Benzopyrimidine compounds and their applications

Abstract

The invention discloses a series of benzopyrimidine compounds and applications thereof, and specifically discloses a compound represented by formula (II) and a pharmaceutically acceptable salt thereof.

Description

[0001] This application claims the following priority:

[0002] CN202210072243.0, application date: January 21, 2022;

[0003] CN202210113080.6, application date: January 29, 2022;

[0004] PCT / CN2022 / 075732, filing date: February 9, 2022;

[0005] CN202210239568.3, application date: March 11, 2022;

[0006] CN202210693538.X, application date: June 17, 2022;

[0007] CN202210837790.3, application date: July 15, 2022;

[0008] CN202210989455.5, application date: August 17, 2022. Technical Field

[0009] The present invention relates to a series of benzopyrimidine compounds and applications thereof, and in particular to compounds represented by formula (II) and pharmaceutically acceptable salts thereof. Background Art

[0010] RAS oncogene mutations are the most common activating mutations in human cancers, with RAS mutations present in approximately 30% of human tumors. The RAS gene family includes three subtypes (KRAS, HRAS, and NRAS), of which 85% of RAS-driven cancers are caused by KRAS subtype mutations.

[0011] KRAS is a murine sarcoma viral oncogene and an important member of the RAS protein. KRAS is like a molecular switch. Once it is turned on, it will activate a variety of division and proliferation factors, such as c-RAF, PI3K, etc. Under normal circumstances, KRAS binds to GTP, cuts off the last phosphate group of GTP, and converts it into GDP. After converting GTP to GDP, KRAS is turned off. Under normal circumstances, KRAS can regulate the path of cell growth; after the KRAS gene mutates, the KRAS protein continues to remain activated, and can independently transmit growth and proliferation signals to downstream pathways without relying on upstream growth factor receptor signals, causing uncontrolled cell growth and tumor progression.

[0012] KRAS mutations are common in solid tumors, such as lung adenocarcinoma, pancreatic ductal carcinoma, and colorectal cancer. In KRAS mutant tumors, 80% of carcinogenic 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, whether the KRAS gene is mutated is also an important indicator of tumor prognosis.

[0013] Currently, small molecules that directly target KRAS mutations are mainly focused on KRAS G12C In the field, there are two new drugs, including Amgen's AMG510 and Mirati Therapeutics' MRTX849. Clinical results show that these two compounds have an inhibitory effect on KRAS. G12C Patients with tumors with mutations have shown good treatment effects. G12D The only drug that has entered the clinical stage is HRS-4642 from Jiangsu Hengrui Medicine Co., Ltd., which is an injection. There is currently no oral KRAS C12D Small molecules have entered the clinical research stage, and KRAS C12D There is a huge unmet need for inhibitors of mutations. Summary of the invention

[0014] The present invention provides a compound represented by formula (II) and a pharmaceutically acceptable salt thereof.

[0015]

[0016] in,

[0017] X is selected from O and S;

[0018] R 1 Selected from Said Optional 1, 2 or 3 R a replace;

[0019] R 2 Selected from H, halogen, C 1-3 Alkoxy and C 3-4 Cycloalkyl-O-, the C 1-3 Alkoxy and C 3-4 Cycloalkyl-O- is optionally substituted with 1, 2, 3, 4 or 5 halogens;

[0020] R 3 Selected from H, halogen and C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 Rb;

[0021] R 4is selected from phenyl and naphthyl, wherein the phenyl and naphthyl are independently optionally substituted by 1, 2, 3, 4 or 5 R c replace;

[0022] R 5 Selected from H, halogen and C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 halogens;

[0023] R 6 , R 7 and R 8 are each independently selected from H, halogen, CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 2-3 alkenyl and phenyl, the C 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;

[0024] or R 6 and R 7 Together with the atoms connected to it, it forms a phenyl group,

[0025] Each R a are independently selected from H, halogen, OH, NH 2 , C 1-3 Alkyl and C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3 Alkoxy is optionally substituted with 1, 2, 3, 4 or 5 halogens;

[0026] Each R b are independently selected from H, halogen and OH;

[0027] Each R c are independently selected from H, halogen, OH, NH 2 , CN and C 2-3 Alkynyl;

[0028] R d Does not exist, or each R d are independently selected from H, halogen, OH, CN, C 1-3 Alkyl and C 1-3 Alkylamino, the C 1-3 Alkyl and C 1-3 The alkylamino group is optionally substituted with 1, 2 or 3 halogens;

[0029] When R 1 Selected from When X is selected from S, or, R 4 is selected from naphthyl, wherein the naphthyl is substituted by 5 R c replace.

[0030] In some embodiments of the present invention, the compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of:

[0031]

[0032] Among them, R 3 , R 5 and R c As defined in the present invention;

[0033] m is selected from the group consisting of 0, 1, 2, 3, 4 and 5.

[0034] In some embodiments of the present invention, the compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of:

[0035]

[0036] Among them, R 3 , R 5 and R c As defined in the present invention;

[0037] m is selected from the group consisting of 0, 1, 2, 3, 4 and 5.

[0038] In some embodiments of the present invention, the compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of:

[0039]

[0040] in,

[0041] R 3 Selected from halogen and C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R b replace;

[0042] R 5 Selected from halogen and C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 halogens;

[0043] Each R b are independently selected from H, halogen and OH;

[0044] Each R c are independently selected from H, halogen, OH, NH 2 , CN and C 2-3 Alkynyl;

[0045] Rc1 Selected from halogen, OH, NH 2 , CN and C 2-3 Alkynyl;

[0046] o is selected from 0, 1, 2, 3, 4 and 5;

[0047] n is selected from 0, 1, 2, 3 and 4.

[0048] In some embodiments of the present invention, the R 2 Selected from H, OCH 3 、OCH 2 CH 3 、OCH(CH 3 ) 2 , The OCH 3 、OCH 2 CH 3 、OCH(CH 3 ) 2 , Optionally substituted with 1, 2, 3, 4 or 5 halogens, and the other variables are as defined herein.

[0049] In some embodiments of the present invention, the R 2 Selected from H, F and OCH 3 , other variables are as defined in the present invention.

[0050] In some embodiments of the present invention, the R 3 Selected from H, F, Cl and CH 2 OH, and other variables are as defined in the present invention.

[0051] In some embodiments of the present invention, each R c are independently selected from H, F, OH, NH 2 and --C≡CH, other variables are as defined in the present invention.

[0052] In some embodiments of the present invention, the R 4 Selected from Other variables are as defined in the present invention.

[0053] In some embodiments of the present invention, the R 5 Selected from H, F, Cl, Br, CH 3 , CH 2 CH 3 and CH(CH 3 ) 2 , the CH 3 , CH 2 CH 3 and CH(CH 3 )2 Optionally substituted with 1, 2 or 3 halogens, and the other variables are as defined herein.

[0054] In some embodiments of the present invention, the R 5 Selected from F, CH 2 F and CHF 2 , other variables are as defined in the present invention.

[0055] In some embodiments of the present invention, the R 6 , R 7 and R 8 Each independently selected from H, F, Cl, Br, I, CN, CH 3 , CH 2 CH 3 、CH(CH 3 ) 2 、OCH 3 、OCH 2 CH 3 、OCH(CH 3 ) 2 NHCH 3 NHCH 2 CH 3 、N(CH 3 ) 2 、CH=CH 2 , CH 2 CH=CH 2 、CH=CH 2 CH 3 and phenyl, the CH 3 , CH 2 CH 3 、CH(CH 3 ) 2 、OCH 3 、OCH 2 CH 3 、OCH(CH 3 ) 2 NHCH 3 NHCH 2 CH 3 、N(CH 3 ) 2 、CH=CH 2 , CH 2 CH=CH 2 、CH=CH 2 CH 3 and phenyl is optionally substituted with 1, 2 or 3 halogens, and the other variables are as defined herein.

[0056] In some embodiments of the present invention, the R 6 , R7 and R 8 Each independently selected from H, F, Cl, Br, I, CN, CH 3 , CH 2 F. CHF 2 CF 3 , CH 2 CH 3 , CH 2 CF 3 CF 2 CF 3 、OCH 3 、OCH 2 F. OCHF 2 、OCF 3 、OCH 2 CH 3 、OCH 2 CF 3 、OCF 2 CF 3 NHCH 3 、N(CH 3 ) 2 、CH=CH 2 CF=CH 2 、CH=CHF、CH=CF 2 and phenyl, and other variables are as defined herein.

[0057] In some embodiments of the present invention, the R 6 Selected from H, F, Cl, Br, I, CN, CH 3 , CH 2 F. CHF 2 CF 3 , CH 2 CH 3 , CH 2 CF 3 CF 2 CF 3 、OCH 3 、OCH 2 F. OCHF 2 、OCF 3 、OCH 2 CH 3 、OCH 2 CF 3 、OCF 2 CF 3 NHCH 3 、N(CH 3 ) 2 、CH=CH 2 CF=CH 2 、CH=CHF、CH=CF2 and phenyl, and other variables are as defined herein.

[0058] In some embodiments of the present invention, the R 7 Selected from H, F, Cl, Br, I, CN, CH 3 , CH 2 F. CHF 2 CF 3 , CH 2 CH 3 , CH 2 CF 3 CF 2 CF 3 、OCH 3 、OCH 2 F. OCHF 2 、OCF 3 、OCH 2 CH 3 、OCH 2 CF 3 、OCF 2 CF 3 NHCH 3 、N(CH 3 ) 2 、CH=CH 2 CF=CH 2 、CH=CHF、CH=CF 2 and phenyl, and other variables are as defined herein.

[0059] In some embodiments of the present invention, the R 8 Selected from H, F, Cl, Br, I, CN, CH 3 , CH 2 F. CHF 2 CF 3 , CH 2 CH 3 , CH 2 CF 3 CF 2 CF 3 、OCH 3 、OCH 2 F. OCHF 2 、OCF 3 、OCH 2 CH 3 、OCH 2 CF 3 、OCF 2 CF 3 NHCH 3 、N(CH 3 ) 2 、CH=CH2 CF=CH 2 、CH=CHF、CH=CF 2 and phenyl, and other variables are as defined herein.

[0060] In some embodiments of the present invention, the R 6 is selected from H, and other variables are as defined in the present invention.

[0061] In some embodiments of the present invention, the R 7 Selected from H, F, CN, OCH 3 , OCHF 2 、OCF 3 , CH═CHF and phenyl, and other variables are as defined herein.

[0062] In some embodiments of the present invention, the R 7 is selected from H, and other variables are as defined in the present invention.

[0063] In some embodiments of the present invention, each R d are independently selected from H, F, Cl, B r 、I、OH、CN、CH 3 , CH 2 CH 3 、CH(CH 3 ) 2 NHCH 3 NHCH 2 CH 3 and N(CH 3 ) 2 , the CH 3 , CH 2 CH 3 、CH(CH 3 ) 2 NHCH 3 NHCH 2 CH 3 and N(CH 3 ) 2 Optionally substituted with 1, 2 or 3 halogens, and the other variables are as defined herein.

[0064] In some embodiments of the present invention, each R d are independently selected from H, F, OH, CN, and CH 3 , other variables are as defined in the present invention.

[0065] In some embodiments of the present invention, the R 6 and R 7 With the atoms connected to form phenyl, Other variables are as defined in the present invention.

[0066] In some embodiments of the present invention, the R 8 Selected from H, F, CN, OCH 3 , OCHF 2 、OCF 3 , CH═CHF and phenyl, and other variables are as defined herein.

[0067] In some embodiments of the present invention, the structural unit Selected from Other variables are as defined in the present invention.

[0068] The present invention also provides a compound represented by formula (II) and a pharmaceutically acceptable salt thereof

[0069]

[0070] in,

[0071] X is selected from O and S;

[0072] R 1 Selected from Said Optional 1, 2 or 3 R a replace;

[0073] R 2 Selected from H, halogen, C 1-3 Alkoxy and C 3-4 Cycloalkyl-O-, the C 1-3 Alkoxy and C 3-4 Cycloalkyl-O- is optionally substituted with 1, 2, 3, 4 or 5 halogens;

[0074] R 3 Selected from H, halogen and C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 Rb;

[0075] R 4 is selected from phenyl and naphthyl, wherein the phenyl and naphthyl are independently optionally substituted by 1, 2, 3, 4 or 5 R c replace;

[0076] R 5 Selected from H, halogen and C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 halogens;

[0077] R 6 , R 7 and R 8are each independently selected from H, halogen, CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 2-3 alkenyl and phenyl, the C 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;

[0078] Or R6 and R7 form a phenyl group with the atoms they are connected to,

[0079] Each R a are independently selected from H, halogen, OH, NH 2 , C 1-3 Alkyl and C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3 Alkoxy is optionally substituted with 1, 2, 3, 4 or 5 halogens;

[0080] Each R b are independently selected from H, halogen and OH;

[0081] Each R c are independently selected from H, halogen, OH, NH 2 , CN and C 2-3 Alkynyl;

[0082] R d Does not exist, or each R d are independently selected from H, halogen, C 1-3 Alkyl and C 1-3 Alkylamino, the C 1-3 Alkyl and C 1-3 The alkylamino group is optionally substituted with 1, 2 or 3 halogens;

[0083] When R 1 Selected from When X is selected from S, or, R 4 is selected from naphthyl, wherein the naphthyl is substituted by 5 R c replace.

[0084] In some embodiments of the present invention, the R 2 Selected from H, OCH 3 、OCH 2 CH 3 、OCH(CH 3 ) 2 , The OCH 3 、OCH 2 CH3 、OCH(CH 3 ) 2 , Optionally substituted with 1, 2, 3, 4 or 5 halogens, and the other variables are as defined herein.

[0085] In some embodiments of the present invention, the R 2 Selected from H, F and OCH 3 , other variables are as defined in the present invention.

[0086] In some embodiments of the present invention, the R 3 Selected from H, F, Cl and CH 2 OH, and other variables are as defined in the present invention.

[0087] In some embodiments of the present invention, each R c are independently selected from H, F, OH, NH 2 and --C≡CH, other variables are as defined in the present invention.

[0088] In some embodiments of the present invention, the R4 is selected from Other variables are as defined in the present invention.

[0089] In some embodiments of the present invention, the R 5 Selected from H, F, Cl, Br, CH 3 , CH 2 CH 3 and CH(CH 3 ) 2 , the CH 3 , CH 2 CH 3 and CH(CH 3 ) 2 Optionally substituted with 1, 2 or 3 halogens, and the other variables are as defined herein.

[0090] In some embodiments of the present invention, the R 5 Selected from F, CH 2 F and CHF 2 , other variables are as defined in the present invention.

[0091] In some embodiments of the present invention, the R 6 , R 7 and R 8 Each independently selected from H, F, Cl, Br, I, CN, CH 3 , CH 2 CH 3 、CH(CH 3 ) 2 、OCH 3 、OCH2 CH 3 、OCH(CH 3 ) 2 NHCH 3 NHCH 2 CH 3 、N(CH 3 ) 2 、CH=CH 2 , CH 2 CH=CH 2 、CH=CH 2 CH 3 and phenyl, the CH 3 , CH 2 CH 3 、CH(CH 3 ) 2 、OCH 3 、OCH 2 CH 3 、OCH(CH 3 ) 2 NHCH 3 NHCH 2 CH 3 、N(CH 3 ) 2 、CH=CH 2 , CH 2 CH=CH 2 、CH=CH 2 CH 3 and phenyl is optionally substituted with 1, 2 or 3 halogens, and the other variables are as defined herein.

[0092] In some embodiments of the present invention, the R 6 , R 7 and R 8 Each independently selected from H, F, Cl, Br, I, CN, CH 3 , CH 2 F. CHF 2 CF 3 , CH 2 CH 3 , CH 2 CF 3 CF 2 CF 3 、OCH 3 、OCH 2 F. OCHF 2 、OCF 3 、OCH 2 CH 3 、OCH 2 CF 3 、OCF2 CF 3 NHCH 3 、N(CH 3 ) 2 、CH=CH 2 CF=CH 2 、CH=CHF、CH=CF 2 and phenyl, and other variables are as defined herein.

[0093] In some embodiments of the present invention, the R 6 is selected from H, and other variables are as defined in the present invention.

[0094] In some embodiments of the present invention, the R 7 Selected from H, F, CN, OCH 3 , OCHF 2 、OCF 3 , CH═CHF and phenyl, and other variables are as defined herein.

[0095] In some embodiments of the present invention, the R 7 is selected from H, and other variables are as defined in the present invention.

[0096] In some embodiments of the present invention, each R d are independently selected from H, F, Cl, Br, I, CN, CH 3 , CH 2 CH 3 、CH(CH 3 ) 2 NHCH 3 NHCH 2 CH 3 and N(CH 3 ) 2 , the CH 3 , CH 2 CH 3 、CH(CH 3 ) 2 NHCH 3 NHCH 2 CH 3 and N(CH 3 ) 2 Optionally substituted with 1, 2 or 3 halogens, and the other variables are as defined herein.

[0097] In some embodiments of the present invention, each R d are independently selected from H, F and CH 3 , other variables are as defined in the present invention.

[0098] In some embodiments of the present invention, the R6 and R 7 Together with the atoms connected to it, it forms a phenyl group, Other variables are as defined in the present invention.

[0099] In some embodiments of the present invention, the R 8 Selected from H, F, CN, OCH 3 , OCHF 2 、OCF 3 , CH═CHF and phenyl, and other variables are as defined herein.

[0100] In some embodiments of the present invention, the structural unit Selected from Other variables are as defined in the present invention.

[0101] The present invention also provides a compound represented by formula (I) and a pharmaceutically acceptable salt thereof

[0102]

[0103] in,

[0104] X is selected from O and S;

[0105] R 1 Selected from Said Optional 1, 2 or 3 R a replace;

[0106] R 2 Selected from H, C 1-3 Alkoxy and C 3-4 Cycloalkyl-O-, the C 1-3 Alkoxy and C 3-4 Cycloalkyl-O- is optionally substituted with 1, 2, 3, 4 or 5 halogens;

[0107] R 3 Selected from H, halogen and C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R b replace;

[0108] R 4 is selected from phenyl and naphthyl, wherein the phenyl and naphthyl are independently optionally substituted by 1, 2, 3, 4 or 5 R c replace;

[0109] R 5 Selected from H, halogen and C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 halogens;

[0110] R 6 , R 7 and R 8 are each independently selected from H, halogen, CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 2-3 alkenyl and phenyl, the C 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;

[0111] or R 6 and R 7 Together with the atoms connected to it, it forms a phenyl group,

[0112] Each R a are independently selected from H, halogen, OH, NH 2 , C 1-3 Alkyl and C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3 Alkoxy is optionally substituted with 1, 2, 3, 4 or 5 halogens;

[0113] Each R b are independently selected from H, halogen and OH;

[0114] Each R c are independently selected from H, halogen, OH, NH 2 , CN and C 2-3 Alkynyl;

[0115] R d Does not exist, or each R d are independently selected from H, halogen, C 1-3 Alkyl and C 1-3 Alkylamino, the C 1-3 Alkyl and C 1-3 The alkylamino group is optionally substituted with 1, 2 or 3 halogens.

[0116] In some embodiments of the present invention, the R 2 Selected from H and OCH 3 , other variables are as defined in the present invention.

[0117] In some embodiments of the present invention, the R 3 Selected from H, F, Cl and CH 2 OH, and other variables are as defined in the present invention.

[0118] In some embodiments of the present invention, each R b are independently selected from H, F, OH, NH 2 and --C≡CH, other variables are as defined in the present invention.

[0119] In some embodiments of the present invention, the R 4 Selected from Other variables are as defined in the present invention.

[0120] In some embodiments of the present invention, the R 5 Selected from H, F, Cl, Br, CH 3 , CH 2 CH 3 and CH(CH 3 ) 2 , the CH 3 , CH 2 CH 3 and CH(CH 3 ) 2 Optionally substituted with 1, 2 or 3 halogens, and the other variables are as defined herein.

[0121] In some embodiments of the present invention, the R 5 Selected from F, CH 2 F and CHF 2 , other variables are as defined in the present invention.

[0122] In some embodiments of the present invention, the R 6 , R 7 and R 8 Each independently selected from H, F, Cl, Br, I, CN, CH 3 , CH 2 CH 3 、CH(CH 3 ) 2 、OCH 3 、OCH 2 CH 3 、OCH(CH 3 )2. NHCH 3 NHCH 2 CH 3 、N(CH 3 ) 2 、CH=CH 2 , CH 2 CH=CH 2 、CH=CH 2 CH 3 and phenyl, the CH 3 , CH 2 CH 3 、CH(CH3 ) 2 、OCH 3 、OCH 2 CH 3 、OCH(CH 3 ) 2 NHCH 3 NHCH 2 CH 3 、N(CH 3 ) 2 、CH=CH 2 , CH 2 CH=CH 2 、CH=CH 2 CH 3 and phenyl is optionally substituted with 1, 2 or 3 halogens, and the other variables are as defined herein.

