂环烷基分别独立地任选被1、2、3或4个R _aa取代； R _f and R _g are independently selected from H, C _1-4 alkyl and 5-7 membered heterocycloalkyl, wherein C _1-4 alkyl and 5-7 membered heterocycloalkyl are independently optionally 1, 2, 3 or 4 R _aa substitutions;

或者，R _f、R _g和与它们相连的氮原子一起形成5-7元杂环烷基，其中所述5-7元杂环烷基任选被1、2、3或4个R _ab取代； Alternatively, R _f , R _g and the nitrogen atom attached to them together form a 5-7 membered heterocycloalkyl, wherein the 5-7 membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 _Rab ;

各R _h分别独立地选自F、Cl、Br、I、-OH、-NH ₂和-CN； Each _Rh is independently selected from F, Cl, Br, I, -OH, -NH ₂ and -CN;

各R _aa分别独立地选自F、Cl、Br、I、-OH、-NH ₂和-CN； Each R _aa is independently selected from F, Cl, Br, I, -OH, -NH ₂ and -CN;

各R _ab分别独立地选自F、Cl、Br、I、-OH、-NH ₂、-CN和C _1-4烷基； Each R _ab is independently selected from F, Cl, Br, I, -OH, -NH ₂ , -CN and C _1-4 alkyl;

m选自0、1或2；m is selected from 0, 1 or 2;

n选自2、3、4或5；n is selected from 2, 3, 4 or 5;

t选自0、1或2；t is selected from 0, 1 or 2;

所述3-8元杂环烷基、3-7元杂环烷基、-CH ₂-3-8元杂环烷基和5-7元杂环烷基中的“杂”表示1、2、3或4个分别独立地选自-O-、-NH-、-S-和-N-的杂原子或杂原子团。 The "hetero" in the 3-8 membered heterocycloalkyl, 3-7 membered heterocycloalkyl, -CH ₂ -3-8 membered heterocycloalkyl and 5-7 membered heterocycloalkyl means 1, 2 , 3 or 4 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -S- and -N-.
根据权利要求1所述的化合物或其药学上可接受的盐，其化合物具有式(Ⅹ-1)和(Ⅹ-2)所示结构：The compound or pharmaceutically acceptable salt thereof according to claim 1, which has the structures shown in formulas (X-1) and (X-2):

其中，R ₁、R ₂、R ₃、R ₄、R ₅、R ₆、R ₁₁和R ₁₂如权利要求1所定义。 Wherein, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₁₁ and R ₁₂ are as defined in claim 1.
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，各R _a分别独立地选自F和-OH。 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each R _a is independently selected from F and -OH.
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，各R _c分别独立地选自F、Cl、Br、-CH ₃、-OCH ₃和-N(CH ₃) ₂。 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each R _c is independently selected from F, Cl, Br, -CH ₃ , -OCH ₃ and -N(CH ₃ ) ₂ .
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，各R _ab分别独立地选自-CH ₃。 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each R _ab is independently selected from -CH ₃ .
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，R _f和R _g分别独立地选自H、-CH ₃和
The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein _Rf and _Rg are independently selected from H, _-CH3 and
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，R _f、R _g和与它们相连的氮原子一起形成
其中所述
分别独立地任选被1、2、3或4个R _ab取代。 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R _f , R _g and the nitrogen atom connected to them together form
which stated
are each independently optionally substituted with 1, 2, 3 or 4 _Rabs .
根据权利要求7所述的化合物或其药学上可接受的盐，其中，R _f、R _g和与它们相连的氮原子一起形成
The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein R _f , R _g and the nitrogen atom connected to them together form
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，R ₁选自H、-NH ₂和-CN。 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R ₁ is selected from H, -NH ₂ and -CN.
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，R ₂选自H、F、-CN、-CH ₃、-CH ₂CH ₃和-CH ₂CH(CH ₃) ₂，其中所述-CH ₃、-CH ₂CH ₃和-CH ₂CH(CH ₃) ₂分别独立地任选被1、2、或3个R _a取代。 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R ₂ is selected from H, F, -CN, -CH ₃ , -CH ₂ CH ₃ and -CH ₂ CH(CH ₃ ) ₂ , Wherein said -CH ₃ , -CH ₂ CH ₃ and -CH ₂ CH(CH ₃ ) ₂ are independently and optionally substituted by 1, 2 or 3 R _a .
根据权利要求10所述的化合物或其药学上可接受的盐，其中，R ₂选自H、F、-CN、

