Benzopyrimidine compounds and uses thereof

Abstract

A series of benzopyrimidine compounds and uses thereof are disclosed, in particular compounds represented by formula (II) and pharma- ceutically acceptable salts thereof: [Formula 1] TIFF2025505112000157.tif24160

Description

[Technical Field]

[0001] This application is Chinese Patent Application Publication No. 202210072243.0, filed on January 21, 2022; Chinese Patent Application Publication No. 202210113080.6, filed on January 29, 2022; PCT / CN2022 / 075732, filed February 9, 2022; Chinese Patent Application Publication No. 202210239568.3, filed on March 11, 2022; Chinese Patent Application Publication No. 202210693538.X, filed on June 17, 2022; Chinese Patent Application Publication No. 202210837790.3, filed on July 15, 2022; Chinese Patent Application Publication No. 202210989455.5, filed on August 17, 2022 Claims priority of.

[0002] The present disclosure relates to a series of benzopyrimidine compounds and uses thereof, and in particular to compounds represented by formula (II) and pharmaceutically acceptable salts thereof: [Background technology]

[0003] RAS oncogene mutations are the most common activating mutations in human cancers, occurring in approximately 30% of human tumors. The RAS gene family includes three subtypes (KRAS, HRAS, and NRAS), with 85% of tumors caused by mutations in the KRAS subtype.

[0004] KRAS is a rat sarcoma virus oncogene and an important member of the RAS protein family. KRAS acts like a molecular switch, activating various proliferation and growth factors, such as c-RAF and PI3K, when activated. Under normal circumstances, KRAS binds to GTP and cleaves one phosphate group at the end of GTP, converting it to GDP. After GTP is converted to GDP, KRAS is shut down. Under normal circumstances, KRAS regulates cell proliferation pathways. After KRAS gene mutation, the KRAS protein remains activated and can independently transmit growth and proliferation signals to downstream pathways, regardless of upstream growth factor receptor signals, resulting in uncontrolled cell proliferation and tumor progression.

[0005] KRAS mutations are commonly found in solid tumors such as lung adenocarcinoma, pancreatic ductal carcinoma, and colorectal cancer. In KRAS-mutated tumors, 80% of oncogenic mutations occur at codon 12, and the most common mutations include p.G12D (41%), p.G12V (28%), and p.G12C (14%). At the same time, the presence or absence of mutations in the KRAS gene is also an important indicator of tumor prognosis. Summary of the Invention [Problem to be solved by the invention]

[0006] Currently, small molecules that directly target KRAS mutations are primarily KRAS inhibitors, including Amgen's AMG510 and Mirati Therapeutics' MRTX849. G12C Clinical results show that these two compounds inhibit KRAS G12C This indicates that the treatment showed favorable therapeutic effects in patients with KRAS-mutated tumors. G12D Among the drugs targeting KRAS, only one has entered the clinical stage: HRS-4642 from Jiangsu Hengrui Pharmaceutical Co., Ltd., which is an injectable drug. G12D Small molecules have not yet entered clinical studies and are not KRAS inhibitors. G12D There is a large unmet clinical need for inhibitors of the mutation. [Means for solving the problem]

[0007] The present disclosure provides a compound of formula (II) [ka] (In the formula, X is selected from O and S; R1 is [ka] is selected from [ka] is 1, 2 or 3 R a and optionally substituted with R2 is H, halogen, C 1~3 Alkoxy and C 3~4 cycloalkyl-O-, C 1~3 Alkoxy and C 3~4 cycloalkyl-O- is optionally substituted with 1, 2, 3, 4 or 5 halogens; R3 is H, halogen and C 1~3 alkyl, C 1~3 Alkyl can be one, two or three R b and optionally substituted with R4 is selected from phenyl and naphthyl, and phenyl and naphthyl are each independently selected from 1, 2, 3, 4, or 5 R c and optionally substituted with R5 is H, halogen and C 1~3 alkyl, C 1~3 The alkyl is optionally substituted with 1, 2 or 3 halogens; R6, R7 and R8 are each independently H, halogen, CN, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Alkylamino, C 2~3 alkenyl and phenyl; 1~3 Alkyl, C 1~3Alkoxy, C 1~3 Alkylamino, C 2~3 alkenyl and phenyl are optionally substituted with 1, 2 or 3 halogens; Alternatively, R6 and R7, together with the atoms to which they are attached, may form phenyl, [ka] Forming Each R a are independently H, halogen, OH, NH2, C 1~3 Alkyl and C 1~3 alkoxy, C 1~3 Alkyl and C 1~3 The alkoxy is optionally substituted with 1, 2, 3, 4 or 5 halogens; Each R b are independently selected from H, halogen, and OH; Each R c are independently H, halogen, OH, NH2, CN and C 2~3 alkynyl, R d is not present or each R d are independently H, halogen, OH, CN, C 1~3 Alkyl and C 1~3 alkylamino, C 1~3 Alkyl and C 1~3 alkylamino is optionally substituted with 1, 2 or 3 halogens; R1, [ka] When R is selected from the group consisting of 5 R, X is selected from S, and alternatively R is selected from naphthyl, and naphthyl is selected from the group consisting of 5 R c (which has been replaced by and pharmaceutically acceptable salts thereof.

[0008] In some embodiments of the disclosure, provided herein is a compound or a pharmaceutically acceptable salt thereof, wherein the compound is [ka] (Wherein R3, R5 and R c is as defined herein; m is selected from 0, 1, 2, 3, 4 and 5 is selected from.

[0009] In some embodiments of the present disclosure, provided herein is a compound, the compound comprising: [ka] (Wherein R3, R5 and R c is as defined herein; m is selected from 0, 1, 2, 3, 4 and 5 is selected from.

[0010] In some embodiments of the disclosure, provided herein is a compound or a pharmaceutically acceptable salt thereof, wherein the compound is [ka] (In the formula, R3 is halogen and C 1~3 alkyl, C 1~3 Alkyl can be one, two or three R b and optionally substituted with R5 is a halogen and C 1~3 alkyl, C 1~3 The alkyl is optionally substituted with 1, 2 or 3 halogens; Each R b are independently selected from H, halogen, and OH; Each R c are independently H, halogen, OH, NH2, CN and C 2~3 alkynyl, R c1 are halogens, OH, NH2, CN and C 2~3 alkynyl, o is selected from 0, 1, 2, 3, 4 and 5; n is selected from 0, 1, 2, 3 and 4 is selected from.

[0011] In some embodiments of the present disclosure, R2 is H, OCH3, OCH2CH3, OCH(CH3)2, [ka] Selected from OCH3, OCH2CH3, OCH(CH3)2 [ka] is optionally substituted with 1, 2, 3, 4, or 5 halogens, and the other variables are as defined herein.

[0012] In some embodiments of the present disclosure, R2 is selected from H, F, and OCH3, and the other variables are as defined herein.

[0013] In some embodiments of the present disclosure, R3 is selected from H, F, Cl, and CH2OH, and other variables are as defined herein.

[0014] In some embodiments of the present disclosure, each R c are independently H, F, OH, NH2, and --C≡CH, and other variables are as defined herein.

[0015] In some embodiments of the present disclosure, R4 is [ka] and the other variables are as defined herein.

[0016] In some embodiments of the present disclosure, R5 is selected from H, F, Cl, Br, CH3, CH2CH3, and CH(CH3)2, wherein CH3, CH2CH3, and CH(CH3)2 are optionally substituted with 1, 2, or 3 halogens, and the other variables are as defined herein.

[0017] In some embodiments of the present disclosure, R5 is selected from F, CH2F, and CHF2, and the other variables are as defined herein.

[0018] In some embodiments of the present disclosure, R6, R7, and R8 are each independently selected from H, F, Cl, Br, I, CN, CH3, CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH(CH3)2, NHCH3, NHCH2CH3, N(CH3)2, CH=CH2, CH2CH=CH2, CH=CH2CH3, and phenyl, wherein CH3, CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH(CH3)2, NHCH3, NHCH2CH3, N(CH3)2, CH=CH2, CH2CH=CH2, CH=CH2CH3, and phenyl are optionally substituted with 1, 2, or 3 halogens, and the other variables are as defined herein.

[0019] In some embodiments of the present disclosure, R6, R7, and R8 are each independently selected from H, F, Cl, Br, I, CN, CH3, CH2F, CHF2, CF3, CH2CH3, CH2CF3, CF2CF3, OCH3, OCH2F, OCHF2, OCF3, OCH2CH3, OCH2CF3, OCF2CF3, NHCH3, N(CH3)2, CH=CH2, CF=CH2, CH=CHF, CH=CF2, and phenyl, and other variables are as defined herein.

[0020] In some embodiments of the present disclosure, R6 is selected from H, F, Cl, Br, I, CN, CH3, CH2F, CHF2, CF3, CH2CH3, CH2CF3, CF2CF3, OCH3, OCH2F, OCHF2, OCF3, OCH2CH3, OCH2CF3, OCF2CF3, NHCH3, N(CH3)2, CH=CH2, CF=CH2, CH=CHF, CH=CF2, and phenyl, and other variables are as defined herein.

[0021] In some embodiments of the present disclosure, R7 is selected from H, F, Cl, Br, I, CN, CH3, CH2F, CHF2, CF3, CH2CH3, CH2CF3, CF2CF3, OCH3, OCH2F, OCHF2, OCF3, OCH2CH3, OCH2CF3, OCF2CF3, NHCH3, N(CH3)2, CH=CH2, CF=CH2, CH=CHF, CH=CF2, and phenyl, and other variables are as defined herein.

[0022] In some embodiments of the present disclosure, R8 is selected from H, F, Cl, Br, I, CN, CH3, CH2F, CHF2, CF3, CH2CH3, CH2CF3, CF2CF3, OCH3, OCH2F, OCHF2, OCF3, OCH2CH3, OCH2CF3, OCF2CF3, NHCH3, N(CH3)2, CH=CH2, CF=CH2, CH=CHF, CH=CF2, and phenyl, and other variables are as defined herein.

[0023] In some embodiments of the present disclosure, R6 is selected from H, and the other variables are as defined herein.

[0024] In some embodiments of the present disclosure, R7 is selected from H, F, CN, OCH3, OCHF2, OCF3, CH=CHF, and phenyl, and other variables are as defined herein.

[0025] In some embodiments of the present disclosure, R7 is selected from H, and the other variables are as defined herein.

[0026] In some embodiments of the present disclosure, each R d are independently selected from H, F, Cl, Br, I, OH, CN, CH3, CH2CH3, CH(CH3)2, NHCH3, NHCH2CH3, and N(CH3)2, wherein CH3, CH2CH3, CH(CH3)2, NHCH3, NHCH2CH3, and N(CH3)2 are optionally substituted with 1, 2, or 3 halogens, and the other variables are as defined herein.

[0027] In some embodiments of the present disclosure, each R d are independently selected from H, F, OH, CN, and CH3, and other variables are as defined herein.

[0028] In some embodiments of the present disclosure, R6 and R7, together with the atoms to which they are attached, are phenyl, [ka] and the other variables are as defined herein.

[0029] In some embodiments of the present disclosure, R8 is selected from H, F, CN, OCH3, OCHF2, OCF3, CH=CHF, and phenyl, and other variables are as defined herein.

[0030] In some embodiments of the present disclosure, the structural moiety [ka] teeth, [ka] and the other variables are as defined herein.

[0031] The present disclosure provides a compound of formula (II) [ka] (In the formula, X is selected from O and S; R1 is [ka] is selected from [ka] is 1, 2 or 3 R a and optionally substituted with R2 is H, halogen, C 1~3 Alkoxy and C 3~4 cycloalkyl-O-, C 1~3 Alkoxy and C 3~4 cycloalkyl-O- is optionally substituted with 1, 2, 3, 4 or 5 halogens; R3 is H, halogen and C 1~3 alkyl, C 1~3 Alkyl can be one, two or three R b and optionally substituted with R4 is selected from phenyl and naphthyl, and phenyl and naphthyl are each independently selected from 1, 2, 3, 4, or 5 R c and optionally substituted with R5 is H, halogen and C 1~3 alkyl, C 1~3 The alkyl is optionally substituted with 1, 2 or 3 halogens; R6, R7 and R8 are each independently H, halogen, CN, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Alkylamino, C 2~3 alkenyl and phenyl; 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Alkylamino, C 2~3 alkenyl and phenyl are optionally substituted with 1, 2 or 3 halogens; Alternatively, R6 and R7, together with the atoms to which they are attached, may form phenyl, [ka] Forming Each R a are independently H, halogen, OH, NH2, C 1~3 Alkyl and C 1~3 alkoxy, C 1~3 Alkyl and C 1~3 The alkoxy is optionally substituted with 1, 2, 3, 4 or 5 halogens; Each R b are independently selected from H, halogen, and OH; Each R c are independently H, halogen, OH, NH2, CN and C 2~3 alkynyl, R d is not present or each R d are independently H, halogen, C 1~3 Alkyl and C 1~3 alkylamino, C 1~3 Alkyl and C 1~3 alkylamino is optionally substituted with 1, 2 or 3 halogens; R1, [ka] When R is selected from the group consisting of 5 R, X is selected from S, and alternatively R is selected from naphthyl, and naphthyl is selected from the group consisting of 5 R c (which has been replaced by Also provided is a compound represented by the formula: and pharmaceutically acceptable salts thereof.

[0032] In some embodiments of the present disclosure, R2 is H, OCH3, OCH2CH3, OCH(CH3)2, [ka] Selected from OCH3, OCH2CH3, OCH(CH3)2, [ka] is optionally substituted with 1, 2, 3, 4, or 5 halogens, and the other variables are as defined herein.

[0033] In some embodiments of the present disclosure, R2 is selected from H, F, and OCH3, and the other variables are as defined herein.

[0034] In some embodiments of the present disclosure, R3 is selected from H, F, Cl, and CH2OH, and other variables are as defined herein.

[0035] In some embodiments of the present disclosure, each R c are independently H, F, OH, NH2, and --C≡CH, and other variables are as defined herein.

[0036] In some embodiments of the present disclosure, R4 is [ka] and the other variables are as defined herein.

[0037] In some embodiments of the present disclosure, R5 is selected from H, F, Cl, Br, CH3, CH2CH3, and CH(CH3)2, wherein CH3, CH2CH3, and CH(CH3)2 are optionally substituted with 1, 2, or 3 halogens, and the other variables are as defined herein.

[0038] In some embodiments of the present disclosure, R5 is selected from F, CH2F, and CHF2, and the other variables are as defined herein.

[0039] In some embodiments of the present disclosure, R6, R7, and R8 are each independently selected from H, F, Cl, Br, I, CN, CH3, CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH(CH3)2, NHCH3, NHCH2CH3, N(CH3)2, CH=CH2, CH2CH=CH2, CH=CH2CH3, and phenyl, wherein CH3, CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH(CH3)2, NHCH3, NHCH2CH3, N(CH3)2, CH=CH2, CH2CH=CH2, CH=CH2CH3, and phenyl are optionally substituted with 1, 2, or 3 halogens, and the other variables are as defined herein.

[0040] In some embodiments of the present disclosure, R6, R7, and R8 are each independently selected from H, F, Cl, Br, I, CN, CH3, CH2F, CHF2, CF3, CH2CH3, CH2CF3, CF2CF3, OCH3, OCH2F, OCHF2, OCF3, OCH2CH3, OCH2CF3, OCF2CF3, NHCH3, N(CH3)2, CH=CH2, CF=CH2, CH=CHF, CH=CF2, and phenyl, and other variables are as defined herein.

[0041] In some embodiments of the present disclosure, R6 is selected from H, and the other variables are as defined herein.

[0042] In some embodiments of the present disclosure, R7 is selected from H, F, CN, OCH3, OCHF2, OCF3, CH=CHF, and phenyl, and other variables are as defined herein.

[0043] In some embodiments of the present disclosure, R7 is selected from H, and the other variables are as defined herein.

[0044] In some embodiments of the present disclosure, each R dare independently selected from H, F, Cl, Br, I, CN, CH3, CH2CH3, CH(CH3)2, NHCH3, NHCH2CH3, and N(CH3)2, wherein CH3, CH2CH3, CH(CH3)2, NHCH3, NHCH2CH3, and N(CH3)2 are optionally substituted with 1, 2, or 3 halogens, and the other variables are as defined herein.

[0045] In some embodiments of the present disclosure, each R d is independently selected from H, F, and CH3, and the other variables are as defined herein.

[0046] In some embodiments of the present disclosure, R6 and R7, together with the atoms to which they are attached, are phenyl, [ka] and the other variables are as defined herein.

[0047] In some embodiments of the present disclosure, R8 is selected from H, F, CN, OCH3, OCHF2, OCF3, CH=CHF, and phenyl, and other variables are as defined herein.

[0048] In some embodiments of the present disclosure, the structural moiety [ka] teeth, [ka] and the other variables are as defined herein.

[0049] The present disclosure provides a compound of formula (I) [ka] (In the formula, X is selected from O and S; R1 is [ka] is selected from [ka] is 1, 2 or 3 R a and optionally substituted with R2 is H, C 1~3 Alkoxy and C 3~4 cycloalkyl-O-, C 1~3 Alkoxy and C 3~4 cycloalkyl-O- is optionally substituted with 1, 2, 3, 4 or 5 halogens; R3 is H, halogen and C 1~3 alkyl, C 1~3 Alkyl can be one, two or three R b and optionally substituted with R4 is selected from phenyl and naphthyl, and phenyl and naphthyl are each independently selected from 1, 2, 3, 4, or 5 R c and optionally substituted with R5 is H, halogen and C 1~3 alkyl, C 1~3 The alkyl is optionally substituted with 1, 2 or 3 halogens; R6, R7 and R8 are each independently H, halogen, CN, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Alkylamino, C 2~3 alkenyl and phenyl; 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Alkylamino, C 2~3 alkenyl and phenyl are optionally substituted with 1, 2 or 3 halogens; Alternatively, R6 and R7, together with the atoms to which they are attached, may form phenyl, [ka] Forming Each R a are independently H, halogen, OH, NH2, C 1~3 Alkyl and C 1~3 alkoxy, C 1~3 Alkyl and C 1~3 The alkoxy is optionally substituted with 1, 2, 3, 4 or 5 halogens; Each R b are independently selected from H, halogen, and OH; Each R c are independently H, halogen, OH, NH2, CN and C 2~3 alkynyl, R d is not present or each R d are independently H, halogen, C 1~3 Alkyl and C 1~3 alkylamino, C 1~3 Alkyl and C 1~3 The alkylamino is optionally substituted with 1, 2, or 3 halogens. Also provided is a compound represented by the formula: and pharmaceutically acceptable salts thereof.

[0050] In some embodiments of the present disclosure, R2 is selected from H and OCH3, and the other variables are as defined herein.

[0051] In some embodiments of the present disclosure, R3 is selected from H, F, Cl, and CH2OH, and other variables are as defined herein.

[0052] In some embodiments of the present disclosure, each R b is independently selected from H, F, OH, NH2 and --C≡CH, and other variables are as defined herein.

[0053] In some embodiments of the present disclosure, R4 is [ka] and the other variables are as defined herein.

[0054] In some embodiments of the present disclosure, R5 is selected from H, F, Cl, Br, CH3, CH2CH3, and CH(CH3)2, wherein CH3, CH2CH3, and CH(CH3)2 are optionally substituted with 1, 2, or 3 halogens, and the other variables are as defined herein.

[0055] In some embodiments of the present disclosure, R5 is selected from F, CH2F, and CHF2, and the other variables are as defined herein.

[0056] In some embodiments of the present disclosure, R6, R7, and R8 are each independently selected from H, F, Cl, Br, I, CN, CH3, CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH(CH3)2, NHCH3, NHCH2CH3, N(CH3)2, CH=CH2, CH2CH=CH2, CH=CH2CH3, and phenyl, wherein CH3, CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH(CH3)2, NHCH3, NHCH2CH3, N(CH3)2, CH=CH2, CH2CH=CH2, CH=CH2CH3, and phenyl are optionally substituted with 1, 2, or 3 halogens, and the other variables are as defined herein.

[0057] In some embodiments of the present disclosure, R6, R7, and R8 are each independently selected from H, F, Cl, Br, I, CN, CH3, CH2F, CHF2, CF3, CH2CH3, CH2CF3, CF2CF3, OCH3, OCH2F, OCHF2, OCF3, OCH2CH3, OCH2CF3, OCF2CF3, NHCH3, N(CH3)2, CH=CH2, CF=CH2, CH=CHF, CH=CF2, and phenyl, and other variables are as defined herein.

[0058] In some embodiments of the present disclosure, R6 is selected from H, and the other variables are as defined herein.

[0059] In some embodiments of the present disclosure, R7 is selected from H, F, CN, OCH3, OCHF2, OCF3, CH=CHF, and phenyl, and other variables are as defined herein.

[0060] In some embodiments of the present disclosure, R7 is selected from H, and the other variables are as defined herein.

[0061] In some embodiments of the present disclosure, each R d are independently selected from H, F, Cl, Br, I, CN, CH3, CH2CH3, CH(CH3)2, NHCH3, NHCH2CH3, and N(CH3)2, wherein CH3, CH2CH3, CH(CH3)2, NHCH3, NHCH2CH3, and N(CH3)2 are optionally substituted with 1, 2, or 3 halogens, and the other variables are as defined herein.

[0062] In some embodiments of the present disclosure, each R d is independently selected from H, F, and CH3, and the other variables are as defined herein.

[0063] In some embodiments of the present disclosure, R6 and R7, together with the atoms to which they are attached, are phenyl, [ka] and the other variables are as defined herein.

[0064] In some embodiments of the present disclosure, R8 is selected from H, F, CN, OCH3, OCHF2, OCF3, CH=CHF, and phenyl, and other variables are as defined herein.

[0065] In some embodiments of the present disclosure, the structural moiety [ka] teeth, [ka] and the other variables are as defined herein.

[0066] The present disclosure provides a compound of formula (IX) [ka] (In the formula, T6 is selected from CH and N; R 4a is C 6~10 aryl and 5-10 membered heteroaryl; C 6~10 Aryl and 5-10 membered heteroaryl are aryls having 1, 2, 3, 4 or 5 R e and optionally replaced by R 5a are H, F, Cl, CN, NH2, C 1~3 Alkyl and C 1~3 alkoxy, C 1~3 Alkyl and C 1~3 The alkoxy is optionally substituted with 1, 2 or 3 halogens; R 3a are H, F, Cl, C 1~3 Alkyl, C 1~3 Alkoxy, C 2~4 alkenyl and cyclopropyl; 1~3 Alkyl, C 1~3 Alkoxy, C 2~4 alkenyl and cyclopropyl are optionally substituted with 1, 2 or 3 halogens; Each R e are independently F, Cl, Br, I, OH, NH2, CN, C 1~3 Alkyl, C 1~3 Alkoxy, C 2~4 Alkenyl and C 2~4 alkynyl, C 1~3 Alkyl, C 1~3 Alkoxy, C 2~4 Alkenyl and C 2~4The alkynyl is optionally substituted with 1, 2, or 3 halogens. Also provided is a compound represented by the formula: and pharmaceutically acceptable salts thereof.

[0067] In some embodiments of the disclosure, provided herein is a compound or a pharmaceutically acceptable salt thereof, wherein the compound is [ka] (In the formula, T6 is selected from CH and N; R 5a are H, F, Cl, CN, NH2, C 1~3 Alkyl and C 1~3 alkoxy, C 1~3 Alkyl and C 1~3 The alkoxy is optionally substituted with 1, 2 or 3 halogens; R 3a are H, F, Cl, C 1~3 Alkyl, C 1~3 Alkoxy, C 2~4 alkenyl and cyclopropyl; 1~3 Alkyl, C 1~3 Alkoxy, C 2~4 alkenyl and cyclopropyl are optionally substituted with 1, 2 or 3 halogens; R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R b7 , R b8 , R b9 , R b10 and R b11 are each independently H, F, Cl, Br, I, OH, NH2, CN, C 1~3 Alkyl, C 1~3 Alkoxy, C 2~4 Alkenyl and C 2~4 alkynyl, C 1~3 Alkyl, C 1~3 Alkoxy, C 2~4 Alkenyl and C 2~4The alkynyl is optionally substituted with 1, 2, or 3 halogens. is selected from.

[0068] In some embodiments of the present disclosure, R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R b7 , R b8 , R b9 , R b10 and R b11 are each independently selected from F, Cl, Br, I, OH, NH, CN, CH, CHCH, OCH, OCHCH, -CH=CH, -CH-CH=CH and -C≡CH, wherein CH, CHCH, OCH, OCHCH, -CH=CH, -CH-CH=CH and -C≡CH are optionally substituted with 1, 2 or 3 halogens, and the other variables are as defined herein.

[0069] In some embodiments of the present disclosure, R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R b7 , R b8 , R b9 , R b10 and R b11 are each independently selected from F, Cl, OH, NH, CN, CH, CF, CHCH, and —C≡CH, and other variables are as defined herein.

[0070] The present disclosure provides a compound shown below. [ka] and a pharmaceutically acceptable salt thereof, the retention time Rt of the compound after SFC analysis was 1.801 min.

[0071] The analytical conditions for the SFC method were: column: Chiralcel OD-3, 50 × 4.6 mm inner diameter, 3 μm; mobile phase: A (supercritical CO2), B (ethanol containing 0.1% isopropylamine); gradient: B% = 5 to 50% in 3 min; flow rate: 3.4 mL / min; wavelength: 220 nm; pressure: 1800 psi.

[0072] The present disclosure provides a compound shown below. [ka] and a pharmaceutically acceptable salt thereof, the retention time Rt of the compound after SFC analysis was 2.233 min.

[0073] The analytical conditions for the SFC method were: column: Chiralcel OD-3, 50 × 4.6 mm inner diameter, 3 μm; mobile phase: A (supercritical CO2), B (ethanol containing 0.1% isopropylamine); gradient: B% = 5 to 50% in 3 min; flow rate: 3.4 mL / min; wavelength: 220 nm; pressure: 1800 psi.

[0074] The present disclosure also includes embodiments resulting from any combination of the above variables.

[0075] The present disclosure also provides the compounds shown below and pharmaceutically acceptable salts thereof. [ka] [ka] [ka] [ka] [ka]

[0076] In some embodiments of the disclosure, provided herein is a compound or a pharmaceutically acceptable salt thereof, wherein the compound is [ka] [ka] [ka] [ka] [ka] is selected from.

[0077] In some embodiments of the disclosure, provided herein is a compound or a pharmaceutically acceptable salt thereof, wherein the compound is [ka] [ka] [ka] [ka] [ka] [ka] is selected from.

[0078] This disclosure relates to KRAS G12D There is also provided the use of the compounds and pharmaceutically acceptable salts thereof in the manufacture of a medicament for treating a mutation-associated tumor.

[0079] In some embodiments of the present disclosure, tumor refers to colorectal cancer and pancreatic cancer.

[0080] Technical effects The compounds of the present disclosure inhibit KRAS G12D It has a good inhibitory effect on the protein and can effectively inhibit the downstream signal p-ERK and KRAS G12D They have good activity in inhibiting cell proliferation against mutant cells. Furthermore, the compounds of the present disclosure have good pharmacokinetic properties and good oral bioavailability.

[0081] Related Definitions Unless otherwise specified, the following terms and phrases as used herein are intended to have the following meanings: A particular term or phrase should not be considered unclear or ambiguous in the absence of a specific definition, but should be understood in its conventional sense. When a trade name appears herein, it is intended to refer to the corresponding trade name or its active ingredient.

[0082] The term "pharmaceutically acceptable" is used herein in reference to compounds, materials, compositions and / or dosage forms that are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic response, or other problem or complication, within the scope of sound medical judgment, commensurate with a reasonable benefit / risk ratio.

[0083] The term "pharmaceutically acceptable salt" refers to a salt of a compound disclosed herein prepared by reacting a compound having certain substituents disclosed herein with a relatively non-toxic acid or base. When a compound disclosed herein contains a relatively acidic functional group, a base addition salt can be obtained by contacting the compound with a sufficient amount of base in pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts or similar salts. When a compound disclosed herein contains a relatively basic functional group, an acid addition salt can be obtained by contacting the compound with a sufficient amount of acid in pure solution or in a suitable inert solvent. Certain specific compounds disclosed herein contain both basic and acidic functional groups and can be converted into any base or acid addition salt.

[0084] The pharmaceutically acceptable salts disclosed herein can be prepared from a parent compound that contains an acidic or basic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of the compound with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture thereof.

[0085] The compounds disclosed herein may exist in particular geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers, (D)-isomers, (L)-isomers, and racemic and other mixtures, such as mixtures enriched in an enantiomer or diastereoisomer, all of which are encompassed within the scope disclosed herein. Substituents such as alkyl may have additional asymmetric carbon atoms. All such isomers and mixtures thereof are encompassed within the scope of the present invention.

[0086] The compounds disclosed herein may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds. For example, the compounds may contain tritium ( 3H), iodine-125( 125 I) or C-14( 14

[0013] The compounds may be labeled with a radioactive isotope, such as 1,2-dihydrogen (DHT), or 1,2-dihydrogen (C). In another example, hydrogen may be replaced with deuterium to form a deuterated drug. The bond between deuterium and carbon is stronger than the normal hydrogen-carbon bond. Compared to non-deuterated drugs, deuterated drugs have the advantages of reduced toxic side effects, increased drug stability, improved efficacy, and prolonged biological half-life. All variations in the isotopic composition of the compounds disclosed herein, regardless of radioactivity, are included within the scope of the present disclosure.

[0087] The term "optional" or "optionally" means that the subsequent event or condition may, but need not, occur; the term includes instances in which the event or condition occurs and instances in which the event or condition does not occur.

[0088] The term "substituted" means that one or more hydrogen atoms on a particular atom are replaced with a substituent, including deuterium and hydrogen variants, as long as the valence of the particular atom is normal and the substituted compound is stable. If the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced. No position on an aromatic ring can be substituted with oxo. The term "optionally substituted" means that an atom may or may not be substituted with a substituent, and unless otherwise specified, the type and number of substituents can be any as long as it is chemically achievable.

[0089] When any variable (e.g., R) occurs more than one time in any constituent or structure of a compound, its definition at each occurrence is independent. Thus, for example, if a group is substituted with zero to two R, then that group is optionally substituted with up to two R, and the definition of R at each occurrence is independent. Furthermore, combinations of substituents and / or variables thereof are permissible only if such combinations result in stable compounds.

[0090] When the number of linking groups is 0, such as -(CRR)0-, it means that the linking group is a single bond.

[0091] When one of the variables is a single bond, it means that the two groups linked by the single bond are directly linked. For example, if L in ALZ represents a single bond, then the structure of ALZ is actually AZ.

[0092] 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 via a chemical bond. If the linking position of the chemical bond is variable and there is an H atom at a linkable site, when the linkable site with an H atom is linked to a chemical bond, the number of H atoms at this site decreases correspondingly as the number of linked chemical bonds increases, and the group becomes a group of the corresponding valence. The chemical bond between the site and another group is represented by a straight, solid bond ( [ka] ), straight dashed bond ( [ka] ) or wavy line ( [ka] For example, the straight, solid bond in -OCH3 indicates that the group is bonded to another group through the oxygen atom in the group, [ka] A straight, dashed bond in indicates that the group is connected to another group through the two ends of the nitrogen atom in the group, and a wavy [ka] The wavy lines in indicate that the group is attached to another group via one carbon atom and two carbon atoms in the phenyl group, [ka] indicates that any linkable site on the piperidinyl group can be connected to another group via one chemical bond, which provides at least four linkage modes: [ka] Even if an H atom is drawn on the -N-, [ka] The concatenation method: [ka] and when one chemical bond is attached, this site loses one H and the group becomes the corresponding monovalent piperidinyl group. [ka] indicates that any linkable site on the quinazolinyl group can be connected to another group via one chemical bond, which allows for several linking modes: [ka] Includes.

[0093] Unless otherwise stated, solid wedge bonds ( [ka] ) and wedge-shaped dashed bond ( [ka] ) indicates the absolute configuration of the stereocenter, and the solid bond ( [ka] ) and straight dashed bond ( [ka] ) indicates the relative configuration of stereocenters, and the wavy line ( [ka] ) is a wedge-shaped solid bond ( [ka] ) or wedge-shaped dashed bond ( [ka] ) or a wavy line ( [ka] ) is a straight line with a solid bond ( [ka] ), straight dashed bond ( [ka] ) is shown.

[0094] Unless otherwise specified, if a compound contains double bond structures such as carbon-carbon double bonds, carbon-nitrogen double bonds, and nitrogen-nitrogen double bonds, and each atom on the double bond is bonded to two different substituents (in double bonds involving nitrogen atoms, the lone pair on the nitrogen atom is considered to be one of the substituents to which it is bonded), the atoms on the double bond in the compound are shown with a wavy line ( [ka] ), the compound represents a (Z) isomer or an (E) isomer. For example, a compound having the following formula (A) means that the compound exists as a single isomer of formula (A-1) or formula (A-2) or a mixture of the two isomers of formula (A-1) and formula (A-2), and a compound having the following formula (B) means that the compound exists as a single isomer of formula (B-1) or formula (B-2) or a mixture of the two isomers of formula (B-1) and formula (B-2). A compound having the following formula (C) means that the compound exists as a single isomer of formula (C-1) or formula (C-2) or a mixture of the two isomers of formula (C-1) and formula (C-2). [ka]

[0095] Unless otherwise specified, the term "atropisomer (or atropoisomers)" refers to stereoisomers with a specific spatial configuration resulting from restricted rotation around a single bond due to significant steric hindrance. Certain compounds of the present disclosure may exist as atropisomers. The compounds disclosed herein include all atropisomers, which may be pure individual atropisomers or non-specific mixtures thereof enriched in one of the atropisomers. If the rotational potential energy around the single bond is sufficiently high and the interconversion between conformations is sufficiently slow, isomers can be isolated. For example, [ka] is a pair of atropisomers, [ka] indicates that the orientation on this side of the naphthalene ring is outward, [ka] indicates that the orientation of this side is inward.

[0096] Unless otherwise stated, the terms "halo" or "halogen," by themselves or as part of another substituent, refer to a fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) atom.

[0097] Unless otherwise stated, "C 1~3 The term "alkyl" is used to refer to a straight or branched chain saturated hydrocarbon group of 1 to 3 carbon atoms. 1~3 The alkyl group is C 1~2 , C 2~3 alkyl groups, etc. It can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methenyl). 1~3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.

[0098] Unless otherwise stated, "C 1~3 The term "alkoxy" means an alkyl group containing 1 to 3 carbon atoms and attached to the remainder of the molecule by an oxygen atom. 1~3 The alkoxy group is C 1~2 , C 2~3 , C3 and C2 alkoxy groups. 1~3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.

[0099] Unless otherwise stated, "C 1~3 The term "alkylamino" means an alkyl group containing 1 to 3 carbon atoms and attached to the remainder of the molecule by an amino group. 1~3 The alkylamino group is C 1~2 , C3, C2 alkylamino groups, etc. 1~3 Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -NHCH2CH2CH3, -NHCH2(CH3)2, and the like.

[0100] Unless otherwise stated, "C 2~3 "Alkenyl" is used to refer to a straight or branched hydrocarbon group composed of 2 to 3 carbon atoms containing at least one carbon-carbon double bond, which can be located at any position in the group. 2~3 Alkenyl includes C3 and C2 alkenyl. 2~3 Alkenyl can be monovalent, divalent or polyvalent. 2~3 Examples of alkenyl include, but are not limited to, vinyl, propenyl, and the like.