[0123] In some embodiments of the present invention, the R 6 , R 7 and R 8 Each independently selected from H, F, Cl, Br, I, CN, CH 3 , CH 2 F. CHF 2 CF 3 , CH 2 CH 3 , CH 2 CF 3 CF 2 CF 3 、OCH 3 、OCH 2 F. OCHF 2 、OCF 3 、OCH 2 CH 3 、OCH 2 CF 3 、OCF 2 CF 3 NHCH 3 、N(CH 3 ) 2 、CH=CH 2 CF=CH 2 、CH=CHF、CH=CF 2 and phenyl, and other variables are as defined herein.

[0124] In some embodiments of the present invention, the R 6 is selected from H, and other variables are as defined in the present invention.

[0125] In some embodiments of the present invention, the R 7 Selected from H, F, CN, OCH3 , OCHF 2 、OCF 3 , CH═CHF and phenyl, and other variables are as defined herein.

[0126] In some embodiments of the present invention, the R 7 is selected from H, and other variables are as defined in the present invention.

[0127] In some embodiments of the present invention, each R d are independently selected from H, F, Cl, Br, I, CN, CH 3 , CH 2 CH 3 、CH(CH 3 ) 2 NHCH 3 NHCH 2 CH 3 and N(CH 3 ) 2 , the CH 3 , CH 2 CH 3 、CH(CH 3 ) 2 NHCH 3 NHCH 2 CH 3 and N(CH 3 ) 2 Optionally substituted with 1, 2 or 3 halogens, and the other variables are as defined herein.

[0128] In some embodiments of the present invention, each R d are independently selected from H, F and CH 3 , other variables are as defined in the present invention.

[0129] In some embodiments of the present invention, the R 6 and R 7 With the atoms connected to form phenyl, Other variables are as defined in the present invention.

[0130] In some embodiments of the present invention, the R 8 Selected from H, F, CN, OCH 3 , OCHF 2 、OCF 3 , CH═CHF and phenyl, and other variables are as defined herein.

[0131] In some embodiments of the present invention, the structural unit Selected from Other variables are as defined in the present invention.

[0132] The present invention also provides a compound represented by formula (IX) and a pharmaceutically acceptable salt thereof

[0133]

[0134] in,

[0135] T 6 is selected from CH and N;

[0136] R 4a Selected from C 6-10 Aryl and 5-10 membered heteroaryl, the C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with 1, 2, 3, 4 or 5 R e replace;

[0137] R 5a Selected from H, F, Cl, CN, NH 2 , C 1-3 Alkyl and C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3 The alkoxy group is optionally substituted with 1, 2 or 3 halogens;

[0138] R 3a Selected from H, F, Cl, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl and cyclopropyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl and cyclopropyl are optionally substituted with 1, 2 or 3 halogens;

[0139] Each R e Each independently selected from F, Cl, Br, I, OH, NH 2 , CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl and C 2-4 Alkynyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl and C 2-4 Alkynyl is optionally substituted with 1, 2 or 3 halogens.

[0140] In some embodiments of the present invention, the compound or a pharmaceutically acceptable salt thereof is selected from

[0141]

[0142] in,

[0143] T 6 is selected from CH and N;

[0144] R 5a Selected from H, F, Cl, CN, NH 2 , C 1-3 Alkyl and C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3 The alkoxy group is optionally substituted with 1, 2 or 3 halogens;

[0145] R 3a Selected from H, F, Cl, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl and cyclopropyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl and cyclopropyl are optionally substituted with 1, 2 or 3 halogens;

[0146] Each R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R b7 , R b8 , R b9 , R b10 and R b11 Each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl and C 2-4 Alkynyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl and C 2-4 Alkynyl is optionally substituted with 1, 2 or 3 halogens.

[0147] In some embodiments of the present invention, each R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R b7 , R b8 , R b9 , R b10 and R b11 Each independently selected from F, Cl, Br, I, OH, NH 2、CN、CH 3 , CH 2 CH 3 、OCH 3 、OCH 2 CH 3 、-CH=CH 2 、-CH 2 -CH=CH 2 and -C≡CH, the CH 3 , CH 2 CH 3 、OCH 3 、OCH 2 CH 3 、-CH=CH 2 、-CH 2 -CH=CH 2 and -C≡CH are optionally substituted with 1, 2 or 3 halogens, and the other variables are as defined herein.

[0148] In some embodiments of the present invention, each R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R b7 , R b8 , R b9 , R b10 and R b11 are independently selected from F, Cl, OH, NH 2 、CN、CH 3 CF 3 , CH 2 CH 3 and -C≡GH, and other variables are as defined in the present invention.

[0149] The present invention also provides the compounds and pharmaceutically acceptable salts thereof.

[0150]

[0151] Among them, the compound was analyzed by SFC, and its retention time was Rt = 1.801min;

[0152] The analytical conditions of the SFC method are as follows: column: Chiralcel OD-3, 50×4.6 mm ID, 3 μm; mobile phase: A (supercritical CO 2 ), B: (ethanol, containing 0.1% isopropylamine); gradient: B% 5-50%, 3min; flow rate: 3.4mL / min; wavelength: 220nm; pressure: 1800psi.

[0153] The present invention also provides the compounds and pharmaceutically acceptable salts thereof.

[0154]

[0155] Among them, the compound was analyzed by SFC, and its retention time Rt = 2.233min;

[0156] The analytical conditions of the SFC method are as follows: column: Chiralcel OD-3, 50×4.6 mm ID, 3 μm; mobile phase: A (supercritical CO 2 ), B: (ethanol, containing 0.1% isopropylamine); gradient: B% = 5-50%, 3min; flow rate: 3.4mL / min; wavelength: 220nm; pressure: 1800psi.

[0157] Some other solutions of the present invention are obtained by any combination of the above variables.

[0158] The present invention also provides the following compounds and pharmaceutically acceptable salts thereof:

[0159]

[0160]

[0161]

[0162]

[0163]

[0164] In some embodiments of the present invention, the compound and its pharmaceutically acceptable salt are selected from the group consisting of:

[0165]

[0166]

[0167]

[0168]

[0169]

[0170] In some embodiments of the present invention, the compound and its pharmaceutically acceptable salt are selected from the group consisting of:

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177] The present invention also provides the compound and its pharmaceutically acceptable salt for preparing a method for treating KRAS. G12D Application of drugs in mutation-related tumors.

[0178] In some embodiments of the present invention, the tumor refers to colorectal cancer and pancreatic cancer.

[0179] Technical Effects

[0180] The compounds of the present invention have an effect on KRAS G12D The protein has a good inhibitory effect and can effectively inhibit the downstream signal p-ERK and KRAS G12D The mutant cells have good cell proliferation inhibition activity. In addition, the compound of the present invention has good pharmacokinetic properties and good oral bioavailability.

[0181] Related definitions

[0182] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered to be uncertain or unclear in the absence of a special definition, but should be understood according to its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding commercial product or its active ingredient.

[0183] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0184] The term "pharmaceutically acceptable salt" refers to salts of compounds of the present invention, prepared from compounds with specific substituents discovered by the present invention and relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Certain specific compounds of the present invention contain basic and acidic functional groups and can be converted into either base or acid addition salts.

[0185] Pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, the preparation method of such salts is: in water or an organic solvent or a mixture of the two, these compounds in free acid or base form are reacted with a stoichiometric amount of an appropriate base or acid to prepare.

[0186] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present invention.

[0187] The compounds of the invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C). For another example, deuterium can be used to replace hydrogen to form a deuterated drug. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing efficacy, and extending the biological half-life of drugs. All isotopic composition changes of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.

[0188] The terms "optional" or "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0189] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include a variant of deuterium and hydrogen, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may be substituted or not substituted, and unless otherwise specified, the type and number of the substituents may be arbitrary on the basis of chemical achievable.

[0190] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, and each occurrence of R is an independent choice. In addition, combinations of substituents and / or variants thereof are permitted only if such combinations result in stable compounds.

[0191] When the number of a linking group is 0, such as -(CRR) 0 -, indicating that the connecting group is a single bond.

[0192] When one of the variables is selected from a single bond, it means that the two groups it connects are directly connected. For example, when L in ALZ represents a single bond, it means that the structure is actually AZ.

[0193] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection mode is non-positional and there are H atoms at the connectable sites, when the chemical bonds are connected, the number of H atoms at the site will decrease with the number of connected chemical bonds to become a group with the corresponding valence. The chemical bond connecting the site to other groups can be a straight solid bond. Straight dotted key or wavy line For example, -OCH 3 The straight solid bond in the group indicates that it is connected to other groups through the oxygen atom in the group; The straight dashed bond in the group indicates that the two ends of the nitrogen atom in the group are connected to other groups; The wavy line in the phenyl group indicates that it is connected to other groups through the carbon atoms at positions 1 and 2 in the phenyl group; It means that any connectable site on the piperidine group can be connected to other groups through one chemical bond, including at least These four connection methods, even if the H atom is drawn on -N-, Still includes For groups connected in this way, when one chemical bond is connected, the H at that site will be reduced by one and become a corresponding monovalent piperidine group; Indicates that any connectable site on the quinazoline group can be connected to other groups through a chemical bond, including Several connection methods.

[0194] Unless otherwise specified, the key is a solid wedge. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond. and straight dashed key To indicate the relative configuration of a stereocenter, use a wavy line Indicates a wedge-shaped solid key or dotted wedge key Or use a wavy line Represents a straight solid bond or straight dashed key

[0195] Unless otherwise specified, when a compound contains a double bond structure, such as a carbon-carbon double bond, a carbon-nitrogen double bond, and a nitrogen-nitrogen double bond, and each atom on the double bond is connected to two different substituents (in a double bond containing a nitrogen atom, a lone pair of electrons on the nitrogen atom is regarded as a substituent connected to it), if a wavy line is used between the atom on the double bond and its substituent in the compound, If connected, it represents the (Z) isomer and (E) isomer of the compound. For example, the following formula (A) represents that the compound exists in the form of a single isomer of formula (A-1) or formula (A-2) or in the form of a mixture of two isomers of formula (A-1) and formula (A-2); the following formula (B) represents that the compound exists in the form of a single isomer of formula (B-1) or formula (B-2) or in the form of a mixture of two isomers of formula (B-1) and formula (B-2). The following formula (C) represents that the compound exists in the form of a single isomer of formula (C-1) or formula (C-2) or in the form of a mixture of two isomers of formula (C-1) and formula (C-2).

[0196]

[0197] Unless otherwise indicated, the term "atropisomer (atropisomer) (or restricted configuration isomer (atropoisomer)" is a stereoisomer with a specific spatial configuration, which is caused by the restricted rotation around a single bond due to large steric hindrance. Certain compounds of the present invention may exist as atropisomers. The compounds disclosed in the present invention include all atropisomers, which may be pure individual atropisomers, or enriched in one of the atropisomers, or non-specific mixtures of each. If the rotational potential around a single bond is high enough and the mutual conversion between conformations is slow enough, it can allow the separation of isomers. For example, and is a pair of atropisomers, in which Indicates that the side is facing outward. Indicates that the three-dimensional orientation of this side is inward.

[0198]

[0043] Unless otherwise stated, the terms "halo" or "halogen," by themselves or as part of another substituent, mean a fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) atom.

[0199] Unless otherwise specified, the term “C 1-3 "Alkyl" is used to refer to a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms. 1-3 Alkyl groups include C 1-2 and C 2-3 Alkyl, etc.; it may be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 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.

[0200] Unless otherwise specified, the term “C 1-3 "Alkoxy" refers to those alkyl groups containing 1 to 3 carbon atoms which are attached to the rest of the molecule via an oxygen atom. 1-3 Alkoxy includes C 1-2 , C 2-3 , C 3 and C 2 Alkoxy, etc. 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.

[0201] Unless otherwise specified, the term “C 1-3 "Alkylamino" refers to those alkyl groups containing 1 to 3 carbon atoms which are attached to the rest of the molecule through an amino group. 1-3 Alkylamino groups include C 1-2 , C 3 and C2 Alkylamino, etc. 1-3 Examples of alkylamino groups include, but are not limited to, -NHCH 3 、-N(CH 3 ) 2 、-NHCH 2 CH 3 、-N(CH 3 )CH 2 CH 3 、-NHCH 2 CH 2 CH 3 、-NHCH 2 (CH 3 ) 2 wait.

[0202] Unless otherwise specified, “C 2-3 "Alkenyl" is used to refer to a straight or branched hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon double bond, which may be located at any position of the group. 2-3 Alkenyl includes C 3 and C 2 alkenyl; said C 2-3 The alkenyl group may be monovalent, divalent or polyvalent. 2-3 Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, and the like.

[0203] Unless otherwise specified, “C 2-3 "Alkynyl" is used to refer to a straight or branched hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon triple bond, which can be located at any position of the group. It can be monovalent, divalent or polyvalent. The C 2-3 Alkynyl groups include C 3 and C 2 Alkynyl. C 2-3 Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, and the like.

[0204] Unless otherwise specified, “C 3-4 "Cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 3 to 4 carbon atoms, which is a monocyclic system. 3-4 Cycloalkyl includes C 3 and C 4 Cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. 3-4 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, and the like.

[0205] Unless otherwise specified, “C 2-4"Alkenyl" is used to refer to a straight or branched hydrocarbon group consisting of 2 to 4 carbon atoms containing at least one carbon-carbon double bond, which may be located at any position of the group. 2-4 Alkenyl includes C 2-3 , C 4 , C 3 and C 2 alkenyl etc.; said C 2-4 The alkenyl group may be monovalent, divalent or polyvalent. 2-4 Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, butadienyl, and the like.

[0206] Unless otherwise specified, “C 2-4 "Alkynyl" is used to refer to a straight or branched hydrocarbon group consisting of 2 to 4 carbon atoms containing at least one carbon-carbon triple bond, which may be located at any position of the group. 2-4 Alkynyl groups include C 2-3 , C 4 , C 3 and C 2 Alkynyl, etc. It may be monovalent, divalent or polyvalent. 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, and the like.

[0207] Unless otherwise specified, the term "C 6-10 Aromatic rings" and "C 6-10 Aryl" can be used interchangeably, the term "C 6-10 Aromatic ring" or "C 6-10 "Aryl" means a cyclic hydrocarbon group composed of 6 to 10 carbon atoms with a conjugated π electron system, which can be a monocyclic, fused bicyclic or fused tricyclic system, in which each ring is aromatic. It can be monovalent, divalent or polyvalent, C 6-10 Aryl includes C 6-9 , C 9 , C 10 and C 6 Aryl, etc. 6-10 Examples of aryl groups include, but are not limited to, phenyl, naphthyl (including 1-naphthyl and 2-naphthyl, etc.).

[0208] Unless otherwise specified, the terms "5-10 membered heteroaromatic ring" and "5-10 membered heteroaryl" are used interchangeably. The term "5-10 membered heteroaryl" refers to a cyclic group consisting of 5 to 10 ring atoms with a conjugated π electron system, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. It can be a monocyclic, fused bicyclic or fused tricyclic system, wherein 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). The 5-10 membered heteroaryl group may be attached to the rest of the molecule via a heteroatom or a carbon atom. The 5-10 membered heteroaryl group includes 5-8 membered, 5-7 membered, 5-6 membered, 5 membered and 6 membered heteroaryl groups, etc. Examples of the 5-10 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4- thiazolyl and 5-thiazolyl, etc.), furanyl (including 2-furanyl and 3-furanyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl, pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.), benzothiazolyl (including 5-benzothiazolyl, etc.), purinyl, benzimidazolyl (including 2-benzimidazolyl, etc.), benzoxazolyl, indolyl (including 5-indolyl, etc.), isoquinolyl (including 1-isoquinolyl and 5-isoquinolyl, etc.), quinoxalinyl (including 2-quinoxalinyl and 5-quinoxalinyl, etc.), or quinolyl (including 3-quinolyl and 6-quinolyl, etc.).

[0209] Unless otherwise specified, C n-n+m or C n -C n+m Any specific case including n to n+m carbons, such as C 1-12 Including C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , also includes any range from n to n+m, such as C 1-12 Including 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 C9-12 Etc.; similarly, n-membered to n+m-membered means that the number of atoms in the ring is n to n+m, for example, 3-12-membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, and 12-membered ring, and also includes any range from n to n+m, for example, 3-12-membered ring includes 3-6-membered ring, 3-9-membered ring, 5-6-membered ring, 5-7-membered ring, 6-7-membered ring, 6-8-membered ring, and 6-10-membered ring, etc.

[0210] The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the embodiments of the present invention.

[0211] The structure of the compound of the present invention can be confirmed by conventional methods known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction (SXRD) is used to collect diffraction intensity data of the cultured single crystal using a Bruker D8 venture diffractometer, the light source is CuKα radiation, and the scanning mode is: After scanning and collecting relevant data, the crystal structure is further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.

[0212] The solvent used in the present invention can be obtained commercially. hr represents hour; the ratio of the eluent in column chromatography purification is a volume ratio; HCl represents hydrochloric acid; NaOH represents sodium hydroxide; EtOH represents ethanol; Boc represents tert-butyl carbonate; TIPS represents triisopropylsilyl; PMB represents p-methoxybenzyl; Tf represents trifluoromethanesulfonyl; MOM represents methylene methyl ether; and Fmoc represents fluorenylmethoxycarbonyl.

[0213] Compounds are named according to the conventional nomenclature in the art or using The software names were used, and commercially available compounds were named using the supplier's catalog names. DETAILED DESCRIPTION

[0214] The present invention is described in detail below by way of examples, but it is not intended to impose any adverse limitations on the present invention. The present invention has been described in detail herein, and specific embodiments thereof are also disclosed therein. It will be apparent to those skilled in the art that various changes and modifications may be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention.

[0215] Example 1

[0216]

[0217] Step 1: Synthesis of Compound 001-1B

[0218] Compound 001-1A (120 g, 709 mmol) was dissolved in tert-butanol (1200 mL) and water (1200 mL), and potassium osmate (10.4 g, 28.3 mmol) and N-methylmorpholine oxide (249 g, 2.13 mol, 224 mL) were added, and the mixture was stirred at 45°C for 16 hours. After the reaction was completed, 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, filtered, and the organic phase was concentrated. 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: (400 MHz, CDCl 3 )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).

[0219] Step 2: Synthesis of Compound 001-1C

[0220] Compound 001-1B (107 g, 526 mmol) was dissolved in dichloromethane, iodophenyl diacetic acid (254 g, 789 mmol) was added at 0°C, and the mixture was stirred at 25°C for 3 hours. After the reaction, 500 mL of sodium bicarbonate aqueous 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, filtered, and concentrated under reduced pressure to obtain compound 001-1C. 1 HNMR: (400MHz, CDCl 3 )δ=9.73 (d, J=6.8Hz, 2H), 4.28 (s, 2H), 4.06 (s, 2H), 1.29 (s, 9H).

[0221] Step 3: Synthesis of Compound 001-1D

[0222] Compound 001-1C (200 g) was dissolved in tetrahydrofuran (600 mL), and vinylmagnesium bromide (1 M, 1.79 L) was added dropwise at -78 °C, and stirred at 25 °C for 16 hours. After the reaction was completed, it was quenched with 1000 mL of saturated ammonium chloride at 10 °C, extracted with 500 mL of ethyl acetate, and the organic phase was extracted with saturated brine (500 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to obtain compound 001-1D. 1H NMR: (400 MHz, CDCl 3 )δ=5.82-5.89(m, 2H), 5.32(t, J=11.6Hz, 2H), 5.16-5.19(m, 2H), 4.45(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).

[0223] Step 4: Synthesis of Compound 001-1E

[0224] Compound 001-1D (80.0 g, 310 mmol) was dissolved in dichloromethane (1000 mL), and diazabicyclo (23.6 g, 155 mmol, 23.4 mL) and trichloroacetonitrile (269 g, 1.87 mol, 187 mL) were added at 0°C, and stirred at 25°C for 16 hours. After the reaction was completed, the mixture was filtered and concentrated, and the crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain compound 001-1E. 1 HNMR: (400MHz, CDCl 3 )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).