The compound according to claim ₁₀ or a pharmaceutically acceptable salt thereof, wherein R is selected from H, F, -CN,
根据权利要求11所述的化合物或其药学上可接受的盐，其中，R ₂选自H、F、-CN、-CHF ₂、-CF ₃、
The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein R ₂ is selected from H, F, -CN, -CHF ₂ , -CF ₃ ,
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，R ₃选自H、F和-CH ₃。 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R ₃ is selected from H, F and -CH ₃ .
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，各R ₇选自H、-CH ₃、-CH ₂CH ₃、

其中所述-CH ₃、-CH ₂CH ₃、

分别独立地任选被1、2、3或4个R _c取代。 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each R ₇ is selected from H, -CH ₃ , -CH ₂ CH ₃ ,

Wherein -CH ₃ , -CH ₂ CH ₃ ,

are each independently optionally substituted with 1, 2, 3 or 4 R _c .
根据权利要求14所述的化合物或其药学上可接受的盐，其中，各R ₇选自H、-CH ₃、-CH ₂CH ₃、-CH ₂CF ₃、 -CH ₂CH ₂OCH ₃、-CH ₂CH ₂N(CH ₃) ₂、

The compound according to claim 14 or a pharmaceutically acceptable salt thereof, wherein each R ₇ is selected from H, -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CF ₃ , -CH ₂ CH ₂ OCH ₃ , -CH ₂ CH ₂ N(CH ₃ ) ₂ ,
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，各R ₈和R ₉分别独立地选自H、F、-CH ₃、-OCH ₃、-CH ₂CH ₃、
其中所述-CH ₃、-OCH ₃和-CH ₂CH ₃分别独立地任选被1、2或3个R _d取代。 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each R ₈ and R ₉ are independently selected from H, F, -CH ₃ , -OCH ₃ , -CH ₂ CH ₃ ,
Wherein said -CH ₃ , -OCH ₃ and -CH ₂ CH ₃ are independently optionally substituted by 1, 2 or 3 R _d .
根据权利要求16所述的化合物或其药学上可接受的盐，其中，各R ₈和R ₉分别独立地选自H、F、-CH ₃、-OCH ₃、-CH ₂CH ₂OCH ₃、

The compound according to claim 16 or a pharmaceutically acceptable salt thereof, wherein each R ₈ and R ₉ are independently selected from H, F, -CH ₃ , -OCH ₃ , -CH ₂ CH ₂ OCH ₃ ,
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，R ₈、R ₉和与它们相连的碳原子一起形成
其中所述
分别独立地任选被1、2、3或4个R _e取代。 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R ₈ , R ₉ and the carbon atoms connected to them form together
which stated
are each independently optionally substituted by 1, 2, 3 or 4 _Re .
根据权利要求18所述的化合物或其药学上可接受的盐，其中，R ₈、R ₉和与它们相连的碳原子一起形成
The compound according to claim 18 or a pharmaceutically acceptable salt thereof, wherein R ₈ , R ₉ and the carbon atoms connected to them form together
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，各R ₁₃分别独立地选自H和-CH ₃。 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each R ₁₃ is independently selected from H and -CH ₃ .
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 or pharmaceutically acceptable salt thereof according to claim 1, 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，环A选自

The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Ring A is 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，环B选自
The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Ring B is 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，其化合物具有式(I)所示结构：The compound according to claim 1 or a pharmaceutically acceptable salt thereof, its compound has a structure shown in formula (I):

其中，环A、R ₁、R ₂、R ₃、R ₄、R ₅和R ₆如权利要求1所定义。 Wherein, ring A, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are as defined in claim 1.
下式化合物或其药学上可接受的盐，A compound of the following formula or a pharmaceutically acceptable salt thereof,
根据权利要求25所述的化合物或其药学上可接受的盐，其化合物为，The compound or a pharmaceutically acceptable salt thereof according to claim 25, wherein the compound is,
根据权利要求1～26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KRAS突变实体瘤药物中的应用。Use of the compound according to any one of claims 1-26 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating KRAS mutant solid tumors.
一种在需要的受试者中治疗KRAS突变实体瘤的方法，包括向受试者提供有效剂量的权利要求1～26任意一项所述的化合物或其药学上可接受的盐。A method for treating KRAS mutant solid tumors in a subject in need thereof, comprising providing the subject with an effective dose of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-26.