[0101] Unless otherwise stated, "C 2~3 "Alkynyl" is used to represent a straight or branched hydrocarbon group composed of 2 to 3 carbon atoms containing at least one carbon-carbon triple bond, which can be located at any position in the group. It can be monovalent, divalent, or polyvalent. 2~3 Alkynyl includes C3 and C2 alkynyl. 2~3 Examples of alkynyl include, but are not limited to, ethynyl, propynyl, and the like.

[0102] Unless otherwise stated, "C 3~4 "Cycloalkyl" means a monocyclic saturated cyclic hydrocarbon group of 3 to 4 carbon atoms. 3~4 Cycloalkyl includes C3 and C4 cycloalkyl, which can be monovalent, divalent, or polyvalent. C 3~4 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, and the like.

[0103] Unless otherwise stated, "C 2~4 "Alkenyl" is used to refer to a straight or branched hydrocarbon group composed of 2 to 4 carbon atoms containing at least one carbon-carbon double bond, which can be located at any position in the group. 2~4 Alkenyl is C 2~3, C4, C3 and C2 alkenyl, etc. 2~4 Alkenyl can be monovalent, divalent or polyvalent. 2~4 Examples of alkenyl include, but are not limited to, vinyl, propenyl, and the like.

[0104] Unless otherwise stated, "C 2~4 "Alkynyl" is used to refer to a straight or branched hydrocarbon group composed of 2 to 4 carbon atoms containing at least one carbon-carbon triple bond, which can be located at any position in the group. 2~4 Alkynyl is C 2~3 , C4, C3 and C2 alkynyl, etc. It can be monovalent, divalent or polyvalent. 2~4 Examples of alkynyl include, but are not limited to, ethynyl, propynyl, butynyl, and the like.

[0105] Unless otherwise stated, "C 6~10 aromatic ring” and “C 6~10 The terms "aryl" and "aryl" may be used interchangeably in this disclosure. 6~10 Aromatic ring" or "C 6~10 The term "aryl" means a cyclic hydrocarbon group having a conjugated pi-electron system and composed of 6 to 10 carbon atoms. It can be a monocyclic, fused bicyclic, or fused tricyclic ring system, in which each ring is aromatic. It can be monovalent, divalent, or polyvalent. 6~10 As aryl, C 6~9 , C9, C 10 and C6 aryl. 6~10 Examples of aryl include, but are not limited to, phenyl, naphthyl (including 1-naphthyl and 2-naphthyl, etc.).

[0106] Unless otherwise specified, the terms "5-10 membered heteroaromatic ring" and "5-10 membered heteroaryl" may be used interchangeably. The term "5-10 membered heteroaryl" refers to a cyclic group having a conjugated π electron system and composed of 5 to 10 ring atoms, where 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms. This may be a monocyclic, fused bicyclic, or fused tricyclic ring system, where each ring is aromatic, the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)). p, p is 1 or 2). A 5- to 10-membered heteroaryl can be attached to the remainder of the molecule via a heteroatom or a carbon atom. Examples of 5- to 10-membered heteroaryl groups include 5- to 8-membered, 5- to 7-membered, 5- to 6-membered, 5-membered and 6-membered heteroaryl groups. Examples of 5- to 10-membered heteroaryl include pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl, 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, etc.), thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl, etc.). and the like), furyl (including 2-furyl, 3-furyl, and the like), thienyl (including 2-thienyl and 3-thienyl, and the like), pyridyl (including 2-pyridyl, 3-pyridyl, 4-pyridyl, and the like), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl, 4-pyrimidinyl, and the like), benzothiazolyl (including 5-benzothiazolyl, and the like), purinyl, benzimidazolyl (including 2-benzimidazolyl, and the like), benzoxazolyl, indolyl (including 5-indolyl, and the like), isoquinolyl (including 1-isoquinolyl, 5-isoquinolyl, and the like), quinoxalinyl (including 2-quinoxalinyl, 5-quinoxalinyl, and the like), or quinolyl (including 3-quinolyl, 6-quinolyl, and the like).

[0107] Unless otherwise stated, C n~n+m or C n ~C n+m includes any specific case of n to n+m carbons, e.g., C 1~12 are C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 and C 12 and any range from n to n+m, for example, C1~12 is 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 Similarly, n- to n+m-membered rings indicate that the number of atoms on the ring is n to n+m. For example, a 3- to 12-membered ring includes a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, and 12-membered ring, and also includes any range of n to n+m. For example, a 3- to 12-membered ring includes a 3- to 6-membered ring, a 3- to 9-membered ring, a 5- to 6-membered ring, a 5- to 7-membered ring, a 6- to 7-membered ring, a 6- to 8-membered ring, and a 6- to 10-membered ring.

[0108] The compounds disclosed herein can be prepared by a variety of synthetic methods known to those skilled in the art, including the embodiments listed below, embodiments formed by the embodiments listed below in combination with other chemical synthetic methods, and equivalent alternatives known to those skilled in the art. Alternative embodiments include, but are not limited to, the embodiments disclosed herein.

[0109] The structures of the compounds disclosed herein can be confirmed by conventional methods known to those skilled in the art. Where the present disclosure relates to the absolute configuration of a compound, the absolute configuration can be confirmed by conventional techniques in the art, such as single crystal X-ray diffraction (SXRD). In single crystal X-ray diffraction (SXRD), diffraction intensity data of the grown single crystal is collected using a Bruker D8 venture diffractometer with a CuKα radiation source in φ / ω scan mode. After collecting the relevant data, the crystal structure is further analyzed by a direct method (Shelxs97) to confirm the absolute configuration.

[0110] The solvents used in this disclosure are commercially available. Hr represents time, the ratio of eluents in column chromatography purification is a volume ratio, HCl represents hydrochloric acid, NaOH represents sodium hydroxide, EtOH represents ethanol, Boc represents tert-butoxycarbonyl, TIPS represents triisopropylsilyl, PMB represents p-methoxybenzyl, Tf represents trifluoromethanesulfonyl, MOM represents methylene methyl ether, and Fmoc represents fluorenylmethyloxycarbonyl.

[0111] Compounds are named according to common naming principles in the art or by ChemDraw® software; commercially available compounds are named by their vendor directory name. DETAILED DESCRIPTION OF THE INVENTION

[0112] The present disclosure will be described in detail below through examples. However, these examples are not intended to have any adverse limitations on the present disclosure. The present disclosure is described in detail herein, and embodiments are also disclosed herein. It will be apparent to those skilled in the art that various changes and modifications can be made to the embodiments disclosed herein without departing from the spirit and scope of the present disclosure. [Example]

[0113] Example 1 [ka] Step 1: Synthesis of Compound 001-1B Compound 001-1A (120 g, 709 mmol) was dissolved in tert-butanol (1200 mL) and water (1200 mL). Potassium osmate (10.4 g, 28.3 mmol) and N-methylmorpholine oxide (249 g, 2.13 mol, 224 mL) were then added. The mixture was stirred at 45 °C for 16 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure and extracted with ethyl acetate and aqueous sodium sulfite solution (1000 mL). The organic phase was washed three times with 500 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The organic phase was concentrated, and the crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to obtain compound 001-1B. 1 H NMR:(400MHz,CDCl3)δ=4.23(t,J=3.6Hz,2H),3.55-3.58(m,2H),3.33(d,J=10.4Hz,2H),2.85(s,2H),1.45(s,9H).

[0114] Step 2: Synthesis of Compound 001-1C Compound 001-1B (107 g, 526 mmol) was dissolved in dichloromethane. Iodobenzene diacetate (254 g, 789 mmol) was added at 0° C. The mixture was stirred at 25° C. for 3 hours. After the reaction was completed, 500 mL of aqueous sodium bicarbonate solution and 100 mL of dichloromethane were added to the reaction solution, and the mixture was stirred for 0.5 hours. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain compound 001-1C. 1 H NMR: (400MHz, CDCl3)δ=9.73(d,J=6.8Hz,2H),4.28(s,2H),4.06(s,2H),1.29(s,9H).

[0115] Step 3: Synthesis of Compound 001-1D Compound 001-1C (200 g) was dissolved in tetrahydrofuran (600 mL). Vinyl magnesium bromide (1 M, 1.79 L) was added dropwise at -78 °C. The mixture was stirred at 25 °C for 16 hours. After the reaction was completed, the mixture was quenched with 1000 mL of saturated ammonium chloride at 10 °C and extracted with 500 mL of ethyl acetate. The organic phase was then extracted with saturated brine (500 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to obtain compound 001-1D. 1 H NMR:(400MHz,CDCl3)δ=5.82-5.89(m,2H),5.32(t,J=11.6Hz,2H),5.16-5.19(m,2H),4.4 5(s,2H),3.60-3.70(m,1H),3.37(s,2H),3.25(s,1H),2.95(d,J=8.8Hz,1H),1.48(s,9H).

[0116] Step 4: Synthesis of Compound 001-1E Compound 001-1D (80.0 g, 310 mmol) was dissolved in dichloromethane (1000 mL). Diazabicycle (23.6 g, 155 mmol, 23.4 mL) and trichloroacetonitrile (269 g, 1.87 mol, 187 mL) were added at 0 °C. The mixture was stirred at 25 °C for 16 hours. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain compound 001-1E. 1 H NMR:(400MHz,CDCl3)δ=8.37(s,2H),5.81-5.87(m,2H),5.45(s,2H),5.39-5.43(m,2H),5.25-5.30(m,2H),3.61-3.81(m,4H),1.48(s,9H).

[0117] Step 5: Synthesis of Compound 001-1F Compound α, α-dimethylbenzylamine (32.1 g, 238 mmol) was dissolved in 1,2-dichloroethane. Chloro(1,5-cyclooctadiene)iridium(I) dimer (12.3 g, 18.3 mmol) was then added. Compound 001-1E was dissolved in 1,2-dichloroethane (1.00 L) and then added dropwise to the reaction mixture at 0°C. The mixture was stirred at 25°C for 16 hours. After the reaction was complete, it was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 10:1) to obtain compound 001-1F. 1 H NMR:(400MHz,CDCl3)δ=7.52-7.55(m,2H),7.30(t,J=7.2Hz,2H),7.22(t,J=7.2Hz,1H),5.94-6.03(m,2H) ,5.10(t,J=19.2Hz,2H),4.99(d,J=10.4Hz,2H),3.51-3.61(m,4H),3.33(t,J=13.6Hz,2H),1.48(s,15H).

[0118] Step 6: Synthesis of Compound 001-1G Compound 001-1F (36.0 g, 50.4 mmol) was dissolved in toluene (900 mL). 1,3-bis(2,4,6-trimethylphenyl)-2-(imidazolidinylidene)(dichlorophenylmethylene)(tricyclohexylphosphine)ruthenium (2.14 g, 2.52 mmol) was added. The mixture was stirred at 125 °C for 16 hours. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 10:1) to obtain compound 001-1G. LCMS: (ESI) m / z = 329.2 [M+H] + . 1 H NMR:(400MHz,CDCl3)δ=7.60(t,J=1.2Hz,2H),7.31(t,J=7.2Hz,2H),7.22(s,1H),5.96(t,J=9.2Hz ,2H),3.60-3.65(m,2H),3.46-3.53(m,2H),3.09-3.14(m,2H),1.42(s,9H),1.25(d,J=6.0Hz,6H).

[0119] Step 7: Synthesis of Compound 001-1H Compound 001-1G (26.8 g, 81.6 mmol) was dissolved in methanol (201 mL). Hydrochloric acid / methanol (4 M, 67.3 mL) was added. The mixture was reacted at 35° C. for 16 hours. After the reaction was completed, the pH was adjusted to 12 with 4 M sodium hydroxide and extracted with 30 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give compound 001-1H. LCMS: (ESI) m / z=229.2 [M+H] + . 1 H NMR:(400MHz,CDCl3)δ=7.62(t,J=7.2Hz,2H),7.31(t,J=7.6Hz,2H),7.21(s,1H ),6.01(s,2H),3.42(s,2H),2.89-2.93(m,2H),2.30-2.34(m,2H),1.23(s,6H).

[0120] Step 8: Synthesis of Compound 001-5C Compound 001-5B (2 g, 5.58 mmol), dichloromethane, and N,N-diisopropylethylamine (4.33 g, 33.47 mmol, 5.83 mL) were added to a pre-dried reaction flask. Trifluoromethanesulfonic anhydride (6.30 g, 22.31 mmol, 3.68 mL) was added at 0 °C. The mixture was stirred at 0 °C for 1 hour. After the reaction was completed, water (5 mL) was added. The mixture was extracted with dichloromethane (5 mL × 4). The combined organic phase was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (gradient elution: petroleum ether: ethyl acetate = 10:1) to give compound 001-5C.

[0121] Step 9: Synthesis of Compound 001-5D Compound 001-5C (3.2 g, 5.14 mmol), diphenylimine (1.86 g, 10.28 mmol, 1.72 mL), and anhydrous toluene (64 mL) were added to a reaction flask, followed by the addition of cesium carbonate (5.02 g, 15.42 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (594.75 mg, 1.03 mmol) under nitrogen. Tris(dibenzylideneacetone)dipalladium (470.62 mg, 513.94 μmol, 0.1 equiv.) was added, and the mixture was stirred at 100 °C for 2 h. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by column chromatography (gradient elution: petroleum ether:ethyl acetate = 10:1) to give compound 001-5D. LCMS: (ESI) m / z=654.2 [M+H] + . 1 H NMR(400MHz,CDCl3)δ ppm 7.83-7.78(m,5H),7.60-7.49(m,9H),1.20-1.16(m,21H).

[0122] Step 10: Synthesis of Compound 001-5A Compound 001-5D (2.4 g, 3.67 mmol), bis(pinacolato)diboron (1.86 g, 7.34 mmol), and potassium acetate (1.08 g, 11.01 mmol) were dissolved in anhydrous toluene (48 mL). 1,1'-Bis(diphenylphosphino)ferrocenepalladium dichloride (537.20 mg, 734.17 μmol) was added. The mixture was stirred at 130 °C for 12 hours under nitrogen. After the reaction was complete, the mixture was concentrated under reduced pressure, and the crude product was purified by column chromatography (gradient elution: petroleum ether: ethyl acetate = 10:1) to obtain compound 001-5A. LCMS: (ESI) m / z = 632.3 [M+H] + . 1H NMR(400MHz,DMSO)δ ppm 7.80-7.87(m,1H),7.68-7.74(m,2H),7.55-7.62(m,1H),7.47-7.53(m,2H),7.39-7.47(m,1H ),7.27-7.35(m,4H),7.18-7.23(m,2H),7.10-7.15(m,1H),1.26(s,12H),1.07-1.15(m,21H).

[0123] Step 11: Synthesis of Compound 001-2 Compound 001-1 (138.23 mg, 605.38 μmol) and 001-1H (0.2 g, 605.38 μmol) were dissolved in N,N-dimethylformamide (2 mL). N,N-diisopropylethylamine (234.72 mg, 1.82 mmol, 316.34 μL) was added. The mixture was stirred and reacted at 25° C. for 2 hours. After the reaction was completed, 10 mL of water was added to precipitate the solid. The solid was filtered to obtain compound 001-2. LCMS: (ESI) m / z=521.02 [M+H] + . 1 H NMR(400MHz,CDCl3)δ ppm 1.23(s,6H)3.58-3.74(m,4H)4.22(br d,J=11.04Hz,2H)5.91(s,2H)7.16-7.23(m,2H)7.26-7.34(m,2H)7.54(s,1H)7.69(d,J=2.01Hz,1H).

[0124] Step 12: Synthesis of Compound 001-3 Trifluoroacetate Compound 001-2 (300 mg, 574.45 μmol) was dissolved in trifluoroacetic acid (2 mL). The mixture was stirred at 75° C. for 1 hour. After the reaction was completed, the mixture was concentrated to give compound 001-3 trifluoroacetate. LCMS: (ESI) m / z=402.92 [M+H] + .

[0125] Step 13: Synthesis of Compound 001-4 Compound 001-3 (220 mg, 544.47 μmol, trifluoroacetate) was dissolved in tetrahydrofuran (2 mL). Then, di-tert-butyl dicarbonate (142.60 mg, 653.36 μmol, 150.10 μL) and triethylamine (165.28 mg, 1.63 mmol, 227.35 μL) were added. The mixture was reacted at 25 °C for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 10:1 to 3:1) to obtain compound 001-4. LCMS: (ESI) m / z = 502.92 [M+H] + . 1 H NMR(400MHz,CDCl3)δ=1.55(s,9H)3.62-3.90(m,2H)4.27-4.52(m,2H)4.60-4.82(m,2H)6.19(s,2H)7.75(d,J=2.01Hz,1H).

[0126] Step 14: Synthesis of Compound 001-5 Compound 001-4 (250 mg, 495.86 μmol) was dissolved in N,N-dimethylformamide (5 mL) and tetrahydrofuran (5 mL). Then, triethylenediamine (5.56 mg, 49.59 μmol, 5.45 μL), 001-4A (94.73 mg, 595.03 μmol), and cesium carbonate (242.34 mg, 743.78 μmol) were added. The mixture was stirred at 25 °C for 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (eluent: dichloromethane / methanol = 10:1 to 5:1) to obtain compound 001-5. LCMS: (ESI) m / z = 626.12 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ ppm 1.47(s,9H)1.77-1.92(m,2H)1.96-2.16(m,3H)2.74(s,1H)2.79-2.90(m,2H)3.04-3.19(m,2H)3.66(br d,J=10.54Hz,2H)3.90-4.11(m,2H)4.30(br s,2H)4.60(br s,2H)5.15-5.38(m,1H)6.06-6.22(m,1H)6.16(br s,1H)7.92-8.05(m,1H).

[0127] Step 15: Synthesis of Compound 001-6 Compound 001-5 (0.25, 398.78 μmol), compound 001-5A (327.48 mg, 518.41 μmol), and potassium phosphate (253.94 mg, 1.20 mmol) were added to 1,4-dioxane and water (0.4 mL). The atmosphere was replaced with nitrogen three times, and chloro[(bis(1-adamantyl)-n-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (26.66 mg, 39.88 μmol) was added under nitrogen. The mixture was reacted at 80 °C for 12 hours. After the reaction was completed, 3 mL of water was added to the reaction mixture, which was then extracted with ethyl acetate (2 mL × 2). The combined organic phase was washed with 5 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 100:0 to 1:2, dichloromethane:methanol = 10:1) to give compound 001-6. LCMS: (ESI) m / z = 1051.4 [M+H] + .

[0128] Step 16: Synthesis of Compound 001-7 Hydrochloride Compound 001-6 (0.13 g, 123.60 μmol) was added to hydrochloric acid / methanol (2 mL). The mixture was reacted at 18° C. for 2 hours. After the reaction was completed, the reaction solution was concentrated. The crude product was stirred with 5 mL of ethyl acetate for 1 hour and then filtered. The filter cake was rinsed with 2 mL of ethyl acetate and concentrated under reduced pressure to give compound 001-7 hydrochloride salt. LCMS: (ESI) m / z=787.3 [M+H] +.

[0129] Step 17: Synthesis of Compound 001A and Compound 001B Compound 001-7 (0.2 g, 242.75 μmol, hydrochloride salt) was added to N,N-dimethylformamide (3 mL). Potassium carbonate (335.51 mg, 2.43 mmol) and cesium fluoride (73.75 mg, 485.50 μmol, 17.90 μL) were added. The mixture was reacted at 60° C. for 16 hours. After the reaction was completed, 5 mL of water was added to the reaction solution. The mixture was extracted with ethyl acetate (3 mL × 2). The combined organic phase was washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude compound. The crude product was purified by preparative high-performance liquid chromatography (column: Phenomenex Luna 80 × 30 mm × 3 μm; mobile phase A: water (0.05% HCl), mobile phase B: acetonitrile; gradient run: B%: 5% to 30%, run for 8 min) to give compound 001 hydrochloride. The fraction solution was adjusted to pH 7 by adding aqueous ammonia, and then purified by supercritical fluid chromatography (SFC) (column: DAICEL CHIRALPAK IC (250 mm × 30 mm, 10 μm); mobile phase: A (supercritical CO2) and B (ethanol with 0.1% ammonia); gradient run: B% = 60% to 60%, run for 20 min) to give compound 001A and compound 001B.

[0130] The analysis and characterization of compound 001A was as follows:

[0131] SFC analytical method (Column: Chiralpak IC-3, 50 × 4.6 mm i.d., 3 μm; Mobile phase: A (supercritical CO), B: (ethanol containing 0.1% isopropylamine); Gradient: B% = 50–50%, 4 min; Flow rate: 4 mL / min; Wavelength: 220 nm; Pressure: 1800 psi, Rt = 1.059 min, 100% ee). LCMS: MS m / z (ESI) = 631.1 [M+H] + . 1H NMR(400MHz,CD3OD)δ=7.79(s,1H),7.71(dd,J=6.0,9.2Hz,1H),7.21(t,J=8.8Hz,1H),7.16( d,J=2.4Hz,1H),6.96(d,J=2.4Hz,1H),6.30-6.22(m,2H),5.38-5.20(m,1H),4.51-4.37(m,2 H),4.26-4.19(m,1H),4.15-4.10(m,1H),3.98(dd,J=1.2,11.6Hz,2H),3.84-3.71(m,2H),3. 29-3.15(m,4H),3.05-2.95(m,1H),2.37-2.17(m,2H),2.15-2.08(m,1H),2.02-1.84(m,3H).

[0132] The analysis and characteristic evaluation of compound 001B are as follows.

[0133] SFC analysis method(カラム: Chiralpak IC-3, 50×4.6mm inner diameter, 3μm; mobile phase: A (supercritical CO2), B: (0.1% イソプロピルアミンをcontaining むエタノール); グラジエント: B%=50~50%, 4 minutes; flow rate: 4mL / minute; wavelength: 220nm; pressure: 1800psi, Rt=1.917 minutes, 96.54%ee LCMS: MS. m / z(ESI)=631.1[M+H] + . 1 H NMR(400MHz,CD3OD)δ=7.80(d,J=1.2Hz,1H),7.72(dd,J=5.6,8.8Hz,1H),7.22(t,J=8.8 Hz,1H),7.16(d,J=2.4Hz,1H),6.96(d,J=2.4Hz,1H),6.33-6.23(m,2H),5.40-5.21(m,1H ),4.44(t,J=12.0Hz,2H),4.24-4.12(m,2H),4.02-3.95(m,2H),3.83-3.73(m,2H),3.29- 3.27(m,1H),3.26-3.16(m,3H),3.05-2.95(m,1H),2.38-2.09(m,3H),2.04-1.85(m,3H).

[0134] Example 2

change

[0135] Step 2: Synthesis of Compound 002-3 Compound 002-2 (0.35 g, 691.99 μmol) was added to anhydrous tetrahydrofuran (2 mL) and N,N-dimethylformamide (2 mL). Cesium carbonate (676.40 mg, 2.08 mmol), compound 001-4A (132.20 mg, 830.39 μmol), and triethylenediamine (23.29 mg, 207.60 μmol, 22.83 μL) were added. The mixture was reacted at 25 °C for 17 hours. After the reaction was complete, the reaction solution was added to 10 mL of methyl tert-butyl ether, washed twice with 10 mL of saturated ammonium chloride, then washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 002-3. LCMS: (ESI) m / z = 628.0 [M+H] + .1 H NMR(400MHz,CDCl3)δ=7.65-7.60(m,2H),7.40-7.32(m,3H),7.30-7.28(m,1H),5. 97-5.93(m,2H),5.40-5.15(m,1H),4.34-4.22(m,2H),4.16(d,J=10.0Hz,1H),4.02 (d,J=10.4Hz,1H),3.75-3.71(m,2H),3.69-3.60(m,2H),3.30-3.17(m,2H),3.15- 3.08(m,1H),3.01-2.92(m,1H),2.33-2.06(m,3H),1.98-1.80(m,3H),1.30(s,6H).

[0136] Step 3: Synthesis of Compound 002-4 Compound 002-3 (0.3 g, 477.31 μmol), compound 001-5A (452.27 mg, 715.96 μmol), and potassium phosphate (303.95 mg, 1.43 mmol) were added to toluene (3 mL) and water (0.6 mL). The atmosphere was replaced with nitrogen three times, and chloro[(bis(1-adamantyl)-n-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (31.91 mg, 47.73 μmol) was added under nitrogen. The mixture was reacted at 80°C for 4.5 hours. 20 mL of water was added to the reaction mixture. The mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:0 to 0:1, dichloromethane:methanol = 10:1) to give compound 002-4. LCMS: (ESI) m / z = 1053.5 [M+H] + . 1H NMR(400MHz,CDCl3)δ=7.81-7.76(m,2H),7.67-7.62(m,3H),7.52-7.47(m,1H),7.46-7.31(m,5H),7.30-7.28(m,1H),7.26-7.2 2(m,3H),7.21-7.17(m,2H),7.15-7.10(m,2H),6.96-6.90(m,1H),6.12-6.06(m,1H),5.98-5.94(m,1H),5.36-5.18(m,1H),4.65 -4.58(m,1H),4.22-4.08(m,1H),4.06-3.97(m,1H),3.94-3.87(m,1H),3.85-3.77(m,2H),3.70-3.68(m,1H),3.50-3.43(m,1H), 3.30-3.13(m,3H),3.02-2.92(m,1H),2.33-2.13(m,3H),1.94-1.85(m,3H),1.25(s,6H),0.93-0.81(m,18H),0.59-0.51(m,3H).

[0137] Step 4: Synthesis of Compound 002-5 Compound 002-4 (0.23 g, 218.35 μmol) was added to trifluoroacetic acid (2 mL). The mixture was heated to 70° C. and reacted for 0.5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and diluted with 5 mL of ethyl acetate. The mixture was washed with 5 mL of water twice, 10 mL of saturated sodium bicarbonate solution, and 10 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give compound 002-5. LCMS: (ESI) m / z=771.3 [M+H] + .

[0138] Step 5: Synthesis of Compound 002A and Compound 002B Compound 002-5 (0.27 g, 350.21 μmol) was added to N,N-dimethylformamide (3 mL). Potassium carbonate (242.01 mg, 1.75 mmol) and cesium fluoride (106.39 mg, 700.41 μmol, 25.82 μL) were added. The mixture was reacted at 60° C. for 5 hours. After the reaction was completed, the reaction solution was diluted with 10 mL of ethyl acetate and washed with 10 mL of water. The aqueous phase was further extracted with 5 mL of ethyl acetate. The organic phases were combined, washed three times with 10 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was stirred with a mixed solvent (n-heptane:ethyl acetate=5:1) for 1 hour and filtered. The filter cake was washed three times with 3 mL of the mixed solvent in the same ratio, dried, and purified by preparative high-performance liquid chromatography (column: Phenomenex Luna 80 × 30 mm × 3 μm; mobile phase A: water (0.04% hydrochloric acid), mobile phase B: acetonitrile; gradient run: acetonitrile %: 10% to 35%, run for 8 min). The fractions were adjusted to pH 8 with 10 mL of saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 002, which was purified by supercritical fluid chromatography (SFC) (column: DAICEL CHIRALCEL OD (250 mm × 30 mm, 10 μm); mobile phase: A (supercritical CO) and B (ethanol containing 0.1% ammonia); gradient: B% = 50% to 50%, run for 20 min) to give 002A and 002B.

[0139] The analysis and characterization of compound 002A was as follows:

[0140] SFC analytical method (column: Chiralcel OD-3, 50 × 4.6 mm i.d., 3 μm; mobile phase: A (supercritical CO2), B: (ethanol containing 0.1% isopropylamine); gradient: B% = 5 to 50%, 3 min; flow rate: 3.4 mL / min; wavelength: 220 nm; pressure: 1800 psi), Rt = 1.801 min, enantiomeric excess: 100%. LCMS: MS m / z (ESI) = 615.2 [M+H]+ . 1 H NMR(400MHz,CD3OD)δ=7.81-7.71(dd,J=6.0,8.8Hz,1H),7.56(d,J=10.0Hz ,1H),7.29-7.21(m,2H),7.06(s,1H),6.48-6.35(m,2H),5.67-5.48(m,1H), 4.69-4.64(m,4H),4.18-4.00(m,3H),3.98-3.77(m,3H),3.53-3.40(m,3H), 2.77-2.55(m,2H),2.51-2.41(m,1H),2.37-2.28(m,2H),2.25-2.13(m,1H).

[0141] The analysis and characteristic evaluation of compound 002B are as follows.

[0142] SFC analysis method (カラム:Chiralcel OD-3, 50×4.6mm inner diameter, 3μm; mobile phase: A (supercritical CO2), B: (0.1% イソプロピルアミンをcontaining むエタノール); グラジエント: B%=5~50%, 3 minutes; flow rate: 3.4mL / min; wavelength: 220nm; pressure: 1800psi), Rt=2.233 minutes, mirror image passing rate: 93.58%. LCMS:MS m / z(ESI)=615.2[M+H] + . 1 H NMR(400MHz,CD3OD)δ=7.75(dd,J=6.0,9.2Hz,1H),7.51(dd,J=1.6,10.0Hz,1H),7.25(t,J=8.8Hz,1H),7.19(d,J =2.4Hz,1H),7.05(d,J=2.4Hz,1H),6.33-6.30(m,1H),6.28-6.26(m,1H),5.4-5.25(m,1H),4.51(d,J=11.6Hz,1H ),4.42(d,J=12.4Hz,1H),4.32-4.27(m,1H),4.21-4.16(m,1H),4.02(dd,J=2.0,12.0Hz,2H),3.85-3.69(m,2H), 3.29-3.20(m,4H),3.07-3.00(m,1H),2.44-2.24(m,2H),2.23-2.14(m,1H),2.09-1.99(m,2H),1.98-1.88(m,1H).

[0143] Example 3 [ka] Step 1: Synthesis of Compound 003-1A Compound 001-1H (18.6 g) was dissolved in tetrahydrofuran (190 mL). Then, 9-fluorenylmethyl chloroformate (20.5 g, 79.4 mmol) and sodium carbonate (25.2 g, 238.2 mmol) were added. The mixture was stirred at 0° C. for 1 hour. After the reaction was completed, the reaction solution was extracted with 100 mL of ethyl acetate and 200 mL of water. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give compound 003-1A. LCMS: (ESI) m / z=451.3 [M+H] + . 1 H NMR:(400MHz,CDCl3)δ=7.76(d,J=13.6Hz,2H),7.54-7.61(m,4H),7.24-7.40(m,7H),5.93-6.01(m,2H),4.3 4-4.40(m,2H),4.21(s,1H),3.70(t,J=2Hz,2H),3.55-3.59(m,2H),3.15-3.23(m,2H),1.27(d,J=2.4Hz,6H).

[0144] Step 2: Synthesis of Compound 003-1B Compound 003-1A (9.52 g, 21.1 mmol) was dissolved in trifluoroacetic acid (192 mL). The solution was stirred at 75° C. for 16 hours. After the reaction was completed, 20 mL of water was added to the reaction solution, and the pH was adjusted to 9 with 2 M sodium hydroxide. The mixture was then extracted with 20 mL of dichloromethane. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to obtain the crude product. The crude product was stirred with 6 mL of n-heptane at 25° C. for 2 hours and filtered to obtain compound 003-1B. LCMS: (ESI) m / z=333.3 [M+H] + . 1H NMR:(400MHz,CDCl3)δ=7.77(d,J=7.6Hz,2H),7.56(d,J=7.2Hz,2H),7.41(t,J=7.6Hz,2H),7.33(t,J=6Hz,2H),6.18-6.27(m ,2H),4.38-4.42(m,2H),4.23(s,1H),3.88(d,J=2.0Hz,2H),3.82(d,J=2.4Hz,1H),3.72(d,J=2.0Hz,1H),3.21-3.60(m,2H).

[0145] Step 3: Synthesis of Compound 003-1C Compound 003-1B (1.00 g) was dissolved in tetrahydrofuran (10.0 mL). Then, di-tert-butyl dicarbonate (764 mg, 3.50 mmol, 804 μL) and triethylamine (885 mg, 8.75 mmol, 1.22 mL) were added. The mixture was stirred at 25°C for 1 hour. After the reaction was completed, it was extracted with 10 mL of ethyl acetate and 10 mL of water. The organic phase was washed with 15 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=3:1) to give compound 003-1C. LCMS: (ESI) m / z=433.2 [M+H] + .

[0146] Step 4: Synthesis of Compound 003-1D Compound 003-1C (5.69 g) was dissolved in ethanol (60.0 mL). Then, dimethylamine (34.4 g, 251.8 mmol, content 33%) was added. The mixture was stirred at 25° C. for 3 hours. After the reaction was completed, it was extracted with 40 mL of ethyl acetate and 40 mL of citric acid. The aqueous phase was adjusted to pH 9 with 2 M sodium hydroxide and filtered. The filtrate was extracted with 40 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give compound 003-1D. LCMS: (ESI) m / z=211.2 [M+H] + . 1H NMR: (400MHz, CDCl3)δ=6.22(d,J=10Hz,2H),4.40(d,J=38.8Hz,2H),2.89-3.01(m,2H),2.40(d,J=13.2Hz,2H),1.49(s,9H).

[0147] Step 5: Synthesis of Compound 003-2 Compound 003-1 (0.5 g, 1.69 mmol) was dissolved in anhydrous dichloromethane (5 mL). Triethylamine (512.92 mg, 5.07 mmol, 705.53 μL) and 003-1D (426.34 mg, 2.03 mmol) were added. The mixture was stirred at 15° C. for 1 hour. After the reaction was completed, the mixture was concentrated. The residue was dissolved in 20 mL of dichloromethane, then washed once with 10 mL of water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give compound 003-2. LCMS: (ESI) m / z=468.9 [M+H] + . 1 H NMR(400MHz,CDCl3)δ ppm 7.55-7.39(m,2H),6.17(s,2H),4.80-4.60(m,2H),4.51-4.25(m,2H),3.88-3.58(m,2H),1.57-1.51(m,9H).

[0148] Step 6: Synthesis of Compound 003-3 Compound 003-2 (0.9 g, 1.92 mmol) was dissolved in N,N-dimethylformamide (9 mL) and anhydrous tetrahydrofuran (9 mL). Then, compound 001-4A (366.03 mg, 2.30 mmol), cesium carbonate (1.87 g, 5.75 mmol), and triethylenediamine (64.47 mg, 574.79 μmol, 63.21 μL) were added. The mixture was stirred at 30° C. for 12 hours. After the reaction was complete, 10 mL of water and 15 mL of ethyl acetate were added to the reaction mixture. The mixture was stirred for 5 minutes and then allowed to settle. The layers were separated. The aqueous phase was extracted once with 15 mL of ethyl acetate. The organic phases were combined, washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (gradient elution: petroleum ether:ethyl acetate = 100:0 to 50:50, triethylamine in ethyl acetate 5 parts / 1000) to obtain compound 003-3. LCMS: (ESI) m / z = 592.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ ppm 7.37(d,J=9.2Hz,1H),7.29-7.23(m,1H),6.13(s,2H),5.38-5.17(m,1H),4.76-4.56(m,2H),4.45-4.25(m,2H),4.24-4.04 (m,2H),3.81-3.53(m,2H),3.30-3.11(m,3H),3.02-2.92(m,1H),2.32-2.09(m,3H),2.00-1.81(m,3H),1.56-1.48(m,9H).