[0225] Step 5: Synthesis of Compound 001-1F

[0226] Compound α, α-dimethylbenzylamine (32.1 g, 238 mmol) was dissolved in 1,2-dichloroethane, and 1,5-cyclooctadiene iridium chloride dimer (12.3 g, 18.3 mmol) was added. Compound 001-1E was dissolved in 1,2-dichloroethane (1.00 L) and then added dropwise to the reaction solution at 0°C. The mixture was stirred at 25°C for 16 hours. After the reaction was completed, the mixture was filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 10:1) to obtain compound 001-1F. 1 H NMR: (400 MHz, CDCl 3 )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).

[0227] Step 6: Synthesis of Compound 001-1G

[0228] Compound 001-1F (36.0 g, 50.4 mmol) was dissolved in toluene (900 mL), and 1,3-bis(2,4,6-trimethylphenyl)-2-(imidazolidinyl) (dichlorobenzylidene) (tricyclohexylphosphine) ruthenium (2.14 g, 2.52 mmol) was added, and stirred at 125°C for 16 hours. After the reaction was completed, the mixture was filtered and concentrated, and 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: (400 MHz, CDCl 3 )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), 3.6 0-3.65 (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).

[0229] Step 7: Synthesis of compound 001-1H

[0230] Compound 001-1G (26.8 g, 81.6 mmol) was dissolved in methanol (201 mL), and hydrochloric acid / methanol (4 M, 67.3 mL) was added, and the mixture was reacted at 35°C for 16 hours. After the reaction, the pH was adjusted to 12 with 4 M sodium hydroxide, and the mixture was extracted with 30 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 001-1H. LCMS: (ESI) m / z=229.2 [M+H] + . 1 H NMR: (400 MHz, CDCl 3 )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).

[0231] Step 8: Synthesis of Compound 001-5C

[0232] Compound 001-5B (2 g, 5.58 mmol), dichloromethane (40 mL), N,N-diisopropylethylamine (4.33 g, 33.47 mmol, 5.83 mL) were added to a pre-dried reaction bottle, and 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 hr. After the reaction, water (5 mL) was added, and the mixture was extracted with dichloromethane (5 mL x 4). The combined organic phases were washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (gradient elution: petroleum ether: ethyl acetate = 10: 1) to obtain compound 001-5C.

[0233] Step 9: Synthesis of Compound 001-5D

[0234] Compound 001-5C (3.2 g, 5.14 mmol), diphenylimine (1.86 g, 10.28 mmol, 1.72 mL), anhydrous toluene (64 mL) were added to the reaction flask, and then cesium carbonate (5.02 g, 15.42 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (594.75 mg, 1.03 mmol) were added. Under nitrogen protection, tridibenzylideneacetone dipalladium (470.62 mg, 513.94 μmol, 0.1 eq) was added, and the mixture was stirred at 100 °C for 2 hr. After the reaction, the reaction solution 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 obtain compound 001-5D.

[0235] LCMS: (ESI) m / z=654.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 )δppm 7.83~7.78(m, 5H), 7.60~7.49(m, 9H), 1.20~1.16(m, 21H).

[0236] Step 10: Synthesis of Compound 001-5A

[0237] Compound 001-5D (2.4 g, 3.67 mmol), bis-pinacol borate (1.86 g, 7.34 mmol), potassium acetate (1.08 g, 11.01 mmol) were dissolved in anhydrous toluene (48 mL), and 1,1′-bisdiphenylphosphinoferrocenepalladium dichloride (537.20 mg, 734.17 μmol) was added, and nitrogen was protected, and stirred at 130° C. for 12 hours. After the reaction was completed, it 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) δppm 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).

[0238] Step 11: Synthesis of Compound 001-2

[0239] 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), and N, N-diisopropylethylamine (234.72 mg, 1.82 mmol, 316.34 μL) was added, and the mixture was stirred at 25°C for 2 hours. After the reaction, 10 mL of water was added to the reaction solution, and a solid was precipitated, which was filtered to obtain compound 001-2. LCMS: (ESI) m / z=521.02 [M+H] + . 1 H NMR (400 MHz, CDCl 3 )δppm 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).

[0240] Step 12: Synthesis of trifluoroacetate salt of compound 001-3

[0241] Compound 001-2 (300 mg, 574.45 μmol) was dissolved in trifluoroacetic acid (2 mL), stirred at 75°C for 1 hour, and concentrated after the reaction to obtain the trifluoroacetate salt of compound 001-3. LCMS: (ESI) m / z=402.92 [M+H] + .

[0242] Step 13: Synthesis of Compound 001-4

[0243] Compound 001-3 (220 mg, 544.47 μmol, trifluoroacetate) was dissolved in tetrahydrofuran (2 mL), and 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, and the mixture was reacted at 25° C. for 2 hours. After the reaction, the mixture was concentrated under reduced pressure, and the crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 10:1-3:1) to obtain compound 001-4. LCMS: (ESI) m / z = 502.92 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) 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).

[0244] Step 14: Synthesis of Compound 001-5

[0245] Compound 001-4 (250 mg, 495.86 μmol) was dissolved in N, N-dimethylformamide (5 mL) and tetrahydrofuran (5 mL), and 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, and the mixture was stirred at 25°C for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (eluent: dichloromethane / methanol = 10:1-5:1) to obtain compound 001-5. LCMS: (ESI) m / z = 626.12 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δppm 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).

[0246] Step 15: Synthesis of Compound 001-6

[0247] 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), and the nitrogen atmosphere was replaced three times. [(di(1-adamantyl)-n-butylphosphine)-2-(2-aminobiphenyl)]palladium (II) chloride (26.66 mg, 39.88 μmol) was added under nitrogen protection, and the mixture was reacted at 80°C for 12 hours. After the reaction, 3 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (2 mL*2). The combined organic phase was washed with 5 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 100: 0-1: 2, dichloromethane: methanol = 10: 1) to obtain compound 001-6. LCMS: (ESI) m / z = 1051.4 [M+H] + .

[0248] Step 16: Synthesis of the hydrochloride salt of compound 001-7

[0249] Compound 001-6 (0.13 g, 123.60 μmol) was added to hydrochloric acid / methanol (2 mL) and reacted at 18°C ​​for 2 hours. After the reaction was completed, the reaction solution was concentrated, and the crude product was stirred with 5 mL of ethyl acetate for 1 hour, filtered, and the filter cake was rinsed with 2 mL of ethyl acetate and concentrated under reduced pressure to obtain the hydrochloride of compound 001-7. LCMS: (ESI) m / z=787.3[M+H] + .

[0250] Step 17: Synthesis of Compound 001A and Compound 001B

[0251] Compound 001-7 (0.2 g, 242.75 μmol, hydrochloride) was added to N,N-dimethylformamide (3 mL), and potassium carbonate (335.51 mg, 2.43 mmol) and cesium fluoride (73.75 mg, 485.50 μmol, 17.90 μL) were added, and the mixture was reacted at 60° C. for 16 hours. After the reaction, 5 mL of water was added to the reaction solution, and 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, filtered, and concentrated to obtain a crude product, which was separated and purified by high performance liquid chromatography (chromatographic column: Phenomenex Luna 80*30 mm*3 μm; mobile phase A: water (0.05% HCl), mobile phase B: acetonitrile; running gradient: B%: 5%-30%, running for 8 min) to obtain the hydrochloride of compound 001, and ammonia water was added to the liquid to adjust the pH to 7, and then separated and purified by supercritical liquid chromatography (SFC) (column: DAICEL CHIRALPAK IC (250 mm*30 mm, 10 μ m); mobile phase: A (supercritical CO 2 ) and B (ethanol containing 0.1% ammonia water); gradient: B% = 60%-60%, running time 20min) to give Compound 001A and Compound 001B.

[0252] The analysis and characterization of compound 001A are as follows:

[0253] SFC analysis method (column: Chiralpak IC-3, 50×4.6 mm ID, 3 μm; mobile phase: A (supercritical CO 2 ), B: (ethanol, containing 0.1% isopropylamine); gradient: B% = 50-50%, 4min; flow rate: 4mL / min; wavelength: 220nm; pressure: 1800psi, Rt = 1.059min, 100%ee. LCMS: MSm / z(ESI) = 631.1[M+H] + . 1 H NMR (400 MHz, CD 3OD) 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, 2H), 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).

[0254] The analysis and characterization of compound 001B are as follows

[0255] SFC analysis method (column: Chiralpak IC-3, 50×4.6 mm ID, 3 μm; mobile phase: A (supercritical CO 2 ), B: (ethanol, containing 0.1% isopropylamine); gradient: B% = 50-50%, 4min; flow rate: 4mL / min; wavelength: 220nm; pressure: 1800psi, Rt = 1.917min, 96.54%ee. LCMS: MS m / z (ESI) = 631.1 [M+H] + . 1 H NMR (400 MHz, CD 3 OD) δ=7.80 (d, J=1.2Hz, 1H), 7.72 (dd, J=5.6, 8.8Hz, 1H), 7.22 (t, J=8.8Hz, 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), 3.29-3.2 7 (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).

[0256] Example 2

[0257]

[0258] Step 1: Synthesis of Compound 002-2

[0259] Compound 002-1 (0.5 g, 1.59 mmol) was added to anhydrous dichloromethane (10 mL), and compound 001-1H (400.05 mg, 1.75 mmol) and triethylamine (322.35 mg, 3.19 mmol, 443.40 μL) were added, and the mixture was reacted at 18°C ​​for 1 hour. After the reaction, the mixture was washed twice with 10 mL of saturated ammonium chloride, washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was stirred with a mixed solvent (petroleum ether: methyl tert-butyl ether = 3:1, 10 mL) for 1 hour, filtered, and the filter cake was washed with 10 mL of the solvent in the same ratio. The filter cake was compound 002-2. LCMS: (ESI) m / z = 505.1 [M+H] + . 1 H NMR (400 MHz, CDCl 3 )δ=7.63(d, J=7.6Hz, 2H), 7.44-7.34(m, 3H), 7.30-7.25(m, 1H), 5.99(s, 2H ), 4.29 (d, J=11.2Hz, 2H), 3.78 (s, 2H), 3.70 (d, J=11.6Hz, 2H), 1.31 (s, 6H).

[0260] Step 2: Synthesis of Compound 002-3

[0261] Compound 002-2 (0.35 g, 691.99 μmol) was added to anhydrous tetrahydrofuran (2 mL) and N, N-dimethylformamide (2 mL), and 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, and the mixture was reacted at 25°C for 17 hours. After the reaction, the reaction solution was added to 10 mL of methyl tert-butyl ether, washed twice with 10 mL of saturated ammonium chloride, and then washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 002-3. LCMS: (ESI) m / z=628.0 [M+H] + . 1 H NMR (400 MHz, CDCl 3)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). 2.33-2.06 (m, 3H), 1.98-1.80 (m, 3H), 1.30 (s, 6H).

[0262] Step 3: Synthesis of Compound 002-4

[0263] 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), and the atmosphere was replaced with nitrogen three times. [(di(1-adamantyl)-n-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) chloride (31.91 mg, 47.73 μmol) was added under nitrogen protection, and the reaction was carried out at 80° C. for 4.5 hours. Then, 20 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL*2). The organic phases were combined and washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1: 0-0: 1, dichloromethane: methanol = 10: 1) to obtain compound 002-4. LCMS: (ESI) m / z = 1053.5 [M+H] + . 1 H NMR (400 MHz, CDCl 3)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), 7.26-7.22(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).

[0264] Step 4: Synthesis of Compound 002-5

[0265] Compound 002-4 (0.23 g, 218.35 μmol) was added to trifluoroacetic acid (2 mL), and the temperature was raised to 70°C for reaction for 0.5 hours. After the reaction, the reaction solution was concentrated under reduced pressure, diluted with 5 mL of ethyl acetate, washed twice with 5 mL of water, washed with 10 mL of saturated sodium bicarbonate solution, washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 002-5. LCMS: (ESI) m / z=771.3 [M+H] + .

[0266] Step 5: Synthesis of Compound 002A and Compound 002B

[0267] Compound 002-5 (0.27 g, 350.21 μmol) was added to N,N-dimethylformamide (3 mL), and potassium carbonate (242.01 mg, 1.75 mmol) and cesium fluoride (106.39 mg, 700.41 μmol, 25.82 μL) were added, and the mixture was reacted at 60° C. for 5 hours. After the reaction, the reaction solution was diluted with 10 mL of ethyl acetate, and then washed with 10 mL of water. The aqueous phase was further extracted with 5 mL of ethyl acetate, and the organic phases were combined, washed with 10 mL of saturated brine for 3 times, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was stirred with a mixed solvent (n-heptane: ethyl acetate = 5:1) for 1 hour, filtered, and the filter cake was rinsed with 3 mL of the same ratio of mixed solvent for 3 times, dried, and then separated and purified by high performance liquid preparative chromatography (chromatographic column: Phenomenex Luna 80*30mm*3μm; mobile phase A: water (0.04% hydrochloric acid), mobile phase B: acetonitrile; running gradient: acetonitrile%: 10%-35%, running 8min). The separated fractions were adjusted to pH 8 with 10 mL of saturated sodium bicarbonate solution, extracted with ethyl acetate (20 mL*2), and the organic phases were combined, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 002. The product was separated and purified by supercritical fluid chromatography (SFC) (column: DAICEL CHIRALCEL OD (250 mm*30 mm, 10 μm); mobile phase: A (supercritical CO 2 ) and B (ethanol containing 0.1% ammonia water); gradient: B% = 50%-50%, running time 20min) to obtain 002A and 002B.

[0268] The analytical characterization of compound 002A is as follows:

[0269] SFC analysis method (column: Chiralcel OD-3, 50×4.6 mm ID, 3 μm; mobile phase: A (supercritical CO 2 ), B: (ethanol, containing 0.1% isopropylamine); gradient: B% = 5-50%, 3min; flow rate: 3.4mL / min; wavelength: 220nm; pressure: 1800psi), Rt = 1.801min, chiral isomer excess: 100%. LCMS: MS m / z (ESI) = 615.2 [M+H] + . 1 HNMR (400 MHz, CD 3OD)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), 2.7 7-2.55(m, 2H), 2.51-2.41(m, 1H), 2.37-2.28(m, 2H), 2.25-2.13(m, 1H).

[0270] The analytical characterization of compound 002B is as follows:

[0271] SFC analysis method (column: Chiralcel OD-3, 50×4.6 mm ID, 3 μm; mobile phase: A (supercritical CO 2 ), B: (ethanol, containing 0.1% isopropylamine); gradient: B% = 5-50%, 3min; flow rate: 3.4mL / min; wavelength: 220nm; pressure: 1800psi), Rt = 2.233min, chiral isomer excess: 93.58%. LCMS: MS m / z (ESI) = 615.2 [M+H] + . 1 H NMR (400 MHz, CD 3 OD) 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=12.4(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).

[0272] Example 3

[0273]

[0274] Step 1: Synthesis of Compound 003-1A

[0275] Compound 001-1H (18.6 g) was dissolved in tetrahydrofuran (190 mL), and then 9-fluorenylmethyl chloroformate (20.5 g, 79.4 mmol) and sodium carbonate (25.2 g, 238.2 mmol) were added, and stirred at 0°C for 1 hour. After the reaction was completed, 100 mL of ethyl acetate and 200 mL of water were added to the reaction solution for extraction, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 003-1A. LCMS: (ESI) m / z=451.3 [M+H] + . 1 H NMR: (400 MHz, CDCl 3 )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), 4.34-4.40(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).

[0276] Step 2: Synthesis of Compound 003-1B

[0277] Compound 003-1A (9.52 g, 21.1 mmol) was dissolved in trifluoroacetic acid (192 mL) and stirred at 75°C for 16 hours. After the reaction, 20 mL of water was added to the reaction solution, and the pH was adjusted to 9 with 2M sodium hydroxide, and then extracted with 20 mL of dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. 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] + . 1 H NMR: (400 MHz, CDCl 3 )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), 4.3 8-4.42 (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).

[0278] Step 3: Synthesis of Compound 003-1C

[0279] Compound 003-1B (1.00 g) was dissolved in tetrahydrofuran (10.0 mL), and di-tert-butyl dicarbonate (764 mg, 3.50 mmol, 804 μL) was added.

[0280] Step 3: Synthesis of Compound 003-1C

[0281] Compound 003-1B (1.00 g) was dissolved in tetrahydrofuran (10.0 mL), and di-tert-butyl dicarbonate (764 mg, 3.50 mmol, 804 μL) and triethylamine (885 mg, 8.75 mmol, 1.22 mL) were added, and stirred at 25°C for 1 hour. After the reaction, it was extracted with 10 mL of ethyl acetate and 10 mL of water, and then washed with 15 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 3: 1) to obtain compound 003-1C. LCMS: (ESI) m / z = 433.2 [M+H] + .

[0282] Step 4: Synthesis of Compound 003-1D

[0283] Compound 003-1C (5.69 g) was dissolved in ethanol (60.0 mL), and dimethylamine (34.4 g, 251.8 mmol, 33% content) was added, and 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 2M sodium hydroxide, filtered, and extracted with 40 mL of ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 003-1D. LCMS: (ESI) m / z=211.2 [M+H] + . 1 H NMR: (400 MHz, CDCl 3 )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).

[0284] Step 5: Synthesis of Compound 003-2

[0285] Compound 003-1 (0.5 g, 1.69 mmol) was dissolved in anhydrous dichloromethane (5 mL), and triethylamine (512.92 mg, 5.07 mmol, 705.53 μL) and 003-1D (426.34 mg, 2.03 mmol) were added, and stirred at 15°C for 1 hour. After the reaction was completed, the mixture was concentrated, and then the residue was dissolved with 20 mL of dichloromethane, washed once with 10 mL of water, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 003-2. LCMS: (ESI) m / z=468.9 [M+H] + . 1 H NMR (400 MHz, CDCl 3 )δppm 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).

[0286] Step 6: Synthesis of Compound 003-3

[0287] Compound 003-2 (0.9 g, 1.92 mmol) was dissolved in N, N-dimethylformamide (9 mL) and anhydrous tetrahydrofuran (9 mL), and then compound 001-4A (366.03 mg, 2.30 mmol), cesium carbonate (1.87 g, 5.75 mmol), triethylenediamine (64.47 mg, 574.79 μmol, 63.21 μL) were added, and stirred at 30°C for 12 hours. After the reaction was completed, 10 mL of water and 15 mL of ethyl acetate were added to the reaction solution, stirred for 5 minutes, and then allowed to stand for separation. 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, filtered, concentrated, and then purified by silica gel column chromatography (gradient elution: petroleum ether: ethyl acetate = 100:0-50:50, 0.5% triethylamine was added to ethyl acetate) to obtain compound 003-3. LCMS: (ESI) m / z=592.1 [M+H] + . 1 H NMR (400 MHz, CDCl 3)δppm 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).

[0288] Step 7: Synthesis of Compound 003-4

[0289] Compound 003-3 (0.8 g, 1.35 mmol), anhydrous tetrahydrofuran (8 mL), anhydrous potassium phosphate (859.87 mg, 4.05 mmol), water (4 mL) were added to the pre-dried reaction bottle, and nitrogen was replaced three times before adding chloro[(n-butyldi(1-adamantyl)phosphine)-2-(2-aminobiphenyl)]palladium(II) (98.34 mg, 135.03 μmol), and nitrogen was replaced three times again, and the temperature was raised to 60°C, and then a solution of compound 001-5A (1.19 g, 1.89 mmol) in anhydrous tetrahydrofuran (8 mL) was added, and then reacted at 60°C for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure to remove tetrahydrofuran, 20 mL of ethyl acetate was added, and the mixture was washed with saturated brine (20 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (gradient elution: petroleum ether: ethyl acetate = 100:0 to 50:50, 0.5% triethylamine was added to ethyl acetate) to obtain compound 003-4. LCMS: (ESI) m / z = 1017.5 [M+H] + . 1 H NMR (400 MHz, CDCl 3)δppm 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).

[0290] Step 8: Synthesis cake of the hydrochloride salt of compound 003-5 to obtain the hydrochloride salt of compound 003-5. LCMS: (ESI) m / z=753.3 [M+H] + .

[0291] Step 9: Synthesis of Compound 003

[0292] Compound 003-5 (0.7 g, 847.56 μmol, hydrochloride) 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, and stirred at 65°C for 4 hours. After the reaction was completed, the temperature was lowered to room temperature, the reaction solution was filtered, the filter cake was rinsed with 20 mL of ethyl acetate, and then the mother liquor was washed with saturated brine (20 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was separated and purified by high performance liquid preparative chromatography (chromatographic column: Phenomenex Luna 80*30 mm*3 μm; mobile phase: [water (0.04% hydrochloric acid)-acetonitrile]; acetonitrile%: 5%-25%, 8 min), and the obtained fraction was added with ammonia water to adjust the pH to 9, and the acetonitrile was removed by vacuum concentration, and the ethyl acetate (50 mL*2) was extracted and concentrated under reduced pressure to obtain compound 003. LCMS: (ESI) m / z = 597.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3)δppm 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).