[0149] Step 7: Synthesis of Compound 003-4 Compound 003-3 (0.8 g, 1.35 mmol), anhydrous tetrahydrofuran (8 mL), anhydrous potassium phosphate (859.87 mg, 4.05 mmol), and water (4 mL) were added to a pre-dried reaction flask. The atmosphere was flushed with nitrogen three times, and [(n-butylbis(1-adamantyl)phosphine)-2-(2-aminobiphenyl)]palladium(II) chloride (98.34 mg, 135.03 μmol) was added. The atmosphere was flushed with nitrogen three times, and the mixture was heated to 60 °C. A solution of compound 001-5A (1.19 g, 1.89 mmol) in anhydrous tetrahydrofuran (8 mL) was added, and the mixture was then reacted at 60 °C for 3 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove the tetrahydrofuran. 20 mL of ethyl acetate was added. The organic phase was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by silica gel column chromatography (gradient elution: petroleum ether: ethyl acetate = 100:0 to 50:50, triethylamine in ethyl acetate 5 parts / 1000) to give compound 003-4. LCMS: (ESI) m / z = 1017.5 [M+H] + . 1 H NMR(400MHz,CDCl3)δ ppm 7.83-7.71(m,2H),7.65(dd,J=9.0,5.8Hz,1H),7.53-7.40(m,4H),7.36-7.10(m,8H),6.93(t,J=7.0Hz,1H),6.89-6.86(m,1H),6.25(br s,1H),6.18-6.12(m,1H),5.39-5.12(m,1H),4.85-4.49(m,3H),4.26-4.00(m,2H),3.96-3.68(m,1H),3.66-3.38(m,1H),3.3 2-3.11(m,3H),3.05-2.90(m,1H),2.36-2.14(m,3H),2.00-1.80(m,3H),1.59(s,9H),0.90-0.76(m,18H),0.59-0.43(m,3H).

[0150] Step 8: Synthesis of Compound 003-5 Hydrochloride Compound 003-4 (0.8 g, 786.39 μmol) was added with hydrochloric acid / methanol (4 M, 8.00 mL). The mixture was stirred at 15° C. for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure. A mixture solution (ethyl acetate:dichloromethane=5:1, 20 mL) was added, and the mixture was stirred for 0.5 hours. The mixture was filtered, and the filter cake was dried under vacuum to obtain compound 003-5 hydrochloride. LCMS: (ESI) m / z=753.3 [M+H] + .

[0151] Step 9: Synthesis of Compound 003 Compound 003-5 (0.7 g, 847.56 μmol, hydrochloride salt) was dissolved in N,N-dimethylformamide (7 mL). Anhydrous potassium carbonate (2.34 g, 16.95 mmol) and cesium fluoride (643.73 mg, 4.24 mmol) were added. The mixture was stirred at 65 °C for 4 hours. After the reaction was complete, the reaction solution was cooled to room temperature and then filtered. The filter cake was rinsed with 20 mL of ethyl acetate. The mother liquor was washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (Phenomenex Luna 80 × 30 mm × 3 μm column; mobile phase: [water (0.04% hydrochloric acid)-acetonitrile]; acetonitrile %: 5% to 25%, 8 min). The fraction was adjusted to pH 9 by adding ammonia dropwise and then concentrated under reduced pressure to remove acetonitrile. The residue was extracted with ethyl acetate (50 mL x 2) and concentrated under reduced pressure to give compound 003. LCMS: (ESI) m / z = 597.2 [M + H] + . 1H NMR(400MHz,CDCl3)δ ppm 7.65(dd,J=9.0,5.8Hz,1H),7.52(d,J=9.2Hz,1H),7.21(t,J=8.8Hz,1H),7.12-7.01(m, 2H),6.95(d,J=2.4Hz,1H),6.29-6.22(m,2H),5.38-5.18(m,1H),4.48-4.38(m,2H),4.29 -4.18(m,1H),4.00-3.93(m,2H),3.90(s,1H),3.79-3.72(m,2H),3.31-3.22(m,2H),3.1 7(s,1H),3.01-2.94(m,1H),2.72(d,J=2.0Hz,1H),2.34-2.15(m,3H),2.03-1.84(m,3H).

[0152] Example 4 [ka] Step 1: Synthesis of Compound 004-1 Anhydrous tetrahydrofuran (20 mL) was added to a pre-dried reaction flask. Diisopropyl azodicarboxylate (2.54 g, 12.56 mmol, 2.44 mL) and triphenylphosphine (3.30 g, 12.56 mmol) were added at 0 °C. The mixture was stirred at 0 °C for 0.5 h, allowing a solid to precipitate. Compound 001-4A (1 g, 6.28 mmol) and compound 004-1A (634.24 mg, 8.17 mmol, 592.75 μL) dissolved in anhydrous tetrahydrofuran (10 mL) were added, and the mixture was stirred at 0-15 °C for 2 h. After completion of the reaction, 5 mL of water was added to quench the reaction. 20 mL of ethyl acetate was added, and the mixture was stirred for several minutes. The mixture was allowed to settle, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and then 20 mL of n-heptane was added. The mixture was stirred for 1 hour. The mixture was filtered. The mother liquor was collected and concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by silica gel column chromatography (gradient elution: petroleum ether: ethyl acetate = 100:0 to 30:70, 5 parts triethylamine in ethyl acetate / 1000) to obtain compound 004-1. LCMS m / z = 217.9 [M+H]+ . 1 H NMR(400MHz,CDCl3)δ ppm 5.28-5.08(m,1H),3.26-3.06(m,4H),2.99-2.83(m,2H),2.34(s,3H),2.20-2.04(m,1H),1.96-1.76(m,5H).

[0153] Step 2: Synthesis of Compound 004-2 Compound 004-1 (180 mg, 828.34 μmol) and dimethyl sulfoxide (8 mL) were added to a reaction flask. Sodium hydroxide (2 M, 753.03 μL) was added at 15°C. The mixture was stirred at 15°C for 2 hours. Then, compound 004-1B (381.18 mg, 753.03 μmol) and dimethyl sulfoxide (8 mL) were added. The mixture was stirred at 60°C for 48 hours. After the reaction was completed, the reaction solution was cooled to room temperature. 20 mL of ethyl acetate was added. The mixture was washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and then purified by silica gel column chromatography (gradient elution: petroleum ether: ethyl acetate = 100:0 to 60:40) to obtain compound 004-2. LCMS m / z = 644.0 [M+H] + .

[0154] Step 3: Synthesis of Compound 004-3 Compound 004-2 (170 mg, 263.57 μmol), anhydrous toluene (2.5 mL), anhydrous potassium phosphate (167.84 mg, 790.70 μmol), water (0.5 mL), and compound 001-5A (249.74 mg, 395.35 μmol) were added to a pre-dried reaction flask. The atmosphere was replaced with nitrogen three times, and [(n-butylbis(1-adamantyl)phosphine)-2-(2-aminobiphenyl)]palladium(II) chloride (17.62 mg, 26.36 μmol) was added. The atmosphere was replaced with nitrogen three times again. The mixture was heated to 80°C and reacted for 12 hours. After completion of the reaction, the reaction solution was cooled to room temperature. 10 mL of water and 20 mL of ethyl acetate were added. The mixture was stirred for 5 minutes and then allowed to settle. The layers were separated. The aqueous phase was extracted once with 10 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain a crude product. The crude compound was purified by silica gel column chromatography (gradient elution: petroleum ether: ethyl acetate = 100:0 to 60:40, triethylamine in ethyl acetate 5 parts / 1000) to obtain compound 004-3. LCMS m / z = 1069.4 [M+H] + .

[0155] Step 4: Synthesis of Compound 004-4 Hydrochloride Compound 004-3 (40 mg, 37.39 μmol) was added with hydrochloric acid / methanol (4 M, 2.00 mL). The mixture was stirred at 15° C. for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to give crude compound 004-4 hydrochloride. LCMS m / z=805.2 [M+H] + .

[0156] Step 5: Synthesis of Compound 004A and Compound 004B Compound 004-4 (30 mg, 34.15 μmol, hydrochloride salt) was added to N,N-dimethylformamide (1 mL). Anhydrous potassium carbonate (94.40 mg, 683.04 μmol) and cesium fluoride (25.94 mg, 170.76 μmol, 6.30 μL) were added. The mixture was stirred at 65° C. for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature and then filtered. The filter cake was rinsed with 20 mL of ethyl acetate. The mother liquor was washed with saturated brine (20 mL×3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by supercritical fluid chromatography (column: DAICEL CHIRALPAK IC (250 mm × 30 mm, 10 μm); mobile phase: A: supercritical CO2, B: [0.1% ammonia-isopropyl alcohol]; B%: 60% to 60%, 16 min). The fractions were adjusted to pH 9 by dropwise addition of ammonia and then concentrated under reduced pressure to remove acetonitrile. The residue was extracted with ethyl acetate (20 mL × 2) and concentrated under reduced pressure to give Compound 004A and Compound 004B.

[0157] The characteristics of compound 004A were as follows:

[0158] SFC analytical method: Column: Chiralpak IC-3, 3 μm, 50 × 4.6 mm ID; Mobile phase: A (supercritical CO2) and B (isopropyl alcohol containing 0.1% isopropylamine); Gradient: B% = 5 to 40%, 5 min; Flow rate: 4.0 mL / min; Wavelength: 220 nm; Pressure: 124.14 bar, Rt = 2.13 min, Enantiomeric excess: 83.48%. LCMS m / z = 649.2 [M+H] + . 1H NMR(400MHz,CD3OD)δ ppm 7.82(s,1H),7.74(dd,J=9.2,6.0Hz,1H),7.23(t,J=9.2Hz,1H),7.18(d,J=2.4Hz,1H),6.98(d,J=2.4Hz,1H),5.39-5.19(m,1H),4.51(br d,J=13.6Hz,1H),4.41(br d,J=13.6Hz,1H),3.71-3.64(m,2H),3.57(br t,J=14.0Hz,2H),3.50-3.41(m 2H),3.29-3.26(m,1H),3.08(s,1H),2.42-2.19(m,4H),2.14-2.01(m,3H),1.93-1.74(m,6H).

[0159] The characterization of compound 004B was as follows:

[0160] SFC analytical method: Column: Chiralpak IC-3, 3 μm, 50 × 4.6 mm ID; Mobile phase: A (supercritical CO2) and B (isopropyl alcohol containing 0.1% isopropylamine); Gradient: B% = 5 to 40%, 5 min; Flow rate: 4.0 mL / min; Wavelength: 220 nm; Pressure: 124.14 bar, Rt = 1.38 min, Enantiomeric excess: 91.90%. LCMS m / z = 649.2 [M+H] + . 1 H NMR(400MHz,CD3OD)δ ppm 7.82(s,1H),7.74(dd,J=9.2,6.0Hz,1H),7.24(t,J=8.8Hz,1H),7.18(d,J=2.8Hz,1H),6.98(d,J =2.4Hz,1H),5.44-5.19(m,1H),4.58-4.50(m,1H),4.42-4.36(m,1H),3.70-3.63(m,2H),3.56(br d,J=11.8Hz,2H),3.48-3.40(m,2H),3.27(s,1H),3.16-3.02(m,1H),2.46-2.18(m,4H),2.14-1.94(m,3H),1.93-1.69(m,6H).

[0161] Example 5 [ka] Step 1: Synthesis of Compound 005-1 Compound 003-3 (0.3 g, 506.35 μmol), anhydrous tetrahydrofuran (3 mL), and water (1 mL) were added to a reaction flask, followed by anhydrous potassium phosphate (322.45 mg, 1.52 mmol). The atmosphere was replaced with nitrogen three times, and CataCXium® A Pd G3 (CAS: 1651823-59-4) (36.88 mg, 50.64 μmol) was added. The atmosphere was replaced with nitrogen three times, and the mixture was heated to 60° C. Then, a solution of compound 005-1A (519.04 mg, 1.01 mmol) in anhydrous tetrahydrofuran (3 mL) was added dropwise with stirring, and the mixture was stirred at 60° C. for 3 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the crude product was purified by column chromatography (ethyl acetate / petroleum ether = 0-45%, triethylamine in ethyl acetate 5 parts / 1000) to obtain compound 005-1. LCMS m / z = 898.4 [M+H] + .

[0162] Step 2: Synthesis of Compound 005-2 Hydrochloride Compound 005-1 (0.4 g, 445.37 μmol) and hydrochloric acid / methanol (4 M, 4.00 mL) were added to a pre-dried reaction flask. The mixture was stirred under nitrogen at 15° C. for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to give the crude product of compound 005-2 hydrochloride, which was used directly in the next step. LCMS m / z=754.3 [M+H] + .

[0163] Step 3: Synthesis of Compound 005 Compound 005-2 (0.2 g, 241.87 μmol, hydrochloride salt) was added to N,N-dimethylformamide (4 mL). Anhydrous potassium carbonate (668.56 mg, 4.84 mmol) and cesium fluoride (183.70 mg, 1.21 mmol, 44.59 μL) were added. The mixture was stirred at 65 °C for 4 hours. After the reaction was complete, the reaction solution was cooled to room temperature and then filtered. The filter cake was rinsed with 20 mL of ethyl acetate. The mother liquor was washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (Phenomenex Luna 80 × 30 mm × 3 μm column; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile %: 1% to 25%, 8 min). The fraction was adjusted to pH 9 by adding ammonia dropwise, and then concentrated under reduced pressure to remove acetonitrile. The residue was extracted with ethyl acetate (20 mL x 2) and concentrated under reduced pressure to give compound 005. LCMS m / z = 598.2 [M+H] + . 1 H NMR(400MHz,CD3OD)δ=7.82(dd,J=9.2,6.0Hz,1H),7.75(d,J=8.8Hz,1H),7.32-7.26( m,2H),7.19(dd,J=8.6,7.0Hz,1H),7.06(d,J=2.6Hz,1H),6.34-6.25(m,2H),5.24(br s,1H),4.56-4.45(m,2H),4.27-4.13(m,2H),4.01-3.96(m,2H),3.81-3.73(m,2H),3.38- 3.33(m,1H),3.29-3.14(m,3H),3.08-2.96(m,1H),2.40-2.11(m,3H),2.07-1.83(m,3H).

[0164] Example 6 [ka] Step 1: Synthesis of Compound 006-2 Compound 006-1 (0.3 g, 1.07 mmol) and compound 003-1D (246.50 mg, 1.17 mmol) were added to anhydrous dichloromethane (5 mL). Triethylamine (323.52 mg, 3.20 mmol, 445.01 μL) was added. The mixture was reacted at 18 °C for 1 hour. After the reaction was completed, the reaction solution was diluted with 5 mL of dichloromethane. The mixture was washed with saturated ammonium chloride (10 mL × 2), followed by 10 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product. The crude product was stirred with a mixed solvent (petroleum ether:methyl tert-butyl ether = 4:1, 10 mL) for 1 hour and filtered. The filter cake was rinsed with the mixed solvent in the same ratio (3 mL × 2) and dried to obtain compound 006-2. LCMS m / z (ESI) = 455.0 [M+H] + . 1 H NMR(400MHz,CDCl3)δ=6.69(d,J=5.6Hz,1H),6.04(s,2H),4.60(s,2H),3.92(s,3H),3.83-3.43(m,3H),3.19-2.89(m,1H),1.52(s,9H).

[0165] Step 2: Synthesis of Compound 006-3 Compound 006-2 (0.3 g, 658.89 μmol) was added to anhydrous tetrahydrofuran (1.5 mL) and N,N-dimethylformamide (1.5 mL). Cesium carbonate (644.04 mg, 1.98 mmol), compound 001-4A (125.88 mg, 790.67 μmol), and triethylenediamine (22.17 mg, 197.67 μmol, 21.74 μL) were added. The mixture was reacted at 25 °C for 17 h. After the reaction was complete, the reaction solution was added to 10 mL of methyl tert-butyl ether. The mixture was washed with 10 mL of water, followed by 10 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:0 to 1:2, dichloromethane:methanol = 10:1) to give compound 006-3. LCMS m / z(ESI)=578.2[M+H] + .1 H NMR(400MHz,CDCl3)δ=6.49(d,J=5.2Hz,1H),5.99(s,2H),5.37-5.16(m,1 H),4.57(s,2H),4.16(d,J=10.4Hz,1H),4.00(d,J=10.0Hz,1H),3.88(s,4H) ),3.70-3.57(m,1H),3.54-3.41(m,1H),3.30-3.18(m,3H),3.18-3.09(m, 1H),3.02-2.95(m,1H),2.32-2.07(m,3H),1.98-1.79(m,3H),1.52(s,9H).

[0166] Step 3: Synthesis of Compound 006-4 Compound 006-3 (0.3 g, 518.99 μmol), compound 001-5A (393.41 mg, 622.78 μmol), and potassium phosphate (220.33 mg, 1.04 mmol) were added to 1,4-dioxane (3 mL) and water (0.6 mL). The atmosphere was replaced with nitrogen three times, and (2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenylyl)[2-(2'-amino-1,1'-biphenylyl)]palladium(II) chloride (37.40 mg, 51.90 μmol) was added under nitrogen. The mixture was heated to 100°C and reacted for 1.5 hours. After completion of the reaction, the reaction solution was diluted with 10 mL of ethyl acetate, washed with 10 mL of water and 10 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:0 to 1:2, dichloromethane:methanol = 10:1) to give compound 006-4. LCMS m / z (ESI) = 1047.5 [M+H] + .

[0167] Step 4: Synthesis of compound 006-5 hydrochloride Compound 006-4 (0.3 g, 286.44 μmol) was added to hydrochloric acid / methanol (5 mL). The mixture was reacted at 18° C. for 3 hours. After the reaction was completed, the reaction solution was directly concentrated. The crude product was stirred with 10 mL of ethyl acetate for 1 hour and then filtered. The filter cake was rinsed with ethyl acetate (2 mL×2) and dried to obtain compound 006-5 hydrochloride. LCMS m / z (ESI) = 783.3 [M+H] + .

[0168] Step 5: Synthesis of Compound 006 Compound 006-5 (0.16 g, 195.25 μmol, hydrochloride salt) was added to N,N-dimethylformamide (2 mL). Potassium carbonate (269.85 mg, 1.95 mmol) and cesium fluoride (59.32 mg, 390.50 μmol, 14.40 μL) were added. The mixture was reacted at 60° C. for an additional 16 hours. After the reaction was completed, 20 mL of water was added to the reaction mixture. The mixture was extracted with ethyl acetate (10 mL×2). The combined organic phase was washed with saturated brine (20 mL×3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude compound. The crude product was purified by preparative high-performance liquid chromatography (column: P Phenomenex Luna 80 x 30 mm x 3 μm; mobile phase A: water (0.05% hydrochloric acid), mobile phase B: acetonitrile; gradient run: B%: 1% to 35%, run for 8 min). The fractions were adjusted to approximately pH 9 by dropwise addition of ammonia and then concentrated under reduced pressure to remove acetonitrile. The residue was extracted with ethyl acetate (20 mL x 2) and concentrated under reduced pressure to give compound 006. LCMS m / z (ESI) = 627.2 [M+H] + . 1H NMR(400MHz,CD3OD)δ=7.76(dd,J=5.8,9.2Hz,1H),7.30-7.20(m,2H),7.08(d,J=2.4Hz,1 H),6.84(d,J=5.2Hz,1H),6.40-6.28(m,2H),5.65-5.44(m,1H),4.72-4.50(m,5H),4.49- 4.33(m,1H),4.07-4.00(m,1H),3.98(s,4H),3.94-3.78(m,3H),3.48-3.38(m,1H),3.35- 3.381(m,1H),2.75-2.54(m,2H),2.50-2.40(m,1H),2.37-2.27(m,2H),2.21-2.08(m,1H).

[0169] Example 7 [ka] Step 1: Synthesis of Compound 007-2 Compound 001-5 (0.05 g, 79.76 μmol), compound 005-1A (53.14 mg, 103.68 μmol), and potassium phosphate (50.79 mg, 239.27 μmol) were added to 1,4-dioxane (1.5 mL) and water (0.3 mL). The atmosphere was replaced with nitrogen three times, and chloro[(bis(1-adamantyl)-n-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (5.33 mg, 7.98 μmol) was added under nitrogen. The mixture was reacted at 100° C. for 1 hour under nitrogen. The reaction solution was diluted with 5 mL of ethyl acetate and washed with 10 mL of water. The aqueous phase was extracted with 5 mL of ethyl acetate. The organic phases were combined, washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give compound 007-2. LCMS m / z(ESI)=932.4[M+H] + .

[0170] Step 2: Synthesis of compound 007-3 Compound 007-2 (0.06 g, 64.34 μmol) was added to HCl / methanol (3 mL, 4 M). The mixture was reacted at 18° C. for 2 hours. The reaction solution was concentrated. The crude product was stirred with 5 mL of ethyl acetate for 16 hours and then filtered. The filter cake was rinsed with 2 mL of ethyl acetate and dried to obtain compound 007-3 hydrochloride. LCMS m / z (ESI) = 788.3 [M+H] + .

[0171] Step 3: Synthesis of Compound 007 Hydrochloride Compound 007-3 (0.06 g, hydrochloride salt) was added to N,N-dimethylformamide (1.5 mL). Potassium carbonate (100.53 mg, 727.38 μmol) and cesium fluoride (22.10 mg, 145.48 μmol, 5.36 μL) were added. The mixture was reacted at 60° C. for 16 hours. Additional potassium carbonate (0.1 g) and cesium fluoride (22 mg) were added, and the mixture was reacted for an additional 20 hours. 5 mL of water was added to the reaction mixture. The mixture was extracted with ethyl acetate (3 mL × 2). The combined organic phase was washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by preparative high-performance liquid chromatography (column: Phenomenex Luna 80 x 30 mm x 3 μm; mobile phase A: water (0.05% hydrochloric acid), mobile phase B: acetonitrile; gradient run B%: 1% to 35%; analysis time: 8 min) to give compound 007 hydrochloride. LCMS m / z (ESI) = 632.2 [M+H] + .

[0172] Example 8 [ka] Step 1: Synthesis of Compound 008-1 Compound 002-3 (0.5 g, 795.51 μmol), compound 005-1A (611.59 mg, 1.19 mmol), and potassium phosphate (506.59 mg, 2.39 mmol) were added to anhydrous toluene (5 mL) and water (1 mL). The atmosphere was replaced with nitrogen three times, and chloro[(bis(1-adamantyl)-n-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (53.19 mg, 79.55 μmol) was added under nitrogen. The mixture was reacted at 80 °C for 16 h. 10 mL of water was added to the reaction mixture, which was then extracted with ethyl acetate (10 mL × 2). The combined organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:0 to 0:1) to give compound 008-1. LCMS m / z(ESI)=934.5[M+H] + . 1 H NMR(400MHz,CDCl3)δ=7.77(dd,J=5.6,9.2Hz,1H),7.65(d,J=7.6Hz,2H),7.50(d,J=2.4Hz ,1H),7.41-7.28(m,4H),7.27-7.24(m,1H),7.20(d,J=2.0Hz,1H),6.20-5.91(m,2H),5.38 -5.13(m,3H),4.69-4.59(m,1H),4.23-4.15(m,1H),4.08-3.99(m,1H),3.97-3.90(m,1H), 3.88-3.78(m,2H),3.70(s,1H),3.52(s,3H),3.50-3.43(m,1H),3.30-3.20(m,2H),3.15(br s,1H),3.01-2.91(m,1H),2.33-2.11(m,3H),1.99-1.81(m,3H),1.33(d,J=10.8Hz,6H),0.96-0.76(m,18H),0.63-0.49(m,3H).

[0173] Step 2: Synthesis of Compound 008-2 Hydrochloride Compound 008-1 (0.4 g, 428.18 μmol) was added to trifluoroacetic acid (5 mL). The mixture was reacted at 70° C. for 1 hour. The reaction solution was concentrated, and 10 mL of ethyl acetate was added to the concentrated reaction solution. The mixture was washed successively with 10 mL of water, 20 mL of saturated sodium bicarbonate, and 10 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was then concentrated to give compound 008-2 hydrochloride. LCMS m / z (ESI) = 772.3 [M+H] + .

[0174] Step 3: Synthesis of Compound 008A and Compound 008B Compound 008-2 (0.35 g, hydrochloride salt) was added to N,N-dimethylformamide (4 mL). Potassium carbonate (313.32 mg, 2.27 mmol) and cesium fluoride (137.74 mg, 906.78 μmol, 33.43 μL) were added. The mixture was reacted at 60 °C for 8 h. The reaction solution was diluted with 10 mL of ethyl acetate and washed with 10 mL of water. The aqueous phase was extracted with 5 mL of ethyl acetate. The combined organic phases were washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the crude product was purified by preparative high-performance liquid chromatography (Phenomenex Luna 80 x 30 mm x 3 μm column; mobile phase A: water (0.05% hydrochloric acid), mobile phase B: acetonitrile; gradient run: B: 1% to 30%; analysis time: 8 min). The fraction solution was adjusted to pH 7 by adding aqueous ammonia and then purified by supercritical fluid chromatography (SFC) (column: DAICEL CHIRALPAK IG (250 mm × 30 mm, 10 μm); mobile phase: A (supercritical CO) and B (isopropyl alcohol containing 0.1% ammonia); gradient run: 50%–50%; analysis time: 17 min) to give compounds 008A and 008B.

[0175] The analysis and characterization of compound 008A was as follows:

[0176] SFC analytical method (Column: Chiralpak IG-3, 50 × 4.6 mm i.d., 3 μm; Mobile phase: A (supercritical CO), B: (ethanol containing 0.1% isopropylamine); Gradient: B% = 5 to 50%, 3 min; Flow rate: 3.4 mL / min; Wavelength: 220 nm; Pressure: 1800 psi, Rt = 1.449 min, Enantiomeric excess: 100%. LCMS: MS m / z (ESI) = 616.2 [M+H] + . 1 H NMR(400MHz,CD3OD)δ=7.84(dd,J=6.0,9.2Hz,1H),7.50(dd,J=1.6,10.0Hz,1H),7 .35-7.30(m,2H),7.10(d,J=2.8Hz,1H),6.32-6.25(m,2H),5.41-5.23(m,1H),4.53 -4.36(m,2H),4.30-4.14(m,2H),4.05-3.95(m,2H),3.84-3.68(m,2H),3.39-3.33( m,1H),3.29-3.19(m,3H),3.09-3.00(m,1H),2.41-2.10(m,3H),2.06-1.85(m,3H).

[0177] The analysis and characterization of compound 008B was as follows:

[0178] SFC analytical method (Column: Chiralpak IG-3, 50 × 4.6 mm i.d., 3 μm; Mobile phase: A (supercritical CO), B: (ethanol containing 0.1% isopropylamine); Gradient: B% = 5 to 50%, 3 min; Flow rate: 3.4 mL / min; Wavelength: 220 nm; Pressure: 1800 psi, Rt = 2.084 min, Enantiomeric excess: 93.62%). LCMS: MS m / z (ESI) = 616.2 [M+H] + . 1H NMR(400MHz,CD3OD)δ=7.84(dd,J=6.0,9.2Hz,1H),7.53-7.46(m,1H),7.35-7.2 7(m,2H),7.10(d,J=2.0Hz,1H),6.32-6.25(m,2H),5.40-5.20(m,1H),4.51-4.36 (m,2H),4.27-4.12(m,2H),4.01-3.95(m,2H),3.83-3.69(m,2H),3.37-3.32(m, 1H),3.29-3.15(m,3H),3.07-2.96(m,1H),2.37-2.10(m,3H),2.06-1.87(m,3H).

[0179] Example 9 [ka] Step 1: Synthesis of Compound 009-1 Compound 003-1 (0.5 g, 1.69 mmol), anhydrous dichloromethane (10 mL), triethylamine (512.92 mg, 5.07 mmol, 705.52 μL), and compound 009-1A (170.54 mg, 811.02 μmol) were added to a reaction flask. The mixture was stirred at 15° C. for 1 hour. This reaction mixture was combined with a 0.1 g batch of compound 003-1 for workup. Water (10 mL) was added, and the mixture was extracted with dichloromethane (10 mL×3). The combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give compound 009-1. LCMS m / z=389.0 [M+H] + . 1 H NMR(400MHz,CDCl3)δ ppm:7.55(dd,J=8.8,6.0Hz,1H),7.40-7.33(m,1H),7.12-6.90(m,1H),3. 85-3.71(m,2H),2.42-2.25(m,8H),1.93-1.73(m,2H),1.72-1.60(m,2H).

[0180] Step 2: Synthesis of Compound 009-2 Compound 009-1 (0.4 g, 1.03 mmol) and dioxane (4.0 mL) were added to a reaction flask. Compound 001-4A (492.78 mg, 3.10 mmol) and cesium carbonate (1.01 g, 3.10 mmol) were added. The mixture was stirred at 140 °C for 12 hours using a microwave. The reaction mixture was filtered, and the filter cake was rinsed with 10 mL of ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (column: Phenomenex Luna C18 250 × 50 mm × 10 μm; mobile phase A: water (0.05% hydrochloric acid), mobile phase B: acetonitrile; gradient run: B%: 5% to 35%, run for 10 min) to obtain the target compound 009-2. LCMS m / z = 510.3 [M+H] + . 1 H NMR(400MHz,CDCl3)δ ppm 7.36-7.31(m,1H),7.30-7.25(m,1H),6.70(br s,1H),5.41-5.11(m,1H),4.37-4.15(m,2H),3.85-3.65(m,2H),3.33-3.19(m,2H),3. 18(s,1H),3.07-2.89(m,1H),2.39-2.27(m,8H),2.25-2.17(m,2H),2.01-1.59(m,8H).

[0181] Step 3: Synthesis of Compound 009-3 A reaction flask was charged with compound 009-2 (130 mg, 254.69 μmol), anhydrous tetrahydrofuran (2.6 mL), water (0.65 mL), anhydrous potassium phosphate (162.19 mg, 764.08 μmol), and compound 001-5A (482.67 mg, 764.08 μmol). The atmosphere was replaced with nitrogen three times, and [n-butylbis(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) mesylate (18.55 mg, 25.47 μmol) was added. The atmosphere was replaced with nitrogen three times, and the mixture was heated to 60°C and stirred for 16 hours. Additional compound 001-5A (18.55 mg, 25.47 μmol) was added. The atmosphere was replaced with nitrogen three times, and the mixture was stirred at 60°C for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove the solvent. The residue was dissolved in 10 mL of ethyl acetate and washed once with 10 mL of water. 1N hydrogen chloride solution (10 mL) was added to the organic phase. The mixture was stirred for 10 minutes. The aqueous phase was collected and adjusted to about pH 9 with sodium carbonate. The mixture was extracted with dichloromethane (10 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give compound 009-3. LCMS m / z = 771.4 [M+H] + .

[0182] Step 4: Synthesis of Compound 009 Compound 009-3 (178 mg) was added to N,N-dimethylformamide (2 mL). Anhydrous potassium carbonate (159.53 mg, 1.15 mmol) and cesium fluoride (175.34 mg, 1.15 mmol, 42.56 μL) were added. The mixture was stirred at 65 °C for 4 hours. This reaction mixture was combined with a 24 mg batch of compound 009-3 for workup. The reaction mixture was cooled to room temperature and then filtered. The filter cake was rinsed with 20 mL of ethyl acetate. The mother liquor was washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product, which was purified by preparative high-performance liquid chromatography (Phenomenex Luna 80 × 30 mm × 3 μm column; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile %: 1% to 30%, 8 min). The resulting fraction was adjusted to approximately pH 9 by adding aqueous ammonia, concentrated, and purified by preparative high-performance liquid chromatography (Waters Xbridge BEH C18 100 x 30 mm x 10 μm column; mobile phase: [water (10 mM ammonium bicarbonate)-acetonitrile]; acetonitrile %: 35%-60%, 8 min) to obtain compound 009. LCMS m / z = 615.5 [M+H] + . 1 H NMR(400MHz,CDCl3)δ ppm 7.66(dd,J=8.8,5.6Hz,1H),7.46-7.33(m,1H),7.24-7.13(m,2H),7.08(d,J=2.4Hz,1H),6.94(d,J=2.0Hz,1H),6.71(br s,1H),5.40-5.18(m,1H),4.38-4.16(m,2H),3.90(s,2H),3.80(br s,2H),3.31-3.22(m,2H),3.19(br s,1H),3.07-2.91(m,1H),2.78(s,1H),2.56-2.26(m,8H),2.25(br s,2H),2.01-1.61(m,8H).

[0183] Example 10 [ka] Step 1: Synthesis of Compound 010-12 Compound 010-11 (30 g, 144.23 mmol) and silver sulfate (44.97 g, 144.23 mmol, 24.44 mL) were dissolved in ethanol (300 mL). Iodine (40.27 g, 158.65 mmol, 31.96 mL) was then added. The mixture was stirred at 25 °C for 2 h. After completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified on a silica gel column (gradient elution: petroleum ether: ethyl acetate = 100:1 to 20:1) to obtain compound 010-12.

[0184] Step 2: Synthesis of Compound 010-13 Compound 010-12 (22 g, 65.89 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride dichloromethane (5.38 g, 6.59 mmol) were dissolved in methanol (100 mL) under a carbon monoxide atmosphere at 50 Psi pressure and 30 °C. The mixture was stirred for 5 minutes, and then triethylamine (46.67 g, 461.22 mmol, 64.20 mL) was added. The mixture was stirred for an additional 24 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified on a silica gel column (gradient elution: petroleum ether: ethyl acetate = 20:1 to 5:1) to give compound 010-13. LCMS: (ESI) m / z = 265.8 [M+H] + .

[0185] Step 3: Synthesis of Compound 010-14 Compound 010-13 (15 g, 56.38 mmol) was dissolved in methanol (50 mL). A solution of sodium hydroxide (9.02 g, 225.53 mmol) in water (50 mL) was added. The mixture was stirred at 25° C. for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and adjusted to pH 5 using 2 mol / L hydrochloric acid. A white solid was precipitated and suction filtered under reduced pressure to obtain compound 010-14. LCMS: (ESI) m / z=251.8 [M+H] + .

[0186] Step 4: Synthesis of Compound 010-15 Compound 010-14 (12 g, 47.62 mmol) and urea (85.79 g, 1.43 mol, 76.60 mL) were added to a reaction flask. The mixture was reacted at 200° C. for 4 hours. The reaction solution was cooled to room temperature. 200 mL of water was added and the mixture was stirred. The mixture was suction filtered under reduced pressure to obtain a filter cake, which was compound 010-15. LCMS: (ESI) m / z=276.9 [M+H] + .

[0187] Step 5: Synthesis of Compound 002-1 N,N-Diisopropylethylamine (11.66 g, 90.25 mmol, 15.72 mL) was added dropwise to phosphorus oxychloride (82.50 g, 538.05 mmol, 50 mL) at 0 °C, followed by the batchwise addition of compound 010-15 (5 g, 18.05 mmol). After the addition was complete, the mixture was refluxed at 80 °C for 20 h and then concentrated under reduced pressure. The crude product was purified on a silica gel column (gradient elution: petroleum ether: ethyl acetate = 20:1 to 10:1) to give compound 002-1. LCMS: (ESI) m / z = 312.9 [M+H] + .