[0293] Example 4

[0294]

[0295] Step 1: Synthesis of Compound 004-1

[0296] Add anhydrous tetrahydrofuran (20 mL) to a pre-dried reaction bottle, add diisopropyl azodicarboxylate (2.54 g, 12.56 mmol, 2.44 mL) and triphenylphosphine (3.30 g, 12.56 mmol) at 0°C, stir at 0°C for 0.5 hour to precipitate a solid, then add 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), and stir at 0-15°C for 2 hours. After the reaction was completed, 5 mL of water was added to the reaction solution to quench the reaction, 20 mL of ethyl acetate was added and stirred for minutes, the mixture was allowed to stand and separated, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and 20 mL of n-heptane was added and stirred for 1 hour, then the mother liquor was collected by filtration and concentrated under reduced pressure to obtain a crude compound, which was purified by silica gel column chromatography (gradient elution: petroleum ether: ethyl acetate = 100: 0 to 30: 70, 0.5% triethylamine was added to ethyl acetate) to obtain 004-1. LCMS m / z = 217.9 [M+H] + . 1 H NMR (400 MHz, CDCl 3 )δppm 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).

[0297] Step 2: Synthesis of Compound 004-2

[0298] Compound 004-1 (180 mg, 828.34 μmol) and dimethyl sulfoxide (8 mL) were added to the reaction flask, and sodium hydroxide (2M, 753.03 μL) was added at 15°C, and stirred at 15°C for 2 hours. Compound 004-1B (381.18 mg, 753.03 μmol) and dimethyl sulfoxide (8 mL) were then added, and stirred at 60°C for 48 hours. After the reaction was completed, the reaction solution was returned to room temperature, 20 mL of ethyl acetate was added, and the mixture was washed with saturated brine (20 ml*2), dried over anhydrous sodium sulfate, filtered, concentrated, and 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] + .

[0299] Step 3: Synthesis of Compound 004-3

[0300] 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), compound 001-5A (249.74 mg, 395.35 μmol) were added to the pre-dried reaction bottle, and chloro[(n-butyldi(1-adamantyl)phosphine)-2-(2-aminobiphenyl)]palladium (II) (17.62 mg, 26.36 μmol) was added after nitrogen replacement three times, and then the temperature was raised to 80°C for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature, 10 mL of water and 20 mL of ethyl acetate were added, stirred for 5 min, and then allowed to stand for separation. The aqueous phase was extracted once with 10 mL of ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (gradient elution: petroleum ether: ethyl acetate = 100: 0 to 60: 40, 0.5% triethylamine was added to ethyl acetate) to obtain compound 004-3. LCMS m / z = 1069.4 [M+H] + .

[0301] Step 4: Synthesis of the hydrochloride salt of compound 004-4

[0302] Hydrochloric acid / methanol (4M, 2.00 mL) was added to compound 004-3 (40 mg, 37.39 μmol), and stirred at 15°C for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude hydrochloride of compound 004-4. LCMS m / z=805.2[M+H] + .

[0303] Step 5: Synthesis of Compound 004A and Compound 004B

[0304] Compound 004-4 (30 mg, 34.15 μmol, hydrochloride) was added to N, N-dimethylformamide (1 mL), and anhydrous potassium carbonate (94.40 mg, 683.04 μmol) and cesium fluoride (25.94 mg, 170.76 μmol, 6.30 μL) were added, and stirred at 65°C for 2 hours. After the reaction, the reaction solution was cooled to room temperature, filtered, and 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, filtered, and concentrated to obtain a crude product. The crude product was separated and purified by supercritical fluid chromatography (SFC column: DAICEL CHIRALPAKIC (250 mm*30 mm, 10 μm); mobile phase: A: supercritical CO 2 The obtained fraction was separated and purified by adding ammonia water dropwise to adjust the pH to 9, and concentrated under reduced pressure to remove acetonitrile, and then extracted with ethyl acetate (20 mL*2), and concentrated under reduced pressure to obtain compound 004A and compound 004B.

[0305] The characterization of compound 004A is as follows:

[0306] SFC analysis method: Column: Chiralpak IC-3, 3 μm, 50×4.6 mm ID; Mobile phase: A (supercritical CO 2 ) and B (isopropanol, containing 0.1% isopropylamine); gradient: B% = 5-40%, 5min; flow rate: 4.0mL / min; wavelength: 220nm; pressure: 124.14bar, Rt = 2.13min, chiral isomer excess 83.48%. LCMS m / z = 649.2 [M+H] + . 1 H NMR (400 MHz, CD 3 OD) δppm 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).

[0307] The characterization of compound 004B is as follows: SFC analysis method: column: Chiralpak IC-3, 3 μm, 50×4.6 mm I.D; mobile phase: A (supercritical CO 2 ) and B (isopropanol, containing 0.1% isopropylamine); gradient: B% = 5-40%, 5min flow rate: 4.0mL / min; wavelength: 220nm; pressure: 124.14bar, Rt = 1.38min, chiral isomer excess 91.90%. LCMS m / z = 649.2 [M+H] + . 1 H NMR (400 MHz, CD 3 OD)δppm 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).

[0308] Example 5

[0309]

[0310] Step 1: Synthesis of Compound 005-1

[0311] Compound 003-3 (0.3 g, 506.35 μmol), anhydrous tetrahydrofuran (3 mL) and water (1 mL) were added to the reaction flask, followed by anhydrous potassium phosphate (322.45 mg, 1.52 mmol). After nitrogen replacement three times, the reaction mixture was added. A Pd G3 (CAS: 1651823-59-4) (36.88 mg, 50.64 μmol). After nitrogen replacement three times, the temperature was raised to 60°C, and then a solution of compound 005-1A (519.04 mg, 1.01 mmol) in anhydrous tetrahydrofuran (3 mL) was added dropwise under stirring, and 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%, 0.5% triethylamine was added to ethyl acetate) to obtain compound 005-1. LCMS m / z = 898.4 [M+H] + .

[0312] Step 2: Synthesis of the hydrochloride salt of compound 005-2

[0313] Add compound 005-1 (0.4 g, 445.37 μmol) and hydrochloric acid / methanol (4 M, 4.00 mL) to a pre-dried reaction bottle. Stir at 15°C for 1 hour under nitrogen protection. After the reaction is complete, concentrate the reaction solution under reduced pressure to obtain the crude hydrochloride of compound 005-2, which is used directly in the next step. LCMS m / z=754.3[M+H] + .

[0314] Step 3: Synthesis of Compound 005

[0315] Compound 005-2 (0.2 g, 241.87 μmol, hydrochloride) was added to N,N-dimethylformamide (4 mL), and anhydrous potassium carbonate (668.56 mg, 4.84 mmol) and cesium fluoride (183.70 mg, 1.21 mmol, 44.59 μL) were added, and stirred at 65° C. for 4 hours. After the reaction, 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, filtered, and concentrated. The crude product was separated and purified by high performance liquid preparative chromatography (chromatographic column: Phenomenex Luna 80*30 mm*3 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile%: 1%-25%, 8 min). The obtained fraction was added with ammonia water to adjust the pH to about 9, concentrated under reduced pressure to remove acetonitrile, extracted with ethyl acetate (20 mL*2), and concentrated under reduced pressure to obtain compound 005. LCMS m / z=598.2[M+H] + . 1 H NMR (400 MHz, CD 3 OD)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).

[0316] Example 6

[0317]

[0318] Step 1: Synthesis of Compound 006-2

[0319] 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), and triethylamine (323.52 mg, 3.20 mmol, 445.01 μL) was added, and the mixture was reacted at 18°C ​​for 1 hour. After the reaction, the reaction solution was diluted with 5 mL of dichloromethane, washed with saturated ammonium chloride (10 mL*2), and then washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was stirred with a mixed solvent (petroleum ether: methyl tert-butyl ether = 4:1, 10 mL) for 1 hour, filtered, and the filter cake was washed with the same proportion of the mixed solvent (3 mL*2), and the filter cake was dried to obtain compound 006-2. LCMS m / z (ESI) = 455.0 [M+H] + . 1 H NMR (400 MHz, CDCl 3 )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).

[0320] Step 2: Synthesis of Compound 006-3

[0321] Compound 006-2 (0.3 g, 658.89 μmol) was added to anhydrous tetrahydrofuran (1.5 mL) and N,N-dimethylformamide (1.5 mL), and 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, and the mixture was reacted at 25°C for 17 hours. After the reaction, the reaction solution was added to 10 mL of methyl tert-butyl ether, washed with 10 mL of water, and then washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1: 0-1: 2, dichloromethane: methanol = 10: 1) to obtain compound 006-3. LCMS m / z(ESI)=578.2[M+H] + . 1 H NMR (400 MHz, CDCl 3)δ=6.49 (d, J=5.2Hz, 1H), 5.99 (s, 2H), 5.37-5.16 (m, 1H), 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).

[0322] Step 3: Synthesis of Compound 006-4

[0323] 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), and the atmosphere was replaced with nitrogen three times. Under nitrogen protection, (2-dicyclohexylphosphine-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium (II) chloride (37.40 mg, 51.90 μmol) was added, the temperature was raised to 100° C., and the reaction was continued for 1.5 min. After 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, filtered, and concentrated. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 1: 0-1: 2, dichloromethane: methanol = 10: 1) to obtain compound 006-4. After 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, filtered, and concentrated. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 1: 0-1: 2, dichloromethane: methanol = 10: 1) to obtain compound 006-4. LCMS m / z (ESI) = 1047.5 [M+H] + .

[0324] Step 4: Synthesis of the hydrochloride salt of compound 006-5

[0325] Compound 006-4 (0.3 g, 286.44 μmol) was added to hydrochloric acid / methanol (5 mL) and reacted at 18°C ​​for 3 hours. After the reaction, the reaction solution was directly concentrated, and the crude product was added with 10 mL of ethyl acetate and stirred for 1 hour, then filtered. The filter cake was rinsed with ethyl acetate (2 mL*2), and the filter cake was dried to obtain the hydrochloride salt of compound 006-5. LCMS m / z (ESI) = 783.3 [M+H] + .

[0326] Step 5: Synthesis of Compound 006

[0327] Compound 006-5 (0.16 g, 195.25 μmol, hydrochloride) was added to N,N-dimethylformamide (2 mL), and potassium carbonate (269.8 5 mg, 1.95mmol) and cesium fluoride (59.32mg, 390.50μmol, 14.40μL), the reaction was continued at 60°C for 16 hours. After the reaction, 20mL of water was added to the reaction solution, extracted with ethyl acetate (10mL*2), the organic phases were combined, washed with saturated brine (20mL*3), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was separated and purified by high performance liquid preparative chromatography (chromatographic column: P Phenomenex Luna 80*30mm*3μm; mobile phase A: water (0.05% hydrochloric acid), mobile phase B: acetonitrile; running gradient: B%: 1%-35%, running 8min), the obtained fraction was added dropwise with ammonia water to adjust the pH to about 9, concentrated under reduced pressure to remove acetonitrile, extracted with ethyl acetate (20mL*2), and concentrated under reduced pressure to obtain compound 006. LCMS m / z(ESI)=627.2[M+H] + . 1 H NMR (400 MHz, CD 3 OD) δ=7.76 (dd, J=5.8, 9.2Hz, 1H), 7.30-7.20 (m, 2H), 7.08 (d, J=2.4Hz, 1H), 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), 3.35-3.38 1(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).

[0328] Example 7

[0329]

[0330] Step 1: Synthesis of Compound 007-2

[0331] 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), and nitrogen was replaced three times. [(di(1-adamantyl)-n-butylphosphine)-2-(2-aminobiphenyl)]palladium (II) chloride (5.33 mg, 7.98 μmol) was added under nitrogen protection, and the mixture was reacted at 100° C. for 1 hour under nitrogen protection. The reaction solution was diluted with 5 mL of ethyl acetate and then washed with 10 mL of water. The aqueous phase was further extracted with 5 mL of ethyl acetate. The organic phases were combined and washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 007-2. LCMS m / z (ESI) = 932.4 [M+H] + .

[0332] Step 2: Synthesis of Compound 007-3

[0333] Compound 007-2 (0.06 g, 64.34 μmol) was added to hydrogen chloride / methanol (3 mL, 4 M), reacted at 18°C ​​for 2 hours, the reaction solution was concentrated, the crude product was added to 5 mL of ethyl acetate and stirred for 16 hours, filtered, the filter cake was rinsed with 2 mL of ethyl acetate, and the filter cake was dried to obtain the hydrochloride salt of compound 007-3. LCMS m / z (ESI) = 788.3 [M+H] + .

[0334] Step 3: Synthesis of the hydrochloride salt of compound 007

[0335] Compound 007-3 (0.06 g, hydrochloride) was added to N,N-dimethylformamide (1.5 mL), and potassium carbonate (100.53 mg, 727.38 μmol) and cesium fluoride (22.10 mg, 145.48 μmol, 5.36 μL) were added, and the reaction was continued at 60° C. for 16 hours. Potassium carbonate (0.1 g) and cesium fluoride (22 mg) were added, and the reaction was continued for 20 hours. 5 mL of water was added to the reaction solution, and then extracted with ethyl acetate (3 mL*2). The organic phases were combined and washed with saturated brine (10 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated. The hydrochloride of compound 007 was obtained by separation and purification by high performance liquid preparative chromatography (chromatographic column: Phenomenex Luna 80*30 mm*3 μm; mobile phase A: water (0.05% hydrochloric acid); mobile phase B: acetonitrile; running gradient B%: 1%-35%; running time: 8 min). LCMS m / z (ESI) = 632.2 [M+H] + .

[0336] Example 8

[0337]

[0338] Step 1: Synthesis of Compound 008-1

[0339] 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), and the mixture was replaced with nitrogen three times. [(di(1-adamantyl)-n-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) chloride (53.19 mg, 79.55 μmol) was added under nitrogen protection, and the mixture was reacted at 80°C for 16 hours. 10 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL*2). The organic phases were combined and washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1:0-0:1) to obtain compound 008-1. LCMS m / z (ESI) = 934.5 [M+H] + . 1 H NMR (400 MHz, CDCl 3 )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).

[0340] Step 2: Synthesis of the hydrochloride salt of compound 008-2

[0341] Compound 008-1 (0.4 g, 428.18 μmol) was added to trifluoroacetic acid (5 mL), and the mixture was reacted at 70 °C for 1 hour. The reaction solution was concentrated, 10 mL of ethyl acetate was added to the concentrated reaction solution, and the mixture was washed with 10 mL of water, and then with 20 mL of saturated sodium bicarbonate. 10 mL of saturated sodium bicarbonate was added to the mixture.

[0342] Compound 008-2 (0.35 g, hydrochloride) 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, and the reaction was continued at 60°C for 8 hours. The reaction solution was diluted with 10 mL of ethyl acetate and then washed with 10 mL of water. The aqueous phase was further extracted with 5 mL of ethyl acetate, and the organic phases were combined and washed with saturated brine (10 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by high performance liquid preparative chromatography (chromatographic column: Phenomenex Luna 80*30mm*3μm; mobile phase A: water (0.05% hydrochloric acid); mobile phase B: acetonitrile; running gradient: B: 1%-30%; running time: 8min), and then ammonia water was added to adjust the pH to 7, and then separated and purified by supercritical liquid chromatography SFC (chromatographic column: DAICEL CHIRALPAK IG (250mm*30mm, 10μm); mobile phase: A (supercritical CO 2 ) and B (isopropanol, containing 0.1% ammonia water); running gradient: 50%-50%; running time: 17 min) to obtain compounds 008A and 008B.

[0343] The analytical characterization of compound 008A is as follows:

[0344] SFC analysis method (column: Chiralpak IG-3, 50×4.6 mm ID, 3 μm; mobile phase: A (supercritical CO 2 ), B: (ethanol, containing 0.1% isopropylamine); gradient: B% = 5-50%, 3min; flow rate: 3.4mL / min; wavelength: 220nm; pressure: 1800psi, Rt = 1.449min, chiral isomer excess: 100%. LCMS: MS m / z (ESI) = 616.2 [M+H] + . 1 H NMR (400 MHz, CD 3OD)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, 1 H), 3.29-3.19(m, 3H), 3.09-3.00(m, 1H), 2.41-2.10(m, 3H), 2.06-1.85(m, 3H).

[0345] The analytical characterization of compound 008B is as follows:

[0346] SFC analysis method (column: Chiralpak IG-3, 50×4.6 mm ID, 3 μm; mobile phase: A (supercritical CO 2 ), B: (ethanol, containing 0.1% isopropylamine); gradient: B% = 5-50%, 3min; flow rate: 3.4mL / min; wavelength: 220nm; pressure: 1800psi, Rt = 2.084min, chiral isomer excess: 93.62%. LCMS: MS m / z (ESI) = 616.2 [M+H] + . 1 H NMR (400 MHz, CD 3 OD)δ=7.84 (dd, J=6.0, 9.2Hz, 1H), 7.53-7.46 (m, 1H), 7.35-7.27 (m, 2H), 7.1 0(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).

[0347] Example 9

[0348]

[0349] Step 1: Synthesis of Compound 009-1

[0350] 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 the reaction flask. Stir at 15°C for 1 hour. The reaction was combined with a batch of 0.1 g of compound 003-1. 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, filtered, and concentrated under reduced pressure. Compound 009-1 was obtained. LCMS m / z=389.0[M+H] + . 1 H NMR (400 MHz, CDCl 3 )δppm: 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).

[0351] Step 2: Synthesis of Compound 009-2

[0352] Compound 009-1 (0.4 g, 1.03 mmol), dioxane (4.0 mL), compound 001-4A (492.78 mg, 3.10 mmol) and cesium carbonate (1.01 g, 3.10 mmol) were added to the reaction flask, and stirred at 140°C for 12 hours in a microwave. The reaction solution was filtered, the filter cake was washed with 10 mL of ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by high performance liquid preparative chromatography (chromatographic column: Phenomenex luna C18 250*50mm*10μm; mobile phase A: water (0.05% hydrochloric acid), mobile phase B: acetonitrile; running gradient: B%: 5%-35%, running 10min) to obtain the target compound 009-2. LCMS m / z=510.3[M+H] + . 1 H NMR (400 MHz, CDCl 3 )δppm 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).

[0353] Step 3: Synthesis of Compound 009-3

[0354] Compound 009-2 (130 mg, 254.69 μmol), anhydrous tetrahydrofuran (2.6 mL) and water (0.65 mL), anhydrous potassium phosphate (162.19 mg, 764.08 μmol), and compound 001-5A (482.67 mg, 764.08 μmol) were added to the reaction flask. After nitrogen replacement three times, methanesulfonic acid [n-butyldi(1-adamantyl)phosphine] (2-amino-1,1′-biphenyl-2-yl) palladium (II) (18.55 mg, 25.47 μmol) was added. After nitrogen replacement three times, the temperature was raised to 60°C and stirred for 16 hours. Compound 001-5A (18.55 mg, 25.47 μmol) was added and nitrogen replacement three times, and then 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 with 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 and stirred for 10 min. The aqueous phase was then collected and the pH was adjusted to about 9 with sodium carbonate. The mixture was then extracted with dichloromethane (10 mL*2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 009-3. LCMS m / z=771.4[M+H] + .

[0355] Step 4: Synthesis of Compound 009

[0356] Compound 009-3 (178 mg) was added to N, N-dimethylformamide (2 mL), and anhydrous potassium carbonate (159.53 mg, 1.15 mmol) and cesium fluoride (175.34 mg, 1.15 mmol, 42.56 μL) were added, and stirred at 65°C for 4 hours. The mixture was combined with a batch of 24 mg of compound 009-3, cooled to room temperature, and then the reaction solution was 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, filtered, and concentrated to obtain a crude product. The crude product was separated and purified by high performance liquid preparative chromatography (chromatographic column: Phenomenex Luna 80*30mm*3μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile%: 1%-30%, 8min) to obtain a fraction, and ammonia water was added dropwise to adjust the pH to about 9. After concentration, it was separated and purified by high performance liquid preparative chromatography (column: Waters Xbridge BEH C18 100*30mm*10μm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 35%-60%, 8min) to obtain compound 009. LCMS m / z=615.5[M+H] + . 1 H NMR (400 MHz, CDCl 3)δppm 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).

[0357] Example 10

[0358]

[0359] Step 1: Synthesis of compound 010-12

[0360] 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), and iodine (40.27 g, 158.65 mmol, 31.96 mL) was added, and stirred at 25°C for 2 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column (gradient elution: petroleum ether: ethyl acetate = 100: 1-20: 1) to obtain compound 010-12.

[0361] Step 2: Synthesis of Compound 010-13

[0362] In a carbon monoxide environment, at a pressure of 50 Psi and a temperature of 30° C., compound 010-12 (22 g, 65.89 mmol) and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane (5.38 g, 6.59 mmol) were dissolved in methanol (100 mL), stirred for 5 minutes, and then triethylamine (46.67 g, 461.22 mmol, 64.20 mL) was added, and stirring was continued for 24 hours. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column (gradient elution: petroleum ether: ethyl acetate = 20: 1-5: 1) to obtain compound 010-13. LCMS: (ESI) m / z = 265.8 [M+H] + .

[0363] Step 3: Synthesis of Compound 010-14

[0364] Compound 010-13 (15 g, 56.38 mmol) was dissolved in methanol (50 mL), and a solution of sodium hydroxide (9.02 g, 225.53 mmol) in water (50 mL) was added, and stirred at 25°C for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the pH was adjusted to 5 with 2 mol / L hydrochloric acid. A white solid precipitated, and it was filtered under reduced pressure to obtain compound 010-14. LCMS: (ESI) m / z=251.8 [M+H] + .

[0365] Step 4: Synthesis of Compound 010-15

[0366] 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, reacted at 200°C for 4 hours, the reaction solution was cooled to room temperature, 200 mL of water was added and stirred, and the filter cake was obtained by vacuum filtration to obtain compound 010-15. LCMS: (ESI) m / z=276.9 [M+H] + .

[0367] Step 5: Synthesis of Compound 002-1

[0368] At 0°C, 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), and then compound 010-15 (5 g, 18.05 mmol) was added in batches. After the addition, the mixture was refluxed at 80°C for 20 hours, concentrated under reduced pressure, and the crude product was purified by silica gel column (gradient elution: petroleum ether: ethyl acetate = 20: 1-10: 1) to obtain compound 002-1. LCMS: (ESI) m / z = 312.9 [M+H] + .

[0369] Step 6: Synthesis of Compound 010-17

[0370] Compound 010-16A (1.2 g, 3.82 mmol) was dissolved in N, N-dimethylformamide (2 mL), and compound 002-1 (811.51 mg, 3.82 mmol) and N, N-diisopropylethylamine (1.48 g, 11.47 mmol, 2.00 mL) were added, and the mixture was stirred at 25°C for 2 hours. The reaction solution was poured into 50 mL of water, and a solid was precipitated. The solid was washed with water (3*20 mL) to obtain compound 010-17. LCMS: (ESI) m / z=489.0 [M+H] + .

[0371] Step 7: Synthesis of compound 010-7A

[0372] Compound 010-17 (1.6 g, 3.27 mmol) was dissolved in N, N-dimethylformamide (10 mL) and tetrahydrofuran (10 mL), and then cesium carbonate (3.19 g, 9.80 mmol), compound 001-4A (780.17 mg, 4.90 mmol), triethylenediamine (36.65 mg, 326.70 μmol, 35.93 μL) were added, and the mixture was stirred at 25°C for 18 hours. After the reaction, the mixture was extracted with 40 mL of ethyl acetate, washed with water (15 mL), and washed with saturated brine (15 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column (gradient elution: petroleum ether: ethyl acetate = 20: 1-10: 1) to obtain compound 010-7A. LCMS: (ESI) m / z = 612.2 [M+H] + .

[0373] Step 8: Synthesis of Compound 010-2

[0374] Anhydrous tetrahydrofuran (200 mL) and zinc powder (22.47 g, 343.62 mmol) were added to the pre-dried reaction bottle, and trimethylsilyl chloride (2.49 g, 22.91 mmol, 2.91 mL) was added under nitrogen stirring, and then the temperature was raised to 45°C, tert-butyl bromoacetate (37.98 g, 194.72 mmol, 28.77 mL) in anhydrous tetrahydrofuran (60 mL) was added dropwise, and then compound 010-1 (19.6 g, 114.54 mmol) was added under nitrogen protection, and stirred at 45°C for 2 hours. The reaction solution was cooled to room temperature, filtered with diatomaceous earth, and the filter cake was washed with 200 mL of tetrahydrofuran. 200 mL of 1M hydrochloric acid solution was added to the mother liquor and stirred for 2 hours, and then the tetrahydrofuran was removed by concentration under reduced pressure, and then the residue was extracted with 50 mL of ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 010-2. 1 HNMR (400 MHz, CDCl 3 )δppm 7.08-6.85 (m, 2H), 3.89 (s, 2H), 3.55-3.40 (m, 2H), 1.48 (s, 9H).

[0375] Step 9: Synthesis of Compound 010-3

[0376] Compound 010-2 (26.8 g, 92.97 mmol) and trifluoromethanesulfonic acid (455.60 g, 3.04 mol, 268.00 mL) were added to the pre-dried reaction bottle and stirred at 80°C for 4 hours. The reaction solution was cooled to room temperature, slowly poured into 4L saturated sodium bicarbonate aqueous solution, and the temperature was controlled to be less than 10°C by adding ice. After quenching, it was stirred for 10 minutes (aqueous phase pH = 7-8), extracted with ethyl acetate (1L*2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. Purified by silica gel column chromatography (gradient elution: petroleum ether: ethyl acetate = 100:0-90:10), the fraction was concentrated to dryness, 100mL of petroleum ether was added, stirred overnight, the supernatant was removed, and dried to obtain compound 010-3. LCMS m / z = 213.0 [MH] - . 1 H NMR (400 MHz, DMSO-d 6 )δppm 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).

[0377] Step 10: Synthesis of Compound 010-4

[0378] Compound 010-3 (15 g, 70.05 mmol), (2-bromoethynyl) triisopropylsilane (20.13 g, 77.05 mmol), dioxane (150 mL), potassium acetate (13.75 g, 140.09 mmol) were added to a pre-dried reaction bottle, and dichlorobis(4-methylisopropylphenyl)ruthenium (II) (6.43 g, 10.51 mmol) was added after nitrogen replacement three times. After nitrogen replacement three times, the temperature was raised to 110°C and stirred for 2 hours. The reaction solution was cooled to room temperature, combined with compound 010-3 (1.0 g), cooled to room temperature, filtered, and the filter cake was washed with 200 mL of ethyl acetate. The mother liquor was concentrated under reduced pressure to remove the solvent and then dissolved with 200 mL of ethyl acetate, washed twice with 100 mL of water and 100 mL of saturated brine, respectively, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (gradient elution: petroleum ether: ethyl acetate = 100: 0 to 90: 10) to obtain compound 010-4. LCMS m / z = 393.2 [MH] - . 1 H NMR (400 MHz, DMSO-d 6 )δppm 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).

[0379] Step 11: Synthesis of Compound 010-5

[0380] Compound 010-4 (15 g, 38.02 mmol), anhydrous dichloromethane (300 mL), N, N-diisopropylethylamine (19.66 g, 152.09 mmol, 26.49 mL) were added to a pre-dried reaction bottle, trifluoromethanesulfonic anhydride (22.53 g, 79.85 mmol, 13.17 mL) was added in three batches at 0°C, and stirred at 0°C for 0.5 hours. Combined with compound 010-4 (1 g), 200 mL of saturated ammonium chloride solution was added to the reaction solution and stirred for 5 minutes, then washed once with 200 mL of saturated ammonium chloride, washed twice with half-saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product 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 [MH] - . 1 H NMR (400 MHz, DMSO-d 6 )δppm 8.56 (d, J=2.4Hz, 1H), 8.21 (d, J=2.0Hz, 1H), 1.29-1.04 (m, 21H).

[0381] Step 12: Synthesis of Compound 010-6

[0382] To a pre-dried reaction bottle, compound 010-5 (19 g, 28.85 mmol), benzophenone imine (6.27 g, 34.62 mmol, 5.81 mL), dioxane (190 mL), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene (3.34 g, 5.77 mmol), and cesium carbonate (18.80 g, 57.70 mmol) were added. After nitrogen substitution three times, tris(dibenzylideneacetone)dipalladium(0) (2.64 g, 2.88 mmol) was added. After nitrogen substitution three times, the mixture was stirred at 90°C for 2 hours. The reaction solution was cooled to room temperature and then 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 with 100 mL of ethyl acetate. The residue was washed with 50 mL of water and saturated brine (50 mL*2) respectively, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20: 1) to obtain a crude product. The crude product was added with 60 mL of ethanol and stirred for 48 hours, 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 (400 MHz, CDCl 3)δppm 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).

[0383] Step 13: Synthesis of Compound 010-7

[0384] To a pre-dried reaction bottle, compound 010-6 (1 g, 1.45 mmol), dioxane (10 mL), potassium acetate (426.84 mg, 4.35 mmol), bis(pinacol)diboron (1.10 g, 4.35 mmol, 42.07 μL), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (138.22 mg, 289.95 μmol) were added. After nitrogen replacement three times, 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (106.08 mg, 144.97 μmol) was added. The reaction mixture was replaced with nitrogen three times and the temperature was raised to 120°C and stirred for 2 hours. Combined with compound 010-6 (0.5 g and 0.1 g), cooled to room temperature, filtered, the mother liquor was concentrated to one-half under reduced pressure, 30 mL of ethyl acetate was added, washed with saturated brine (30 mL*2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was separated by column chromatography (using 1000 mesh silica gel, gradient elution ethyl acetate: petroleum ether = 0%, 2%, 3%, 4%, 5%) to obtain compound 010-7. 1 H NMR (400 MHz, CDCl 3 )δppm 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).

[0385] Step 14: Synthesis of Compound 010-8

[0386] 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), compound 010-7 (408.80 mg, 612.26 μmol) were added to the pre-dried reaction bottle, and the atmosphere was replaced with nitrogen three times before adding chloro[(di(1-adamantyl)-n-butylphosphine)-2-(2-aminobiphenyl)]palladium (II) (27.29 mg, 40.82 μmol), and the atmosphere was replaced with nitrogen three times, and the temperature was raised to 105°C and stirred for 24 hours. The reaction solution was cooled to room temperature, combined with compound 010-7A (20 mg), concentrated under reduced pressure to remove the solvent, and the residue was dissolved with 10 mL of ethyl acetate. The organic phase was washed twice with 10 mL of water, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (gradient elution: petroleum ether: ethyl acetate = 100:0 to 50:50, 0.5% triethylamine was added to ethyl acetate) to obtain compound 010-8. LCMS m / z = 1073.4 [M+H] + .

[0387] Step 15: Synthesis of the hydrochloride salt of compound 010-9

[0388] Hydrogen chloride / methanol (4M, 3.75 mL) was added to compound 010-8 (0.3 g, 279.51 μmol) and stirred at 15°C for 1 hour. The mixture was combined with compound 010-8 (40 mg) and the reaction solution was concentrated to dryness under reduced pressure to obtain the hydrochloride salt of compound 010-9. LCMS m / z=809.5[M+H] + .

[0389] Step 16: Synthesis of compounds 010A and 010B

[0390] Compound 010-9 (0.28 g, hydrochloride), N,N-dimethylformamide (2.8 mL), anhydrous potassium carbonate (712.40 mg, 5.15 mmol), cesium fluoride (195.74 mg, 1.29 mmol, 47.51 μL) were added to a pre-dried reaction bottle and stirred at 65°C for 4 hours. The mixture was combined with compound 010-9 (50 mg), cooled to room temperature, and then the reaction solution was filtered, the filter cake was rinsed with 20 mL of ethyl acetate, and then the mother liquor was washed with saturated brine (20 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was separated by high performance liquid chromatography (chromatographic column: Phenomenex luna C18 OBD 80*40mm*3μm; mobile phase A: water (0.05% HCl), mobile phase B: acetonitrile; running gradient: B%: 5%-40%, running 7min), and ammonia water was added dropwise to adjust the pH to about 9, and then the acetonitrile was removed by vacuum concentration, and the mixture was extracted twice with 20mL of ethyl acetate and then concentrated under reduced pressure to obtain a mixture. It was separated and purified by supercritical liquid chromatography (column: DAICEL CHIRALPAK IC (250mm*30mm, 10μm); mobile phase: A (supercritical CO 2 ) and B (isopropanol containing 0.1% ammonia water); gradient: B% = 60%-60%, running time 15min) to give compounds 010A and 010B.

[0391] The characterization of compound 010A is as follows:

[0392] SFC analysis method: Column: Chiralpak IC-3, 3μm, 50×4.6mm I.D.; Mobile phase: A (supercritical CO 2 ) and B (isopropanol, containing 0.1% isopropylamine); gradient: AB = 60:40, 3min; flow rate: 4.0mL / min; wavelength: 220nm; column temperature: 35°C; pressure: 1800psi, Rt = 0.881min, chiral isomer excess 100%. LCMS m / z = 653.3 [M+H] + . 1 HNMR (400 MHz, CDCl 3)δppm7.31-7.28(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), 3.62-3.43(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).

[0393] The characterization of compound 010B is as follows:

[0394] SFC analysis method: Column: Chiralpak IC-3, 3 μm, 50×4.6 mm ID; Mobile phase: A (supercritical CO 2 ) and B (isopropanol, containing 0.1% isopropylamine); gradient: A:B=60:40, 3min; flow rate: 4.0mL / min; wavelength: 220nm; column temperature: 35°C; pressure: 1800psi, Rt=1.364min, chiral isomer excess 96.69%. LCMS m / z=653.3[M+H] + . 1 HNMR (400 MHz, CDCl 3 )δppm 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).

[0395] Embodiment 11

[0396]

[0397] Step 1: Synthesis of Compound 011-1

[0398] 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), compound 010-7 (318.48 mg, 477.00 μmol) were added to the pre-dried reaction bottle. After nitrogen replacement three times, chloro[(di(1-adamantyl)-n-butylphosphine)-2-(2-aminobiphenyl)]palladium (II) (21.26 mg, 31.80 μmol) was added. The nitrogen replacement was carried out three times and the temperature was raised to 105°C and stirred for 24 hours. The reaction solution was cooled to room temperature, combined with compound 011-1A (20 mg), concentrated under reduced pressure to remove the solvent, and the residue was dissolved with 10 mL of ethyl acetate. The organic phase was washed twice with 10 mL of water, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (gradient elution ∶ Petroleum ether: ethyl acetate = 100: 0-40: 60 (5 / 1000 triethylamine was added to ethyl acetate) to purify and obtain compound 011 - 1. LCMS m / z=1089.2[M+H] + .

[0399] Step 2: Synthesis of the hydrochloride salt of compound 011-2

[0400] Hydrogen chloride / methanol (4M, 6.25 mL) was added to compound 011-1 (250 mg, 229.41 μmol) and stirred at 15°C for 1 hour. The mixture was combined with compound 011-1 (20 mg) and the reaction solution was concentrated under reduced pressure to obtain the hydrochloride salt of compound 011-2. LCMS m / z=825.2 [M+H] +

[0401] Step 3: Synthesis of Compound 011A and Compound 011B

[0402] Compound 011-2 (220 mg, hydrochloride), N,N-dimethylformamide (4 mL), anhydrous potassium carbonate (499.11 mg, 3.61 mmol), cesium fluoride (137.14 mg, 902.81 μmol, 33.29 μL) were added to a pre-dried reaction bottle and stirred at 65°C for 4 hours. The mixture was combined with compound 011-2 (50 mg), cooled to room temperature, and then the reaction solution was filtered, the filter cake was rinsed with 20 mL of ethyl acetate, and then the mother liquor was washed with saturated brine (20 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was analyzed by high performance liquid chromatography (chromatographic column: Phenomenex luna C18 OBD 80*30mm*3μm; mobile phase A: water (0.05% HCl), mobile phase B: acetonitrile; running gradient: B%: 15%-50%, running 8min), and the fractions were collected, and ammonia water was added dropwise to adjust the pH to about 9, and then the acetonitrile was removed by vacuum concentration, and the mixture was extracted twice with 20mL of ethyl acetate and then concentrated under reduced pressure to obtain a mixture. It was then separated and purified by supercritical liquid chromatography (column: DAICEL CHIRALPAK IC (250mm*30mm, 10μm); mobile phase: A (supercritical CO 2 ) and B (isopropanol containing 0.1% ammonia water); gradient: B% = 50%-50%, running time 15min) to give compounds 011A and 011B.

[0403] The characterization of compound 011A is as follows:

[0404] SFC analysis method: Column: Chiralpak IC-3, 3 μm, 50×4.6 mm ID; Mobile phase: A (supercritical CO 2 ) and B (isopropanol, containing 0.1% isopropylamine); gradient: A: B = 50: 50, 3 min; flow rate: 3.4 mL / min; wavelength: 220 m; column temperature: 35°C; pressure: 1800 psi, Rt = 1.656 min, chiral isomer excess 100%. LCMS m / z = 669.3 [M+H] +. 1 HNMR (400 MHz, CDCl 3)δppm 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).

[0405] The characterization of compound 011B is as follows:

[0406] SFC analysis method: Column: Chiralpak IC-3, 3 μm, 50×4.6 mm 1.D; Mobile phase: A (supercritical CO 2 ) and B (isopropanol, containing 0.1% isopropylamine); gradient: A:B=50:50, 3min; flow rate: 3.4mL / min; wavelength: 220nm; column temperature: 35°C; pressure: 1800psi, Rt=1.930min, chiral isomer excess 96.56%. LCMS m / z=669.3[M+H] + . 1 HNMR (400 MHz, CDCl 3 )δppm 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).

[0407] Example 12

[0408]

[0409] Step 1: Synthesis of Compound 012-1

[0410] Compound 002-1 (1 g, 3.19 mmol) was added to anhydrous dichloromethane (10 mL), and compound 003-1D (736.82 mg, 3.50 mmol) and triethylamine (644.70 mg, 6.37 mmol, 886.79 μL) were added, and the mixture was reacted at 18°C ​​for 1 hour. The reaction solution was washed with saturated ammonium chloride (20 mL*2), and then washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was added to a mixed solution (petroleum ether: methyl tert-butyl ether = 4:1, 20 mL) and stirred for 1 hour, then filtered. The filter cake was rinsed with the same proportion of solvent (5 mL*2), and then dried under reduced pressure to obtain compound 012-1. LCMS m / z (ESI) = 487.0 [M+H] + .

[0411] Step 2: Synthesis of Compound 012-2

[0412] Compound 012-1 (0.6 g, 1.23 mmol) was added to dry tetrahydrofuran (3 mL) and N, N-dimethylformamide (3 mL), and 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, and the mixture was reacted at 30°C for 16 hours. The reaction solution was added to 10 mL of methyl tert-butyl ether, washed with saturated ammonium chloride (20 mL*2), and the aqueous phase was further 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, filtered, and concentrated to obtain compound 012-2. LCMS m / z (ESI) = 610.1 [M+H] + . 1 H NMR (400 MHz, CDCl 3 )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).

[0413] Step 3: Synthesis of Compound 012-3

[0414] 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), and the mixture was replaced with nitrogen three times. [(di(1-adamantyl)-n-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) chloride ((54.76 mg, 81.90 μmol)) was added under nitrogen protection, and the mixture was reacted at 100° C. for 3 hours. 10 mL of water was added to the reaction solution for washing, and the mixture was extracted with ethyl acetate (5 mL*2). The organic phases were combined and washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1:0-0:1) to obtain compound 012-3. LCMS m / z (ESI) = 1071.4 [M+H] + .

[0415] Step 4: Synthesis of the hydrochloride salt of compound 012-4

[0416] Compound 012-3 (0.2 g, 186.69 μmol) was added to hydrogen chloride / methanol (4 mL, 4 M), reacted at 18°C ​​for 1 hour, and combined with compound 012-3 (50 mg batch), and the reaction solution was directly concentrated. The crude product was stirred with 5 mL of ethyl acetate for 2 hours, filtered, and the filter cake was rinsed with ethyl acetate (2 mL*2), and then dried under reduced pressure to obtain the hydrochloride salt of compound 012-4. LCMS m / z (ESI) = 807.3 [M+H] + .