[0188] Step 6: Synthesis of Compound 010-17 Compound 010-16A (1.2 g, 3.82 mmol) was dissolved in N,N-dimethylformamide (2 mL). Compound 002-1 (811.51 mg, 3.82 mmol) and N,N-diisopropylethylamine (1.48 g, 11.47 mmol, 2.00 mL) were added. The mixture was stirred and reacted at 25° C. for 2 hours. The reaction solution was poured into 50 mL of water to precipitate a solid. The solid was washed with water (3×20 mL) to obtain compound 010-17. LCMS: (ESI) m / z=489.0 [M+H] + .

[0189] Step 7: Synthesis of Compound 010-7A Compound 010-17 (1.6 g, 3.27 mmol) was dissolved in N,N-dimethylformamide (10 mL) and tetrahydrofuran (10 mL). Then, cesium carbonate (3.19 g, 9.80 mmol), compound 001-4A (780.17 mg, 4.90 mmol), and triethylenediamine (36.65 mg, 326.70 μmol, 35.93 μL) were added. The mixture was stirred and reacted at 25 °C for 18 h. After the reaction was completed, it was extracted with 40 mL of ethyl acetate and washed with water (15 mL) and saturated brine (15 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to obtain the crude product. The crude product was purified on a silica gel column (gradient elution: petroleum ether: ethyl acetate = 20:1 to 10:1) to obtain compound 010-7A. LCMS: (ESI) m / z=612.2 [M+H] + .

[0190] Step 8: Synthesis of Compound 010-2 Anhydrous tetrahydrofuran (200 mL) and zinc powder (22.47 g, 343.62 mmol) were added to a pre-dried reaction flask. Trimethylchlorosilane (2.49 g, 22.91 mmol, 2.91 mL) was added with stirring under nitrogen, and the mixture was then warmed to 45 °C. A solution of tert-butyl bromoacetate (37.98 g, 194.72 mmol, 28.77 mL) in anhydrous tetrahydrofuran (60 mL) was added dropwise, followed by compound 010-1 (19.6 g, 114.54 mmol) under nitrogen. The mixture was stirred at 45 °C for 2 hours. The reaction was cooled to room temperature and filtered through diatomaceous earth. The filter cake was rinsed with 200 mL of tetrahydrofuran. 200 mL of 1 M hydrochloric acid solution was added to the mother liquor, and the mixture was stirred for 2 hours. The mixture was then concentrated under reduced pressure to remove tetrahydrofuran, and the residue was extracted with 50 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give compound 010-2. 1 H NMR(400MHz,CDCl3)δ ppm 7.08-6.85(m,2H),3.89(s,2H),3.55-3.40(m,2H),1.48(s,9H).

[0191] Step 9: Synthesis of Compound 010-3 Compound 010-2 (26.8 g, 92.97 mmol) and trifluoromethanesulfonic acid (455.60 g, 3.04 mol, 268.00 mL) were added to a pre-dried reaction flask. The mixture was stirred at 80 °C for 4 h. The reaction solution was cooled to room temperature and then slowly poured into 4 L of saturated aqueous sodium bicarbonate solution. Ice was added to control the temperature below 10 °C. The mixture was quenched and then stirred for 10 min (aqueous phase pH = 7-8), extracted with ethyl acetate (1 L × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (gradient elution: petroleum ether: ethyl acetate = 100:0 to 90:10). The fractions were concentrated to dryness, and 100 mL of petroleum ether was added. The mixture was stirred overnight, and then the supernatant was removed. The mixture was dried to obtain compound 010-3. LCMS m / z=213.0[MH] - . 1 H NMR(400MHz,DMSO-d6)δ ppm 10.63(s,1H),9.99(s,1H),7.72-7.56(m,1H),6.65(d,J=2.0Hz,1H),6.59(d,J=2.0Hz,1H).

[0192] Step 10: Synthesis of Compound 010-4 A pre-dried reaction flask was charged with compound 010-3 (15 g, 70.05 mmol), (2-bromoethynyl)triisopropylsilane (20.13 g, 77.05 mmol), dioxane (150 mL), and potassium acetate (13.75 g, 140.09 mmol). The atmosphere was flushed with nitrogen three times, and bis(4-methylisopropylphenyl)ruthenium(II) dichloride (6.43 g, 10.51 mmol) was added. The atmosphere was flushed with nitrogen three times, and the mixture was heated to 110 °C and stirred for 2 hours. The reaction mixture was cooled to room temperature. This reaction mixture was combined with a batch of compound 010-3 (1.0 g) for workup. The mixture was cooled to room temperature and filtered. The filter cake was rinsed with 200 mL of ethyl acetate. The mother liquor was concentrated under reduced pressure to remove the solvent and then dissolved in 200 mL of ethyl acetate. The solution was washed twice with 100 mL of water and twice with 100 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product. The crude compound was purified by silica gel column chromatography (gradient elution: petroleum ether: ethyl acetate = 100:0 to 90:10) to give compound 010-4. LCMS m / z = 393.2 [M−H] - . 1 H NMR(400MHz,DMSO-d6)δ ppm 10.53(s,1H),10.08(s,1H),6.67(d,J=2.0Hz,1H),6.63(d,J=2.0Hz,1H),1.11(s,21H).

[0193] Step 11: Synthesis of Compound 010-5 Compound 010-4 (15 g, 38.02 mmol), anhydrous dichloromethane (300 mL), and N,N-diisopropylethylamine (19.66 g, 152.09 mmol, 26.49 mL) were added to a pre-dried reaction flask. Trifluoromethanesulfonic anhydride (22.53 g, 79.85 mmol, 13.17 mL) was added in three portions, and the mixture was stirred at 0 °C for 0.5 h. This reaction mixture was combined with a batch of compound 010-4 (1 g) for workup. 200 mL of saturated ammonium chloride solution was added to the reaction mixture. The mixture was stirred for 5 min, washed once with 200 mL of saturated ammonium chloride, then twice with half-saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product. The crude compound was purified by silica gel column chromatography (gradient elution: petroleum ether: ethyl acetate = 100:0 to 95:5) to obtain compound 010-5. LCMS m / z = 657.1 [M−H] - . 1 H NMR(400MHz,DMSO-d6)δ ppm 8.56(d,J=2.4Hz,1H),8.21(d,J=2.0Hz,1H),1.29-1.04(m,21H).

[0194] Step 12: Synthesis of Compound 010-6 A pre-dried reaction flask was charged with compound 010-5 (19 g, 28.85 mmol), diphenylmethanimine (6.27 g, 34.62 mmol, 5.81 mL), dioxane (190 mL), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (3.34 g, 5.77 mmol), and cesium carbonate (18.80 g, 57.70 mmol). The atmosphere was flushed with nitrogen three times, and tris(dibenzylideneacetone)dipalladium(0) (2.64 g, 2.88 mmol) was added. The atmosphere was flushed with nitrogen three times, and the mixture was stirred at 90 °C for 2 h. The reaction was cooled to room temperature and filtered. The filter cake was rinsed with 50 mL of ethyl acetate. The mother liquor was concentrated under reduced pressure to remove the solvent, and the residue was dissolved in 100 mL of ethyl acetate. The solution was washed with 50 mL of water and saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain the crude product. 60 mL of ethanol was added to the crude product. The mixture was stirred for 48 hours and then filtered. The filter cake was rinsed with 20 mL of ethanol. The filter cake was collected and dried to obtain compound 010-6. 1 H NMR(400MHz,CDCl3)δ ppm 7.88-7.70(m,2H),7.55(t,J=7.0Hz,1H),7.46(t,J=7.6Hz,2H),7.34-7.21(m,5H),7.17-7.11(m,2H),1.27-1.10(m,21H).

[0195] Step 13: Synthesis of Compound 010-7 A pre-dried reaction flask was charged with compound 010-6 (1 g, 1.45 mmol), dioxane (10 mL), potassium acetate (426.84 mg, 4.35 mmol), bis(pinacolato)diboron (1.10 g, 4.35 mmol, 42.07 μL), and 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (138.22 mg, 289.95 μmol). The atmosphere was flushed with nitrogen three times, and 1,1-bis(diphenylphosphino)ferrocene palladium chloride (106.08 mg, 144.97 μmol) was added. The atmosphere was flushed with nitrogen three times. The mixture was heated to 120°C and stirred for 2 hours. This reaction mixture was combined with batches of compound 010-6 (0.5 g and 0.1 g) for further workup. The reaction mixture was cooled to room temperature and filtered. The mother liquor was concentrated to 1 / 2 under reduced pressure. 30 mL of ethyl acetate was added. The mixture was washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product. The crude product was separated by column chromatography (1000 mesh silica gel, gradient elution with ethyl acetate: petroleum ether = 0%, 2%, 3%, 4%, 5%) to give compound 010-7. 1 H NMR(400MHz,CDCl3)δ ppm 7.84-7.72(m,2H),7.55-7.39(m,2H),7.32-7.22(m,6H),7.15(br d,J=6.6Hz,2H),1.35(s,12H),1.21-1.11(m,21H).

[0196] Step 14: Synthesis of Compound 010-8 Compound 010-7A (250 mg, 408.18 μmol), anhydrous toluene (6 mL), water (1.25 mL), anhydrous potassium phosphate (259.93 mg, 1.22 mmol), and compound 010-7 (408.80 mg, 612.26 μmol) were added to a pre-dried reaction flask. The atmosphere was replaced with nitrogen three times, and [(bis(1-adamantyl)-n-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) chloride (27.29 mg, 40.82 μmol) was added. The atmosphere was replaced with nitrogen three times, and the mixture was heated to 105°C and stirred for 24 hours. The reaction mixture was cooled to room temperature. This reaction mixture was combined with a batch of compound 010-7A (20 mg) for workup. The mixture was concentrated under reduced pressure to remove the solvent, and the residue was dissolved in 200 mL of ethyl acetate. The organic phase was washed twice with 10 mL of water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product. The crude compound was purified by silica gel column chromatography (gradient elution: petroleum ether: ethyl acetate = 100:0 to 50:50, triethylamine in ethyl acetate 5 parts / 1000) to obtain compound 010-8. LCMS m / z = 1073.4 [M+H] + .

[0197] Step 15: Synthesis of Compound 010-9 Hydrochloride Compound 010-8 (0.3 g, 279.51 μmol) was added with hydrogen chloride / methanol (4 M, 3.75 mL). The mixture was stirred at 15° C. for 1 hour. This reaction mixture was combined with a batch of compound 010-8 (40 g) for workup. The reaction mixture was concentrated to dryness under reduced pressure to give compound 010-9 hydrochloride. LCMS m / z=809.5 [M+H] + .

[0198] Step 16: Synthesis of Compounds 010A and 010B Compound 010-9 (0.28 g, hydrochloride salt), N,N-dimethylformamide (2.8 mL), anhydrous potassium carbonate (712.40 mg, 5.15 mmol), and cesium fluoride (195.74 mg, 1.29 mmol, 47.51 μL) were added to a pre-dried reaction flask. The mixture was stirred at 65 °C for 4 hours. This reaction mixture was combined with a batch of compound 010-9 (50 mg) for workup. The reaction mixture was cooled to room temperature and filtered. The filter cake was rinsed with 20 mL of ethyl acetate. The mother liquor was washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by preparative high-performance liquid chromatography (column: Phenomenex Luna C18 OBD 80 × 40 mm × 3 μm; mobile phase A: water (0.05% HCl), mobile phase B: acetonitrile; gradient run: B%: 5% to 40%, run for 7 min). The fractions were adjusted to approximately pH 9 by dropwise addition of ammonia and then concentrated under reduced pressure to remove acetonitrile. The residue was extracted twice with 20 mL of ethyl acetate and concentrated under reduced pressure to obtain a mixture. The mixture was purified by supercritical fluid chromatography (column: DAICEL CHIRALPAK IC (250 mm × 30 mm, 10 μm); mobile phase: A (supercritical CO2) and B (isopropyl alcohol with 0.1% ammonia); gradient run: B% = 60% to 60%, run for 15 min) to obtain compounds 010A and 010B.

[0199] The characteristics of compound 010A were as follows:

[0200] SFC analytical method: Column: Chiralpak IC-3, 3 μm, 50 × 4.6 mm ID; Mobile phase: A (supercritical CO2) and B (isopropyl alcohol containing 0.1% isopropylamine); Gradient: A:B = 60:40%, 3 min; Flow rate: 4.0 mL / min; Wavelength: 220 nm; Column temperature: 35 °C; Pressure: 1800 psi, Rt = 0.881 min, Enantiomeric excess: 100%. LCMS m / z = 653.3 [M+H] + . 1H NMR(400MHz,CDCl3)δ ppm 7.31-7.28(m,2H),6.98-6.94(m,1H),5.41-5.19(m,1H),4.43-4.30(m,2H),4.30-4.25(m,1H),4.21-4.04(m,3H),3.67(s,2H),3.6 2-3.43(m,2H),3.34-3.24(m,2H),3.19(s,1H),3.04-2.95(m,1H),2.79(s,1H),2.31(s,1H),2.26-2.16(m,2H),2.02-1.82(m,8H).

[0201] The characteristics of compound 010B were as follows:

[0202] SFC analytical method: Column: Chiralpak IC-3, 3 μm, 50 × 4.6 mm ID; Mobile phase: A (supercritical CO2) and B (isopropyl alcohol containing 0.1% isopropylamine); Gradient: A:B = 60:40%, 3 min; Flow rate: 4.0 mL / min; Wavelength: 220 nm; Column temperature: 35 °C; Pressure: 1800 psi, Rt = 1.364 min, Enantiomeric excess: 96.69%. LCMS m / z = 653.3 [M+H] + . 1 H NMR(400MHz,CDCl3)δ ppm 7.29(d,J=2.0Hz,2H),6.96(d,J=2.0Hz,1H),5.47-5.12(m,1H),4.36(br t,J=14.0Hz,2H),4.26(d,J=10.4Hz,1H),4.17(br d,J=10.4Hz,1H),4.11(br s,2H),3.67(br s,2H),3.53(br t,J=10.8Hz,2H),3.38-3.24(m,2H),3.24-3.15(m,1H),3.09-2.90(m,1H),2.80(s,1H),2.31(br s,1H),2.27-2.15(m,2H),2.06-1.81(m,8H).

[0203] Example 11 [ka] Step 1: Synthesis of Compound 011-1 Compound 011-1A (0.2 g, 318.00 μmol), anhydrous toluene (5 mL), water (1.25 mL), anhydrous potassium phosphate (202.50 mg, 953.99 μmol), and compound 010-7 (318.48 mg, 477.00 μmol) were added to a pre-dried reaction flask. The atmosphere was flushed with nitrogen three times, and [(bis(1-adamantyl)-n-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) chloride (21.26 mg, 31.80 μmol) was added. The atmosphere was flushed with nitrogen three times, and the mixture was heated to 105°C and stirred for 24 hours. The reaction mixture was cooled to room temperature. This reaction mixture was combined with a batch of compound 011-1A (20 mg) for workup. The mixture was concentrated under reduced pressure to remove the solvent, and the residue was dissolved in 10 mL of ethyl acetate. The organic phase was washed twice with 10 mL of water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product. The crude compound was purified by silica gel column chromatography (gradient elution: petroleum ether: ethyl acetate = 100:0 to 40:60, triethylamine in ethyl acetate 5 parts / 1000) to obtain compound 011-1. LCMS m / z = 1089.2 [M+H] + .

[0204] Step 2: Synthesis of Compound 011-2 Hydrochloride Compound 011-1 (250 mg, 229.41 μmol) was added with hydrogen chloride / methanol (4 M, 6.25 mL). The mixture was stirred at 15° C. for 1 hour. This reaction mixture was combined with a batch of compound 011-1 (20 g) for workup. The reaction mixture was concentrated under reduced pressure to give compound 011-2 hydrochloride. LCMS m / z=825.2 [M+H] +

[0205] Step 3: Synthesis of Compound 011A and Compound 011B Compound 011-2 (220 mg, hydrochloride salt), N,N-dimethylformamide (4 mL), anhydrous potassium carbonate (499.11 mg, 3.61 mmol), and cesium fluoride (137.14 mg, 902.81 μmol, 33.29 μL) were added to a pre-dried reaction flask. The mixture was stirred at 65° C. for 4 hours. This reaction mixture was combined with a batch of compound 011-2 (50 mg) for workup. The reaction mixture was cooled to room temperature and filtered. The filter cake was rinsed with 20 mL of ethyl acetate. The mother liquor was washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product. The crude product was analyzed by preparative high-performance liquid chromatography (column: Phenomenex Luna C18 OBD 80 × 30 mm × 3 μm; mobile phase A: water (0.05% HCl), mobile phase B: acetonitrile; gradient run: B%: 15% to 50%, run for 8 min). Fractions were collected and adjusted to approximately pH 9 by dropwise addition of ammonia, then concentrated under reduced pressure to remove acetonitrile. The residue was extracted twice with 20 mL of ethyl acetate and concentrated under reduced pressure to obtain a mixture. The mixture was purified by supercritical fluid chromatography (column: DAICEL CHIRALPAK IC (250 mm × 30 mm, 10 μm); mobile phase: A (supercritical CO2) and B (isopropyl alcohol with 0.1% ammonia); gradient run: B% = 50% to 50%, run for 15 min) to obtain compounds 011A and 011B.

[0206] The characteristics of compound 011A were as follows:

[0207] SFC analytical method: Column: Chiralpak IC-3, 3 μm, 50 × 4.6 mm ID; Mobile phase: A (supercritical CO2) and B (isopropyl alcohol with 0.1% isopropylamine); Gradient: A:B = 50:50, 3 min; Flow rate: 3.4 mL / min; Wavelength: 220 nm; Column temperature: 35 °C; Pressure: 1800 psi, Rt = 1.656 min, Enantiomeric excess: 100%. LCMS m / z = 669.3 [M+H] + . 1H NMR(400MHz,CDCl3)δ ppm 7.64(s,1H),7.31(br s,1H),6.90(s,1H),5.42-5.19(m,1H),4.48-4.33(m,2H),4.29(br d,J=10.4Hz,1H),4.17(br d,J=10.4Hz,1H),4.11(s,2H),3.68(br s,2H),3.56(br dd,J=18.2,12.6Hz,2H),3.38-3.25(m,2H),3.21(br s,1H),3.01(br s,1H),2.76(s,1H),2.32(br s,1H),2.28-2.15(m,2H),2.01-1.79(m,8H).

[0208] The characteristics of compound 011B were as follows:

[0209] SFC analytical method: Column: Chiralpak IC-3, 3 μm, 50 × 4.6 mm ID; Mobile phase: A (supercritical CO2) and B (isopropyl alcohol with 0.1% isopropylamine); Gradient: A:B = 50:50, 3 min; Flow rate: 3.4 mL / min; Wavelength: 220 nm; Column temperature: 35 °C; Pressure: 1800 psi, Rt = 1.930 min, Enantiomeric excess: 96.56%. LCMS m / z = 669.3 [M+H] + . 1 H NMR(400MHz,CDCl3)δ ppm 7.56(s,1H),7.30-7.28(m,1H),6.81(d,J=2.0Hz,1H),5.40-5.19(m,1H),4.43(br d,J=13.0Hz,1H),4.37-4.26(m,3H),4.06(s,2H),3.95-3.82(m,3H),3.69(br d,J=12.6Hz,1H),3.61-6.41(m,2H),3.32-3.18(m,1H),3.01(br s,1H),2.82-2.66(m,1H),2.41-2.14(m,3H),2.05-1.85(m,8H).

[0210] Example 12 [ka] Step 1: Synthesis of Compound 012-1 Compound 002-1 (1 g, 3.19 mmol) was added to anhydrous dichloromethane (10 mL). Compound 003-1D (736.82 mg, 3.50 mmol) and triethylamine (644.70 mg, 6.37 mmol, 886.79 μL) were added. The mixture was reacted at 18 °C for 1 hour. The reaction solution was washed successively with saturated ammonium chloride (20 mL × 2) and 20 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the crude product was stirred with a mixed solvent (petroleum ether:methyl tert-butyl ether = 4:1, 20 mL) for 1 hour and filtered. The filter cake was rinsed with the same ratio of mixed solvent (5 mL × 2) and dried under reduced pressure to obtain compound 012-1. LCMS m / z (ESI) = 487.0 [M+H] + .

[0211] Step 2: Synthesis of Compound 012-2 Compound 012-1 (0.6 g, 1.23 mmol) was added to anhydrous tetrahydrofuran (3 mL) and N,N-dimethylformamide (3 mL). Cesium carbonate (1.20 g, 3.69 mmol), compound 001-4A (235.02 mg, 1.48 mmol), and triethylenediamine (41.40 mg, 369.06 μmol, 40.59 μL) were added. The mixture was reacted at 30° C. for 16 hours. The reaction solution was added to 10 mL of methyl tert-butyl ether. The mixture was washed with saturated ammonium chloride (20 mL×2), and the aqueous phase was extracted with 10 mL of methyl tert-butyl ether. The organic phases were combined, washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give compound 012-2. LCMS m / z (ESI) = 610.1 [M+H] + . 1H NMR(400MHz,CDCl3)δ=7.30-7.28(m,1H),6.20-6.12(m,2H),5.42-5.20(m,1H),4.78-4.58(m,2H),4.40-4.26(m,2H),4.23-4.16(m, 1H),4.12-4.02(m,1H),3.81-3.59(m,2H),3.32-3.19(m,3H),3.04-2.96(m,1H),2.31-2.11(m,3H),2.02-1.88(m,3H),1.56(s,9H).

[0212] Step 3: Synthesis of Compound 012-3 Compound 012-2 (0.25 g, 409.52 μmol), compound 010-7 (300.77 mg, 450.48 μmol), and potassium phosphate (260.79 mg, 1.23 mmol) were added to toluene (3 mL) and water (0.6 mL). The atmosphere was replaced with nitrogen three times, and chloro[(bis(1-adamantyl)-n-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (54.76 mg, 81.90 μmol) was added under nitrogen. The mixture was reacted at 100° C. for 3 hours. 10 mL of water was added to the reaction mixture. The mixture was extracted with ethyl acetate (5 mL × 2). The layers were separated. The organic phases were combined, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:0 to 0:1) to obtain compound 012-3. LCMS m / z (ESI) = 1071.4 [M+H] + .

[0213] Step 4: Synthesis of compound 012-4 hydrochloride Compound 012-3 (0.2 g, 186.69 μmol) was added to HCl / methanol (4 mL, 4 M). The mixture was reacted at 18° C. for 1 hour. This reaction mixture was combined with compound 012-3 (50 mg batch) for workup. The reaction mixture was directly concentrated. The crude product was stirred with 5 mL of ethyl acetate for 2 hours and then filtered. The filter cake was rinsed with ethyl acetate (2 mL×2) and dried under reduced pressure to give compound 012-4 hydrochloride. LCMS m / z (ESI) = 807.3 [M+H]+ .

[0214] Step 5: Synthesis of Compound 012A and Compound 012B Compound 012-4 (0.1 g, hydrochloride salt) was added to N,N-dimethylformamide (2 mL). Potassium carbonate (85.64 mg, 619.61 μmol) and cesium fluoride (37.65 mg, 247.85 μmol, 9.14 μL) were added. The mixture was reacted at 60° C. for 16 hours. This reaction mixture was combined with compound 012-4 (50 mg batch) for workup. The reaction mixture was diluted with 5 mL of ethyl acetate and washed with 10 mL of water. The aqueous phase was extracted with 5 mL of ethyl acetate. The organic phases were combined, washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the crude product was purified by preparative high-performance liquid chromatography (column: Phenomenex Luna C18 80 × 40 mm × 3 μm; mobile phase A: water (0.05% hydrochloric acid), mobile phase B: acetonitrile; gradient run: B: 1% to 40%; analysis time: 7 min). One drop of ammonia was added to the separated solution to obtain the crude product. The crude product was purified by supercritical fluid chromatography (SFC) (column: DAICEL CHIRALCEL OD (250 mm × 30 mm, 10 μm); mobile phase: A (supercritical CO2) and B (ethanol with 0.1% ammonia); gradient run: B% = 50% to 50%, 13 min run) to obtain Compound 012A and Compound 012B.

[0215] The analysis and characterization of compound 012A was as follows:

[0216] SFC analytical method (Column: Chiralcel OD-3, 50 × 4.6 mm i.d., 3 μm; Mobile phase: A (supercritical CO), B: (ethanol containing 0.1% isopropylamine); Gradient: B% = 5–50%, 3 min; Flow rate: 3.4 mL / min; Wavelength: 220 nm; Pressure: 1800 psi, Rt = 1.516 min, 100% ee. LCMS: m / z (ESI) = 651.3 [M+H] + . 1H NMR(400MHz,CD3OD)δ=7.57(d,J=10.0Hz,1H),7.28(d,J=2.0Hz,1H),7.07(d,J=2.0Hz,1H),6.47-6.31(m,2H),5 .68-5.45(m,1H),4.72-4.59(m,6H),4.13-3.77(m,5H),3.54-3.40(m,2H),2.80-2.42(m,3H),2.39-2.15(m,3H).

[0217] The analysis and characterization of compound 012B was as follows:

[0218] SFC analytical method (Column: Chiralcel OD-3, 50 × 4.6 mm i.d., 3 μm; Mobile phase: A (supercritical CO), B: (ethanol containing 0.1% isopropylamine); Gradient: B% = 5–50%, 3 min; Flow rate: 3.4 mL / min; Wavelength: 220 nm; Pressure: 1800 psi, Rt = 1.751 min, 96.64% ee. LCMS: m / z (ESI) = 651.3 [M+H] + . 1 H NMR(400MHz,CD3OD)δ=7.60-7.55(m,1H),7.27(d,J=2.4Hz,1H),7.06(d,J=2.4Hz,1H),6.39-6.27(m,2H),5.59-5.38(m,1H),4.66-4.41(m ,4H),4.26(d,J=14.8Hz,2H),3.97-3.65(m,5H),3.42(s,1H),3.37-3.33(m,1H),2.65-2.45(m,2H),2.40-2.16(m,3H),2.11-1.99(m,1H).

[0219] Example 13 [ka] Step 1: Synthesis of Compound 013-1A Compound 013-1 (1.8 g, 5.57 mmol) was added to anhydrous tetrahydrofuran (20 mL). The atmosphere was replaced with nitrogen three times, and the mixture was cooled to 10° C. Lithium aluminum hydride (633.94 mg, 16.70 mmol) was added in three portions under a nitrogen atmosphere. The reaction mixture was slowly warmed to 20° C. and reacted for 10 minutes, then heated to 70° C. and refluxed for 2 hours. The mixture was cooled to 0° C. The reaction mixture was quenched by slowly adding 0.6 mL of water. Then, 0.6 mL of 15% sodium hydroxide solution and 1.8 mL of water were added. The mixture was stirred for 5 minutes, and 5 g of solid sodium sulfate was added. The mixture was stirred for 30 minutes and filtered. The filtrate was concentrated to give compound 013-1A. 1 H NMR(400MHz,CDCl3)δ=4.88(d,J=11.2Hz,2H),3.67-3.55(m,1H),3.32-3.18(m,3H),3.13 -2.97(m,1H),2.70-2.58(m,1H),2.51-2.40(m,1H),2.37-2.22(m,1H),1.95-1.54(m,5H).

[0220] Step 2: Synthesis of Compound 013-2 Compound 012-1 (0.55 g, 1.13 mmol) was added to anhydrous tetrahydrofuran (2.5 mL) and N,N-dimethylformamide (2.5 mL). Cesium carbonate (10 g, 3.38 mmol), compound 013-1A (190.06 mg, 1.24 mmol), and triethylenediamine (37.95 mg, 338.31 μmol, 37.20 μL) were added. The mixture was reacted at 30° C. for 20 hours. This reaction mixture was combined with a batch of compound 012-1 (50 mg) for workup. The reaction mixture was added to 10 mL of methyl tert-butyl ether and washed with saturated ammonium chloride (20 mL × 2). The aqueous phase was extracted with 10 mL of methyl tert-butyl ether. The organic phases were combined, washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate=100:0 to 1:4) to obtain compound 013-2. LCMS: MS m / z (ESI)=604.1 [M+H] + .

[0221] Step 3: Synthesis of Compound 013-3 Compound 001-5A (517.29 mg, 818.88 μmol), compound 013-2 (0.45 g, 744.44 μmol), and potassium phosphate (474.06 mg, 2.23 mmol) were added to toluene (5 mL) and water (1 mL). The atmosphere was replaced with nitrogen three times, and chloro[(bis(1-adamantyl)-n-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (99.55 mg, 148.89 μmol) was added under nitrogen. The reaction mixture was reacted at 90 °C for 3.5 h. The reaction mixture was washed with 10 mL of water and extracted with ethyl acetate (5 mL × 2). The combined organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:0 to 0:1) to obtain compound 013-3. LCMS: MS m / z(ESI)=1029.3[M+H] + .

[0222] Step 4: Synthesis of compound 013-4 hydrochloride Compound 013-3 (0.5 g, 485.76 μmol) was added to hydrogen chloride / methanol (10 mL, 4 M). The mixture was reacted at 20° C. for 1 hour. The reaction solution was concentrated under reduced pressure. 5 mL of ethyl acetate was added to the crude product. The mixture was stirred for 16 hours and then filtered. The filter cake was washed with ethyl acetate (2 mL×2) and dried under reduced pressure to obtain compound 013-4 hydrochloride. LCMS: MS m / z (ESI) = 765.3 [M+H] + . 1 H NMR(400MHz,CD3OD)δ=8.31-8.20(m,2H),7.94-7.84(m,1H),7.75-7.61(m,2H),6.62-6.48(m,1H ),6.44-6.28(m,1H),5.36-5.34(m,2H),5.28-5.18(m,1H),4.86-4.75(m,2H),4.72-4.61(m,2H) ,4.55-4.38(m,2H),4.07-3.91(m,2H),3.91-3.79(m,1H),3.16-3.04(m,1H),2.91-2.84(m,1H), 2.58-2.34(m,2H),2.33-2.11(m,3H),1.94-1.72(m,1H),1.03-0.84(m,18H),0.71-0.54(m,3H).

[0223] Step 5: Synthesis of Compound 013A and Compound 013B Compound 013-4 (0.42 g, hydrochloride salt) was added to N,N-dimethylformamide (5 mL). Potassium carbonate (362.14 mg, 2.62 mmol) and cesium fluoride (159.21 mg, 1.05 mmol, 38.64 μL) were added. The mixture was reacted at 60 °C for 15 h. The reaction solution was diluted with 10 mL of ethyl acetate and washed with 20 mL of water. The aqueous phase was extracted with 10 mL of ethyl acetate. The combined organic phases were washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the crude product was purified by preparative high-performance liquid chromatography (column: Phenomenex Luna C18 75 × 30 mm × 3 μm; mobile phase A: water (0.05% hydrochloric acid), mobile phase B: acetonitrile; gradient run: B% = 10% to 40%; analysis time: 8 min). The fractions were adjusted to approximately pH 7 by dropwise addition of ammonia to give the crude product. The crude product was purified by supercritical fluid chromatography (SFC) (column: DAICEL CHIRALPAK IG (250 mm × 30 mm, 10 μm); mobile phase: A (supercritical CO2) and B (ethanol containing 0.1% ammonia); gradient: B% = 50% to 50%, run for 15 min) to give Compounds 013A and 013B. Carbon atoms marked with "*" and "#" are chiral carbon atoms and exist as single enantiomers (R) or (S). Compound 013A has the configuration "1S,2R" or "1S,2S" or "1R,2R" or "1R,2S" or "1S" or "1R" or "2S" or "2R" and compound 013B has the configuration "1S,2R" or "1S,2S" or "1R,2R" or "1R,2S" or "1S" or "1R" or "2S" or "2R".

[0224] The analysis and characterization of compound 013A was as follows:

[0225] SFC analytical method (Column: Chiralpak IG-3, 50 × 4.6 mm i.d., 3 μm; Mobile phase: A (supercritical CO), B: (ethanol containing 0.1% isopropylamine); Gradient: B% = 50–50%, 6 min; Flow rate: 4.0 mL / min; Wavelength: 220 nm; Pressure: 1800 psi, Rt = 0.662 min, 100% ee). LCMS: MS m / z (ESI) = 609.1 [M+H] + . 1 H NMR(400MHz,CD3OD)δ=7.74(dd,J=6.0,9.2Hz,1H),7.57(d,J=10.0Hz,1H),7. 30-7.17(m,2H),7.04(s,1H),6.42-6.24(m,2H),5.24(s,2H),4.69-4.46(m,4 H),4.36-4.14(m,3H),3.96-3.79(m,3H),3.74-3.61(m,1H),3.28-3.12(m,2H ),3.06-2.88(m,1H),2.82-2.71(m,1H),2.41-2.28(m,1H),2.23-2.04(m,3H).

[0226] The analysis and characterization of compound 013B was as follows:

[0227] SFC analytical method (Column: Chiralpak IG-3, 50 × 4.6 mm i.d., 3 μm; Mobile phase: A (supercritical CO), B: (ethanol containing 0.1% isopropylamine); Gradient: B% = 50–50%, 6 min; Flow rate: 4.0 mL / min; Wavelength: 220 nm; Pressure: 1800 psi, Rt = 1.152 min, 99.38% ee). LCMS: MS m / z (ESI) = 609.1 [M+H] + . 1H NMR(400MHz,CD3OD)δ=7.74(dd,J=5.6,9.2Hz,1H),7.57(d,J=10.4Hz,1H),7.29-7.16(m,2H) ,7.05-7.02(m,1H),6.34-6.26(m,2H),5.18(s,2H),4.57-4.40(m,4H),4.20-4.09(m,1H),4.0 7-4.03(m,2H),3.87-3.79(m,1H),3.78-3.69(m,2H),3.62-3.52(m,1H),3.28-3.24(m,1H),3 .15-3.03(m,1H),3.01-2.90(m,1H),2.76-2.63(m,1H),2.40-2.24(m,1H),2.19-1.98(m,3H).

[0228] Example 14 [ka] Step 1: Synthesis of Compound 014-2 Compound 014-1 (3.00 g, 17.52 mmol) was added to N,N-dimethylformamide (30 mL). Potassium carbonate (3.63 g, 26.28 mmol) and compound 014-1A (4.47 g, 17.87 mmol) were added. The mixture was reacted at 20 °C for 2 hours. 30 mL of water was added to the reaction mixture, which was then extracted with methyl tert-butyl ether (20 mL × 2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 100:0 to 10:1) to obtain compound 014-2. LCMS: MS m / z (ESI) = 340.1 [M+H] + .

[0229] Step 2: Synthesis of compound 014-3 Lithium tert-butoxide (1.18 g, 14.69 mmol, 1.32 mL), tris(dibenzylideneacetone)dipalladium (134.56 mg, 146.95 μmol), and 2-dicyclohexylphosphino-2-(N,N-dimethylamino)-biphenyl (144.58 mg, 367.37 μmol) were added to 1,4-dioxane (35 mL). The atmosphere was replaced with argon three times, and the mixture was stirred for 5 minutes. Dodecane (1.25 g, 7.35 mmol, 1.67 mL) and compound 014-2 (2.5 g, 7.35 mmol) were added. The atmosphere was replaced with argon three times, and the mixture was reacted at 85 °C under an argon atmosphere for 16 hours. 50 mL of water was added to the reaction mixture, which was then extracted with ethyl acetate (20 mL × 2). The organic phase was washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The concentrated organic phase was purified by column chromatography (petroleum ether: ethyl acetate = 100:0-0:1) to obtain compound 014-3. LCMS: MS m / z (ESI) = 260.1 [M+H] + .