[0417] Step 5: Synthesis of Compound 012A and Compound 012B

[0418] Compound 012-4 (0.1 g, hydrochloride) was added to N,N-dimethylformamide (2 mL), and potassium carbonate (85.64 mg, 619.61 μmol) and cesium fluoride (37.65 mg, 247.85 μmol, 9.14 μL) were added. The reaction was continued at 60°C for 16 hours, and the mixture was combined with compound 012-4 (50 mg batch). The reaction solution was diluted with 5 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 with saturated brine (10 mL*2), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by high performance liquid preparative chromatography (chromatographic column: Phenomenex luna C18 80*40mm*3μm; mobile phase A: water (0.05% hydrochloric acid); mobile phase B: acetonitrile; running gradient: B: 1%-40%; running time: 7min), and a drop of ammonia water was added to the separation liquid to obtain the crude product, which was then separated and purified by supercritical liquid chromatography (SFC) (chromatographic column: DAICELCHIRALCEL OD (250mm*30mm, 10μm); flowability: A (supercritical CO 2 ) and B (ethanol containing 0.1% ammonia water); gradient: B% = 50%-50%, running time 13min) to give compound 012A and compound 012B.

[0419] The analytical characterization of compound 012A is as follows:

[0420] SFC analysis method (column: Chiralcel OD-3, 50×4.6 mm ID, 3 μm; mobile phase: A (supercritical CO 2 ), B: (ethanol, containing 0.1% isopropylamine); gradient: B% = 5-50%, 3min; flow rate: 3.4mL / min; wavelength: 220nm; pressure: 1800psi, Rt = 1.516min, 100%ee. LCMS: m / z (ESI) = 651.3 [M+H] + . 1 H NMR (400 MHz, CD 3 OD) 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), 5.68-5.4 5 (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).

[0421] The analytical characterization of compound 012B is as follows:

[0422] SFC analysis method (column: Chiralcel OD-3, 50×4.6 mm ID, 3 μm; mobile phase: A (supercritical CO 2 ), B: (ethanol, containing 0.1% isopropylamine); gradient: B% = 5-50%, 3min; flow rate: 3.4mL / min; wavelength: 220nm; pressure: 1800psi, Rt = 1.751min, 96.64%ee. LCMS: m / z (ESI) = 651.3 [M+H] + . 1 H NMR (400 MHz, CD 3 OD)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).

[0423] Embodiment 13

[0424]

[0425] Step 1: Synthesis of Compound 013-1A

[0426] Compound 013-1 (1.8 g, 5.57 mmol) was added to anhydrous tetrahydrofuran (20 mL), replaced with nitrogen three times, cooled to 10°C, and lithium aluminum hydride (633.94 mg, 16.70 mmol) was added three times under nitrogen atmosphere, slowly heated to 20°C for reaction for 10 minutes, and heated to 70°C for reflux reaction for 2 hours. Cooled to 0°C, 0.6 mL of water was slowly added to the reaction solution to quench the reaction, and then 0.6 mL of 15% sodium hydroxide solution and 1.8 mL of water were added, stirred for 5 minutes, 5 g of sodium sulfate solid was added, stirred for 30 minutes, filtered, and the filtrate was concentrated to obtain compound 013-1A. 1 H NMR (400 MHz, CDCl 3 )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).

[0427] Step 2: Synthesis of Compound 013-2

[0428] Compound 012-1 (0.55 g, 1.13 mmol) was added to anhydrous tetrahydrofuran (2.5 mL) and N, N-dimethylformamide (2.5 mL), and 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, and the mixture was reacted at 30°C for 20 hours. The mixture was combined with compound 012-1 (50 mg), the reaction solution was added to 10 mL of methyl tert-butyl ether, washed with saturated ammonium chloride (20 mL*2), the aqueous phase was further 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, filtered and concentrated, and the crude product was purified by column (petroleum ether: ethyl acetate = 100: 0-1: 4) to obtain compound 013-2. LCMS: MS m / z(ESI)=604.1[M+H] + .

[0429] Step 3: Synthesis of Compound 013-3

[0430] 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), and the atmosphere was replaced with nitrogen three times. [(di(1-adamantyl)-n-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) chloride (99.55 mg, 148.89 μmol) was added under nitrogen protection, and the reaction was carried out at 90° C. for 3.5 hours. 10 mL of water was added to the reaction solution for washing, and the mixture was extracted with ethyl acetate (5 mL*2). The organic phases were combined, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1:0-0:1) to obtain compound 013-3. LCMS: MS m / z(ESI)=1029.3[M+H] + .

[0431] Step 4: Synthesis of the hydrochloride salt of compound 013-4

[0432] Compound 013-3 (0.5 g, 485.76 μmol) was added to hydrogen chloride / methanol (10 mL, 4 M), reacted at 20°C for 1 hour, and the reaction solution was concentrated under reduced pressure. 5 mL of ethyl acetate was added to the crude product and stirred for 16 hours, filtered, and the filter cake was rinsed with ethyl acetate (2 mL*2), and then dried under reduced pressure to obtain the hydrochloride salt of compound 013-4. LCMS: MS m / z (ESI) = 765.3 [M+H] + . 1 H NMR (400 MHz, CD 3 OD)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),6.44-6.2 8(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), 2.5 8-2.34 (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).

[0433] Step 5: Synthesis of Compound 013A and Compound 013B

[0434] Compound 013-4 (0.42 g, hydrochloride) was added to N,N-dimethylformamide (5 mL), and potassium carbonate (362.14 mg, 2.62 mmol) and cesium fluoride (159.21 mg, 1.05 mmol, 38.64 μL) were added, and the mixture was reacted at 60° C. for 15 hours. The reaction solution was diluted with 10 mL of ethyl acetate and then washed with 20 mL of water. The aqueous phase was further extracted with 10 mL of ethyl acetate. The organic phases were combined, washed with saturated brine (20 mL*2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was separated and purified by high performance liquid preparative chromatography (chromatographic column: Phenomenex luna C1875*30 mm*3 μm; mobile phase A: water (0.05% hydrochloric acid); mobile phase B: acetonitrile; running gradient: B%=10%-40%; running time: 8 min). Ammonia water was added dropwise to the machine liquid to adjust the pH to ~7 to obtain a crude product. The crude product was separated and purified by supercritical liquid chromatography (SFC) chromatographic column: DAICEL DAICEL CHIRALPAKIG (250 mm*30 mm, 10 μm); flowability: A (supercritical CO 2) and B (ethanol, containing 0.1% ammonia water); gradient: B% = 50%-50%, running for 15 min) to obtain compound 013A and compound 013B. The carbon atoms with "*" and "#" are chiral carbon atoms, existing in the form of (R) or (S) single enantiomers. The configuration of compound 013A is: "1S, 2R" or "1S, 2S" or "1R, 2R" or "1R, 2S" or "1S" or "1R" or "2S" or "2R"; the configuration of compound 013B is: "1S, 2R" or "1S, 2S" or "1R, 2R" or "1R, 2S" or "1S" or "1R" or "2S" or "2R"

[0435] The analytical characterization of compound 013A is as follows:

[0436] SFC analysis method (column: Chiralpak IG-3, 50×4.6 mm ID, 3 μm; mobile phase: A (supercritical CO 2 ), B: (ethanol, containing 0.1% isopropylamine); gradient: B% = 50-50%, 6min; flow rate: 4.0mL / min; wavelength: 220nm; pressure: 1800psi, Rt = 0.662min, 100%ee. LCMS: MS m / z (ESI) = 609.1 [M+H] + . 1 H NMR (400 MHz, CD 3 OD)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, 4H), 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).

[0437] The analytical characterization of compound 013B is as follows:

[0438] SFC analysis method (column: Chiralpak IG-3, 50×4.6 mm ID, 3 μm; mobile phase: A (supercritical CO 2), B: (ethanol, containing 0.1% isopropylamine): gradient: B% = 50-50%, 6min; flow rate: 4.0mL / min; wavelength: 220nm; pressure: 1800psi, Rt = 1.152min, 99.38%ee. LCMS: MS m / z (ESI) = 609.1 [M+H] + . 1 H NMR (400 MHz, CD 3 OD) 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), 4.07-4.03 ( 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).

[0439] Embodiment 14

[0440]

[0441] Step 1: Synthesis of Compound 014-2

[0442] 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, and the mixture was reacted at 20°C for 2 hours. 30 mL of water was added to the reaction solution, and the mixture was extracted with methyl tert-butyl ether (20 mL*2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column (petroleum ether: ethyl acetate = 100: 0-10: 1) to obtain compound 014-2. LCMS: MS m / z (ESI) = 340.1 [M+H] + .

[0443] Step 2: Synthesis of Compound 014-3

[0444] Lithium tert-butoxide (1.18 g, 14.69 mmol, 1.32 mL), tris(dibenzylideneacetone)dipalladium (134.56 mg, 146.95 μmol) and 2-dicyclohexylphosphine-2-(N,N-dimethylamine)-biphenyl (144.58 mg, 367.37 μmol) were added to 1,4-dioxane (35 mL), argon was replaced three times, 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, argon was replaced three times again, and the reaction was carried out at 85° C. for 16 hours under argon atmosphere. 50 mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL*2), and the organic phase was washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrated organic phase was purified by column purification (petroleum ether: ethyl acetate = 100: 0-0: 1) to obtain compound 014-3. LCMS: MS m / z (ESI) = 260.1 [M+H] + .

[0445] Step 3: Synthesis of trifluoroacetate salt of compound 014-4

[0446] Compound 014-3 (1 g, 3.86 mmol) was added to trifluoroacetic acid (5 mL), reacted at 20°C for 3 hours, and the reaction solution was concentrated under reduced pressure to obtain the trifluoroacetate salt of compound 014-4. LCMS: MS m / z (ESI) = 204.2 [M+H] + .

[0447] Step 4: Synthesis of Compound 014-5A and Compound 014-5B

[0448] Compound 014-4 (2.5 g, 7.88 mmol, trifluoroacetate) was added to anhydrous tetrahydrofuran (30 mL), cooled to 10°C, lithium aluminum hydride (897.14 mg, 23.64 mmol) was added, and the mixture was reacted at 20°C for 2 hours. 1 mL of water was added to the reaction solution to quench the reaction, and then 1 mL of 15% sodium hydroxide solution and 3 mL of water were added, stirred for 5 minutes, 5 g of sodium sulfate solid was added, stirred for 30 minutes, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was separated and purified by HPLC (chromatographic column: Phenomenexluna C18 250*50mm*10μm; mobile phase A: water (0.05% hydrochloric acid); mobile phase B: acetonitrile; running gradient: B%=1%-30%; running time: 10min), and the racemate was separated and purified by supercritical liquid chromatography (SFC) (chromatographic column: Phenomenex-Cellulose-2 (250mm*30mm, 5μm); flowability: A (supercritical CO 2) and B (ethanol containing 0.1% ammonia water); gradient: B% = 35%-35%, running 9min) to give compound 14-5A and compound 14-5B.

[0449] The analytical characterization of compound 14-5A is as follows:

[0450] SFC analysis method (column: Lux Cellulose-2, 100×4.6 mm ID, 3 μm; mobile phase: A (supercritical CO 2 ), B: (ethanol, containing 0.1% isopropylamine); gradient: B% = 40-60%, 3min; flow rate: 4.0mL / min; wavelength: 220nm; pressure: 1800psi, Rt = 1.118min, 99.44%ee. LCMS: MS m / z (ESI) = 190.2 [M+H] + .

[0451] The analytical characterization of compound 14-5B is as follows:

[0452] SFC analysis method (column: Lux Cellulose-2, 100×4.6 mm ID, 3 μm; mobile phase: A (supercritical CO 2 ), B: (ethanol, containing 0.1% isopropylamine); gradient: B% = 40-60%, 3min; flow rate: 4.0mL / min; wavelength: 220nm; pressure: 1800psi, Rt = 2.285min, 100%ee. LCMS: MS m / z (ESI) = 190.2 [M+H] + .

[0453] Step 5: Synthesis of Compound 014-6

[0454] Compound 002-2 (0.2 g, 395.43 gmol) was added to anhydrous tetrahydrofuran (1.0 mL) and N, N-dimethylformamide (1.0 mL), and 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, and the mixture was reacted at 30°C for 20 hours. The mixture was combined with compound 002-2 (30 mg batch), and the reaction solution was added to 10 mL of methyl tert-butyl ether, washed with saturated ammonium chloride (20 mL*2), and the aqueous phase was further extracted with 10 mL of methyl tert-butyl ether, and the organic phases were combined, washed with saturated brine (20 mL*2), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 100: 0-1: 4) to obtain compound 014-6. LCMS: MS m / z (ESI) = 658.1 [M+H] + .

[0455] Step 6: Synthesis of Compound 014-7

[0456] 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), and nitrogen was replaced three times. [(di(1-adamantyl)-n-butylphosphine)-2-(2-aminobiphenyl)]palladium (II) chloride (30.46 mg, 45.55 μmol) was added under nitrogen protection, and the mixture was reacted at 90°C for 8 hours. 10 mL of water was added to the reaction solution for washing, and the mixture was extracted with ethyl acetate (5 mL*2). The organic phases were combined, washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1:0-0:1) to obtain compound 014-7. LCMS: MS m / z(ESI)=1083.3[M+H] + . 1 H NMR (400 MHz, CDCl 3)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), 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).

[0457] Step 7: Synthesis of Compound 014-8

[0458] Compound 014-7 (0.15 g, 138.45 μmol) was added to trifluoroacetic acid (2 mL), and the temperature was raised to 70°C for reaction for 1 hour. After the reaction solution was concentrated, it was diluted with 5 mL of ethyl acetate, washed with 10 mL of water, washed with 10 mL of saturated sodium bicarbonate solution, and then washed with 20 mL of 1M hydrochloric acid solution. The aqueous phase was further extracted with 10 mL of ethyl acetate, the organic phase was discarded, the aqueous phase was collected, the pH was slowly adjusted to 9 with sodium carbonate solid, extracted with ethyl acetate (10 mL*2), the organic phases were combined, washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 014-8. LCMS: MS m / z (ESI) = 801.5 [M+H] + .

[0459] Step 8: Synthesis of Compound 014A and Compound 014B

[0460] 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, and the reaction was continued at 60°C for 15 hours. The reaction solution was diluted with 5 mL of ethyl acetate, washed with 10 mL of water, and the aqueous phase was further extracted with 5 mL of ethyl acetate. The organic phases were combined, washed with saturated brine (10 mL*2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by high performance liquid chromatography (chromatographic column: Phenomenex Luna C18 75*30mm*3μm; mobile phase A: water (0.05% hydrochloric acid); mobile phase B: acetonitrile; running gradient: B%=13%-43%; running time: 8min) and ammonia was added to adjust the pH to 7, and then separated and purified by supercritical liquid chromatography (SFC) chromatographic column: DAICEL CHIRALCEL AD (250mm*30mm, 10μm); flowability: A (supercritical CO 2 ) and B (ethanol containing 0.1% ammonia water); gradient: B% = 50%-50%, running time 15 min) to give compound 014A and compound 014B.

[0461] The analytical characterization of compound 014A is as follows:

[0462] SFC analysis method (column: Chiralpak AD-3, 50×4.6 mm ID, 3 μm; mobile phase: A (supercritical CO 2 ), B: (ethanol, containing 0.1% isopropylamine); gradient: B% = 5-50%, 3min; flow rate: 3.4mL / min; wavelength: 220nm: pressure: 1800psi, Rt = 1.533min, 100%ee. LCMS: MSm / z(ESI) = 645.2[M+H] + . 1 H NMR (400 MHz, CD 3OD)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), 4.53-4.46(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).

[0463] The analytical characterization of compound 014B is as follows:

[0464] SFC analysis method (column: Chiralpak AD-3, 50×4.6 mm ID, 3 μm; mobile phase: A (supercritical CO 2 ), B: (ethanol, containing 0.1% isopropylamine); gradient: B% = 5-50%, 3min; flow rate: 3.4mL / min; wavelength: 220nm; pressure: 1800psi, Rt = 1.794min, 100%ee. LCMS: MSm / z(ESI) = 645.2[M+H] + . 1 H NMR (400 MHz, CD 3 OD)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), 4.40-4.24( 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, 1H), 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).

[0465] Embodiment 15

[0466]

[0467] Step 1: Synthesis of Compound 015-2

[0468] 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 temperature was raised to 80°C, and a solution of compound 015-1 (10 g, 42.02 mmol) in ethanol (100 mL) was slowly added, the mixture was reacted for 0.5 hours, and the mixture was combined with compound 015-1 (1 g batch), 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, and the mixture was washed with 100 mL of saturated sodium bicarbonate and then 200 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 015-2. LCMS: MS m / z (ESI) = 249.0 [M+42] + .

[0469] Step 2: Synthesis of Compound 015-3

[0470] Compound trichloroaldehyde 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), and 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, and the mixture was reacted at 70° C. for 20 hours. The mixture was combined with compound 015-2 (1 g batch), the reaction solution 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 (400 MHz, CD 3 OD) δ = 8.01-7.97 (m, 1H), 7.61 (s, 1H), 7.24-7.19 (m, 1H).

[0471] Step 3: Synthesis of Compound 015-4

[0472] Compound 015-3 (7 g, 25.09 mmol) was added to concentrated sulfuric acid (35 mL), reacted at 90°C for 1 hour, the reaction solution was added to 100 mL of ice water, extracted with ethyl acetate (50 mL*2), the organic phases were combined, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 015-4.

[0473] Step 4: Synthesis of Compound 015-5

[0474] Compound 015-4 (6.7 g, 25.57 mmol) was added to sodium hydroxide (2M, 115.07 mL), and hydrogen peroxide (11.50 g, 101.44 mmol, 9.75 mL, 30% content) was added, and the mixture was reacted at 18°C ​​for 1 hour. The mixture was combined with compound 015-4 (0.5 g batch), and the reaction solution was added to 100 mL of sodium thiosulfate solution, and impurities were removed by extraction with 50 mL of ethyl acetate. The aqueous phase was collected, and the pH was adjusted to 6 with 1 M hydrochloric acid. After the starch-KI test paper test showed negative, the pH was further adjusted to 3 with hydrochloric acid, and the solid was precipitated. The solid was extracted with ethyl acetate (50 mL*2), and the organic phases were combined, washed with 150 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 015-5. LCMS: MS m / z (ESI) = 251.9 [M+H] + . 1 H NMR (400 MHz, CD 3 OD)δ=6.54 (dd, J=5.2, 10.4Hz, 1H).

[0475] Step 5: Synthesis of Compound 015-6

[0476] Compound 015-5 (2.5 g, 9.92 mmol) was added to N, N-dimethylformamide (20 mL), and 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 (7M, 1.98 mL) were added, and the mixture was reacted at 18°C ​​for 20 hours. The mixture was heated to 30°C and reacted for 4 hours. 40 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL*3). The organic phases were combined, washed with saturated brine (50 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 015-6. LCMS: MS m / z (ESI) = 250.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ=8.28-8.05(m, 2H), 7.20-7.09(m, 1H), 6.78(s, 2H).

[0477] Step 6: Synthesis of Compound 015-7

[0478] 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]undecane-7-ene (2.43 g, 15.93 mmol, 2.40 mL) were added, and 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), the organic phase was discarded, the aqueous phase was adjusted to pH 2-3 with 1 M hydrochloric acid solution, the solid was precipitated, filtered, the filter cake was rinsed with water (5 mL*2), and the filter cake was dried under reduced pressure to obtain compound 015-7. LCMS: MSm / z(ESI)=276.9[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ=11.75-11.40(m, 2H), 7.50-7.35(m, 1H).

[0479] Step 7: Synthesis of Compound 015-8

[0480] Compound 015-7 (1.5 g, 5.41 mmol) was added to phosphorus oxychloride (15 mL), and N, N-diisopropylethylamine (3.50 g, 27.07 mmol, 4.72 mL) was added, and the mixture was reacted at 100° C. for 2 hours. The reaction solution was concentrated, and the concentrated product was diluted with 30 mL of ethyl acetate, and then slowly added to 50 mL of glacial sodium bicarbonate solution, and the liquids were separated and extracted. The aqueous phase was further extracted with 20 mL of ethyl acetate, and the organic phases were combined, and the organic phases were washed with 50 mL of saturated ammonium chloride and 50 mL of saturated brine in sequence, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 015-8.

[0481] Step 8: Synthesis of Compound 015-9

[0482] Compound 015-8 (0.5 g, 1.59 mmol) was added to anhydrous dichloromethane (5 mL), and compound 003-1D (368.41 mg, 1.75 mmol) and triethylamine (322.35 mg, 3.19 mmol, 443.40 μL) were added, and the mixture was reacted at 18°C ​​for 2 hours. The reaction solution was washed with saturated ammonium chloride (20 mL*2), washed with 20 mL saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 100: 0-1: 1) to obtain compound 015-9. LCMS: MSm / z (ESI) = 487.0 [M+H] + . 1 H NMR (400 MHz, CDCl 3)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).

[0483] Step 9: Synthesis of Compound 015-10

[0484] Compound 015-9 (0.48 g, 984.16 μmol) was added to anhydrous tetrahydrofuran (2.5 mL) and N, N-dimethylformamide (2.5 mL), and 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, and the mixture was reacted at 20°C for 20 hours. The reaction solution was added to 10 mL of methyl tert-butyl ether, washed with saturated ammonium chloride (20 mL*2), and the aqueous phase was further 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, filtered, and concentrated to obtain compound 015-10. LCMS: MSm / z(ESI)=610.2[M+H] + . 1 H NMR (400 MHz, CDCl 3 )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, 21), 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, 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).

[0485] Step 10: Synthesis of Compound 015-11

[0486] 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), and the mixture was replaced with nitrogen three times. [(di(1-adamantyl)-n-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) chloride (54.76 mg, 81.90 μmol) was added under nitrogen protection, and the mixture was reacted at 90° C. for 3 hours. 10 mL of water was added to the reaction solution for washing, and the mixture was separated and extracted with ethyl acetate (5 mL*2). The organic phases were combined and washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1:0-0:1) to obtain compound 015-11. LCMS: MS m / z(ESI)=1035.3[M+H] + . 1 H NMR (400 MHz, CDCl 3 )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).

[0487] Step 11: Synthesis of the hydrochloride salt of compound 015-12

[0488] Compound 015-11 (0.2 g, 193.18 μmol) was added to hydrogen chloride / methanol (4 mL, 4 M), reacted at 18°C ​​for 1 hour, the reaction solution was directly concentrated, the crude product was added to 5 mL of ethyl acetate and stirred for 2 hours, filtered, the filter cake was rinsed with ethyl acetate (2 mL*2), and concentrated under reduced pressure to obtain the hydrochloride of compound 015-12. LCMS: MS m / z (ESI) = 771.3 [M+H] + .

[0489] Step 12: Synthesis of Compound 015

[0490] Compound 015-12 (0.1 g, hydrochloride) was added to N,N-dimethylformamide (2 mL), and potassium carbonate (85.59 mg, 619.25 μmol) and cesium fluoride (37.63 mg, 247.70 μmol, 9.13 μL) were added. The reaction was continued at 60°C for 5 hours, and the mixture was combined with compound 015-12 (50 mg batch). The reaction solution was diluted with 5 mL of ethyl acetate, washed with 10 mL of water, and the aqueous phase was further extracted with 5 mL of ethyl acetate. The organic phases were combined and washed with saturated brine (10 mL*2), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by high performance liquid preparative chromatography (chromatographic column: Phenomenex luna C18 150*40mm*10μm; mobile phase A: water (10mM ammonium bicarbonate); mobile phase B: acetonitrile; running gradient B%=50%-80%; running time: 8min) to obtain compound 015. LCMS: MSm / z(ESI)=615.2[M+H] + . 1 H NMR (400 MHz, CD 3 OD) 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).

[0491] Example 16

[0492]

[0493]

[0494] Step 1: Synthesis of Compound 016-5

[0495] Compound 016-4 (15 g) was purified by supercritical fluid chromatography (column: ChiralPak IH, 250*50 mm, 10 μm; mobile phase: A (supercritical CO 2), B: [0.1% ammonia-ethanol]; B%: 20%-20%,), to obtain compound 016-5. SFC analysis method (column: Chiralpak IH-3, 100×4.6mm 1.D., 3μm; mobile phase: A (supercritical CO 2 ) 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 value is 98.82%. 1 H NMR (400 MHz, CDCl 3 )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).

[0496] Step 2: Synthesis of Compound 016-1A

[0497] Lithium aluminum tetrahydride (1.55 g, 40.15 mmol, 98% purity) was dissolved in anhydrous tetrahydrofuran (30 mL), cooled to 0°C, and a solution of compound 016-5 (2.8 g, 13.38 mmol) in anhydrous tetrahydrofuran (2 mL) was added under nitrogen protection. The temperature was raised to 70°C and reacted for 1 hour. After the reaction, 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, the filter cake was washed with 10 mL of tetrahydrofuran, and the filtrate was concentrated to obtain compound 016-1A. 1 HNMR (400 MHz, CDCl 3 )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).

[0498] Step 3: Synthesis of Compound 016-1

[0499] Compound 002-2 (0.6 g, 1.19 mmol) was added to anhydrous tetrahydrofuran (3 mL) and N, N-dimethylformamide (3 mL), and 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, and the mixture was reacted for 16 hours at 25°C. The reaction solution was added to 10 mL of methyl tert-butyl ether, washed with 20 mL of water, and the aqueous phase was further extracted with 10 mL of methyl tert-butyl ether. The organic phases were combined, washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 100: 0-1: 4) to obtain compound 016-1. MS m / z (ESI) = 622.2 [M+H] + Step 4: Synthesis of Compound 016-2

[0500] 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 mixed solution of toluene (5 mL) and water (1 mL), and the mixture was replaced with nitrogen three times. [(di(1-adamantyl)-n-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) chloride (90.22 mg, 134.93 μmol) was added under nitrogen protection, and the temperature was raised to 90° C. for reaction for 3 hours. 10 mL of water was added to the reaction solution for washing, and the mixture was extracted with ethyl acetate (5 mL x 2). The organic phases were combined, washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1:0-0:1) to obtain compound 016-2. MS m / z (ESI) = 1047.3 [M+H] + .

[0501] Step 5: Synthesis of Compound 016-3

[0502] Compound 016-2 (250.00 mg, 238.69 μmol) was added to trifluoroacetic acid (2 mL), and the temperature was raised to 70 ° C for 0.5 hours. After the reaction solution was concentrated, it was diluted with 5 mL of ethyl acetate, washed with 10 mL of water, washed with 10 mL of saturated sodium bicarbonate solution, the organic phase was washed with 1M hydrochloric acid solution (8 mL x 2), and the aqueous phase was further extracted with 10 mL of ethyl acetate, the organic phase was discarded, the aqueous phase was collected, the pH was slowly adjusted to 9 with sodium carbonate solid, extracted with ethyl acetate (10 mL x 2), the organic phases were combined, washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 016-3. MSm / z(ESI)=765.3[M+H] + .

[0503] Step 6: Synthesis of Compound 016A and Compound 016B

[0504] 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, and stirred at 60°C for 5 hours. Filtered, separated by HPLC (column: Phenomenex luna C18 80*40mm*3μm; mobile phase: [water (0.05% hydrogen chloride)-acetonitrile]; acetonitrile%: 10%-45%, 7 min). The separated liquid was added with saturated sodium bicarbonate solution (5 mL), concentrated, acetonitrile was removed, ethyl acetate (5 mL x 3) was added for extraction, the organic phases were combined and concentrated to obtain a crude product, which was separated and purified by supercritical liquid chromatography (SFC) (column: DAICEL CHIRALPAK IG (250 mm*30 mm, 10 μm); mobile phase: A (supercritical CO 2 ), mobile phase: B [0.1% ammonia water-ethanol]; B%: 50%-50%, 16 min) to obtain compounds 016A and 016B.

[0505] 016A analysis and characterization are as follows:

[0506] LCMS: m / z (ESI) = 609.3 [M+H] + .

[0507] 016B is analyzed and characterized as follows:

[0508] SFC analysis method (column: Chiralpak IG-3, 50×4.6 mm ID, 3 μm; mobile phase: A (supercritical CO 2) and B (EtOH, containing 0.1% isopropylamine); gradient: B% = 50-40%, running 3min; flow rate: 4.0mL / min; wavelength: 220nm; pressure: 1800psi), Rt = 1.25min, ee value is 98.2%. LCMS: m / z (ESI) = 609.3 [M+H] + . 1 H NMR (400 MHz, CDCl 3 )δppm 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).

[0509] Embodiment 17

[0510]

[0511]

[0512]

[0513] Step 1: Synthesis of compound 017-5

[0514] Compound 017-4 (1.0 g, 4.11 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL), and the temperature was lowered to 0°C under nitrogen protection. Dibromodifluoromethane (1.90 g, 9.04 mmol, 835.93 μL) was slowly added dropwise to the reaction solution, and then hexamethyltriaminophosphine (2.95 g, 18.09 mmol, 3.29 mL) was slowly added dropwise to the reaction solution, and the temperature was naturally raised to 25°C and stirred for 14 hours. The reaction solution was cooled to room temperature, and the reaction solution was filtered, and water (10 mL) was added to the filtrate, and ethyl acetate (5 mL) was added for liquid extraction, washed with saturated brine (5 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 1 / 1) to obtain compound 017-5. 1 H NMR (400 MHz, CDCl 3)δppm 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).

[0515] Step 2: Synthesis of Compound 017-6

[0516] Compound 017-5 (2g, 7.21mmol) was dissolved in anhydrous tetrahydrofuran (20mL), nitrogen was protected, the temperature was lowered to -60°C, lithium hexamethyldisilazide (1M, 7.93mL) was added, stirred for 10min, 1-chloro-3-iodopropane (2.21g, 10.82mmol, 1.16mL) was added dropwise to the reaction solution, naturally warmed to room temperature (30°C), and stirred for 10 hours. The reaction solution was filtered, water (10mL) was added, ethyl acetate (5mL) was used for liquid extraction, saturated brine (5mL x 2) was washed, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to obtain compound 017-6. 1 H NMR (400 MHz, CDCl 3 )δppm 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).

[0517] Step 3: Synthesis of the hydrochloride salt of compound 017-7

[0518] Compound 017-6 (20 g, 56.53 mmol) was dissolved in hydrochloric acid / ethyl acetate (4 M, 120 mL) and reacted at 25°C for 2 hours. The reaction solution was concentrated to obtain the hydrochloride of compound 017-7, which was used directly in the next step.

[0519] Step 4: Synthesis of Compound 017-8

[0520] Compound 017-7 (20 g, 56.5 mmol, hydrochloride) was dissolved in N, N-dimethylformamide (65 mL), and potassium carbonate (14.2 g, 102 mmol) was added. The reaction mixture was reacted at 25°C for 12 hours. The reaction solution was diluted with 500 mL of ethyl acetate, washed with water (300 mL x 2), washed with 300 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to obtain 017-8.

[0521] Step 5: Synthesis of Compound 017-9

[0522] Compound 017-8 (1.5 g, 6.91 mmol) was added to anhydrous tetrahydrofuran (15 mL), cooled to 0°C, replaced with nitrogen three times, and red aluminum toluene solution (3.5 M, 7.89 mL) was added dropwise under nitrogen atmosphere, and the temperature was slowly raised to 25°C for reaction for 16 hours. The temperature was lowered to 0°C, 10 mL of ethyl acetate was slowly added to the reaction solution, and then 1 mL of water, 1 mL of 15% sodium hydroxide solution, 3 mL of water, and solid sodium sulfate were added, stirred for 1 hr, filtered, and the filter cake was further dispersed in 20 mL of ethyl acetate, stirred for 0.5 hr, filtered, and repeated twice until there was no product in the filtrate, and the filtrate was concentrated to obtain a mixture 017-9.

[0523] Step 6: Synthesis of Compound 017-10

[0524] Compound 017-9 (2 g, 11.68 mmol) was added to anhydrous dichloromethane (20 mL), cooled to 0°C, imidazole (1.19 g, 17.52 mmol) and tert-butyldiphenylsilyl chloride (3.85 g, 14.02 mmol, 3.60 mL) were added, and reacted at 25°C for 1 hour. The reaction solution was washed with 20 mL of water, 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 100: 0-10: 1) to obtain compound 017-10. LCMS: m / z (ESI) = 410.2 [M+H] + .

[0525] Step 7: Synthesis of Compound 017-11B and Compound 017-11A

[0526] Compound 017-10 (0.6 g) was separated and purified by supercritical fluid chromatography (SFC) (column: DAICELCHIRALCEL OZ 250*25 mm ID 10 μm; mobile phase: A (supercritical CO 2 ), mobile phase: B [0.1% ammonia water-methanol]; B%: 30%-30%) to obtain compounds 017-11A and 017-11B.

[0527] 017-11A is analyzed and characterized as follows:

[0528] SFC analysis method (column: Lux Cellulose-2, 100×4.6 mm ID, 3 μm; mobile phase: A (supercritical CO 2) and B (MeOH, containing 0.1% isopropylamine); gradient: B% = 10-50%, running 4min; flow rate: 3.4mL / min; wavelength: 220nm; pressure: 2000psi), Rt = 1.546min, ee value is 96.74%. 1 H NMR (400 MHz, CDCl 3 )δppm 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).

[0529] 017-11B is analyzed and characterized as follows:

[0530] SFC analysis method (column: Lux Cellulose-2, 100×4.6 mm ID, 3 μm; mobile phase: A (supercritical CO 2 ) and B (MeOH, containing 0.1% isopropylamine); gradient: B% = 10-50%, running 4min; flow rate: 3.4mL / min; wavelength: 220nm; pressure: 2000psi), Rt = 1.865min, ee value is 99.83%. 1 H NMR (400 MHz, CDCl 3 )δppm 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).

[0531] Step 8: Synthesis of the hydrochloride salt of compound 017-1A

[0532] Compound 017-11B (1.2 g, 2.93 mmol) was dissolved in 24 mL of 1,4-dioxane, and concentrated hydrochloric acid (12 M, 7.20 mL) was added, and the mixture was reacted at 95°C for 12 hours. After the reaction solution was cooled, it was diluted with 10 mL of water and washed with 10 mL of ethyl acetate to obtain the hydrochloride of compound 017-1A. 1H NMR (400 MHz, D 2 O) δppm6.53-6.90 (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).

[0533] Step 9: Synthesis of Compound 017-1

[0534] Compound 002-2 (500 mg, 988.56 μmol), N,N-dimethylformamide (5 mL), compound 017-1A (220.03 mg, 1.29 mmol, hydrochloride), anhydrous tetrahydrofuran (5 mL), triethylenediamine (33.27 mg, 296.57 μmol, 32.61 μL), anhydrous cesium carbonate (966.28 mg, 2.97 mmol), 4A molecular sieve (100 mg) were added to a pre-dried reaction bottle, stirred at 25 ° C for 16 hours, then heated to 45 ° C and stirred for 24 hours. Cooled to room temperature, then filtered, 20 mL of ethyl acetate was used to rinse the filter cake, washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (added with 0.5% triethylamine) = 100: 0 to 70: 30) to obtain compound 017-1. LCMS m / z = 640.1 [M+H] + .

[0535] Step 10: Synthesis of Compound 017-2

[0536] 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), water (0.7 mL) were added to a pre-dried reaction bottle, and nitrogen was replaced three times before adding chloro[(n-butyldi(1-adamantyl)phosphine)-2-(2-aminobiphenyl)]palladium(II) (14.61 mg, 21.86 μmol), and the temperature was raised to 105° C. and stirred for 10 hours. The reaction solution was filtered and then concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (0.5% triethylamine added) = 100: 0-70: 30), then dissolved with 20 mL of ethyl acetate, extracted with 2N hydrochloric acid (15 mL x 2), the aqueous phase was extracted once with 20 mL of methyl tert-butyl ether, then sodium carbonate solid was added to adjust the aqueous phase to pH about 8, extracted with ethyl acetate (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 017-2. LCMS m / z = 901.3 [M+H] + .

[0537] Step 11: Synthesis of trifluoroacetate salt of compound 017-3

[0538] 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 bottle and stirred at 70°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the trifluoroacetate salt of compound 017-3. LCMS m / z=783.3 [M+H] + .

[0539] Step 12: Synthesis of Compound 017A and Compound 017B

[0540] Compound 017-3 (02 g, 222.96 μmol, trifluoroacetate), N,N-dimethylformamide (0.5 mL), anhydrous potassium carbonate (308.16 mg, 2.23 mmol), cesium fluoride (169.34 mg, 1.11 mmol, 41.10 μL) were added to a pre-dried reaction bottle and stirred at 65°C for 12 hours. The mixture was cooled to room temperature, and then the reaction solution was filtered, the filter cake was washed with 20 mL of ethyl acetate, and then washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was separated by high performance liquid chromatography (chromatographic column: Phenomenex luna C18 OBD 80*40mm*3μm; mobile phase A: water (0.05% hydrochloric acid), mobile phase B: acetonitrile; running gradient: B%: 5%-30%, running 7min) and ammonia was added to adjust the pH to 7, and then purified by supercritical liquid chromatography (column: DAICEL CHIRALPAK IG (250mm*30mm, 10μm); mobile phase: A (supercritical CO 2 ), mobile phase B: [0.1% ammonia water-ethanol]; B%: 50%-50%, 13 min), to obtain compounds 017A and 017B.

[0541] The analysis and characterization of compound 017A are as follows:

[0542] SFC analysis method (column: Chiralpak IC-3, 3 μm, 50×4.6 mm ID; mobile phase: A (supercritical CO 2 ) 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 value is 100%. LCMS m / z = 627.2 [M+H] + .

[0543] The analysis and characterization of compound 017B are as follows:

[0544] SFC analysis method (column: Chiralpak IC-3, 3 μm, 50×4.6 mm ID; mobile phase: A (supercritical CO 2 ) 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 = 2.128 min, ee value is 98.10%. LCMS m / z = 627.2 [M+H] + . 1 H NMR (400 MHz, CD3 OD)δppm 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).

[0545] Embodiment 18

[0546]

[0547]

[0548] Step 1: Synthesis of Compound 004-1B

[0549] Compound 001-1 (3.95 g, 11.96 mmol, 1 eq) and compound 010-16A (2.54 g, 11.96 mmol, 1 eq) were dissolved in N, N-dimethylformamide (100 mL), and diisopropylethylamine (3.87 g, 29.91 mmol, 5.21 mL, 2.5 eq) was added, and the mixture was reacted at 20°C for 16 hours. 200 mL of water was added, and the mixture was extracted with ethyl acetate 3 times, 100 mL each time. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was dried to obtain a crude product. The crude product was separated by silica gel column (petroleum ether: ethyl acetate = 20: 1-10: 1-5: 1) to obtain compound 004-1B. LCMS: (ESI) m / z: 506.8 [M+H] + .

[0550] Step 2: Synthesis of compound 011-1A

[0551] Compound 004-1B (1.5 g, 2.96 mmol, 1 eq) was dissolved in tetrahydrofuran (6 mL) and N, N-dimethylformamide (6 mL). 001-4A (707.64 mg, 4.44 mmol, 1.5 eq), cesium carbonate (2.90 g, 8.89 mmol, 3 eq) and triethylenediamine (33.24 mg, 296.33 μmol, 32.59 μL, 0.1 eq) were added in sequence under nitrogen protection. After the addition, the mixture was reacted at 20°C for 16 hours. Water was added to the reaction solution, extracted with ethyl acetate (10 mL*3), washed with water, and the organic phase was concentrated and dried to obtain a 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] + .

[0552] Step 3: Synthesis of Compound 001-5C

[0553] Compound 001-5B (2 g, 5.58 mmol, 1 eq), dichloromethane (40 mL), N,N-diisopropylethylamine (4.33 g, 33.47 mmol, 5.83 mL, 6 eq) were added to a pre-dried reaction bottle, and trifluoromethanesulfonic anhydride (6.30 g, 22.31 mmol, 3.68 mL, 4 eq) was added at 0°C. The mixture was stirred at 0°C for 1 hr. After the reaction, water (5 mL) was added, and the mixture was extracted with dichloromethane (5 mL x 4). The combined organic phases were washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (gradient elution: petroleum ether: ethyl acetate = 10: 1) to obtain compound 001-5C.

[0554] Step 4: Synthesis of Compound 001-5D

[0555] Compound 001-5C (3.2 g, 5.14 mmol, 1 eq), diphenylimine (1.86 g, 10.28 mmol, 1.72 mL, 2 eq), anhydrous toluene (64 mL), cesium carbonate (5.02 g, 15.42 mmol, 3 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (594.75 mg, 1.03 mmol, 0.2 eq) were added to the reaction flask. Under nitrogen protection, tris(dibenzylideneacetone)dipalladium (470.62 mg, 513.94 μmol, 0.1 eq) was added, and the mixture was stirred at 100° C. for 2 hr. After the reaction was completed, the reaction solution 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 obtain compound 001-5D. LCMS: (ESI) m / z = 654.2 [M+H] + . 1H NMR (400 MHz, CDCl 3 )δppm 7.83~7.78(m, 5H), 7.60~7.49(m, 9H), 1.20~1.16(m, 21H).