[0230] Step 3: Synthesis of Compound 014-4 Trifluoroacetate Compound 014-3 (1 g, 3.86 mmol) was added to trifluoroacetic acid (5 mL). The mixture was reacted at 20° C. for 3 hours. The reaction solution was concentrated under reduced pressure to give compound 014-4 trifluoroacetate. LCMS: MS m / z (ESI) = 204.2 [M+H] + .

[0231] Step 4: Synthesis of Compound 014-5A and Compound 014-5B Compound 014-4 (2.5 g, 7.88 mmol, trifluoroacetate) was added to anhydrous tetrahydrofuran (30 mL). The mixture was cooled to 10 °C. Lithium aluminum hydride (897.14 mg, 23.64 mmol) was added. The mixture was allowed to react at 20 °C for 2 h. The reaction mixture was quenched by adding 1 mL of water to the reaction solution, followed by 1 mL of 15% sodium hydroxide solution and 3 mL of water. The mixture was stirred for 5 min. 5 g of solid sodium sulfate was added, and the mixture was stirred for 30 min. The mixture was filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by high-performance liquid chromatography (column: Phenomenex Luna C18 250 × 50 mm × 10 μm; mobile phase A: water (0.05% hydrochloric acid), mobile phase B: acetonitrile; gradient run: B% = 1% to 30%; analysis time: 10 min). The racemate was purified by supercritical fluid chromatography (SFC) (column: Phenomenex-Cellulose-2 (250 mm × 30 mm, 5 μm); mobile phase: A (supercritical CO) and B (ethanol containing 0.1% ammonia); gradient: B% = 35% to 35%, run for 9 min) to give compound 14-5A and compound 14-5B.

[0232] The analysis and characterization of compound 14-5A was as follows.

[0233] SFC analytical method (Column: Lux Cellulose-2, 100 × 4.6 mm i.d., 3 μm; Mobile phase: A (supercritical CO), B: (ethanol containing 0.1% isopropylamine); Gradient: B% = 40–60%, 3 min; Flow rate: 4.0 mL / min; Wavelength: 220 nm; Pressure: 1800 psi, Rt = 1.118 min, 99.44% ee). LCMS: MS m / z (ESI) = 190.2 [M+H] + .

[0234] The analysis and characterization of compound 14-5B was as follows.

[0235] SFC analytical method (Column: Lux Cellulose-2, 100 × 4.6 mm i.d., 3 μm; Mobile phase: A (supercritical CO), B: (ethanol containing 0.1% isopropylamine); Gradient: B% = 40–60%, 3 min; Flow rate: 4.0 mL / min; Wavelength: 220 nm; Pressure: 1800 psi, Rt = 2.285 min, 100% ee). LCMS: MS m / z (ESI) = 190.2 [M+H] + .

[0236] Step 5: Synthesis of Compound 014-6 Compound 002-2 (0.2 g, 395.43 μmol) was added to anhydrous tetrahydrofuran (1.0 mL) and N,N-dimethylformamide (1.0 mL). Cesium carbonate (386.51 mg, 1.19 mmol), compound 014-5A (82.32 mg, 434.97 μmol), and triethylenediamine (13.31 mg, 118.63 μmol, 13.05 μL) were added. The mixture was reacted at 30° C. for 20 hours. This reaction mixture was combined with compound 002-2 (30 mg batch) for workup. The reaction mixture was added to 10 mL of methyl tert-butyl ether and washed with saturated ammonium chloride (20 mL × 2). The aqueous phase was extracted with 10 mL of methyl tert-butyl ether. The organic phases were combined, washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate=100:0 to 1:4) to give compound 014-6. LCMS: MS m / z (ESI)=658.1 [M+H] + .

[0237] Step 6: Synthesis of Compound 014-7 Compound 001-5A (158.27 mg, 250.54 μmol), compound 014-6 (0.15 g, 227.76 μmol), and potassium phosphate (145.04 mg, 683.29 μmol) were added to toluene (2 mL) and water (0.4 mL). The atmosphere was replaced with nitrogen three times, and chloro[(bis(1-adamantyl)-n-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (30.46 mg, 45.55 μmol) was added under nitrogen. The reaction mixture was reacted at 90 °C for 8 hours. The reaction mixture was washed with 10 mL of water and extracted with ethyl acetate (5 mL × 2). The combined organic phase was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:0 to 0:1) to give compound 014-7. LCMS: MS m / z(ESI)=1083.3[M+H] + . 1 H NMR(400MHz,CDCl3)δ=7.81-7.74(m,2H),7.69-7.59(m,3H),7.56-7.46(m,2H),7.45-7.31(m,5H),7.30-7.28(m,1H),7.26- 7.07(m,10H),6.95-6.86(m,1H),6.11-6.01(m,1H),5.94-5.91(m,1H),4.59(d,J=12.0Hz,1H),4.53-4.43(m,1H),4.34-4.29 (m,1H),3.98-3.86(m,2H),3.83-3.81(m,1H),3.79-3.72(m,1H),3.67(s,1H),3.49-3.39(m,1H),3.37-3.26(m,1H),2.73-2. 43(m,2H),2.04-1.94(s,2H),1.87-1.79(m,1H),1.7-1.61(m,1H),1.35-1.29(m,6H),0.92-0.74(m,18H),0.58-0.44(m,3H).

[0238] Step 7: Synthesis of compound 014-8 Compound 014-7 (0.15 g, 138.45 μmol) was added to trifluoroacetic acid (2 mL). The mixture was heated to 70° C. and reacted for 1 hour. The reaction mixture was concentrated and diluted with 5 mL of ethyl acetate. The mixture was washed with 10 mL of water, 10 mL of saturated sodium bicarbonate solution, and 20 mL of 1 M hydrochloric acid solution. The aqueous phase was extracted with 10 mL of ethyl acetate, and the organic phase was discarded. The aqueous phase was collected, slowly adjusted to pH 9 using solid sodium carbonate, and extracted with ethyl acetate (10 mL × 2). The organic phases were combined, washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give compound 014-8. LCMS: MS m / z (ESI) = 801.5 [M+H] + .

[0239] Step 8: Synthesis of Compound 014A and Compound 014B Compound 014-8 (0.08 g, 95.52 μmol) was added to N,N-dimethylformamide (1.5 mL). Potassium carbonate (66.01 mg, 477.62 μmol) and cesium fluoride (29.02 mg, 191.05 μmol, 7.04 μL) were added. The mixture was reacted at 60° C. for 15 hours. The reaction solution was diluted with 5 mL of ethyl acetate and washed with 10 mL of water. The aqueous phase was extracted with 5 mL of ethyl acetate. The organic phases were combined, washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the crude product was purified by preparative high-performance liquid chromatography (column: Phenomenex Luna C18 75 × 30 mm × 3 μm; mobile phase A: water (0.05% hydrochloric acid), mobile phase B: acetonitrile; gradient run: B% = 13% to 43%; analysis time: 8 min). The fraction solution was adjusted to pH 7 by adding aqueous ammonia, and then purified by supercritical fluid chromatography (SFC) (column: DAICEL CHIRALCEL AD (250 mm × 30 mm, 10 μm); mobile phase: A (supercritical CO2) and B (ethanol with 0.1% ammonia); gradient run: B% = 50% to 50%, 15 min run) to give Compound 014A and Compound 014B.

[0240] The analysis and characterization of compound 014A was as follows:

[0241] SFC analytical method (Column: Chiralpak AD-3, 50 × 4.6 mm i.d., 3 μm; Mobile phase: A (supercritical CO), B: (ethanol containing 0.1% isopropylamine); Gradient: B% = 5 to 50%, 3 min; Flow rate: 3.4 mL / min; Wavelength: 220 nm; Pressure: 1800 psi, Rt = 1.533 min, 100% ee). LCMS: MS m / z (ESI) = 645.2 [M+H] + . 1 H NMR(400MHz,CD3OD)δ=7.74(dd,J=6.0,9.2Hz,1H),7.55-7.42(m,2H),7.42-7.30(m,3H),7.28-7 .16(m,2H),7.07-7.00(m,1H),6.33-6.22(m,2H),4.80-4.76(m,1H),4.70-4.55(m,2H),4.53-4.4 6(m,1H),4.45-4.31(m,2H),4.15-4.07(m,2H),3.87-3.72(m,2H),3.68-3.63(m,1H),3.21(s,1H) ),3.17-3.06(m,1H),2.63-2.49(m,1H),2.33-2.21(m,1H),2.17-2.05(m,1H),2.03-1.93(m,1H).

[0242] The analysis and characterization of compound 014B was as follows:

[0243] SFC analytical method (Column: Chiralpak AD-3, 50 × 4.6 mm i.d., 3 μm; Mobile phase: A (supercritical CO), B: (ethanol containing 0.1% isopropylamine); Gradient: B% = 5–50%, 3 min; Flow rate: 3.4 mL / min; Wavelength: 220 nm; Pressure: 1800 psi, Rt = 1.794 min, 100% ee). LCMS: MS m / z (ESI) = 645.2 [M+H] + . 1H NMR(400MHz,CD3OD)δ=7.63(dd,J=6.0,9.2Hz,1H),7.41-7.31(m,2H),7.24-7.16(m,3H),7.15-7. 10(m,1H),7.07(d,J=2.4Hz,1H),6.93(d,J=2.0Hz,1H),6.21-6.10(m,2H),4.66-4.44(m,3H),4.4 0-4.24(m,3H),4.05(d,J=15.2Hz,1H),3.91(d,J=10.4Hz,2H),3.72-3.57(m,2H),3.42-3.31(m,1 H),2.84-2.72(m,1H),2.45-2.32(m,1H),2.13-2.01(m,1H),1.99-1.86(m,1H),1.85-1.73(m,1H).

[0244] Example 15 [ka] Step 1: Synthesis of Compound 015-2 Iron powder (11.73 g, 210.10 mmol) and ammonium chloride (224.76 mg, 4.20 mmol) were added to water (10 mL) and acetic acid (5 mL). The mixture was heated to 80° C. A solution of compound 015-1 (10 g, 42.02 mmol) in ethanol (100 mL) was slowly added. The mixture was allowed to react for 0.5 hours. This reaction mixture was combined with 015-1 (1 g batch) for workup. The mixture was filtered, and the filter cake was rinsed with ethyl acetate (100 mL×3). The filtrate was concentrated, and then 100 mL of ethyl acetate was added. The mixture was washed successively with 100 mL of saturated sodium bicarbonate and 200 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give compound 015-2. LCMS: MS m / z (ESI) = 249.0 [M+42] + .

[0245] Step 2: Synthesis of compound 015-3 Compound trichloroacetaldehyde hydrate (11.93 g, 72.11 mmol, 9.39 mL), sodium sulfate (54.63 g, 384.61 mmol, 39.02 mL), and hydroxylamine hydrochloride (11.69 g, 168.27 mmol) were added to water (200 mL). A solution of compound 015-2 (10 g, 48.08 mmol) in ethanol (30 mL) and hydrochloric acid (12 M, 8.41 mL) was added. The mixture was reacted at 70° C. for 20 hours. This reaction mixture was combined with compound 015-2 (1 g batch) for workup. The reaction mixture was filtered, and the filter cake was dried to obtain compound 015-3. LCMS: MS m / z (ESI) = 278.9 [M+H] + . 1 H NMR(400MHz,CD3OD)δ=8.01-7.97(m,1H),7.61(s,1H),7.24-7.19(m,1H).

[0246] Step 3: Synthesis of compound 015-4 Compound 015-3 (7 g, 25.09 mmol) was added to concentrated sulfuric acid (35 mL). The mixture was reacted at 90 °C for 1 hour. The reaction solution was added to 100 mL of ice water, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give compound 015-4.

[0247] Step 4: Synthesis of Compound 015-5 Compound 015-4 (6.7 g, 25.57 mmol) was added to sodium hydroxide (2 M, 115.07 mL). Hydrogen peroxide (11.50 g, 101.44 mmol, 9.75 mL, 30% content) was added. The mixture was reacted at 18 °C for 1 hour. This reaction mixture was combined with compound 015-4 (0.5 g batch) for workup. The reaction solution was added to 100 mL of sodium thiosulfate solution and extracted with 50 mL of ethyl acetate to remove impurities. The aqueous phase was collected and adjusted to pH 6 with 1 M hydrochloric acid. After a negative starch-KI paper test, the pH was further adjusted to 3 with hydrochloric acid. A solid was precipitated. The mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with 150 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give compound 015-5. LCMS: MS m / z(ESI)=251.9[M+H] + . 1 H NMR(400MHz,CD3OD)δ=6.54(dd,J=5.2,10.4Hz,1H).

[0248] Step 5: Synthesis of Compound 015-6 Compound 015-5 (2.5 g, 9.92 mmol) was added to N,N-dimethylformamide (20 mL). N,N-Diisopropylethylamine (1.54 g, 11.90 mmol, 2.07 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (2.28 g, 11.90 mmol), 1-hydroxybenzotriazole (1.61 g, 11.90 mmol), and ammonia / methanol (7 M, 1.98 mL) were added. The mixture was reacted at 18 °C for 20 hours. The reaction mixture was heated to 30 °C and reacted for 4 hours. 40 mL of water was added to the reaction mixture, which was then extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give compound 015-6. LCMS: MS m / z(ESI)=250.9[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ=8.28-8.05(m,2H),7.20-7.09(m,1H),6.78(s,2H).

[0249] Step 6: Synthesis of Compound 015-7 Compound 015-6 (2 g, 7.97 mmol) was added to anhydrous tetrahydrofuran (20 mL). Carbonyldiimidazole (1.94 g, 11.95 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (2.43 g, 15.93 mmol, 2.40 mL) were added. The mixture was reacted at 18 °C for 1 hour. 30 mL of water was added to the reaction solution, and the mixture was reacted at 50 °C for 2 hours. The mixture was extracted with methyl tert-butyl ether (15 mL × 2), and the organic phase was discarded. The aqueous phase was adjusted to pH 2-3 with 1 M hydrochloric acid solution. A solid was precipitated. The mixture was filtered. The filter cake was rinsed with water (5 mL × 2) and then dried under reduced pressure to give compound 015-7. LCMS: MS m / z (ESI) = 276.9 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ=11.75-11.40(m,2H),7.50-7.35(m,1H).

[0250] Step 7: Synthesis of compound 015-8 Compound 015-7 (1.5 g, 5.41 mmol) was added to phosphorus oxychloride (15 mL). N,N-Diisopropylethylamine (3.50 g, 27.07 mmol, 4.72 mL) was added. The mixture was reacted at 100° C. for 2 hours. The reaction solution was concentrated. The concentrate was diluted with 30 mL of ethyl acetate and slowly added to 50 mL of ice-cold sodium bicarbonate solution. The layers were separated. The aqueous phase was extracted with 20 mL of ethyl acetate. The organic phases were combined, washed successively with 50 mL of saturated ammonium chloride and 50 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give compound 015-8.

[0251] Step 8: Synthesis of Compound 015-9 Compound 015-8 (0.5 g, 1.59 mmol) was added to anhydrous dichloromethane (5 mL). Compound 003-1D (368.41 mg, 1.75 mmol) and triethylamine (322.35 mg, 3.19 mmol, 443.40 μL) were added. The mixture was reacted at 18 °C for 2 hours. The reaction solution was washed successively with saturated ammonium chloride (20 mL × 2) and 20 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 100:0 to 1:1) to obtain compound 015-9. LCMS: MS m / z (ESI) = 487.0 [M+H] + . 1 H NMR(400MHz, CDCl3)δ=7.51(d,J=6.0Hz,1H),6.09-5.90(m,2H),4.77-4.42(m,3H),4.02-3.46(m,3H),1.51(s,9H).

[0252] Step 9: Synthesis of Compound 015-10 Compound 015-9 (0.48 g, 984.16 μmol) was added to anhydrous tetrahydrofuran (2.5 mL) and N,N-dimethylformamide (2.5 mL). Cesium carbonate (961.98 mg, 2.95 mmol), compound 001-4A (188.02 mg, 1.18 mmol), and triethylenediamine (33.12 mg, 295.25 μmol, 32.47 μL) were added. The mixture was reacted at 20 °C for 20 hours. The reaction solution was added to 10 mL of methyl tert-butyl ether. The mixture was washed with saturated ammonium chloride (20 mL × 2), and the aqueous phase was extracted with 10 mL of methyl tert-butyl ether. The organic phases were combined, washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give compound 015-10. LCMS: MS m / z(ESI)=610.2[M+H] + . 1H NMR(400MHz,CDCl3)δ=7.03-6.92(m,1H),6.07(d,J=4.0Hz,2H),5.42-5.14(m,1H),4.70-4.54(m,2H),4.23-4.12(m,2H),4.08-3.99( m,2H),3.68-3.53(m,2H),3.35-3.24(m,2H),3.20-3.08(m,1H),3.04-2.90(m,1H),2.28-2.12(m,3H),1.96-1.85(m,3H),1.51(s,9H).

[0253] Step 10: Synthesis of Compound 015-11 Compound 001-5A (284.57 mg, 450.48 μmol), compound 015-10 (0.25 g, 409.52 μmol), and potassium phosphate (260.79 mg, 1.23 mmol) were added to toluene (3 mL) and water (0.6 mL). The atmosphere was replaced with nitrogen three times, and chloro[(bis(1-adamantyl)-n-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (54.76 mg, 81.90 μmol) was added under nitrogen. The mixture was reacted at 90° C. for 3 hours. 10 mL of water was added to the reaction mixture. The mixture was extracted with ethyl acetate (5 mL × 2). The layers were separated. The organic phases were combined, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=1:0 to 0:1) to give compound 015-11. LCMS: MS m / z (ESI) = 1035.3 [M+H] + . 1H NMR(400MHz,CDCl3)δ=7.81-7.76(m,2H),7.68-7.63(m,1H),7.54-7.47(m,1H),7.46-7.39(m,2H),7.37-7.28(m,3H) ),7.25-7.19(m,2H),7.17-7.10(m,2H),6.90-6.82(m,1H),6.66-6.56(m,1H),6.25-6.03(m,2H),5.39-5.16(m,1H) ,4.80-4.40(m,3H),4.25-4.17(m,1H),4.09-3.94(m,1H),3.87-3.55(m,2H),3.52-3.32(m,1H),3.31-3.08(m,3H), 3.03-2.91(m,1H),2.36-2.10(m,3H),2.00-1.85(m,3H),1.62-1.39(m,9H),0.95-0.77(m,18H),0.61-0.48(m,3H).

[0254] Step 11: Synthesis of Compound 015-12 Hydrochloride Compound 015-11 (0.2 g, 193.18 μmol) was added to HCl / methanol (4 mL, 4 M). The mixture was reacted at 18° C. for 1 hour. The reaction solution was directly concentrated. The crude product was stirred with 5 mL of ethyl acetate for 2 hours and then filtered. The filter cake was rinsed with ethyl acetate (2 mL×2) and concentrated under reduced pressure to give compound 015-12 hydrochloride. LCMS: MS m / z (ESI) = 771.3 [M+H] + .

[0255] Step 12: Synthesis of Compound 015 Compound 015-12 (0.1 g, hydrochloride salt) was added to N,N-dimethylformamide (2 mL). Potassium carbonate (85.59 mg, 619.25 μmol) and cesium fluoride (37.63 mg, 247.70 μmol, 9.13 μL) were added. The mixture was reacted at 60° C. for 5 hours. This reaction mixture was combined with compound 015-12 (50 mg batch) for workup. The reaction mixture was diluted with 5 mL of ethyl acetate and washed with 10 mL of water. The aqueous phase was extracted with 5 mL of ethyl acetate. The organic phases were combined, washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the crude product was purified by preparative high-performance liquid chromatography (column: Phenomenex Luna C18 150 x 40 mm x 10 μm; mobile phase A: water (10 mM ammonium bicarbonate); mobile phase B: acetonitrile; gradient run B% = 50% to 80%; analysis time: 8 min) to give compound 015. LCMS: MS m / z (ESI) = 615.2 [M+H] + . 1 H NMR(400MHz,CD3OD)δ=7.71(dd,J=6.0,9.2Hz,1H),7.22(t,J=8.8Hz,1H),7.14( d,J=2.4Hz,1H),7.02(d,J=2.4Hz,1H),6.90(dd,J=5.2,11.6Hz,1H),6.27-6.18 (m,2H),5.41-5.22(m,1H),4.30-4.07(m,4H),3.95-3.90(m,2H),3.77-3.64(m, 2H),3.29-3.18(m,4H),3.07-2.97(m,1H),2.40-2.10(m,3H),2.07-1.85(m,3H).

[0256] Example 16 [ka] Step 1: Synthesis of Compound 016-5 Compound 016-4 (15 g) was purified by supercritical fluid chromatography (ChiralPak IH, 250 × 50 mm, 10 μm column; mobile phase: A (supercritical CO), B (0.1% ammonia-ethanol); B%: 20%–20%) to obtain compound 016-5. SFC analysis was performed using a ChiralPak IH-3 column (100 × 4.6 mm i.d., 3 μm column; mobile phase: A (supercritical CO) and B (EtOH containing 0.1% isopropylamine); gradient: B% = 10–50%, 4 min; flow rate: 3.4 mL / min; wavelength: 220 nm; pressure: 2000 psi). Rt = 1.489 min, ee = 98.82%. 1 H NMR(400MHz,CDCl3)δ=4.99-4.86(m,2H),4.26-3.95(m,3H),3.59(m,1H),3.00-2.88(m,1H),2.87-2.12(m,4H),1.91(s,1H),1.20-1.08(m,3H).

[0257] Step 2: Synthesis of Compound 016-1A Lithium tetrahydroaluminum (1.55 g, 40.15 mmol, 98% purity) was dissolved in anhydrous tetrahydrofuran (30 mL). The solution was cooled to 0°C. A solution of compound 016-5 (2.8 g, 13.38 mmol) in anhydrous tetrahydrofuran (2 mL) was added under nitrogen, heated to 70°C, and reacted for 1 hour. After the reaction was completed, 1.5 mL of water was added at 0°C, 1.5 mL of 15% NaOH solution was added, and 4.5 mL of water was added. The mixture was stirred for 20 minutes. The reaction solution was filtered, and the filter cake was washed with 10 mL of tetrahydrofuran. The filtrate was concentrated to give compound 016-1A. 1 H NMR(400MHz,CDCl3)δ=4.99-4.86(m,2H),4.26-3.95(m,3H),3.59(m,1H),3.00-2.88(m,1H),2.74-2.27(m,4H),1.91(s,1H),1.20-1.08(m,3H).

[0258] Step 3: Synthesis of Compound 016-1 Compound 002-2 (0.6 g, 1.19 mmol) was added to anhydrous tetrahydrofuran (3 mL) and N,N-dimethylformamide (3 mL). Cesium carbonate (1.16 g, 3.56 mmol), compound 016-1A (199.94 mg, 1.30 mmol), and triethylenediamine (39.92 mg, 355.88 μmol, 39.14 μL) were added. The mixture was reacted at 25 °C for 16 h. The reaction solution was added to 10 mL of methyl tert-butyl ether. The mixture was washed with 20 mL of water. The aqueous phase was extracted with 10 mL of methyl tert-butyl ether. The organic phases were combined, washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 100:0 to 1:4) to obtain compound 016-1. MS m / z(ESI)=622.2[M+H] + .

[0259] Step 4: Synthesis of Compound 016-2 Compound 001-5A (639.26 mg, 1.01 mmol), compound 016-1 (0.42 g, 674.65 μmol), and potassium phosphate (429.62 mg, 2.02 mmol) were added to a mixture of toluene (5 mL) and water (1 mL). The atmosphere was replaced with nitrogen three times, and chloro[(bis(1-adamantyl)-n-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (90.22 mg, 134.93 μmol) was added under nitrogen. The reaction mixture was heated to 90°C and reacted for 3 hours. The reaction mixture was washed with 10 mL of water and extracted with ethyl acetate (5 mL × 2). The layers were separated. The combined organic phase was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:0 to 0:1) to obtain compound 016-2. MS m / z (ESI) = 1047.3 [M+H] + .

[0260] Step 5: Synthesis of Compound 016-3 Compound 016-2 (250.00 mg, 238.69 μmol) was added to trifluoroacetic acid (2 mL). The mixture was heated to 70° C. and reacted for 0.5 hours. The reaction mixture was concentrated and diluted with 5 mL of ethyl acetate. The mixture was washed with 10 mL of water and 10 mL of saturated sodium bicarbonate solution. The organic phase was washed with 1 M hydrochloric acid solution (8 mL × 2). The aqueous phase was extracted with 10 mL of ethyl acetate, and the organic phase was discarded. The aqueous phase was collected, slowly adjusted to pH 9 using solid sodium carbonate, and extracted with ethyl acetate (10 mL × 2). The organic phases were combined, washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give compound 016-3. MS m / z (ESI) = 765.3 [M+H] + .

[0261] Step 6: Synthesis of Compound 016A and Compound 016B Compound 016-3 (80 mg, 104.58 μmol) was dissolved in N,N-dimethylformamide (2 mL). Potassium carbonate (72.27 mg, 522.88 μmol) and cesium fluoride (47.66 mg, 313.73 μmol, 11.57 μL) were added. The mixture was stirred at 60 °C for 5 h. The mixture was filtered, and the filtrate was purified by preparative high-performance liquid chromatography (column: Phenomenex Luna C18 80 × 40 mm × 3 μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile %: 10% to 45%, 7 min). The fraction solution was added to saturated sodium bicarbonate solution (5 mL). The mixture was concentrated. The acetonitrile was removed, and the residue was extracted with ethyl acetate (5 mL × 3). The organic phases were combined and concentrated to give the crude product, which was purified by supercritical fluid chromatography (SFC) (column: DAICEL CHIRALPAK IG (250 mm × 30 mm, 10 μm); mobile phase: A (supercritical CO), mobile phase: B [0.1% ammonia-ethanol]; B%: 50% to 50%, 16 min) to give compounds 016A and 016B.

[0262] The analysis and characterization of 016A was as follows:

[0263] LCMS: m / z(ESI)=609.3[M+H] + .

[0264] Analysis and characterization of 016B was as follows:

[0265] SFC analytical method (Column: Chiralpak IG-3, 50 × 4.6 mm i.d., 3 μm; Mobile phase: A (supercritical CO2) and B (EtOH containing 0.1% isopropylamine); Gradient: B% = 50–40%, run for 3 min; Flow rate: 4.0 mL / min; Wavelength: 220 nm; Pressure: 1800 psi), Rt = 1.25 min, ee = 98.2%. LCMS: m / z (ESI) = 609.3 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ ppm 7.63-7.74(m,1H),7.20-7.27(m,2H),7.11-7.16(m,1H),6.95-7.02(m,1H), 6.20-6.38(m,2H),4.94-5.06(m,2H),4.32-4.48(m,2H),4.16-4.28(m,2H), 3.90-4.04(m,4H),3.69-3.88(m,3H),3.29-3.42(m,2H),2.84-2.94(m,1H), 2.65-2.81(m,2H),2.38-2.50(m,1H),2.20-2.31(m,1H),1.93-2.03(m,2H).

[0266] Example 17 [ka] [ka] [ka] Step 1: Synthesis of Compound 017-5 Compound 017-4 (1.0 g, 4.11 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL) under nitrogen, and the mixture was cooled to 0 °C. Dibromodifluoromethane (1.90 g, 9.04 mmol, 835.93 μL) was slowly added dropwise to the reaction mixture, and hexamethylphosphoramide (2.95 g, 18.09 mmol, 3.29 mL) was slowly added dropwise to the reaction mixture. The mixture was warmed to 25 °C and stirred for 14 h. The reaction mixture was cooled to room temperature and filtered. Water (10 mL) was added to the filtrate, and the mixture was extracted with ethyl acetate (5 mL). The layers were separated. The organic layer was washed with saturated brine (5 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 1 / 1) to give compound 017-5. 1 H NMR(400MHz,CDCl3)δ ppm 4.41-4.62(m,1H),4.04-4.22(m,2H),3.67-3.88(m,3H),2.82-3.03(m,1H),2.60-2.73(m,1H),1.37-1.55(m,9H).

[0267] Step 2: Synthesis of compound 017-6 Compound 017-5 (2 g, 7.21 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) under nitrogen and the mixture was cooled to -60 °C. Lithium hexamethyldisilazide (1 M, 7.93 mL) was added and the mixture was stirred for 10 minutes. 1-Chloro-3-iodopropane (2.21 g, 10.82 mmol, 1.16 mL) was added dropwise to the reaction mixture. The mixture was warmed to room temperature (30 °C) and stirred for 10 hours. The reaction mixture was filtered, and water (10 mL) was added. The mixture was extracted with ethyl acetate (5 mL), washed with saturated brine (5 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to give compound 017-6. 1H NMR(400MHz,CDCl3)δ ppm 4.03-4.36(m,2H),3.74(s,3H),3.47-3.64(m,2H),2.61-2.93(m,2H), 2.33-2.49(m,1H),1.93-2.14(m,1H),1.71-1.84(m,2H),1.44(m,9H).

[0268] Step 3: Synthesis of compound 017-7 hydrochloride Compound 017-6 (20 g, 56.53 mmol) was dissolved in hydrochloric acid / ethyl acetate (4 M, 120 mL). The mixture was reacted at 25° C. for 2 hours, and then the reaction solution was concentrated to give compound 017-7 hydrochloride, which was used directly in the next step.

[0269] Step 4: Synthesis of compound 017-8 Compound 017-7 (20 g, 56.5 mmol, hydrochloride salt) was dissolved in N,N-dimethylformamide (65 mL). Potassium carbonate (14.2 g, 102 mmol) was added. The mixture was reacted at 25 °C for 12 hours. The reaction solution was diluted with 500 mL of ethyl acetate, washed successively with water (300 mL × 2) and 300 mL of brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to obtain 017-8.

[0270] Step 5: Synthesis of Compound 017-9 Compound 017-8 (1.5 g, 6.91 mmol) was added to anhydrous tetrahydrofuran (15 mL). The mixture was cooled to 0 °C. The atmosphere was replaced with nitrogen three times, and a solution of vitride in toluene (3.5 M, 7.89 mL) was added dropwise under nitrogen. The mixture was slowly heated to 25 °C and reacted for 16 hours. The mixture was cooled to 0 °C, and 10 mL of ethyl acetate was slowly added to the reaction solution, followed by 1 mL of water, 1 mL of 15% sodium hydroxide solution, 3 mL of water, and solid sodium sulfate. The mixture was stirred for 1 hour and filtered. The filter cake was dispersed in 20 mL of ethyl acetate, and the mixture was stirred for 0.5 hours and filtered. The procedure was repeated twice until the filtrate contained no product. The filtrate was concentrated to give compound 017-9.

[0271] Step 6: Synthesis of compound 017-10 Compound 017-9 (2 g, 11.68 mmol) was added to anhydrous dichloromethane (20 mL). The mixture was cooled to 0 °C. Imidazole (1.19 g, 17.52 mmol) and tert-butyldiphenylchlorosilane (3.85 g, 14.02 mmol, 3.60 mL) were added, and the mixture was reacted at 25 °C for 1 hour. The reaction mixture was washed with 20 mL of water and 20 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 100:0 to 10:1). The upper fraction was isolated to give compound 017-10. LCMS: m / z (ESI) = 410.2 [M+H] + .

[0272] Step 7: Synthesis of Compound 017-11B and Compound 017-11A Compound 017-10 (0.6 g) was purified by supercritical fluid chromatography (SFC) (column: DAICEL CHIRALCEL OZ 250 × 25 mm, inner diameter 10 μm; mobile phase: A (supercritical CO2), mobile phase: B [0.1% ammonia-methanol]; B%: 30%-30%) to obtain compounds 017-11A and 017-11B.

[0273] The analysis and characterization of 017-11A was as follows:

[0274] SFC analytical method (Column: Lux Cellulose-2, 100 × 4.6 mm i.d., 3 μm; Mobile phase: A (supercritical CO) and B (MeOH containing 0.1% isopropylamine); Gradient: B% = 10–50%, run for 4 min; Flow rate: 3.4 mL / min; Wavelength: 220 nm; Pressure: 2000 psi), Rt = 1.546 min, ee = 96.74%. 1 H NMR(400MHz,CDCl3)δ ppm 7.63-7.69(m,4H),7.35-7.44(m,6H),6.27-6.55(m,1H),3.69-3.88(m,1H),3.30-3.48(m,2H),2.53- 2.69(m,2H),2.14-2.28(m,1H),1.96-2.08(m,1H),1.79-1.90(m,2H),1.57-1.72(m,3H),1.08(s,9H).

[0275] The analysis and characterization of 017-11B was as follows:

[0276] SFC analytical method (Column: Lux Cellulose-2, 100 × 4.6 mm i.d., 3 μm; Mobile phase: A (supercritical CO) and B (MeOH containing 0.1% isopropylamine); Gradient: B% = 10–50%, run for 4 min; Flow rate: 3.4 mL / min; Wavelength: 220 nm; Pressure: 2000 psi), Rt = 1.865 min, ee = 99.83%. 1 H NMR(400MHz,CDCl3)δ ppm 7.62-7.69(m,4H),7.33-7.46(m,6H),6.26-6.53(m,1H),3.70-3.78(m,1H),3.42(d,J=3.10Hz,2H),3.29-3.38(m,1H),3.0 2-3.13(m,1H),2.52-2.65(m,2H),2.16-2.24(m,1H),1.97-2.04(m,1H),1.69-1.91(m,2H),1.58-1.69(m,1H),1.07(s,9H).

[0277] Step 8: Synthesis of Compound 017-1A Hydrochloride Compound 017-11B (1.2 g, 2.93 mmol) was dissolved in 24 mL of 1,4-dioxane. Concentrated hydrochloric acid (12 M, 7.20 mL) was added. The mixture was reacted at 95° C. for 12 hours. The reaction mixture was cooled, diluted with 10 mL of water, and washed with 10 mL of ethyl acetate to obtain compound 017-1A hydrochloride. 1 H NMR(400MHz,D2O)δ ppm6.53-6.90(m,1H),4.22(br d,J=15.04Hz,1H),3.97(br d,J=15.04Hz,1H),3.69-3.79(m,1H),3.55-3.67(m,2H),3.14-3.24(m,1H),2.67-2.76(m,1H),2.54-2.64(m,1H),1.94-2.19(m,4H).

[0278] Step 9: Synthesis of Compound 017-1 Compound 002-2 (500 mg, 988.56 μmol), N,N-dimethylformamide (5 mL), compound 017-1A (220.03 mg, 1.29 mmol, hydrochloride salt), anhydrous tetrahydrofuran (5 mL), triethylenediamine (33.27 mg, 296.57 μmol, 32.61 μL), anhydrous cesium carbonate (966.28 mg, 2.97 mmol), and 4A molecular sieves (100 mg) were added to a pre-dried reaction flask. The mixture was stirred at 25° C. for 16 hours, then warmed to 45° C. and stirred for 24 hours. The mixture was cooled to room temperature and then filtered. The filter cake was rinsed with 20 mL of ethyl acetate, washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product. The crude compound was purified by silica gel column chromatography (petroleum ether: ethyl acetate (triethylamine 5 parts / 1000) = 100:0 to 70:30) to obtain compound 017-1. LCMS m / z = 640.1 [M+H] + .

[0279] Step 10: Synthesis of Compound 017-2 Compound 017-1 (140 mg, 218.57 μmol), compound 001-5A (207.10 mg, 327.85 μmol), anhydrous toluene (3.5 mL), anhydrous potassium phosphate (139.19 mg, 655.70 μmol), and water (0.7 mL) were added to a pre-dried reaction flask. The atmosphere was replaced with nitrogen three times, and [(n-butylbis(1-adamantyl)phosphine)-2-(2-aminobiphenyl)]palladium(II) chloride (14.61 mg, 21.86 μmol) was added. The mixture was heated to 105°C and stirred for 10 hours. The reaction mixture was filtered and then concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (0.5% triethylamine) = 100:0 to 70:30), then dissolved in 20 mL of ethyl acetate and extracted with 2N hydrochloric acid (15 mL × 2). The aqueous phase was extracted once with 20 mL of methyl tert-butyl ether, and then adjusted to approximately pH 8 by adding solid sodium carbonate. The mixture was extracted with ethyl acetate (20 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give compound 017-2. LCMS m / z = 901.3 [M+H] + .

[0280] Step 11: Synthesis of Compound 017-3 Trifluoroacetate Compound 017-2 (0.2 g, 221.94 μmol) and trifluoroacetic acid (3.08 g, 27.01 mmol, 2 mL) were added to a pre-dried reaction flask. The mixture was stirred at 70° C. for 1 hour. The reaction solution was concentrated under reduced pressure to give compound 017-3 trifluoroacetate. LCMS m / z=783.3 [M+H] + .

[0281] Step 12: Synthesis of Compound 017A and Compound 017B Compound 017-3 (0.2 g, 222.96 μmol, trifluoroacetate), N,N-dimethylformamide (0.5 mL), anhydrous potassium carbonate (308.16 mg, 2.23 mmol), and cesium fluoride (169.34 mg, 1.11 mmol, 41.10 μL) were added to a pre-dried reaction flask. The mixture was stirred at 65 °C for 12 hours. The reaction was cooled to room temperature and filtered. The filter cake was rinsed with 20 mL of ethyl acetate, washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by preparative high-performance liquid chromatography (column: Phenomenex Luna C18 OBD 80 × 40 mm × 3 μm; mobile phase A: water (0.05% hydrochloric acid), mobile phase B: acetonitrile; gradient run: B%: 5% to 30%, run for 7 min). The fractions were adjusted to approximately pH 7 by adding ammonia, and purified by supercritical fluid chromatography (column: DAICEL CHIRALPAK IG (250 mm × 30 mm, 10 μm); mobile phase: A (supercritical CO2), mobile phase B: [0.1% ammonia-ethanol]; B%: 50% to 50%, run for 13 min) to obtain compounds 017A and 017B.

[0282] The analysis and characterization of compound 017A was as follows:

[0283] SFC analytical method (column: Chiralpak IC-3, 3 μm, 50 × 4.6 mm ID; mobile phase: A (supercritical CO2) and B (EtOH containing 0.1% isopropylamine); gradient: A:B = 50:50, 3 min; flow rate: 3.4 mL / min; wavelength: 220 nm; column temperature: 35 °C; pressure: 1800 psi), Rt = 1.723 min, ee = 100%. LCMS m / z = 627.2 [M+H] + .

[0284] The analysis and characterization of compound 017B was as follows:

[0285] SFC analysis method (カラム: Chiralpak IC-3, 3μm, 50×4.6mm ID; mobile phase: A (supercritical CO2) and びB (0.1% イソプロピルアミンをcontaining むEtOH); グラジエント: A:B=50:50, 3 minutes; Flow rate: 3.4mL / min; wavelength: 220nm; temperature: 35℃; pressure: 1800psi), Rt=2.128 min, ee=98.10%. LCMS m / z=627.2[M+H] + . 1 H NMR(400MHz,CD3OD)δ ppm 7.73(dd,J=9.0,5.8Hz,1H),7.48(dd,J=10.0,1.6Hz,1H),7.23(t,J=8.8Hz,1H),7.17 (d,J=2.4Hz,1H),7.03(d,J=2.4Hz,1H),6.78-6.51(m,1H),6.33-6.25(m,2H),4.43(br t,J=14.2Hz,2H),4.26-4.15(m,2H),3.98(br dd,J=8.8,2.0Hz,2H),3.84(br d,J=14.9Hz,1H),3.81-3.70(m,2H),3.46(br d,J=14.8Hz,1H),3.25(s,1H),3.19-3.12(m,1H),2.76-2.66(m,2H),2.43(br d,J=15.8Hz,1H),2.18-2.06(m,1H),2.04-1.79(m,3H).

[0286] Example 18

change

[0287] Step 2: Synthesis of Compound 011-1A Compound 004-1B (1.5 g, 2.96 mmol, 1 equiv.) was dissolved in tetrahydrofuran (6 mL) and N,N-dimethylformamide (6 mL). 001-4A (707.64 mg, 4.44 mmol, 1.5 equiv.), cesium carbonate (2.90 g, 8.89 mmol, 3 equiv.), and triethylenediamine (33.24 mg, 296.33 μmol, 32.59 μL, 0.1 equiv.) were added sequentially under nitrogen. After the addition was complete, the mixture was reacted at 20 °C for 16 h. Water was added to the reaction mixture, which was then extracted with ethyl acetate (10 mL × 3). The organic phase was washed with water and concentrated to dryness by rotary evaporation to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 10:1) to obtain compound 011-1A. LCMS: (ESI) m / z: 628.1 [M+H] + .

[0288] Step 3: Synthesis of Compound 001-5C Compound 001-5B (2 g, 5.58 mmol, 1 equiv.), dichloromethane (40 mL), and N,N-diisopropylethylamine (4.33 g, 33.47 mmol, 5.83 mL, 6 equiv.) were added to a pre-dried reaction flask. Trifluoromethanesulfonic anhydride (6.30 g, 22.31 mmol, 3.68 mL, 4 equiv.) was added at 0 °C. The mixture was stirred at 0 °C for 1 h. After the reaction was completed, water (5 mL) was added. The mixture was extracted with dichloromethane (5 mL × 4). The combined organic phase was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (gradient elution: petroleum ether: ethyl acetate = 10:1) to give compound 001-5C.

[0289] Step 4: Synthesis of Compound 001-5D Compound 001-5C (3.2 g, 5.14 mmol, 1 equiv.), diphenylimine (1.86 g, 10.28 mmol, 1.72 mL, 2 equiv.), and anhydrous toluene (64 mL) were added to a reaction flask, followed by the addition of cesium carbonate (5.02 g, 15.42 mmol, 3 equiv.) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (594.75 mg, 1.03 mmol, 0.2 equiv.) under nitrogen. Tris(dibenzylideneacetone)dipalladium (470.62 mg, 513.94 μmol, 0.1 equiv.) was added, and the mixture was stirred at 100 °C for 2 h. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by column chromatography (gradient elution: petroleum ether:ethyl acetate = 10:1) to give compound 001-5D. LCMS: (ESI) m / z=654.2 [M+H] + . 1 H NMR(400MHz,CDCl3)δ ppm 7.83-7.78(m,5H),7.60-7.49(m,9H),1.20-1.16(m,21H).

[0290] Step 5: Synthesis of Compound 001-5A Compound 001-5D (2.4 g, 3.67 mmol, 1 equiv.), bis(pinacolato)diboron (1.86 g, 7.34 mmol, 2 equiv.), and potassium acetate (1.08 g, 11.01 mmol, 3 equiv.) were dissolved in anhydrous toluene (48 mL). 1,1'-Bis(diphenylphosphino)ferrocenepalladium dichloride (537.20 mg, 734.17 μmol, 0.2 equiv.) was added. The mixture was stirred at 130 °C under nitrogen for 12 h. After the reaction was complete, the mixture was concentrated under reduced pressure, and the crude product was purified by column chromatography (gradient elution: petroleum ether: ethyl acetate = 10:1) to obtain compound 001-5A. LCMS: (ESI) m / z = 632.3 [M+H] + . 1 H NMR(400MHz,DMSO)δ ppm 7.80-7.87(m,1H),7.68-7.74(m,2H),7.55-7.62(m,1H),7.47-7.53(m,2H),7.39-7.47(m,1H ),7.27-7.35(m,4H),7.18-7.23(m,2H),7.10-7.15(m,1H),1.26(s,12H),1.07-1.15(m,21H).

[0291] Step 6: Synthesis of Compound 018-2 Compound 011-1A (0.15 g, 238.50 μmol, 1 eq.), compound 001-5A (225.99 mg, 357.75 μmol, 1.5 eq.), and potassium phosphate (151.88 mg, 715.50 μmol, 3 eq.) were added to toluene (4 mL) and water (1 mL). The atmosphere was replaced with nitrogen three times. Chloro[(bis(1-adamantyl)-n-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (15.95 mg, 23.85 μmol, 0.1 eq.) was added under nitrogen. The atmosphere was replaced with nitrogen three times. The mixture was reacted at 100°C for 1.5 hours. After the reaction was complete, the reaction solution was cooled to room temperature, and 20 mL of ethyl acetate and 10 mL of water were added. The mixture was allowed to stand, and the layers were separated. The aqueous phase was extracted once with 10 mL of ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (gradient elution: petroleum ether: ethyl acetate = 100:0 to 60:40, with 5 parts / 1000 of triethylamine added to the ethyl acetate) to obtain compound 018-2. LCMS: (ESI) m / z = 1053.6 [M+H] + . 1 H NMR(400MHz,CD3OD)δ ppm 7.83(dd,J=9.2,5.6Hz,1H),7.77-7.71(m,3H),7.55-7.48(m,1H),7.47-7.40(m,2H),7 .38-7.24(m,5H),7.17-7.12(m,2H),6.81(d,J=2.0Hz,1H),5.30-5.23(m,1H),4.73(br t,J=14.0Hz,1H),4.44-4.33(m,2H),4.30-4.22(m,1H),4.19-4.04(m,3H),3.76(s,1H),3.37-3.16 (m,4H),3.06-2.97(m,1H),2.34-1.82(m,9H),1.52(s,9H),0.95-0.81(m,18H),0.61-0.43(m,3H).

[0292] Step 7: Synthesis of compound 018-3 Compound 018-2 (0.15 g, 142.35 μmol, 1 eq) was added to hydrogen chloride / methanol (4 M, 4 mL, 112.40 eq). The mixture was reacted at 15° C. for 2 hours. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by slurrying it in 4 mL of ethyl acetate overnight and filtering. The filter cake was collected and dried under vacuum to give compound 018-3. LCMS: (ESI) m / z=789.5 [M+H] + .

[0293] Step 8: Synthesis of Compound 018 Compound 018-3 (0.1 g, 115.96 μmol, 1 equiv.) was added to N,N-dimethylformamide (1 mL). Potassium carbonate (256.42 mg, 1.86 mmol, 16 equiv.) and cesium fluoride (2.84 mg, 347.88 μmol, 3 equiv.) were added. The mixture was stirred at 65 °C for 3 hours. After the reaction was complete, the mixture was cooled to room temperature and then filtered. The filter cake was rinsed with 10 mL of ethyl acetate. The mother liquor was then washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (HPLC) using the following method: Column: Phenomenex Luna 80 × 30 mm × 3 μm; Mobile phase: [water (hydrochloric acid)-acetonitrile]; Acetonitrile%: 1% to 40%, 8 min. The resulting fractions were adjusted to approximately pH 8 by adding ammonia dropwise and then concentrated under reduced pressure to remove acetonitrile. The residue was extracted twice with 20 mL of ethyl acetate, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give product 018. The product was purified using an SFC chromatography column: DAICEL CHIRALPAK IC (250 mm × 30 mm, 10 μm); mobile phase: [0.1% ammonia-isopropanol]; isopropanol %: 60% to 60% in 16 minutes, and then concentrated under reduced pressure to remove the solvent, giving compounds 018A and 018B.

[0294] The analysis and characterization of compound 018A was as follows:

[0295] SFC analytical method: Column: Chiralpak IC-3, 3 μm, 50 × 4.6 mm ID; Mobile phase: A (CO₂) and B (IPA with 0.1% isopropylamine); Gradient: B% = 5 to 50%, 5 min; Flow rate: 4.0 mL / min; Wavelength: 220 nm; Pressure: 124.14 bar, Rt = 1.13 min, Enantiomeric excess: 100%. LCMS: (ESI) m / z = 633.3 [M+H] + . 1 H NMR(400MHz,CD3OD)δ ppm 7.81(s,1H),7.73(dd,J=8.8,5.6Hz,1H),7.23(t,J=8.8Hz,1H),7.17(d,J=2.2Hz,1H),6.97(d, J=2.2Hz,1H),5.24-5.42(m,1H),4.54(d,J=12.8Hz,1H),4.43(d,J=12.8Hz,1H),4.33(d,J=10. 4Hz,1H),4.23(d,J=10.8Hz,1H),3.73-3.66(m,3H),3.60(d,J=12.4Hz,1H),3.35-3.23(m,3H), 3.21-3.19(m,1H),3.10-3.02(m,1H),2.44-2.13(m,3H),2.06-1.98(m,2H),1.94-1.81(m,5H).

[0296] The analysis and characterization of compound 018B was as follows:

[0297] SFC analytical method: Column: Chiralpak IC-3, 3 μm, 50 × 4.6 mm ID; Mobile phase: A (CO₂) and B (IPA with 0.1% isopropylamine); Gradient: B% = 5 to 50%, 5 min; Flow rate: 4.0 mL / min; Wavelength: 220 nm; Pressure: 124.14 bar, Rt = 2.20 min, Enantiomeric excess: 97.76%. LCMS: (ESI) m / z = 633.3 [M+H] + . 1H NMR(400MHz,CD3OD)δ ppm 7.80(s,1H),7.73(dd,J=8.8,6.0Hz,1H),7.23(t,J=9.0Hz,1H),7.17(d,J =2.2Hz,1H),6.97(d,J=2.4Hz,1H),5.39-5.25(m,1H),4.54-4.40(m,2H), 4.26(dd,J=23.2Hz,10.4Hz,2H),3.70-3.59(m,4H),3.29-3.19(m,4H),3. 08-3.01(m,1H),2.40-2.13(m,3H),2.06-1.96(m,2H),1.92-1.82(m,5H).

[0298] Example 19 [ka] Step 1: Synthesis of compound 019-6 Compound 019-5 (4 g, 17.09 mmol, 1 eq) and urea (10.27 g, 170.92 mmol, 9.17 mL, 10 eq) were added to a flask. The mixture was reacted at 200° C. for 1.5 hours. After the reaction was completed, the reaction was cooled to room temperature. The reaction solid was slurried with 30 mL of ethyl acetate for 1 hour and filtered. The filter cake was concentrated by rotary evaporation to dryness, then slurried with 30 mL of water for 1 hour and filtered. The filter cake was rotary evaporated to dryness to obtain compound 019-6. 1 H NMR(400MHz,DMSO-d6)δ=11.45-11.06(m,2H),7.67-7.56(m,1H),7.45-7.35(m,1H).

[0299] Step 2: Synthesis of Compound 003-1 Compound 019-6 (2.5 g, 9.65 mmol, 1 equivalent) was added to phosphorus oxychloride (20 mL). Diisopropylethylenediamine (3.74 g, 28.95 mmol, 5.04 mL, 3 equivalents) was added. The mixture was reacted at 100° C. for 3 hours. After the reaction was completed, the reaction solution was directly concentrated. The concentrated product was slowly added to 20 mL of ice water and extracted with 10 mL x 2 of ethyl acetate. The organic phases were combined, washed with 20 mL each of saturated ammonium chloride and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give compound 003-1. 1 H NMR(400MHz,DMSO-d6)δ=8.81-8.59(m,2H);LCMS:(ESI)m / z:296.8[M+H] + .

[0300] Step 3: Synthesis of compound 019-7 Compound 003-1 (1.5 g, 5.07 mmol, 1 eq.) was added to anhydrous dichloromethane (20 mL). Triethylamine (1.54 g, 15.21 mmol, 2.12 mL, 3 eq.) and compound 010-16A (1.29 g, 6.08 mmol, 1.2 eq.) were added. The mixture was reacted at 20 °C for 2 hours. After the reaction was completed, the crude product was purified using a column (petroleum ether: ethyl acetate = 100:0-1:1) to obtain compound 019-7. 1 H NMR(400MHz,DMSO-d6)δ=7.83(d,J=0.8Hz,1H),7.71-7.63(m,1H),4.42-4.30(m,2H),4.23(s,2H),3 .58(d,J=1.2Hz,2H),1.84-1.74(m,2H),1.68-1.59(m,2H),1.45(s,9H);LCMS:(ESI)m / z:473.0[M+H] + .

[0301] Step 4: Synthesis of compound 019-8 Compound 019-7 (0.7 g, 1.48 mmol, 1 equiv.) was added to N,N-dimethylformamide (7 mL) and anhydrous tetrahydrofuran (7 mL). Compound 001-4A (354.34 mg, 2.23 mmol, 1.5 equiv.), cesium carbonate (1.45 g, 4.45 mmol, 3 equiv.), and triethylenediamine (16.64 mg, 148.38 μmol, 16.32 μL, 0.1 equiv.) were added. The mixture was reacted at 20 °C for 20 h. After the reaction was completed, 20 mL of water was added to the reaction mixture, which was then extracted with 10 mL of ethyl acetate twice. The combined organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the crude product was purified using a column (dichloromethane:methanol = 100:0 to 10:1) to obtain compound 019-8. 1 H NMR(400MHz,CDCl3)δ=7.45-7.39(m,1H),7.32-7.28(m,1H),5.40-5.13( m,1H),4.45-4.28(m,4H),4.26-4.21(m,1H),4.18-4.05(m,1H),3.69-3.4 2(m,2H),3.33-3.10(m,3H),3.05-2.92(m,1H),2.30-2.07(m,3H),2.00- 1.84(m,5H),1.81-1.70(m,2H),1.52(s,9H);LCMS:(ESI)m / z:594.1[M+H] + .

[0302] Step 5: Synthesis of Compound 019-2 Compound 019-1 (0.27 g, 1.22 mmol, 1 equiv.) was dissolved in THF (10 mL). Di-tert-butyl dicarbonate (318.41 mg, 1.46 mmol, 335.16 μL, 1.2 equiv.) was slowly added. The mixture was reacted at 80 °C for 12 h. After the reaction was completed, the mixture was directly rotary evaporated to dryness, and the crude product was purified on a silica gel column (gradient elution: petroleum ether: ethyl acetate = 10:1 to 5:1) to obtain compound 019-2.

[0303] Step 6: Synthesis of compound 019-3 Compound 019-2 (0.35 g, 1.09 mmol, 1 equiv.), bis(pinacolato)diboron (413.78 mg, 1.63 mmol, 1.5 equiv.), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (79.48 mg, 108.63 μmol, 0.1 equiv.), and potassium acetate (159.92 mg, 1.63 mmol, 1.5 equiv.) were dissolved in 1,4-dioxane (10 mL) under nitrogen. The mixture was reacted at 80 °C for 16 h. After the reaction was complete, the mixture was directly rotary evaporated to dryness. The crude product was purified on a silica gel column (gradient elution: petroleum ether: ethyl acetate = 50:1 to 20:1) to obtain compound 019-3.

[0304] Step 7: Synthesis of compound 019-4 Compound 019-3 (100 mg, 270.81 μmol, 1 equiv.), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (19.82 mg, 27.08 μmol, 0.1 equiv.), potassium carbonate (74.86 mg, 541.62 μmol, 2 equiv.), and compound 019-8 (160.99 mg, 270.81 μmol, 1 equiv.) were dissolved in 1,4-dioxane (2.5 mL) and water (0.5 mL) under nitrogen. The mixture was reacted at 95 °C for 16 h. After the reaction was completed, the mixture was directly rotary evaporated to dryness, and the crude product was purified on a silica gel column (gradient elution: petroleum ether: ethyl acetate = 50:1 to 20:1) to obtain compound 019-4.

[0305] Step 8: Synthesis of Compound 019 Compound 019-4 (49.93 mg, 65.97 μmol, 1 equivalent) was dissolved in 1,4-dioxane (2 mL). Hydrochloric acid (48.11 mg, 1.32 mmol, 47.17 μL, 20 equivalents) was added. The mixture was reacted at 25° C. for 4 hours. After the reaction was completed, the mixture was directly rotary evaporated to dryness to obtain compound 019 hydrochloride, LCMS: (ESI) m / z=557.3 [M+H] + . 1H NMR(400MHz,CD3OD)δ=8.11(br d,J=7.3Hz,1H),8.05-8.00(m,1H),7.68-7.49(m,5H),5.58-5.46(m,1H),4.43-3.71(m,7H),3 .62-3.56(m,2H),3.44-3.32(m,1H),2.78-2.50(m,2H),2.48-2.38(m,1H),2.34-1.96(m,7H).

[0306] Example 20 [ka] Step 1: Synthesis of compound 020-2 Under nitrogen, compound 020-1 (5 g, 11.70 mmol, 1 equiv.), hexa-n-butyltin (20.36 g, 35.10 mmol, 17.55 mL, 3 equiv.), tris(dibenzylideneindenylacetone)dipalladium (1.07 g, 1.17 mmol, 0.1 equiv.), tricyclohexylphosphine (656.23 mg, 2.34 mmol, 758.64 μL, 0.2 equiv.), lithium chloride (2.48 g, 58.50 mmol, 1.20 mL, 5 equiv.), and 1,4-dioxane (50 mL) were stirred at 110 °C for 2 h. After the reaction was completed, the mixture was rotary evaporated to dryness, and the crude product was purified on a silica gel column (gradient elution: petroleum ether: ethyl acetate = 100:1) to obtain compound 020-2. LCMS: (ESI) m / z=639.3 [M+H] + .

[0307] Step 2: Synthesis of compound 020-3 Compound 004-1B (2.5 g, 4.94 mmol, 1 equiv.) was dissolved in N,N-dimethylacetamide (30 mL). Potassium fluoride (5.74 g, 98.78 mmol, 2.31 mL, 20 equiv.) was added. The mixture was reacted at 120 °C for 18 hours. After the reaction was completed, water was added, and the mixture was extracted with 100 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and rotary evaporated to dryness. The crude product was purified on a silica gel column (gradient elution: petroleum ether: ethyl acetate = 20:1 to 10:1) to obtain compound 020-3. LCMS: (ESI) m / z = 489.1 [M+H] + .

[0308] Step 3: Synthesis of compound 020-4 Compound 020-3 (384.12 mg, 784.34 μmol, 1 equiv.), compound 020-2 (0.5 g, 784.34 μmol, 1 equiv.), tetrakis(triphenylphosphine)palladium (90.63 mg, 78.43 μmol, 0.1 equiv.), cuprous iodide (22.41 mg, 117.65 μmol, 0.15 equiv.), and lithium chloride (39.90 mg, 941.20 μmol, 19.28 μL, 1.2 equiv.) were dissolved in 1,4-dioxane (10 mL). The mixture was reacted at 120 °C for 18 hours. After completion of the reaction, the mixture was directly rotary evaporated to dryness. The crude product was purified by silica gel column (gradient elution: petroleum ether: ethyl acetate = 20:1 to 2:1) to give compound 020-4, LCMS: (ESI) m / z = 757.3 [M+H] + .

[0309] Step 4: Synthesis of compound 020-5 Compound 020-4 (0.1 g, 132.05 μmol, 1 equiv.) was dissolved in N,N-dimethylformamide (5 mL). N-iodosuccinimide (44.57 mg, 198.08 μmol, 1.5 equiv.) was added. The mixture was reacted at 25°C for 1 hour. After the reaction was completed, water was added. The mixture was extracted with 100 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and rotary evaporated to dryness. The crude product was purified on a silica gel column (gradient elution: petroleum ether: ethyl acetate = 20:1 to 5:1) to obtain compound 020-5. LCMS: (ESI) m / z = 883.2 [M+H] + .

[0310] Step 5: Synthesis of compound 020-6 Compound 020-5 (0.1 g, 113.23 μmol, 1 equiv.) was dissolved in N,N-dimethylformamide (2 mL). Then, cuprous iodide (64.69 mg, 339.69 μmol, 3 equiv.) and hexamethylphosphoramide (202.91 mg, 1.13 mmol, 198.93 μL, 10 equiv.) were added. Then, under nitrogen, methyl fluorosulfonyl difluoroacetate (217.53 mg, 1.13 mmol, 144.06 μL, 10 equiv.) was added, and the mixture was reacted at 90 °C for 2 h. After the reaction was complete, water was added. The mixture was extracted with 100 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and rotary evaporated to dryness. The crude product was purified on a silica gel column (gradient elution: petroleum ether: ethyl acetate = 20:1 to 5:1) to obtain compound 020-6.

[0311] Step 6: Synthesis of compound 020-7 001-4A (28.94 mg, 181.76 μmol, 3 equiv.) was dissolved in THF (2 mL). Sodium hydride (14.54 mg, 363.52 μmol, 60% content, 6 equiv.) was added at 0 °C. After the addition was complete, the mixture was heated to 25 °C and stirred for 1 h. 020-6 (0.05 g, 60.59 μmol, 1 equiv.) was then added, and the mixture was stirred for 1 h. After the reaction was complete, methanol (0.5 mL) was added to quench the reaction. The mixture was concentrated to dryness to remove the solvent, and the crude product was purified on a silica gel column (gradient elution: petroleum ether: ethyl acetate = 50:1 to 20:1) to obtain compound 020-7.

[0312] Step 7: Synthesis of Compound 020 Compound 020-7 (0.05 g, 51.84 μmol, 1 equivalent) was dissolved in trifluoroacetic acid (2 mL). The mixture was stirred at 50° C. for 5 hours. The mixture was rotary evaporated to dryness and purified on a preparative HPLC column: Welch Xtimate C18 100×40 mm×3 μm; mobile phase: [water (0.1% trifluoroacetic acid)-acetonitrile]; acetonitrile %: 7% to 37%, 8 minutes to give compound 020 trifluoroacetate. LCMS: (ESI) m / z=624.3 [M+H] + . 1 H NMR(400MHz,CD3OD)δ ppm 2.01-2.27(m,5H)2.30-2.41(m,2H)2.45(br d,J=8.78Hz,1H)2.52(br s,3H)2.55-2.85(m,2H)3.41-3.58(m,1H)3.80-4.12(m,5H)4.26(br s,2H)4.60-4.80(m,4H)5.53(br s,1H)5.67(br d,J=3.51Hz,1H)6.64-6.89(m,1H)6.80(s,1H)7.97(s,1H).

[0313] Example 21 [ka] Step 1: Synthesis of Compound 021-1 Compound 019-7 (2 g, 4.24 mmol, 1 equiv.) was dissolved in N,N-dimethylacetamide (30 mL). Potassium fluoride (1.23 g, 21.20 mmol, 496.58 μL, 5 equiv.) was added. The mixture was reacted at 120 °C for 24 hours. After the reaction was completed, water was added and the mixture was extracted with 100 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and rotary evaporated to dryness. The crude product was purified on a silica gel column (gradient elution: petroleum ether: ethyl acetate = 20:1 to 10:1) to obtain compound 021-1. LCMS: (ESI) m / z = 455.0 [M+H] + .

[0314] Step 2: Synthesis of compound 021-2 Compound 021-1 (220 mg, 483.20 μmol, 1 equiv.), compound 020-2 (308.03 mg, 483.20 μmol, 1 equiv.), tetrakis(triphenylphosphine)palladium (55.84 mg, 48.32 μmol, 0.1 equiv.), cuprous iodide (13.80 mg, 72.48 μmol, 0.15 equiv.), and lithium chloride (20.48 mg, 483.20 μmol, 9.90 μL, 1 equiv.) were dissolved in 1,4-dioxane (10 mL). The mixture was reacted at 120 °C for 18 hours. After completion of the reaction, the mixture was directly rotary evaporated to dryness. The crude product was purified by silica gel column (gradient elution: petroleum ether: ethyl acetate = 20:1 to 2:1) to give compound 021-2, LCMS: (ESI) m / z = 723.3 [M+H] + .

[0315] Step 3: Synthesis of compound 021-3 Compound 021-2 (200 mg, 276.69 μmol, 1 equivalent) was dissolved in N,N-dimethylformamide (5 mL). Then, N-iodosuccinimide (186.75 mg, 830.08 μmol, 3 equivalents) was added. The mixture was reacted at 25°C for 5 hours. After the reaction was completed, water was added and the mixture was extracted with 100 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the crude product was purified on a silica gel column (gradient elution: petroleum ether: ethyl acetate = 20:1 to 5:1) to obtain compound 021-3. LCMS: (ESI) m / z = 849.2 [M+H] + .

[0316] Step 4: Synthesis of compound 021-4 Compound 021-3 (120 mg, 141.39 μmol, 1 equiv.) was dissolved in N,N-dimethylformamide (2 mL). Then, cuprous iodide (53.86 mg, 282.78 μmol, 2 equiv.) and hexamethylphosphoramide (126.69 mg, 706.95 μmol, 124.20 μL, 5 equiv.) were added. Then, under nitrogen, methyl fluorosulfonyl difluoroacetate (135.81 mg, 706.95 μmol, 89.94 μL, 5 equiv.) was added, and the mixture was reacted at 80°C for 18 hours. After the reaction was complete, water was added. The mixture was extracted with 100 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column (gradient elution: petroleum ether: ethyl acetate = 20:1 to 5:1) to give compound 021-4. LCMS: (ESI) m / z = 791.3 [M+H] + .

[0317] Step 5: Synthesis of Compound 021-5 Compound 021-4 (200 mg, 252.90 μmol, 1 equiv.) was dissolved in tetrahydrofuran (2 mL) and N,N-dimethylformamide (2 mL). Then, cesium carbonate (164.80 mg, 505.80 μmol, 2 equiv.) and triethylenediamine (14.18 mg, 126.45 μmol, 13.91 μL, 0.5 equiv.) were added. Finally, 001-4A (80.52 mg, 505.80 μmol, 2 equiv.) was added, and the mixture was reacted at 25 °C for 28 h. After the reaction was complete, water was added, and the mixture was extracted with 100 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to obtain the crude product. The crude product was purified on a silica gel column (gradient elution: petroleum ether: ethyl acetate = 50:1 to 20:1) to obtain compound 021-5. LCMS: (ESI) m / z=930.7 [M+H] + .

[0318] Step 6: Synthesis of Compound 021 Compound 021-5 (100 mg, 107.53 μmol, 1 equiv.) was dissolved in trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL, 125.61 equiv.). The mixture was reacted at 55°C for 4 hours and separated by preparative HPLC (column: Phenomenex C18 150 x 40 mm x 5 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile %: 5% to 35%, 10 min) to obtain compound 021 hydrochloride. LCMS: (ESI) m / z = 590.5 [M+H] + . 1 H NMR(400MHz,CD3OD)δ=8.09(d,J=8.8Hz,1H),7.57(t,J=7.5Hz,1H),7.05(s,1H),5.69-5.56(m,1H),4.86-4.75(m,4H),4.31(br s,2H),4.16-3.84(m,5H),3.55-3.44(m,1H),2.86-2.56(m,5H),2.51(br s,1H),2.43-2.32(m,2H),2.31-2.13(m,5H).

[0319] Example 22 [ka] Step 1: Synthesis of Compound 010-12 Compound 010-11 (30 g, 144.23 mmol, 1 equiv.) and silver sulfate (44.97 g, 144.23 mmol, 24.44 mL, 1 equiv.) were dissolved in ethanol (300 mL). Iodine (40.27 g, 158.65 mmol, 31.96 mL, 1.1 equiv.) was then added. The mixture was stirred at 25 °C for 2 h. After completion of the reaction, the reaction solution was filtered, and the filtrate was evaporated to dryness. The crude product was purified on a silica gel column (gradient elution: petroleum ether: ethyl acetate = 100:1 to 20:1) to obtain compound 010-12. 1 H NMR(400MHz,CDCl3)δ:5.08(d,J=7.8Hz,1H),4.30-4.24(m,1H),1.63-1.53(m ,2H),1.32(s,9H),0.70-0.58(m,1H),0.42-0.32(m,2H),0.05--0.05(m,2H).

[0320] Step 2: Synthesis of Compound 010-13 Compound 010-12 (22 g, 65.89 mmol, 1 equiv.) and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride dichloromethane (5.38 g, 6.59 mmol, 0.1 equiv.) were dissolved in methanol (100 mL) under a carbon monoxide atmosphere at 50 Psi pressure and 30 °C. The mixture was stirred for 5 minutes, and then triethylamine (46.67 g, 461.22 mmol, 64.20 mL, 7 equiv.) was added. The mixture was stirred for an additional 24 hours. After the reaction was complete, the mixture was filtered, and the filtrate was evaporated to dryness. The crude product was purified on a silica gel column (gradient elution: petroleum ether: ethyl acetate = 20:1 to 5:1) to give compound 010-13. LCMS: (ESI) m / z = 265.8 [M+H] + .

[0321] Step 3: Synthesis of Compound 010-14 Compound 010-13 (15 g, 56.38 mmol, 1 eq) was dissolved in methanol (50 mL). A solution of sodium hydroxide (9.02 g, 225.53 mmol, 4 eq) in water (50 mL) was added. The mixture was stirred at 25° C. for 2 hours. After the reaction was completed, the reaction solution was concentrated and adjusted to pH 5 using 2 mol / L hydrochloric acid. A white solid was precipitated and suction filtered to obtain compound 010-14. LCMS: (ESI) m / z=251.8 [M+H] + .

[0322] Step 4: Synthesis of Compound 010-15 Compound 010-14 (12 g, 47.62 mmol, 1 eq.) and urea (85.79 g, 1.43 mol, 76.60 mL, 30 eq.) were added to a reaction flask. The mixture was reacted at 200° C. for 4 hours. The reaction solution was cooled to room temperature and slurried with 200 mL of water. The mixture was suction filtered to obtain compound 010-15. LCMS: (ESI) m / z=276.9 [M+H] + .

[0323] Step 5: Synthesis of Compound 002-1 N,N-Diisopropylethylamine (11.66 g, 90.25 mmol, 15.72 mL, 5 equiv.) was added dropwise to phosphorus oxychloride (82.50 g, 538.05 mmol, 50 mL, 29.81 equiv.) at 0 °C, followed by the batchwise addition of compound 010-15 (5 g, 18.05 mmol, 1 equiv.). After the addition was complete, the mixture was refluxed at 80 °C for 20 h. The phosphorus oxychloride was evaporated. The crude product was purified on a silica gel column (gradient elution: petroleum ether: ethyl acetate = 20:1 to 10:1) to give compound 002-1. LCMS: (ESI) m / z = 312.9 [M+H] + .

[0324] Step 6: Synthesis of Compound 010-17 Compound 010-16A (1.2 g, 3.82 mmol, 1 eq.) was dissolved in N,N-dimethylformamide (2 mL). Compound 002-1 (811.51 mg, 3.82 mmol, 1 eq.) and N,N-diisopropylethylamine (1.48 g, 11.47 mmol, 2.00 mL, 3 eq.) were added. The mixture was stirred and reacted at 25° C. for 2 hours. The reaction solution was poured into 50 mL of water to precipitate a solid. The solid was washed with water (3×20 mL) to give compound 010-17. LCMS: (ESI) m / z=489.0 [M+H] + .

[0325] Step 7: Synthesis of Compound 010-7A Compound 010-17 (1.6 g, 3.27 mmol, 1 equiv.) was dissolved in N,N-dimethylformamide (10 mL) and THF (10 mL). Then, cesium carbonate (3.19 g, 9.80 mmol, 3 equiv.), compound 001-4A (780.17 mg, 4.90 mmol, 1.5 equiv.), and triethylenediamine (36.65 mg, 326.70 μmol, 35.93 μL, 0.1 equiv.) were added. The mixture was stirred and reacted at 25 °C for 18 h. After the reaction was complete, the mixture was extracted with 40 mL of ethyl acetate and washed with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the crude product. The crude product was purified on a silica gel column (gradient elution: petroleum ether: ethyl acetate = 20:1 to 10:1) to give compound 010-7A. LCMS: (ESI) m / z=612.2 [M+H] + .

[0326] Step 8: Synthesis of Compound 022-1 Compound 010-7A (0.2 g, 408.38 μmol, 1 equiv.) and compound 022-1A (127.47 mg, 408.38 μmol, 1 equiv.) were dissolved in 1,4-dioxane (2 mL) and water (2 mL). 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (26.62 mg, 40.84 μmol, 0.1 equiv.) and potassium phosphate (130.03 mg, 612.57 μmol, 1.5 equiv.) were added. The mixture was reacted at 90 °C under nitrogen for 18 h. After completion of the reaction, the reaction solution was rotary evaporated to dryness, and the crude product was purified on a silica gel column (gradient elution: petroleum ether: ethyl acetate = 20:1 to 10:1) to obtain compound 022-1. LCMS: (ESI) m / z = 800.3 [M+H] + .

[0327] Step 9: Synthesis of Compound 022 Compound 022-1 (25 mg, 31.25 μmol, 1 equivalent) was dissolved in acetonitrile (1 mL) and hydrochloric acid / 1,4-dioxane (1 mL). The mixture was reacted at 25°C for 12 hours. After the reaction was completed, the mixture was rotary evaporated to dryness to remove the solvent, and the mixture was separated using a Phenomenex C18 150 x 40 mm x 5 μm preparative column; mobile phase: [water (0.2% formic acid)-acetonitrile]; acetonitrile %: 1% to 30% over 10 minutes to obtain compound 022 formate. LCMS: (ESI) m / z = 600.1 [M+H] + .

[0328] Example 23 [ka] Step 1: Synthesis of compound 023-2 Compound 023-1 (15 g, 59.89 mmol, 1 eq) was added to a reaction flask, followed by urea (60 g, 999.08 mmol, 53.57 mL, 16.68 eq). The mixture was heated to 200° C. and refluxed for 4 hours. The mixture was cooled to room temperature and slurried with hot water to give compound 023-2. LCMS: (ESI) m / z=274.9 [M+H] + .

[0329] Step 2: Synthesis of compound 023-3 N,N-Diisopropylethylamine (11.73 g, 90.75 mmol, 15.81 mL, 5 equiv.) was added to phosphorus oxychloride (82.50 g, 538.05 mmol, 50 mL, 29.64 equiv.) at 0 °C. After the addition was complete, 023-2 (5 g, 18.15 mmol, 1 equiv.) was added batchwise, and the mixture was then heated to 100 °C. After the reaction was complete, the reaction mixture was evaporated to dryness to remove phosphorus trichloride. The crude product was purified on a silica gel column (gradient elution: petroleum ether: ethyl acetate = 20:1 to 10:1) to give compound 023-3. 1 H NMR(400MHz,DMSO-d6)δ ppm 8.50(s,1H)8.58(s,1H).

[0330] Step 3: Synthesis of compound 023-4 023-3 (3 g, 9.60 mmol, 1 eq.) and 010-16A (2.04 g, 9.60 mmol, 1 eq.) were dissolved in N,N-dimethylformamide (10 mL). N,N-diisopropylethylamine (3.72 g, 28.81 mmol, 5.02 mL, 3 eq.) was added. The mixture was stirred at 25 °C for 4 hours. The reaction mixture was poured into 200 mL of water and filtered to obtain a solid. The solid was washed three times with 20 mL of water to obtain compound 023-4. LCMS: (ESI) m / z = 487.0 [M+H] + .

[0331] Step 4: Synthesis of compound 023-5 023-4 (1.5 g, 3.07 mmol, 1 equiv.) was dissolved in N,N-dimethylformamide (10 mL) and THF (10 mL). Then, cesium carbonate (3.00 g, 9.22 mmol, 3 equiv.), 001-4A (733.71 mg, 4.61 mmol, 1.5 equiv.), and triethylenediamine (34.46 mg, 307.25 μmol, 33.79 μL, 0.1 equiv.) were added. The mixture was stirred at 25 °C for 18 h. After the reaction was complete, it was extracted with 50 mL of ethyl acetate, washed three times with water, and washed with saturated brine. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the crude product was purified on a silica gel column (gradient elution: petroleum ether: ethyl acetate = 100:1 to 20:1) to give compound 023-5. LCMS: (ESI) m / z=610.2 [M+H] + .

[0332] Step 5: Synthesis of compound 023-6 023-5 (0.4 g, 654.72 μmol, 1 equiv.) and 022-1A (204.36 mg, 654.72 μmol, 1 equiv.) were dissolved in 1,4-dioxane (6 mL) and water (6 mL). 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (42.67 mg, 65.47 μmol, 0.1 equiv.) and potassium phosphate (208.47 mg, 982.09 μmol, 1.5 equiv.) were added. The mixture was reacted under nitrogen at 90 °C for 18 h. After completion of the reaction, the reaction solution was rotary evaporated to dryness, and the crude product was purified on a silica gel column (gradient elution: dichloromethane:methanol = 100:1 to 20:1) to give compound 023-6. LCMS: (ESI) m / z = 798.3 [M+H] + .

[0333] Step 6: Synthesis of Compound 023 023-6 (0.1 g, 125.26 μmol, 1 equiv.) was dissolved in acetonitrile (2 mL). Hydrogen chloride / 1,4-dioxane (2 mL) was added. The mixture was reacted at 25 °C for 15 hours. After the reaction was completed, the reaction solution was evaporated to dryness and separated by preparative HPLC: Column: Phenomenex C18 150 × 40 mm × 5 μm; Mobile phase: [water (0.2% formic acid)-acetonitrile]; Acetonitrile %: 7% to 37% over 10 minutes to obtain compound 023 formate. 1 H NMR(400MHz,DMSO-d6)δ ppm 1.67-1.95(m,8H)1.96-2.06(m,2H)2.10-2.19(m,1H)2.79-2.87(m,1H)2.99-3.15(m,3H)3.63(br d,J=13.30Hz,1H)3.87(br s,2H)3.96-4.12(m,2H)4.32(br d,J=12.80Hz,2H)5.17-5.38(m,1H)7.03(t,J=8.78Hz,1H)7.22(dd,J=8.28,5.77Hz,1H)7.54(s,1H)7.87(s,2H)7.98(s,1H)8.22(s,1H).

[0334] Example 24 [ka] Step 1: Synthesis of Compound 024-1 020-3 (1.8 g, 3.68 mmol, 1 equiv.) and 024-1A (1.50 g, 3.68 mmol, 1 equiv.) were dissolved in 1,4-dioxane (2 mL) and water (2 mL). 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (479.09 mg, 735.08 μmol, 0.2 equiv.) and potassium phosphate (1.17 g, 5.51 mmol, 1.5 equiv.) were added. The mixture was reacted under nitrogen at 90 °C for 18 h. After the reaction was complete, the mixture was extracted twice with 30 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the crude product was purified on a silica gel column (gradient elution: dichloromethane:methanol = 100:1 to 20:1) to obtain compound 024-1. LCMS: (ESI) m / z=774.3 [M+H]+ .

[0335] Step 2: Synthesis of compound 024-2 024-1 (1.3 g, 1.68 mmol, 1 equiv.) was dissolved in N,N-dimethylformamide (2 mL). N-iodosuccinimide (1.13 g, 5.04 mmol, 3 equiv.) was added. The mixture was reacted at 25 °C for 2 hours. After the reaction was completed, the mixture was extracted twice with 30 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the crude product was purified on a silica gel column (gradient elution: petroleum ether: ethyl acetate = 100:1 to 10:1) to obtain compound 024-2. LCMS: (ESI) m / z = 900.2 [M+H] + .

[0336] Step 3: Synthesis of compound 024-3 024-2 (100 mg, 111.09 μmol, 1 equiv.) was dissolved in N-methylpyrrolidone (2 mL). Then, methyl fluorosulfonyl difluoroacetate (3.02 g, 15.72 mmol, 2 mL, 141.50 equiv.) and cuprous iodide (105.79 mg, 555.45 μmol, 5 equiv.) were added. Hexamethylphosphoramide (99.54 mg, 555.45 μmol, 97.59 μL, 5 equiv.) was added under nitrogen. The mixture was refluxed at 80 °C for 18 h. After the reaction was complete, the mixture was extracted twice with 20 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the crude product was purified on a silica gel column (gradient elution: petroleum ether: ethyl acetate = 100:1 to 10:1) to obtain compound 024-3. LCMS: (ESI) m / z=842.3 [M+H] + .

[0337] Step 4: Synthesis of compound 024-4 024-3 (70 mg, 83.11 μmol, 1 equiv.) was dissolved in tetrahydrofuran (1 mL) and N,N-dimethylformamide (1 mL). Then, cesium carbonate (27.08 mg, 83.11 μmol, 1 equiv.), 001-4A (15.88 mg, 99.73 μmol, 1.2 equiv.), and triethylenediamine (932.23 μg, 8.31 μmol, 9.14 e-1 μL, 0.1 equiv.) were added. The mixture was reacted at 25 °C for 18 h. After the reaction was completed, water was added, and the mixture was extracted with 100 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the crude product was purified on a silica gel column (gradient elution: dichloromethane:methanol = 100:1 to 20:1) to obtain compound 024-4. LCMS: (ESI) m / z=981.4 [M+H] + .

[0338] Step 5: Synthesis of Compound 024 024-4 (50 mg, 50.94 μmol, 1 equiv.) was dissolved in trifluoroacetic acid (5.81 mg, 50.94 μmol, 3.77 μL, 1 equiv.). The mixture was stirred at 25 °C for 2 h. After the reaction was complete, the mixture was rotary evaporated to dryness to remove the solvent, and the resulting mixture was separated using a Phenomenex C18 150 x 40 mm x 5 μm preparative column; mobile phase: [water (0.2% formic acid)-acetonitrile]; acetonitrile %: 5% to 35% over 10 min to give compound 024 formate. LCMS: (ESI) m / z = 641.2 [M+H] + .

[0339] Example 25 [ka] Step 1: Synthesis of Compound 025-1 021-1 (1.1 g, 2.42 mmol, 1 equiv.) and 024-1A (988.77 mg, 2.42 mmol, 1 equiv.) were dissolved in 1,4-dioxane (2 mL) and water (2 mL). 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (314.93 mg, 483.20 μmol, 0.2 equiv.) and potassium phosphate (769.27 mg, 3.62 mmol, 1.5 equiv.) were added. The mixture was reacted under nitrogen at 90 °C for 18 h. After the reaction was complete, the mixture was extracted twice with 30 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the crude product was purified on a silica gel column (gradient elution: petroleum ether / ethyl acetate = 10:1 to 5:1) to obtain compound 025-1. LCMS: (ESI) m / z=740.3 [M+H] +

[0340] Step 2: Synthesis of compound 025-2 025-1 (1.1 g, 1.49 mmol, 1 equiv.) was dissolved in N,N-dimethylformamide (2 mL). N-iodosuccinimide (501.77 mg, 2.23 mmol, 1.5 equiv.) was added. The mixture was reacted at 25°C for 2 hours. After the reaction was completed, the mixture was extracted twice with 30 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product. The crude product was purified on a silica gel column (gradient elution: petroleum ether: ethyl acetate = 10:1 to 5:1) to obtain compound 025-2. LCMS: (ESI) m / z = 866.2 [M+H] + .

[0341] Step 3: Synthesis of compound 025-3 025-2 (1.1 g, 1.27 mmol, 1 equiv.) was dissolved in N,N-dimethylformamide (2 mL). Methyl fluorosulfonyl difluoroacetate (1.22 g, 6.35 mmol, 808.29 μL, 5 equiv.), hexamethylphosphoramide (1.14 g, 6.35 mmol, 1.12 mL, 5 equiv.), and cuprous iodide (483.98 mg, 2.54 mmol, 2 equiv.) were added. The mixture was refluxed under nitrogen at 80 °C for 18 h. After the reaction was complete, the mixture was extracted twice with 20 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the crude product was purified on a silica gel column (gradient elution: petroleum ether: ethyl acetate = 10:1 to 5:1) to obtain compound 025-3. LCMS: (ESI) m / z=866.2 [M+H] + .

[0342] Step 4: Synthesis of compound 025-4 025-3 (118.24 mg, 742.74 μmol, 1 equiv.) was dissolved in tetrahydrofuran (2 mL) and N,N-dimethylformamide (2 mL). Cesium carbonate (242.00 mg, 742.74 μmol, 1 equiv.), triethylenediamine (8.33 mg, 74.27 μmol, 8.17 μL, 0.1 equiv.), and 001-4A (0.6 g, 742.74 μmol, 1 equiv.) were added. The mixture was reacted at 25 °C for 18 h. After the reaction was complete, water was added, and the mixture was extracted with 100 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the crude product was purified on a silica gel column (gradient elution: dichloromethane:methanol = 100:1 to 20:1) to obtain compound 025-4. LCMS: (ESI) m / z=947.4 [M+H] + .

[0343] Step 5: Synthesis of Compound 025 025-4 (60 mg, 63.36 μmol, 1 equiv.) was dissolved in trifluoroacetic acid (7.22 mg, 63.36 μmol, 4.69 μL, 1 equiv.), and the solution was stirred at 25 °C for 1 h. After the reaction was complete, the mixture was rotary evaporated to dryness to remove the solvent, and the compound 025 formate was obtained after separation on a preparative column: Phenomenex C18 150 × 40 mm × 5 μm; mobile phase: [water (0.2% formic acid)-acetonitrile]; acetonitrile %: 5% to 35% in 10 min. LCMS: (ESI) m / z = 607.2 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ ppm 1.68-1.80(m,6H)2.00-2.17(m,3H)2.36(br s,3H)2.83(br d,J=5.25Hz,2H)2.95-3.14(m,3H)3.66(br s,2H)3.98-4.12(m,2H)4.27(br d,J=11.76Hz,2H)5.18-5.39(m,1H)6.00(br s,2H)6.80(br d,J=8.75Hz,1H)7.10(br t,J=7.63Hz,1H)7.80(br d,J=8.76Hz,1H)8.24(s,1H).

[0344] Example 26 [ka] Step 1: Synthesis of compound 026-2 026-1 (4.8 g, 19.16 mmol, 1 eq) and urea (69.06 g, 1.15 mol, 61.66 mL, 60 eq) were added to a reaction flask, and the mixture was stirred and reacted at 200 °C for 2 hours. After the reaction was completed, the mixture was cooled to room temperature and 200 mL of water was added. The mixture was suction filtered to obtain compound 026-2. LCMS: (ESI) m / z = 274.9 [M + H] + .

[0345] Step 2: Synthesis of compound 026-3 N,N-Diisopropylethylamine (11.13 g, 86.12 mmol, 15.00 mL, 11.86 equiv.) was added dropwise to phosphorus oxychloride (50 mL) at 0 °C. 026-2 (2 g, 7.26 mmol, 1 equiv.) was added batchwise, and the mixture was refluxed at 80 °C for 20 h. After the reaction was completed, the reaction solution was evaporated to dryness to remove phosphorus trichloride. The crude product was purified on a silica gel column (gradient elution: petroleum ether: ethyl acetate = 10:1 to 3:1) to give compound 026-3. LCMS: (ESI) m / z = 310.8 [M+H] + .

[0346] Step 3: Synthesis of compound 026-4 026-3 (1 g, 3.20 mmol, 1 eq) was dissolved in N,N-dimethylformamide (2 mL). 010-16A (679.59 mg, 3.20 mmol, 1 eq) and N,N-diisopropylethylamine (1.24 g, 9.60 mmol, 1.67 mL, 3 eq) were added. The mixture was stirred and reacted at 25 °C for 2 hours. After the reaction was completed, the reaction solution was poured into 200 mL of water to precipitate a solid. The solid was washed with 60 mL of water to obtain compound 026-4. LCMS: (ESI) m / z = 487.0 [M+H] + .

[0347] Step 4: Synthesis of compound 026-5 026-4 (1.3 g, 2.66 mmol, 1 equiv.) was dissolved in N,N-dimethylformamide (10 mL) and tetrahydrofuran (10 mL). Then, cesium carbonate (867.60 mg, 2.66 mmol, 1 equiv.), 001-4A (635.88 mg, 3.99 mmol, 1.5 equiv.), and triethylenediamine (29.87 mg, 266.28 μmol, 29.28 μL, 0.1 equiv.) were added. The mixture was stirred and reacted at 25 °C for 18 h. After the reaction was complete, the mixture was extracted with 50 mL of ethyl acetate and washed with saturated brine. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the crude product was purified on a silica gel column (gradient elution: petroleum ether: ethyl acetate = 100:1 to 20:1) to give compound 026-5. LCMS: (ESI) m / z=610.2 [M+H] + .

[0348] Step 5: Synthesis of compound 026-6 026-5 (0.2 g, 327.36 μmol, 1 equiv.) and compound 026-1A (91.03 mg, 327.36 μmol, 1 equiv.) were dissolved in 1,4-dioxane (1 mL) and water (0.2 mL). [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (21.34 mg, 32.74 μmol, 0.1 equiv.) and potassium phosphate (104.23 mg, 491.04 μmol, 1.5 equiv.) were added. The mixture was reacted under nitrogen at 90 °C for 18 h. After completion of the reaction, the reaction solution was evaporated to dryness, and the crude product was purified on a silica gel column (gradient elution: petroleum ether: ethyl acetate = 100:1 to 20:1) to obtain compound 026-6. LCMS: (ESI) m / z = 764.3 [M+H] + .

[0349] Step 6: Synthesis of Compound 026 026-6 (100 mg, 130.84 μmol, 1 equiv.) was dissolved in hydrochloric acid / 1,4-dioxane (2 mL). Acetonitrile (2 mL) was added. The mixture was stirred and reacted at 25 °C for 15 h. The reaction solution was rotary evaporated to dryness and purified by preparative HPLC: Column: Phenomenex C18 150 × 40 mm × 5 μm; Mobile phase: [water (0.2% formic acid)-acetonitrile]; Acetonitrile%: 1% to 30% over 10 min to obtain compound 026 formate. 1 H NMR(400MHz,DMSO-d6)δ ppm 0.71(br s,3H)1.69-1.91(m,8H)2.04(br d,J=18.89Hz,2H)2.23(br s,1H)2.83(br s,2H)3.01(br s,2H)3.09(br s,3H)3.92-4.20(m,4H)4.23-4.35(m,2H)5.20-5.38(m,1H)6.83(br s,1H)7.25-7.39(m,3H)7.74(br s,1H)7.95(br d,J=7.25Hz,1H)8.28(br s,1H).

[0350] Example 27 [ka] Step 1: Synthesis of compound 027-1B 027-1A (0.9 g, 4.03 mmol, 1 equiv.) was dissolved in N-methylpyrrolidone (5 mL). Potassium carbonate (1.39 g, 10.09 mmol, 2.5 equiv.), potassium iodide (669.76 mg, 4.03 mmol, 1 equiv.), and p-methoxybenzyl chloride (1.58 g, 10.09 mmol, 1.37 mL, 2.5 equiv.) were added. The mixture was reacted at 25 °C for 15 h. After the reaction was completed, the mixture was extracted twice with 20 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the crude product was purified on a silica gel column (gradient elution: petroleum ether: ethyl acetate = 100:1 to 10:1) to obtain compound 027-1B. LCMS: (ESI) m / z = 463.1 [M+H] + .

[0351] Step 2: Synthesis of compound 027-1 019-8 (0.6 g, 1.01 mmol, 1 equiv.) was dissolved in 1,4-dioxane (10 mL). Bis(pinacolato)diboron (384.44 mg, 1.51 mmol, 1.5 equiv.), bis(diphenylphosphino)ferrocenepalladium dichloride (73.85 mg, 100.93 μmol, 0.1 equiv.), and potassium acetate (148.58 mg, 1.51 mmol, 1.5 equiv.) were added. The mixture was refluxed at 105° C. for 15 h. After the reaction was completed, the reaction mixture was rotary evaporated to dryness and separated by preparative HPLC: Column: Phenomenex C18 150 x 40 mm x 5 μm; Mobile phase: [water (formic acid)-acetonitrile]; Acetonitrile %: 10% to 40% over 10 minutes to obtain compound 027-1 (110 mg, 171.46 μmol, 16.99% yield). LCMS: (ESI) m / z = 560.3 [M-82 + H] + .

[0352] Step 3: Synthesis of compound 027-2 027-1 (82.83 mg, 178.76 μmol, 1 equiv.) and 027-1B (100 mg, 178.76 μmol, 1 equiv.) were dissolved in 1,4-dioxane (2 mL) and water (0.4 mL). Potassium phosphate (56.92 mg, 268.14 μmol, 1.5 equiv.) and 1,1-bis(tert-butylphosphine)ferrocene palladium chloride (11.65 mg, 17.88 μmol, 0.1 equiv.) were added. The mixture was reacted at 80°C under nitrogen for 15 h. After completion of the reaction, the reaction solution was directly evaporated to dryness, and the crude product was purified on a silica gel column (gradient elution: petroleum ether: ethyl acetate = 100:1 to 30:1) to give compound 027-2. LCMS: (ESI) m / z = 898.4 [M+H] + .

[0353] Step 4: Synthesis of Compound 027 027-2 (100 mg, 111.35 μmol, 1 equiv.) was dissolved in trifluoroacetic acid (2 mL). The solution was stirred at 25°C for 2 hours. After the reaction was complete, the reaction mixture was rotary evaporated to dryness to remove the solvent, and the resulting mixture was purified by preparative HPLC: Column: Phenomenex C18 150 x 40 mm x 5 μm; Mobile phase: [water (0.2% formic acid)-acetonitrile]; Acetonitrile %: 55%-85%, 10 min separation to give compound 027 formate. LCMS: (ESI) m / z = 558.3 ​​[M+H] + .

[0354] Example 28 [ka] Step 1: Synthesis of compound 028-1 Compound 011-1A (0.30 g, 477.00 μmol, 1 eq.), compound 028-1A (180.67 mg, 953.99 μmol, 2 eq.), and anhydrous potassium phosphate (506.25 mg, 2.38 mmol, 5 eq.) were added to 1,4-dioxane (15 mL). The atmosphere was replaced with nitrogen three times, and (2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) chloride (37.53 mg, 47.70 μmol, 0.1 eq.) was added under nitrogen. The atmosphere was replaced with nitrogen three times. The mixture was reacted at 100°C for 16 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and 20 mL of water and 20 mL of ethyl acetate were added. The reaction mixture was stirred for 5 minutes and then allowed to settle. The layers were separated. The aqueous phase was extracted once with 20 mL of ethyl acetate. The organic phases were combined and washed three times with 20 mL of saturated brine, then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the crude product, which was purified using a column (petroleum ether:ethyl acetate=100:0 to 0:100) to give compound 028-1. LCMS: (ESI) m / z=693.2 [M+H] + ; 1H NMR(400MHz,CDCl3)δ ppm 7.7(s,1H)7.30-7.23(m,1H),6.67-6.48(m,1H),5.37-5.24(m,1H),4.43-4.21(m,6H),3.79-3.48(m,3H),3.39(s ,2H),3.33-3.15(m,2H),3.11-2.93(m,1H),2.43-2.16(m,3H),2.01-1.94(m,5H),1.85-1.76(m,2H),1.53(s,9H).

[0355] Step 2: Synthesis of compound 028-2 Compound 028-1 (110 mg, 158.60 μmol, 1 equivalent) was added to N,N-dimethylformamide (2 mL). N-chlorosuccinimide (23.30 mg, 174.46 μmol, 1.1 equivalent) was added. The mixture was reacted at 70° C. for 3 hours. After the reaction was completed, 10 mL of ethyl acetate and 5 mL of water were added to the reaction solution, and the mixture was stirred for 5 minutes. The mixture was allowed to stand, and the layers were separated. The aqueous phase was extracted once with 10 mL of ethyl acetate. The organic phases were combined, washed twice with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product, which was purified on a silica gel column (dichloromethane:methanol (1‰ ammonia dropwise added) = 20:1) to give compound 028-2. LCMS: (ESI) m / z = 727.1 [M+H] + . 1 HNMR(400MHz,CDCl3)δ ppm 7.77(s,1H),7.42(d,J=7.25Hz,1H),5.34-5.20(m,1H),4.40-4.27(m,5H),3.7-3.5(s,3H),3.32-3 .21(m,2H),3.15-3.19(m,1H)2.93-3.04(m,2H),2.32-2.10(m,4H),2.00-1.76(m,7H),1.52(s,9H).

[0356] Step 3: Synthesis of Compound 028 Compound 028-2 (40 mg, 54.94 μmol, 1 equiv.) was added to anhydrous dichloromethane (2 mL). Trifluoroacetic acid (308.00 mg, 2.70 mmol, 200.00 μL, 49.16 equiv.) was added. The mixture was reacted at 25 °C for 2 hours. A solid was precipitated. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, and the crude product was purified by preparative chromatography (column: Phenomenex Luna 80 × 30 mm × 3 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile%: 15% to 35%, 7 min) to obtain compound 028 hydrochloride. 1 H NMR(400MHz,CD3OD)THANOL-dMHz,a 80*30mm*3.00 J=7.25Hz,1H),5.34-5.20(m,1H),4.40-4.27(m,5H),3.7-3.5(s,3H),3.32-3.21(m,2H),3.15-3.19m,2H),3.8 4-4.04(m,3H),3.42-3.59(m,1H),2.56-2.82(m,2H),2.44-2.54(m,1H),2.31-2.42(m,2H),2.29-2.14(m,5H).

[0357] Example 29 [ka] Step 1: Synthesis of Compound 029-1 Compound 001-1 (400 mg, 1.21 mmol, 1 equiv.) was dissolved in anhydrous N,N-dimethylformamide (10 mL) at 20 °C, and N,N-diisopropylethylamine (391.21 mg, 3.03 mmol, 527.24 μL, 2.5 equiv.) and 029-1A (257.03 mg, 1.21 mmol, 1 equiv.) were added. The mixture was stirred for 0.5 h. After the reaction was complete, the mixture was diluted with ethyl acetate (150 mL), washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. The organic phase was separated and dried. The organic solvent was removed under reduced pressure to give crude product 029-1. 1H NMR(400MHz,CDCl3)δ=7.79(d,J=2.0Hz,1H),4.93(br d,J=12.8Hz,1H),5.00-4.87(m,1H),4.15-3.90(m,2H),3.42-3.20(m,2H),2.06-1.85(m,4H),1.50(s,9H).

[0358] Step 2: Synthesis of compound 029-2 Compound 029-1 (600 mg, 1.19 mmol, 1 equiv.) was dissolved in tetrahydrofuran (3 mL) and N,N-dimethylformamide (3 mL). 001-4A (284.17 mg, 1.78 mmol, 1.5 equiv.), cesium carbonate (1.16 g, 3.57 mmol, 3 equiv.), and triethylenediamine (13.35 mg, 119.00 μmol, 13.09 μL, 0.1 equiv.) were added sequentially under nitrogen. The reaction solution was stirred at 20 °C for an additional 16 h. After the reaction was complete, 100 mL of ethyl acetate was added to the reaction solution. The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and evaporated. The organic solvent was removed under reduced pressure, and the resulting crude product was separated by silica gel column chromatography (eluent: ethyl acetate:petroleum ether = 0-80%) to obtain compound 029-2. 1 H NMR(400MHz,CDCl3)δ=7.73(d,J=2.0Hz,1H),5.38-5.20(m,1H),4.89-4.75(m,2H),4.29-4.21(m,1H),4.19-4.13(m,1H),4.04(br d,J=12.0Hz,1H),3.91(br d,J=12.0Hz,1H),3.43-3.16(m,5H),3.03-2.97(m,1H),2.34-2.11(m,3H),2.01-1.76(m,8H),1.65(br s,1H),1.50(s,9H).

[0359] Step 3: Synthesis of compound 029-3 Under nitrogen protection, 029-2 (50 mg, 79.50 μmol, 1 equiv.), 029-3A (25.77 mg, 95.40 μmol, 1.2 equiv.), and sodium carbonate (25.28 mg, 238.50 μmol, 3 equiv.) were dissolved in 1,4-dioxane (2 mL) and water (1 mL). [1,1'-Bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (6.49 mg, 7.95 μmol, 0.1 equiv.) was added. After the addition was complete, the mixture was reacted at 100 °C for 3 h. After the reaction was complete, the mixture was cooled, and the organic solvent was removed under reduced pressure. The resulting crude product was purified on a preparative silica gel plate (eluent: dichloromethane:methanol = 10:1) to give compound 029-3. LCMS: (ESI) m / z = 692.2 [M+H] + .

[0360] Step 4: Synthesis of Compound 029 Compound 029-3 (40 mg, 57.79 μmol, 1 equiv) was dissolved in dichloromethane (2 mL) at 20 °C. Trifluoroacetic acid (770.00 mg, 6.75 mmol, 0.5 mL, 116.86 equiv) was added, and the reaction mixture was stirred for 1 h. After completion of the reaction, the reaction mixture was rotary evaporated to dryness, and the resulting crude product was purified by preparative chromatography (column: Phenomenex Synergi C18 150 × 30 mm × 4 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile %: 20% to 50%, 9 min) to obtain compound 029 hydrochloride. LCMS: (ESI) m / z = 592.1 [M+H] + .

[0361] Example 30 [ka] Step 1: Synthesis of Compound 030-1 Compound 011-1A (500 mg, 794.99 μmol, 1 equiv.) was dissolved in tetrahydrofuran (5 mL) at 20 °C, and sodium chloride (85.90 mg, 1.59 mmol, 2 equiv.) was added. The reaction mixture was heated to 70 °C and stirred for 48 h. After the reaction was complete, the mixture was rotary evaporated to dryness to remove the solvent. The resulting crude product was purified on a preparative silica gel plate (eluent: ethyl acetate / petroleum ether = 0-100%) to obtain compound 030-1. 1 H NMR(400MHz,CDCl3)δ=7.65(s,1H),5.37(br s,1H),5.24(br s,1H),4.28(br d,J=7.3Hz,6H),4.15-4.12(m,3H),3.54(br s,2H),3.37-3.17(m,3H),3.01(br s,1H),2.34-2.10(m,3H),2.01-1.88(m,5H),1.81(br d,J=8.0Hz,2H),1.52(s,9H).

[0362] Step 2: Synthesis of compound 030-2 Compound 030-1 (50 mg, 78.01 μmol, 1 equiv.), 029-3A (25.29 mg, 93.61 μmol, 1.2 equiv.), and cesium carbonate (76.25 mg, 234.02 μmol, 3 equiv.) were dissolved in 1,4-dioxane (5 mL) and water (1 mL) under nitrogen, and Pd(PPh3)4 (9.01 mg, 7.80 μmol, 0.1 equiv.) was added. After the addition was complete, the mixture was reacted at 100 °C for 16 h. After the reaction was complete, the mixture was rotary evaporated to dryness to remove the solvent, and the resulting crude product was purified on a preparative silica gel plate (eluent: dichloromethane:methanol = 10:1) to give compound 030-2. LCMS: (ESI) m / z = 704.3 [M+H] + .

[0363] Step 3: Synthesis of Compound 030 Compound 030-2 (20.00 mg, 28.40 μmol, 1 equiv.) was dissolved in dichloromethane (3 mL) at 20 °C, and trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL, 475.58 equiv.) was added. The reaction was stirred for an additional 16 h. After the reaction was complete, the mixture was rotary evaporated to dryness to remove the solvent. The residue was purified by preparative chromatography (column: Welch Xtimate C18 100 × 40 mm × 3 μm; mobile phase: [water (0.1% trifluoroacetic acid)-acetonitrile]; acetonitrile %: 15% to 45%, 8 min) to give compound 030 trifluoroacetate. LCMS: (ESI) m / z = 604.5 [M+H] + .

[0364] Example 31 [ka] Step 1: Synthesis of Compound 031-1 Compound 031-1A (0.22 g, 981.91 μmol, 1 eq) and imidazole (147.07 mg, 2.16 mmol, 2.2 eq) were dissolved in anhydrous dichloromethane (4 mL). The solution was cooled to 0°C. tert-Butyldimethylchlorosilane (162.79 mg, 1.08 mmol, 132.35 μL, 1.1 eq) was added dropwise. The atmosphere was replaced with nitrogen. The reaction was slowly warmed to 20°C and stirred for 3 hours. After completion of the reaction, the reaction was diluted by adding 5 mL of dichloromethane and 10 mL of water. The layers were separated. The organic phase was collected, and the aqueous phase was extracted with 30 mL of dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (gradient elution: petroleum ether: ethyl acetate = 10:0 to 1:10) to give compound 031-1. LCMS: (ESI) m / z = 338.0 [M+H] +

[0365] Step 2: Synthesis of compound 031-2 Compound 027-1 (0.2 g), compound 031-1 (43.54 mg, 128.71 μmol, 1.2 equivalents), and sodium carbonate (34.10 mg, 321.77 μmol, 3 equivalents) were added to 1,4-dioxane (4 mL) and water (0.8 mL). The atmosphere was replaced with nitrogen three times. [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (7.85 mg, 10.73 μmol, 0.1 equivalents) was added under nitrogen. The mixture was reacted at 100°C for 2 hours. After the reaction was completed, 5 mL of ethyl acetate was added to the reaction solution. The organic phase was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the crude product was purified by preparative high-performance liquid chromatography (column: Phenomenex Luna C18 80 x 40 mm x 3 μm; mobile phase A: water (0.05% HCl), mobile phase B: acetonitrile; gradient run: acetonitrile %: 40% to 70%; analysis time: 7 min) to give compound 031-2. LCMS: (ESI) m / z = 773.3 [M+H] + .

[0366] Step 3: Synthesis of Compound 031 Compound 031-2 (0.035 g, 45.28 μmol, 1 equivalent) was added to acetonitrile (2 mL). Hydrochloric acid / 1,4-dioxane (4 M, 226.39 μL, 20 equivalents) was added. The mixture was reacted at 25° C. for 2 hours. After the reaction was completed, the reaction solution was added to 5 mL of water. The mixture was extracted twice with 3 mL of ethyl acetate, and the aqueous phase was concentrated to give compound 031. LCMS: (ESI) m / z=559.3 [M+H] + . 1H NMR(400MHz,CD3OD)δ=8.47-8.43(m,1H),8.15-8.10(m,1H),7.81(d,J=8.8Hz, 1H),7.43-7.27(m,3H),7.14(d,J=2.4Hz,1H),5.40-5.22(m,1H),4.57-4.50(m, 2H),4.33-4.17(m,2H),3.66-3.57(m,4H),3.26-3.13(m,3H),3.03-2.95(m,1H ),2.42-2.27(m,1H),2.41-2.09(m,2H),1.94(s,2H),1.89(s,2H),1.84(s,3H).

[0367] Example 32 [ka] Step 1: Synthesis of Compound 032-2 Ammonium thiocyanate (2.38 g, 31.25 mmol, 2.38 mL, 1.3 equiv) was added to acetone (50 mL). Benzoyl chloride (3.38 g, 24.04 mmol, 2.79 mL, 1 equiv) was added. The mixture was reacted at 70 °C for 0.5 hours. The mixture was cooled to 50 °C, and a solution of compound 032-1 (5 g, 24.04 mmol, 1 equiv) in acetone (7 mL) was added batchwise. The mixture was reacted at 70 °C for 0.5 hours. Sodium hydroxide (2 M, 42.07 mL, 3.5 equiv) was added, and the mixture was refluxed for an additional 0.5 hours. After the reaction was complete, the reaction mixture was cooled to room temperature. The pH of the reaction mixture was adjusted to 5 with hydrochloric acid, followed by adjustment to 8 with ammonia. The mixture was stirred for 0.5 hours and then extracted twice with 30 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product, which was then slurried and stirred with 30 mL of dichloromethane for 1 hour. The mixture was filtered to give compound 032-2. LCMS: (ESI) m / z=266.9 [M+H] + .

[0368] Step 2: Synthesis of compound 032-3 Compound 032-2 (2 g, 7.49 mmol, 1 eq.) was added to dichloroethane (20 mL). A solution of bromine (2.39 g, 14.98 mmol, 772.04 μL, 2 eq.) in dichloroethane (2 mL) was added. The mixture was reacted at 95° C. for 2 hours. After the reaction was complete, the reaction solution was filtered, and the filter cake was rinsed with 20 mL of 1,2-dichloroethane to give compound 032-3. LCMS: (ESI) m / z=264.8 [M+H] + .

[0369] Step 3: Synthesis of compound 032-4 Compound 032-3 (1.0 g, 3.77 mmol, 1 eq) was added to anhydrous tetrahydrofuran (15 mL). N,N-Diethylisopropylamine (1.22 g, 9.43 mmol, 1.64 mL, 2.5 eq) and 4-dimethylaminopyridine (46.09 mg, 377.25 μmol, 0.1 eq) were added. Di-tert-butyl dicarbonate (988.01 mg, 4.53 mmol, 1.04 mL, 1.2 eq) was added to the reaction mixture under nitrogen. The mixture was reacted at 20 °C for 19 hours. After the reaction was complete, 20 mL of water was added to the reaction mixture. The mixture was extracted twice with 10 mL of ethyl acetate. The organic phases were combined, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product. The crude product was slurried with 10 mL of dichloromethane for 1 hour and filtered to give compound 032-4. LCMS: (ESI) m / z=308.8 [M-55] + .

[0370] Step 4: Synthesis of compound 032-5 Compound 027-1 (0.2 g), compound 032-4 (47.00 mg, 128.71 μmol, 1.2 equivalents), and sodium carbonate (34.10 mg, 321.77 μmol, 3 equivalents) were added to 1,4-dioxane (4 mL) and water (0.8 mL). The atmosphere was replaced with nitrogen three times. [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (7.85 mg, 10.73 μmol, 0.1 equivalents) was added under nitrogen. The mixture was reacted at 100° C. for 2 hours. After the reaction was completed, 5 mL of ethyl acetate was added to the reaction solution. The mixture was washed with 8 mL of water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain a crude product. The crude product was purified by preparative high-performance liquid chromatography (column: Phenomenex Luna C18 80 x 40 mm x 3 μm; mobile phase A: water (0.05% hydrochloric acid), mobile phase B: acetonitrile; gradient run: acetonitrile %: 40% to 70%; analysis time: 7 min) to give compound 032-5. LCMS: (ESI) m / z = 800.3 [M+H] + .

[0371] Step 5: Synthesis of Compound 032 Compound 032-5 (0.025 g, 31.25 μmol, 1 equiv.) was added to acetonitrile (1 mL). Hydrochloric acid / 1,4-dioxane (4 M, 156.27 μL, 20 equiv.) was added. The mixture was reacted at 25 °C for 7 hours. After the reaction was complete, the reaction solution was added to 5 mL of water. The mixture was extracted twice with 3 mL of ethyl acetate, and the crude product was purified by preparative high-performance liquid chromatography (column: Phenomenex Luna C18 80 × 40 mm × 3 μm; mobile phase A: water (0.05% hydrochloric acid), mobile phase B: acetonitrile; gradient run: acetonitrile %: 10% to 35%; analysis time: 7 min) to obtain compound 032 hydrochloride. LCMS: (ESI) m / z = 600.2 [M+H] + ; 1H NMR(400MHz,CD3OD)δ=8.09-7.97(m,1H),7.73-7.62(m,1H),7.04-6.93(m,1H),5.70-5.52(m,1H),4.34-4.27(m,2H),4.17-4.03(m,3H) ),4.00-3.85(m,3H),3.52-3.43(m,3H),2.91-2.57(m,3H),2.54-2.45(m,1H),2.42-2.32(m,2H),2.28-2.21(m,1H),2.19-2.09(m,4H).

[0372] Example 33 [ka] Step 1: Synthesis of compound 033-2 Compound 033-1 (5 g, 21.27 mmol, 1 equiv.), N-chlorosuccinimide (4.26 g, 31.90 mmol, 1.5 equiv.), 4-nitro-2-(trifluoromethyl)phenol (1.32 g, 6.38 mmol, 0.3 equiv.), and 4-trifluoromethylaniline (342.71 mg, 2.13 mmol, 263.62 μL, 0.1 equiv.) were dissolved in dichloroethane (20 mL). Trifluoroacetic acid (24.25 g, 212.70 mmol, 15.75 mL, 10 equiv.) and palladium acetate (77.53 mg, 2.13 mmol, 0.1 equiv.) were added under nitrogen. The mixture was reacted at 80 °C for 16 hours. After completion of the reaction, the reaction mixture was cooled to room temperature. The reaction mixture was added with 20 mL of water and extracted twice with 20 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product, which was purified using a column (petroleum ether: ethyl acetate = 10:1) to obtain compound 033-2. LCMS: (ESI) m / z = 268.9 [M + H] + .

[0373] Step 2: Synthesis of compound 033-3 Compound 033-2 (3 g, 11.13 mmol, 1 equivalent) was added to dimethyl sulfoxide (10 mL). Then, hydroxylamine hydrochloride (1.55 g, 22.26 mmol, 2 equivalents) was added. The mixture was reacted at 95 °C for 6 hours. After the reaction was completed, 30 mL of water was added to the reaction solution. The mixture was extracted three times with 30 mL of methyl tert-butyl ether. The organic phases were combined, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated to give compound 033-3. 1 H NMR(400MHz,CD3OD)δ=8.31-8.26(m,1H),7.97-7.91(m,1H),7.83-7.81(m,1H),7.78-7.50(m,2H).

[0374] Step 3: Synthesis of compound 033-4 p-Methoxybenzylamine (617.64 mg, 4.50 mmol, 582.68 μL, 1.2 equiv.) and compound 033-3 (1 g, 3.75 mmol, 1 equiv.) were added to N,N-dimethylformamide (5 mL). Potassium carbonate (1.04 g, 7.50 mmol, 2 equiv.) was then added. The mixture was reacted at 80 °C for 16 hours. After the reaction was completed, 30 mL of water was added to the reaction mixture. The mixture was extracted twice with 20 mL of methyl tert-butyl ether. The organic phases were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 1:1) to give compound 033-4. 1 H NMR(400MHz,CD3OD)δ=7.78-7.73(m,1H),7.61(d,J=8.4Hz,1H),7.58-7.50(m,1H),7.40(d,J=7.2Hz,1H),7.30-7.24(m,3H),6.85-6.78(m,1H).

[0375] Step 4: Synthesis of compound 033-5 Compound 033-4 (70.90 mg, 193.06 μmol, 1.2 equivalents) and sodium bicarbonate (27.03 mg, 321.77 μmol, 12.51 μL, 2 equivalents) were added to 1,4-dioxane (5 mL) and water (3 mL). The atmosphere was replaced with nitrogen three times. [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (11.77 mg, 16.09 μmol, 0.1 equivalents) was added under nitrogen. The mixture was heated to 100°C, and compound 027-1 (0.09 g, 160.88 μmol, 1 equivalents) was added. The atmosphere was replaced with nitrogen three times, and the mixture was reacted at 100°C under nitrogen for 1 hour. After the reaction was completed, the reaction solution was poured into 30 mL of water and extracted three times with 20 mL of ethyl acetate. The combined organic phases were washed with 20 mL of saturated brine, then dried over anhydrous sodium sulfate and concentrated. The crude product was purified by preparative high-performance liquid chromatography (column: Phenomenex Luna C18 80 x 40 mm x 3 μm; mobile phase A: water (0.05% hydrochloric acid), mobile phase B: acetonitrile; gradient run: acetonitrile %: 34% to 54%; analysis time: 7 min) to give compound 033-5. LCMS: (ESI) m / z = 802.2 [M+H] + .

[0376] Step 5: Synthesis of Compound 033 Compound 033-5 (0.002 g, 2.49 μmol, 1 equivalent) was added to anhydrous dichloromethane (0.25 mL) and trifluoroacetic acid (0.05 mL). The mixture was reacted at 25 °C for 5 hours. After the reaction was complete, the mixture was rotary evaporated to dryness to remove the solvent, and the crude product was purified by preparative high-performance liquid chromatography (column: Phenomenex Luna C18 80 × 40 mm × 3 μm; mobile phase A: water (0.04% hydrochloric acid), mobile phase B: acetonitrile; gradient run: acetonitrile %: 10% to 30%; analysis time: 8 min) to obtain compound 033 hydrochloride. LCMS: (ESI) m / z = 582.3 [M+H] + .

[0377] Assay Example 1: KRAS to effector protein c-Raf G12D Assay of SOS1-mediated binding ability 1.Purpose: KRAS to the downstream effector protein c-Raf in the MAPK pathway G12D Compounds that can effectively inhibit the binding of β-glucan were screened using the TR-FRET method.

[0378] 2. Assay Steps 2.1 Preparation of 1x enzyme reaction buffer:

[0379] [Table 1]

[0380] 2.2 Preparation of KRAS G12D enzyme (2x):

[0381] [Table 2]

[0382] 2.3 Preparation of substrate and antibody mixture (2x):

[0383] [Table 3]

[0384] 3. Compound screening: 1) Compounds were serially diluted 5-fold in a dilution plate with DMSO to a final starting concentration of 10 μM.

[0385] 2) Compounds were transferred with Echo to a 384 reaction plate at 100 μL / well.

[0386] 3) 5 μL of KRAS G12D enzyme was added to each well of the reaction plate.

[0387] 4) The plate was sealed with sealing film and centrifuged at 1000 g for 30 seconds, then incubated at room temperature for 15 minutes.

[0388] 5) A 2x cRaf / SOS1 / GTP / MAb anti-6HIS-d2 / MAb anti-GST-Eu mixture was prepared in 1x enzyme reaction buffer, and 5 µL of the mixture was added to the reaction plate.

[0389] 6) The mixture was centrifuged at 1000 g for 30 seconds and allowed to react at room temperature for 2 hours.

[0390] 7) Fluorescence signals at 615 nm (Cryptate) and 665 nm (XL665) were read using a BMG microplate reader.

[0391] 8) Data analysis was performed using Graphpad 7.0 software, and IC 50 obtained.

[0392] 4. Assay Results The results are shown in Table 4.

[0393] [Table 4]

[0394] Assay Conclusion: Compounds of the present disclosure inhibit KRAS G12D The activity can be significantly inhibited.

[0395] Assay Example 2. Anti-cell proliferation effect of compounds in tumor cell line AsPC-1 1. Purpose of the test In this assay, the inhibitory effect of compounds on cell proliferation was tested by detecting the effect of the compounds on in vitro cellular activity in the tumor cell line AsPC-1.

[0396] 2. Assay Materials

[0397] [Table 5]

[0398] Ultra Low Cluster 96-well Plate (Corning-7007)

[0399] Greiner CELLSTAR 96-well plate (#655090)

[0400] Promega CellTiter-Glo 3D Luminescence Cell Viability Detection Kit(Promega-G9683)

[0401] 2104-10 EnVision Plate Reader, PerkinElmer

[0402] RPMI 1640, DMEM, PBS (phosphate buffered saline), FBS (fetal bovine serum), antibiotic-antimycotic agent, L-glutamine, DMSO (dimethyl sulfoxide)

[0403] 3. Assay Methods and Procedures cell culture The tumor cell lines were cultured in a 5% CO2 incubator at 37°C according to the culture conditions indicated in the culture method. Cells were passaged periodically, and cells in the logarithmic growth phase were harvested for plating.

[0404] Cell plating Cells were stained with trypan blue and viable cells were counted.

[0405] The cell concentration was adjusted to an appropriate concentration.

[0406] [Table 6]

[0407] 135 μL of cell suspension was added to each well of the ULA culture plate, and the same volume of culture medium without cells was added to blank control wells.

[0408] Immediately after plating, the ULA plate was centrifuged at 1000 rpm for 10 minutes at room temperature. Note: After centrifugation, be careful not to subject the plate to unnecessary shock in subsequent operations.

[0409] The plates were incubated overnight in an incubator at 37°C, 5% CO2 and 100% relative humidity.

[0410] Preparation of 10x concentration compound working solutions and treatment of cells with compounds (Day 1) After preparing a 10x compound working solution (10x working solution in DMSO), 15 μL of the 10x compound working solution was added to the ULA culture plate, and 15 μL of the DMSO-cell culture medium mixture was added to the vehicle control and blank control, respectively.

[0411] The 96-well cell plates were returned to the incubator and cultured for 120 hours.

[0412] Cell rounding was observed daily until the end of the assay.

[0413] CellTiter-Glo Luminescent Assay for Cell Viability Detection (Day 5) The following steps were performed according to the instructions of the Promega CellTiter-Glo 3D Luminescence Cell Viability Detection Kit (Promega #G9683).

[0414] 150 μL of CellTiter-Glo 3D reagent (equivalent to the volume of cell culture medium in each well) was added to each well. The cell plate was wrapped in aluminum foil to protect it from light.

[0415] The culture plate was shaken on an orbital shaker for 5 minutes.

[0416] Mix thoroughly by carefully pipetting the mixture in the well up and down 10 times. Ensure that the cell spheres are well separated before proceeding to the next step.

[0417] The solution in the ULA culture plate was then transferred to a black bottom culture plate (#655090) and left at room temperature for 25 minutes to stabilize the luminescence signal.

[0418] Luminescent signals were detected using a 2104 EnVision plate reader.

[0419] 4. Data Analysis The inhibition rate (IR) of the assayed compounds was calculated by the following formula: IR (%) = (1 - (RLU of compound - RLU of blank control) / (RLU of vehicle control - RLU of blank control)) x 100%. The inhibition rates of compounds at different concentrations were calculated in Excel, and then the inhibition curves were plotted using GraphPad Prism software to calculate the minimum inhibition rate, maximum inhibition rate and IC 50 The relevant parameters were calculated, including

[0420] 4. Assay Results The results are shown in Table 7.

[0421] [Table 7]

[0422] Assay Conclusion: Compounds of the present disclosure inhibit KRAS G12D It has significant antiproliferative activity against mutant AsPC-1 cells.

[0423] Assay Example 3. Inhibitory effect of compounds on phospho-ERK in GP2D cells 1. Purpose of the test This assay measures KRAS expression in human colon cancer GP2D cells. G12D The inhibitory effect of the assayed compounds on the phosphorylation of ERK protein downstream of the signaling pathway was analyzed.

[0424] 2. Reagents, Consumables and Equipment

[0425] [Table 8]

[0426] [Table 9]

[0427] 3. Assay Process 1.Cell culture 1) GP2D cells were cultured in a cell culture flask at 37°C and 5% CO2 in DMEM medium (supplemented with 10% FBS and 1% P / S).

[0428] 2) After 2 days of culture, the medium was removed and the cells were washed once with sterile PBS buffer.

[0429] 3) 3 mL of trypsin was added, and the cells were digested in a 37°C incubator for 2 to 3 minutes until the cells detached.

[0430] 4) 9 mL of fresh culture medium was added to neutralize the digestion, and the cells were aspirated into a centrifuge tube and centrifuged at 1000 rpm for 5 minutes at room temperature.

[0431] 5) The supernatant was removed, 3 mL of fresh medium was added to resuspend the cells, and the cells were counted using a cell counter.

[0432] 2. Compound screening: 1) 7000 cells per well were plated in a 384 cell culture plate containing 40 μL of culture medium and cultured overnight in a 37° C., 5% CO 2 incubator.

[0433] 2) Using the Echo655 instrument, 40 nL of serially diluted compounds were added (initial compound concentration was 1000 nM, and compounds were serially diluted 3-fold. Final DMSO concentration was 0.1%), and the plate was incubated for 1 hour in a 37°C, 5% CO2 incubator. EGF stimulator (final concentration was 0.1 ng / mL) was added, and the plate was incubated for 15 minutes in a 37°C, 5% CO2 incubator.

[0434] 3) 40 μL of 8% paraformaldehyde fixative was added and incubated at room temperature for 20 minutes.

[0435] 4) PBS buffer was added to wash twice, and 40 μL of pre-chilled methanol was added and incubated at room temperature for 20 minutes.

[0436] 5) PBS buffer was added and the plate was washed twice, and 20 μL of blocking solution was added and blocked at room temperature for 1 hour.

[0437] 6) The blocking solution was removed, and a primary antibody mixture (phospho-p44 / 42 MAPK (T202 / Y204) rabbit mAb diluted 1:1000 and GAPDH (D4C6R) mouse mAb diluted 2:2000) was added, and the mixture was incubated overnight in a refrigerator at 4°C.

[0438] 7) After washing three times with PBST (0.05% Tween 20) buffer, a secondary antibody mixture (IRDye 680RD goat anti-mouse IgG (H+L) diluted 2000-fold and IRDye 800CW goat anti-rabbit IgG (H+L) diluted 2000-fold) was added, and the mixture was incubated at room temperature in the dark for 1 hour.

[0439] 8) The plate was washed three times with PBST (0.05% Tween 20) buffer, centrifuged upside down at 1000 rpm for 1 minute, dried in the dark, and scanned using an Odyssey CLx instrument.

[0440] 4. Data Analysis 1. Data Analysis Relative signal = signal value (total channel 800) / signal value (total channel 700)

[0441] H = Ave (dimethyl sulfoxide), L = Ave (compound), SD(H) = STDEV (dimethyl sulfoxide), SD(L) = STDEV (compound)

[0442] CV%(H)=100×(SD_H / Ave_H),CV%(L)=100×SD_L / Ave_L

[0443] Z'=1-3×(SD_H+SD_L) / (Ave_H-Ave_L)

[0444] Inhibition = (Ave_H - Sample) / (Ave_H - Ave_L) x 100

[0445] 2) Fitting compound IC50s from nonlinear regression equations. Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)×HillSlope))

[0446] X: logarithm of compound concentration, Y: inhibition

[0447] Top and Bottom: Plateau in the same units as Y; logIC50: Same log units as X; HillSlope: Slope coefficient or Hill slope

[0448] 5. Assay Results The results are shown in Table 10.

[0449] [Table 10]

[0450] Assay conclusion: Compounds of the present disclosure have significant inhibitory effects on phospho-ERK in GP2D cells.

[0451] Assay Example 4. KRAS G12DInhibitory activity assay 1.Purpose: Compounds that can effectively inhibit the binding of KRAS to GTP were screened using the TR-FRET method.

[0452] 2. Consumables and Equipment

[0453] [Table 11]

[0454] 3. Reagent Preparation a. Stock Reagents: 1) KRAS Nucleotide Exchange Buffer 20 mL of 1000 mM HEPES, 20 mL of 500 mM EDTA, 10 mL of 5 M sodium chloride, 0.1 mL of 100% Tween 20, and 949.9 mL of water were weighed and combined to make 1 L of solution. The solution was sterilized by filtration and stored at 4°C.

[0455] 2) KRAS assay buffer 20 mL of 1000 mM HEPES, 10 mL of 1000 mM magnesium chloride, 30 mL of 5 M sodium chloride, 0.05 mL of 100% Tween 20, and 939.95 mL of water were weighed and combined to make 1 L of solution. The solution was sterilized by filtration and stored at 4°C.

[0456] 3)KRAS / Bodipy GDP / Tb-SA mixture 9.5 μL of 95 μM KRAS G12D The protein and 440.5 μL of KRAS nucleotide exchange buffer were weighed and mixed. The mixture was incubated at room temperature for 1 hour and then combined with 8.4 μL of 17.9 μM Tb-SA, 1.8 μL of 5 mM Bodipy GDP, and 9539.8 μL of KRAS assay buffer to make a 1 L solution. After mixing, the mixture was left at room temperature for 6 hours and then stored at -80°C.

[0457] b. Assay Reagents: 1) KRAS enzyme solution 73.3 μL of the KRAS / Bodipy GDP / Tb-SA mixture and 2126.7 μL of KRAS assay buffer were weighed and combined to make a 2200 μL solution.

[0458] 2)SOS / GTP mixture 1.59 μL of 166 μM SOS protein, 198 μL of 100 mM GTP, and 2000.41 μL of KRAS assay buffer were weighed and combined to make 2200 μL of solution.

[0459] 4. Assay Process 1) The concentration of the stock solution of the control compound was 1 mM, and the concentration of the stock solution of the compound to be assayed was 10 mM. 9 μL of the control compound and the compound to be assayed were transferred to a 384-LDV plate.

[0460] 2) The compounds on the LDV plate were serially diluted 3-fold to 10 concentrations using Bravo.

[0461] 3) Using ECHO, 9 nL of the compound on the LDV plate was transferred to the assay plate.

[0462] 4) Using a Dragonfly autosampler, 3 μL of a 3 nM Kras / 0.5 nM TB-SA / 30 nM BodipyGDP mixture and 3 μL of Ras buffer were added sequentially to each well of the assay plate, followed by centrifugation at 1000 rpm / min for 1 minute.

[0463] 5) The assay plate was incubated at room temperature for 1 hour.

[0464] 6) Using a Dragonfly autosampler, 3 μL of 120 nM SOS / 9 mM GTP mixture was added to each well of the assay plate and centrifuged at 1000 rpm / min for 1 minute.

[0465] 7) The assay plate was incubated at room temperature for 1 hour.

[0466] 8) The plate was read on Envision and the data was recorded.

[0467] 9) Analyze the data using Excel and Xlfit to obtain the IC values ​​for the compounds being assayed. 50 was calculated.

[0468] 5 Assay Results The results are shown in Table 12.

[0469] [Table 12]

[0470] Assay Conclusion: Compounds of the present disclosure inhibit KRAS G12D It has a significant inhibitory effect on the enzyme.

[0471] Assay Example 5. Assay of p-ERK inhibition in GP2D cells 1.Purpose: Compounds that can effectively inhibit p-ERK in GP2D cells were screened by HTRF method.

[0472] 2. Assay Process 1) GP2D cells were seeded into a transparent 96-well cell culture plate, with each well containing 80 μL of cell suspension and 8,000 cells. The cell plate was placed in a carbon dioxide incubator at 37°C overnight.

[0473] 2) 2 μL of compound was weighed and added to 78 μL of cell culture medium. After the mixture was thoroughly mixed, 20 μL of compound solution was weighed and added to the corresponding well of the cell plate. The cell plate was returned to the carbon dioxide incubator and incubated for an additional hour.

[0474] 3) After the incubation, the cell supernatant was discarded. 50 μL of 1X cell lysate was added to each well. The mixture was incubated at room temperature for 30 minutes with shaking.

[0475] 4) Phospho-ERK1 / 2 Eu Cryptate antibody and phospho-ERK1 / 2 d2 antibody were diluted 20-fold with detection buffer.

[0476] 5) 16 μL of the cell lysate supernatant was weighed and added to each well of a new 384-well white microplate, followed by 2 μL of a diluted phospho-ERK1 / 2 Eu Cryptate antibody solution and 2 μL of a diluted phospho-ERK1 / 2 d2 antibody solution. The mixture was incubated at room temperature for at least 4 hours.

[0477] 6) After the incubation was completed, HTRF was read on a multilabel analyzer: excitation: 320 nm, emission: 615 nm, 665 nm.

[0478] 7) IC of the compound being assayed 50 was calculated.

[0479] 3. Assay Results The results are shown in Table 13.

[0480] [Table 13]

[0481] Assay conclusion: Compounds of the present disclosure have significant inhibitory effects on p-ERK in GP2D cells.

[0482] Assay Example 6. Assay for inhibition of GP2D cell proliferation 1. Purpose of the assay: The purpose of this assay was to examine the inhibitory effects of compounds of the present disclosure on the growth of KRAS G12D mutant GP2D human pancreatic cancer cells.

[0483] 2. Assay Materials: The cell line GP2D, DMEM medium and penicillin / streptomycin antibiotics were purchased from Wisent, fetal bovine serum was purchased from Bioscera, and CellTiter-Glo® 3D Cell Viability Assay (3D Cell Viability Chemiluminescent Assay Reagent) reagent was purchased from Promega.

[0484] 3. Assay Method: GP2D cells were seeded into 96-well U-bottom cell culture plates. Each well contained 80 μL of cell suspension containing 2,000 GP2D cells. The cell plates were incubated overnight in a CO2 incubator. The compounds to be assayed were serially diluted 5-fold by pipette to the eighth concentration, from 200 μM to 2.56 nM. Duplicate well assays were set up. 78 μL of medium was added to the middle plate, and then 2 μL per well of the serially diluted compound was transferred to the corresponding position. The mixture was mixed thoroughly, and 20 μL per well was transferred to the cell plate. The compound concentrations transferred to the cell plate ranged from 1 μM to 0.0128 nM. The cell plates were incubated for 5 days in a CO2 incubator. At the end of the incubation period, 100 μL of cell viability chemiluminescence assay reagent was added to each well of the cell plate. The cell plate was incubated at room temperature for 10 minutes to allow the luminescence signal to stabilize, and the data were read using a multilabel analyzer.

[0485] 4. Data Analysis: Raw data were converted to percent inhibition by using the formula (sample-min) / (max-min) x 100%. IC50 values ​​can be obtained by curve fitting with four parameters ("log(inhibitor) vs. response--variable slope" model in GraphPad Prism).

[0486] 5. Assay Results The results are shown in Table 14.

[0487] [Table 14]

[0488] Assay conclusion: The compounds of the present disclosure have significant inhibitory effects on GP2D cell proliferation.

[0489] Assay Example 7: In vivo Pharmacokinetics Test Intravenous injection vehicle and formulation for Compound 002A: The compound to be assayed was mixed with a solution of 5% dimethyl sulfoxide / 95% (10% hydroxypropyl-β-cyclodextrin in water) and the mixture was adjusted to a clear solution of 0.40 mg / mL. Oral vehicle and formulation: The compound to be assayed was mixed with a solution of 5% dimethyl sulfoxide / 95% (10% hydroxypropyl-β-cyclodextrin in water) and the mixture was stirred until visually homogeneous, and the mixture was adjusted to 3 mg / mL. Intravenous injection vehicle and formulation for Compounds 013B and 017B: The compound to be assayed was mixed with 5% dimethyl sulfoxide / 10% polyethylene glycol-15 hydroxystearate / 85% water and the mixture was adjusted to 0.4 mg / mL and the mixture was stirred until clear. Oral vehicle and formulation: The test compound was mixed with a solution of 5% dimethyl sulfoxide / 95% (10% hydroxypropyl-β-cyclodextrin in water), stirred until the mixture was visually homogeneous, and adjusted to 5 mg / mL. Male C57BL / 6J mice aged 7 to 10 weeks were selected and administered the candidate compound solution intravenously or orally. Whole blood samples were collected at regular intervals. Plasma was prepared. Drug concentrations were analyzed by LC-MS / MS. Pharmacokinetic parameters were calculated using Certara WinNonlin software (Certara Company, USA). The assay results are shown in Table 15.

[0490] [Table 15]

[0491] Assay Conclusions: PK studies show that each compound has good plasma exposure and oral bioavailability in mice.

Claims

1. Formula (II) 【Chemistry 1】 (In the formula, X is selected from O and S; R １ teeth, 【Chemistry 2】 and 【Chemistry 3】 is one, two or three R ａ and optionally substituted with R ２ is H, halogen, C １～３ Alkoxy and C ３～４ cycloalkyl-O-, １～３ Alkoxy and C ３～４ cycloalkyl-O- is optionally substituted with 1, 2, 3, 4 or 5 halogens; R ３ is H, halogen and C １～３ alkyl, １～３ Alkyl is one, two or three R ｂ and optionally substituted with R ４ is selected from phenyl and naphthyl, each of which independently has 1, 2, 3, 4 or 5 R ｃ and optionally substituted with R ５ is H, halogen and C １～３ alkyl, １～３ The alkyl is optionally substituted with 1, 2 or 3 halogens; R ６ , R ７ and R ８ are each independently H, halogen, CN, or C １～３ Alkyl, C １～３ Alkoxy, C １～３ Alkylamino, C ２～３ alkenyl and phenyl; １～３ Alkyl, C １～３ Alkoxy, C １～３ Alkylamino, C ２～３ alkenyl and phenyl are optionally substituted with 1, 2 or 3 halogens; Instead, R ６ and R ７ together with the atom to which they are attached form phenyl, 【Chemistry 4】 Forming Each R ａ are independently H, halogen, OH, NH ２ , C １～３ Alkyl and C １～３ alkoxy, １～３ Alkyl and C １～３ The alkoxy is optionally substituted with 1, 2, 3, 4 or 5 halogens; Each R ｂ is independently selected from H, halogen, and OH; Each R ｃ are independently H, halogen, OH, NH ２ , C.N. and C. ２～３ alkynyl, R ｄ is absent or each R ｄ are independently H, halogen, OH, CN, C １～３ Alkyl and C １～３ alkylamino, １～３ Alkyl and C １～３ alkylamino is optionally substituted with 1, 2 or 3 halogens; R １ but, 【Chemistry 5】 When selected from, X is selected from S, alternatively, R ４ is selected from naphthyl, said naphthyl being selected from five R ｃ (replaced with or a pharma- ceutically acceptable salt thereof.

2. R ２ H, F, O, O ３ 、OCH ２ CH ３ ,OCH(CH ３ ) ２ 、 【Chemistry 6】 and said OCH ３ , O.C.H. ２ CH ３ , OCH(CH ３ ) ２ , 【Chemistry 7】 is optionally substituted with 1, 2, 3, 4 or 5 halogens, or a pharma- ceutically acceptable salt thereof.

3. R ２ is H, F and OCH ３ 3. The compound according to claim 1 or 2, or a pharma- ceutically acceptable salt thereof, selected from:

4. R ３ is H, F, Cl and CH ２ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein: R is selected from the group consisting of: OH;

5. Each R ｃ are independently H, F, OH, NH ２ and --C≡CH; or a pharma- ceutically acceptable salt thereof.

6. R ４ teeth, 【Chemistry 8】 6. The compound according to claim 1 or 5, or a pharma- ceutically acceptable salt thereof, selected from:

7. R ５ is H, F, Cl, Br, CH ３ , C.H. ２ CH ３ and CH(CH ３ ) ２ wherein said CH ３ , C.H. ２ CH ３ and CH(CH ３ ) ２ is optionally substituted with 1, 2 or 3 halogens, or a pharma- ceutically acceptable salt thereof.

8. R ５ , F, CH ２ F and CHF ２ 8. The compound according to claim 1 or 7, or a pharma- ceutically acceptable salt thereof, selected from:

9. R ６ , R ７ and R ８ are each independently H, F, Cl, Br, I, CN, or CH ３ , C.H. ２ CH ３ , CH(CH ３ ) ２ , O.C.H. ３ , O.C.H. ２ CH ３ , OCH(CH ３ ) ２ , N.H.H. ３ , N.H.H. ２ CH ３ , N(CH ３ ) ２ , CH=CH ２ , C.H. ２ CH=CH ２ , CH=CH ２ CH ３ and phenyl, ３ , C.H. ２ CH ３ , CH(CH ３ ) ２ , O.C.H. ３ , O.C.H. ２ CH ３ , OCH(CH ３ ) ２ , N.H.H. ３ , N.H.H. ２ CH ３ , N(CH ３ ) ２ , CH=CH ２ , C.H. ２ CH=CH ２ , CH=CH ２ CH ３ and phenyl is optionally substituted with one, two or three halogens, or a pharma- ceutically acceptable salt thereof.

10. R ６ , R ７ and R ８ are each independently H, F, Cl, Br, I, CN, or CH ３ , C.H. ２ F, C.H.F. ２ , C.F. ３ , C.H. ２ CH ３ , C.H. ２ CF ３ , C.F. ２ CF ３ , O.C.H. ３ , O.C.H. ２ F, O.C.H.F. ２ , O.C.F. ３ , O.C.H. ２ CH ３ , O.C.H. ２ CF ３ , O.C.F. ２ CF ３ , N.H.H. ３ , N(CH ３ ) ２ , CH=CH ２ , CF=CH ２ , CH=CHF, CH=CF ２ 10. The compound of claim 1 or 9, or a pharma- ceutically acceptable salt thereof, wherein said compound is selected from:

11. R ６ or a pharma- ceutically acceptable salt thereof.

2. The compound of claim 1, wherein

12. R ７ or a pharma- ceutically acceptable salt thereof.

2. The compound of claim 1, wherein

13. Each R ｄ are independently H, F, Cl, Br, I, OH, CN, CH ３ , C.H. ２ CH ３ , CH(CH ３ ) ２ , N.H.H. ３ , N.H.H. ２ CH ３ and N(CH ３ ) ２ wherein said CH ３ , C.H. ２ CH ３ , CH(CH ３ ) ２ , N.H.H. ３ , N.H.H. ２ CH ３ and N(CH ３ ) ２ is optionally substituted with 1, 2 or 3 halogens, or a pharma- ceutically acceptable salt thereof.

14. Each R ｄ are independently H, F, OH, CN, and CH ３ 14. The compound of claim 13, selected from:

15. R ６ and R ７ together with the atom to which they are attached form phenyl, 【Chemistry 9】 15. The compound of claim 1, 13 or 14, which forms:

16. R ８ H, F, CN, OCH ３ , O.C.H.F. ２ , O.C.F. ３ 2. The compound of claim 1, wherein the ring is selected from: CH=CHF, CH=CHH, and phenyl; or a pharma- ceutically acceptable salt thereof.

17. structural part 【Chemistry 10】 teeth, 【Chemistry 11】 2. The compound of claim 1, selected from:

18. 【Chemical 12】 wherein m is selected from 0, 1, 2, 3, 4 and 5; R ３ , R ５ and R ｃ is as defined in claim 1) 2. The compound of claim 1, selected from:

19. The following compounds 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 or a pharma- ceutically acceptable salt thereof.

20. 【Catalog 17】 【Chemistry 18】 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemical 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 20. The compound of claim 19, or a pharma- ceutically acceptable salt thereof, selected from:

21. KRAS Ｇ１２Ｄ 21. Use of a compound according to any one of claims 1 to 20, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating a mutation-associated tumor.

22. 22. The use according to claim 21 , wherein the tumor is selected from colorectal cancer and pancreatic cancer.

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