[0556] Step 5: Synthesis of Compound 001-5A

[0557] Compound 001-5D (2.4 g, 3.67 mmol, 1 eq), bis-pinacol borate (1.86 g, 7.34 mmol, 2 eq), potassium acetate (1.08 g, 11.01 mmol, 3 eq) were dissolved in anhydrous toluene (48 mL), and 1,1′-bisdiphenylphosphinoferrocenepalladium dichloride (537.20 mg, 734.17 μmol, 0.2 eq) was added, and nitrogen was protected, and stirred at 130° C. for 12 hours. After the reaction was completed, 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) δppm 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).

[0558] Step 6: Synthesis of Compound 018-2

[0559] Compound 011-1A (0.15 g, 238.50 μmol, 1 eq) and 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), and the atmosphere was replaced with nitrogen three times. [(di(1-adamantyl)-n-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) chloride (15.9 5mg, 23.85μmol, 0.1eq), nitrogen replacement three times, 100℃ reaction for 1.5 hours, after the reaction, cool to room temperature and add 20mL of ethyl acetate and 10mL of water to the reaction solution, stand and separate, extract the aqueous phase with 10mL of ethyl acetate once, combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate, separate and purify by silica gel column chromatography (gradient elution: petroleum ether: ethyl acetate = 100: 0 to 60: 40, ethyl acetate is added with 0.5% triethylamine) to obtain compound 018-2. LCMS: (ESI) m / z = 1053.6 [M+H] + . 1 H NMR (400 MHz, CD 3 OD)δppm 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).

[0560] Step 7: Synthesis of Compound 018-3

[0561] Compound 018-2 (0.15 g, 142.35 μmol, 1 eq) was added with hydrogen chloride / methanol (4 M, 4 mL, 112.40 eq) and reacted at 15°C for 2 hours. After the reaction, the reaction solution was concentrated to dryness under reduced pressure, and then 4 mL of ethyl acetate was added to the residue for pulping and purification overnight, filtered, and the filter cake was collected and dried in vacuo to obtain compound 018-3. LCMS: (ESI) m / z=789.5 [M+H] + .

[0562] Step 8: Synthesis of Compound 018

[0563] Compound 018-3 (0.1 g, 115.96 μmol, 1 eq) was added to N, N-dimethylformamide (1 mL), potassium carbonate (256.42 mg, 1.86 mmol, 16 eq) and cesium fluoride (2.84 mg, 347.88 μmol, 3 eq) were added, and stirred at 65 °C for 3 hours. After the reaction was completed, the mixture was cooled to room temperature and then filtered. The filter cake was washed with 10 mL of ethyl acetate, and the mother liquor was then washed with saturated brine (20 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by HPLC. HPLC preparation method: Chromatographic column: Phenomenex Luna 80*30mm*3μm; mobile phase: [water (hydrochloric acid)-acetonitrile]; acetonitrile%: 1%-40%, 8min, add ammonia water to the obtained fraction to adjust the pH to 8, concentrate under reduced pressure to remove acetonitrile, then extract twice with 20mL ethyl acetate, dry over anhydrous sodium sulfate, filter, and concentrate to obtain product 018. Then SFC separation column: DAICEL CHIRALPAK IC (250mm*30mm, 10μm); mobile phase: [0.1% ammonia water-isopropanol]; isopropanol%: 60%-60%, 16min, concentrate under reduced pressure to remove the solvent, and obtain compound 018A and compound 018B.

[0564] The analysis and characterization of compound 018A are as follows:

[0565] SFC analysis method: Column: Chiralpak IC-3, 3 μm, 50×4.6 mm ID; Mobile phase: A (CO 2 ) and B (IPA, containing 0.1% isopropylamine); gradient: B% = 5-50%, 5min; flow rate: 4.0mL / min; wavelength: 220nm; pressure: 124.14bar, Rt = 1.13min, chiral isomer excess 100%. LCMS: (ESI) m / z = 633.3 [M+H] + . 1 H NMR (400 MHz, CD 3OD)δppm 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).

[0566] The analysis and characterization of compound 018B are as follows:

[0567] SFC analysis method: Column: Chiralpak IC-3, 3 μm, 50×4.6 mm ID; Mobile phase: A (CO 2 ) and B (IPA, containing 0.1% isopropylamine); gradient: B% = 5-50%, 5min; flow rate: 4.0mL / min; wavelength: 220nm; pressure: 124.14bar, Rt = 2.20min, chiral isomer excess 97.76%. LCMS: (ESI) m / z = 633.3 [M+H] + . 1 H NMR (400 MHz, CD 3 OD)δppm 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).

[0568] Embodiment 19

[0569]

[0570] Step 1: Synthesis of Compound 019-6

[0571] 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 and reacted at 200°C for 1.5 hours. After the reaction, the mixture 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 and dried. The mixture was slurried with 30 mL of water for 1 hour, filtered, and the filter cake was dried to obtain compound 019-6. 1 H NMR (400 MHz, DMSO-d 6 )δ=11.45-11.06(m, 2H), 7.67-7.56(m, 1H), 7.45-7.35(m, 1H).

[0572] Step 2: Synthesis of Compound 003-1

[0573] Compound 019-6 (2.5 g, 9.65 mmol, 1 eq) was added to phosphorus oxychloride (20 mL), and diisopropylethylenediamine (3.74 g, 28.95 mmol, 5.04 mL, 3 eq) was added, and the mixture was reacted at 100°C for 3 hours. After the reaction, the reaction solution was directly concentrated, and the concentrated product was slowly added to 20 mL of ice water, and extracted with 10 mL*2 of ethyl acetate. The organic phases were combined, washed with 20 mL of saturated ammonium chloride and saturated brine, respectively, and dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 003-1. 1 H NMR (400 MHz, DMSO-d 6 )δ=8.81-8.59(m,2H); LCMS: (ESI)m / z: 296.8[M+H] + .

[0574] Step 3: Synthesis of Compound 019-7

[0575] Compound 003-1 (1.5 g, 5.07 mmol, 1 eq) was added to anhydrous dichloromethane (20 mL), and 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, and the mixture was reacted at 20°C for 2 hours. After the reaction, the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 100: 0-1: 1) to obtain compound 019-7. 1 HNMR (400 MHz, DMSO-d 6)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] + .

[0576] Step 4: Synthesis of Compound 019-8

[0577] Compound 019-7 (0.7 g, 1.48 mmol, 1 eq) was added to N, N-dimethylformamide (7 mL) and anhydrous tetrahydrofuran (7 mL), and compound 001-4A (354.34 mg, 2.23 mmol, 1.5 eq), cesium carbonate (1.45 g, 4.45 mmol, 3 eq), triethylenediamine (16.64 mg, 148.38 μmol, 16.32 μL, 0.1 eq) were added, and the mixture was reacted at 20°C for 20 hours. After the reaction, 20 mL of water was added to the reaction solution, and the mixture was extracted with 10 mL*2 of ethyl acetate. The organic phases were combined, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (dichloromethane: methanol = 100: 0-10: 1) to obtain compound 019-8. 1 H NMR (400 MHz, CDCl 3 )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), 3.69-3.42(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] + .

[0578] Step 5: Synthesis of Compound 019-2

[0579] THF (10 mL) was added to compound 019-1 (0.27 g, 1.22 mmol, 1 eq) to dissolve, and di-tert-butyl dicarbonate (318.41 mg, 1.46 mmol, 335.16 μL, 1.2 eq) was slowly added. The mixture was reacted at 80° C. for 12 hr. After the reaction, the mixture was directly spin-dried and the crude product was purified by silica gel column (gradient elution: petroleum ether: ethyl acetate = 10: 1-5: 1) to obtain compound 019-2.

[0580] Step 6: Synthesis of Compound 019-3

[0581] Compound 019-2 (0.35 g, 1.09 mmol, 1 eq), pinacol diboron (413.78 mg, 1.63 mmol, 1.5 eq), 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride (79.48 mg, 108.63 μmol, 0.1 eq), and potassium acetate (159.92 mg, 1.63 mmol, 1.5 eq) were dissolved in 1,4-dioxane (10 mL) and reacted at 80° C. for 16 hours under nitrogen protection. After the reaction, the reaction was directly spin-dried and the crude product was purified by silica gel column (gradient elution: petroleum ether: ethyl acetate = 50:1-20:1) to obtain compound 019-3.

[0582] Step 7: Synthesis of Compound 019-4

[0583] Compound 019-3 (100 mg, 270.81 μmol, 1 eq), 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride (19.82 mg, 27.08 μmol, 0.1 eq), potassium carbonate (74.86 mg, 541.62 μmol, 2 eq), and compound 019-8 (160.99 mg, 270.81 μmol, 1 eq) were dissolved in 1,4-dioxane (2.5 mL) and water (0.5 mL) under nitrogen protection at 95° C. for 16 hr. After the reaction was completed, the mixture was directly spin-dried and the crude product was purified by silica gel column (gradient elution: petroleum ether: ethyl acetate = 50:1-20:1) to obtain compound 019-4.

[0584] Step 8: Synthesis of Compound 019

[0585] Compound 019-4 (49.93 mg, 65.97 μmol, 1 eq) was dissolved in 1,4-dioxane (2 mL), and hydrochloric acid (48.11 mg, 1.32 mmol, 47.17 μL, 20 eq) was added, and the mixture was reacted at 25° C. for 4 hr. After the reaction, the mixture was directly spin-dried to obtain the hydrochloride of compound 019. LCMS: (ESI) m / z=557.3 [M+H] + . 1 H NMR (400 MHz, CD3 OD)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).

[0586] Embodiment 20

[0587]

[0588] Step 1: Synthesis of Compound 020-2

[0589] Under nitrogen protection, compound 020-1 (5 g, 11.70 mmol, 1 eq), hexabutyltin (20.36 g, 35.10 mmol, 17.55 mL, 3 eq), tris(dibenzylideneacetone)dipalladium (1.07 g, 1.17 mmol, 0.1 eq, tricyclohexylphosphine (656.23 mg, 2.34 mmol, 758.64 μL, 0.2 eq), lithium chloride (2.48 g, 58.50 mmol, 1.20 mL, 5 eq), 1,4-dioxane (50 mL) were stirred at 110 ° C for 2 hours. After the reaction was completed, the reaction was dried by spin drying. The crude product was purified by silica gel column (gradient elution: petroleum ether: ethyl acetate = 100: 1) to obtain compound 020-2. LCMS: (ESI) m / z = 639.3 [M+H] + .

[0590] Step 2: Synthesis of Compound 020-3

[0591] Compound 004-1B (2.5 g, 4.94 mmol, 1 eq) was dissolved in N, N-dimethylacetamide (30 mL), and potassium fluoride (5.74 g, 98.78 mmol, 2.31 mL, 20 eq) was added, and the mixture was reacted at 120°C for 18 hours. After the reaction, water was added, and the mixture was extracted with 100 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and dried by spin drying. The crude product was purified by silica gel column (gradient elution: petroleum ether: ethyl acetate = 20: 1-10: 1) to obtain compound 020-3. LCMS: (ESI) m / z = 489.1 [M+H] + .

[0592] Step 3: Synthesis of Compound 020-4

[0593] Compound 020-3 (384.12 mg, 784.34 μmol, 1 eq), compound 020-2 (0.5 g, 784.34 μmol, 1 eq), tetrakis(triphenylphosphine)palladium (90.63 mg, 78.43 μmol, 0.1 eq), cuprous iodide (22.41 mg, 117.65 μmol, 0.15 eq) and lithium chloride (39.90 mg, 941.20 μmol, 19.28 μL, 1.2 eq) were dissolved in 1,4-dioxane (10 mL), and the mixture was reacted at 120° C. for 18 hours. After the reaction was completed, the mixture was directly spin-dried and the crude product was purified by silica gel column (gradient elution: petroleum ether: ethyl acetate = 20: 1-2: 1) to obtain compound 020-4. LCMS: (ESI) m / z = 757.3 [M+H] + .

[0594] Step 4: Synthesis of Compound 020-5

[0595] Compound 020-4 (0.1 g, 132.05 μmol, 1 eq) was dissolved in N, N-dimethylformamide (5 mL), and N-iodosuccinimide (44.57 mg, 198.08 μmol, 1.5 eq) was added, and the mixture was reacted at 25°C for 1 hour. After the reaction, water was added, and the mixture was extracted with 100 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and dried by spin drying. The crude product was purified by silica gel column (gradient elution: petroleum ether: ethyl acetate = 20: 1-5: 1) to obtain compound 020-5. LCMS: (ESI) m / z = 883.2 [M+H] + .

[0596] Step 5: Synthesis of Compound 020-6

[0597] Compound 020-5 (0.1 g, 113.23 μmol, 1 eq) was dissolved in N, N-dimethylformamide (2 mL), and cuprous iodide (64.69 mg, 339.69 μmol, 3 eq) and hexamethylphosphoramide (202.91 mg, 1.13 mmol, 198.93 μL, 10 eq) were added. Under nitrogen protection, methyl fluorosulfonyldifluoroacetate (217.53 mg, 1.13 mmol, 144.06 μL, 10 eq) was added, and the mixture was reacted at 90° C. for 2 hours. After the reaction, water was added, and the mixture was extracted with 100 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and spin-dried. The crude product was purified by silica gel column (gradient elution: petroleum ether: ethyl acetate = 20: 1-5: 1) to obtain compound 020-6.

[0598] Step 6: Synthesis of Compound 020-7

[0599] 001-4A (28.94 mg, 181.76 μmol, 3 eq) was dissolved in THF (2 mL), and sodium hydride (14.54 mg, 363.52 μmol, 60% content, 6 eq) was added at 0°C. After the addition, the temperature was raised to 25°C and stirred for 1 hour. Then 020-6 (0.05 g, 60.59 μmol, 1 eq) was added and stirred for 1 hour. After the reaction, methanol (0.5 mL) was added to quench the reaction. The solvent was concentrated to dryness, and the crude product was purified by silica gel column (gradient elution: petroleum ether: ethyl acetate = 50: 1-20: 1) to obtain compound 020-7.

[0600] Step 7: Synthesis of Compound 020

[0601] Compound 020-7 (0.05 g, 51.84 μmol, 1 eq) was dissolved in trifluoroacetic acid (2 mL), stirred at 50 °C for 5 hours, and dried by spin drying. The mixture was separated by preparative HPLC using a Welch Xtimate C18 100*40mm*3 μm column; flowability: [water (0.1% trifluoroacetic acid)-acetonitrile]; acetonitrile%: 7%-37%, 8 min, to obtain the trifluoroacetate salt of compound 020. LCMS: (ESI) m / z=624.3[M+H] + . 1 H NMR (400 MHz, CD 3 OD) δppm 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 (brs, 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).

[0602] Embodiment 21

[0603]

[0604] Step 1: Synthesis of Compound 021-1

[0605] Compound 019-7 (2 g, 4.24 mmol, 1 eq) was dissolved in N, N-dimethylacetamide (30 mL), and potassium fluoride (1.23 g, 21.20 mmol, 496.58 μL, 5 eq) was added, and the mixture was reacted at 120° C. for 24 hours. After the reaction, water was added, and the mixture was extracted with 100 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and spin-dried. The crude product was purified by silica gel column (gradient elution: petroleum ether: ethyl acetate = 20: 1-10: 1) to obtain compound 021-1. LCMS: (ESI) m / z = 455.0 [M+H] + .

[0606] Step 2: Synthesis of Compound 021-2

[0607] Compound 021-1 (220 mg, 483.20 μmol, 1 eq), compound 020-2 (308.03 mg, 483.20 μmol, 1 eq), tetrakis(triphenylphosphine)palladium (55.84 mg, 48.32 μmol, 0.1 eq), cuprous iodide (13.80 mg, 72.48 μmol, 0.15 eq) and lithium chloride (20.48 mg, 483.20 μmol, 9.90 μL, 1 eq) were dissolved in 1,4-dioxane (10 mL), and the mixture was reacted at 120° C. for 18 hours. After the reaction was completed, the mixture was directly spin-dried and the crude product was purified by silica gel column (gradient elution: petroleum ether: ethyl acetate = 20: 1-2: 1) to obtain compound 021-2. LCMS: (ESI) m / z = 723.3 [M+H] + .

[0608] Step 3: Synthesis of Compound 021-3

[0609] Compound 021-2 (200 mg, 276.69 μmol, 1 eq) was dissolved in N, N-dimethylformamide (5 mL), and N-iodosuccinimide (186.75 mg, 830.08 μmol, 3 eq) was added, and the mixture was reacted at 25°C for 5 hours. After the reaction, water was added, and the mixture was extracted with 100 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column (gradient elution: petroleum ether: ethyl acetate = 20: 1-5: 1) to obtain compound 021-3. LCMS: (ESI) m / z = 849.2 [M+H] + .

[0610] Step 4: Synthesis of Compound 021-4

[0611] Compound 021-3 (120 mg, 141.39 μmol, 1 eq) was dissolved in N, N-dimethylformamide (2 mL), and then cuprous iodide (53.86 mg, 282.78 μmol, 2 eq) and hexamethylphosphoric acid triamide (126.69 mg, 706.95 μmol, 124.20 μL, 5 eq) were added. Under nitrogen protection, methyl fluorosulfonyl difluoroacetate (135.81 mg, 706.95 μmol, 89.94 μL, 5 eq) was added, and the mixture was reacted at 80° C. for 18 hours. After the reaction, water was added, and the mixture was extracted with 100 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column (gradient elution: petroleum ether: ethyl acetate = 20: 1-5: 1) to obtain compound 021-4. LCMS: (ESI) m / z = 791.3 [M+H] + .

[0612] Step 5: Synthesis of Compound 021-5

[0613] Compound 021-4 (200 mg, 252.90 μmol, 1 eq) was dissolved in tetrahydrofuran (2 mL) and N,N-dimethylformamide (2 mL), and cesium carbonate (164.80 mg, 505.80 μmol, 2 eq) and triethylenediamine (14.18 mg, 126.45 μmol, 13.91 μL, 0.5 eq) were added, and finally 001-4A (80.52 mg, 505.80 μmol, 2 eq) was added, and the mixture was reacted at 25°C for 28 hours. After the reaction, water was added, and the mixture was extracted with 100 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column (gradient elution: petroleum ether: ethyl acetate = 50: 1-20: 1) to obtain compound 021-5. LCMS: (ESI) m / z = 930.7 [M+H] + .

[0614] Step 6: Synthesis of Compound 021

[0615] Compound 021-5 (100 mg, 107.53 μmol, 1 eq) was dissolved in trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL, 125.61 eq), and the mixture was reacted at 55°C for 4 hours. The mixture was separated by preparative HPLC (chromatographic column: Phenomenex C18 150*40mm*5 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile%: 5%-35%, 10 min) to obtain the hydrochloride of compound 021. LCMS: (ESI) m / z=590.5[M+H] + . 1 H NMR (400 MHz, CD 3OD) 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).

[0616] Embodiment 22

[0617]

[0618] Step 1: Synthesis of compound 010-12

[0619] Compound 010-11 (30 g, 144.23 mmol, 1 eq) and silver sulfate (44.97 g, 144.23 mmol, 24.44 mL, 1 eq) were dissolved in ethanol (300 mL), and iodine (40.27 g, 158.65 mmol, 31.96 mL, 1.1 eq) was added, and the mixture was stirred at 25°C for 2 hours. After the reaction was completed, the reaction solution was filtered, the filtrate was evaporated to dryness, and the crude product was purified by silica gel column (gradient elution: petroleum ether: ethyl acetate = 100: 1-20: 1) to obtain compound 010-12. 1 H NMR (400 MHz, CDCl 3 )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).

[0620] Step 2: Synthesis of Compound 010-13

[0621] In a carbon monoxide environment, at a pressure of 50 Psi and a temperature of 30° C., compound 010-12 (22 g, 65.89 mmol, 1 eq) and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane (5.38 g, 6.59 mmol, 0.1 eq) were dissolved in methanol (100 mL), stirred for 5 minutes, and then triethylamine (46.67 g, 461.22 mmol, 64.20 mL, 7 eq) was added, and stirring was continued for 24 hours. After the reaction was completed, the mixture was filtered, and the filtrate was evaporated to dryness. The crude product was purified by silica gel column (gradient elution: petroleum ether: ethyl acetate = 20: 1-5: 1) to obtain compound 010-13. LCMS: (ESI) m / z = 265.8 [M+H]+ .

[0622] Step 3: Synthesis of Compound 010-14

[0623] Compound 010-13 (15 g, 56.38 mmol, 1 eq) was dissolved in methanol (50 mL), and a solution of sodium hydroxide (9.02 g, 225.53 mmol, 4 eq) in water (50 mL) was added, and stirred at 25°C for 2 hours. After the reaction, the reaction solution was concentrated, and the pH was adjusted to 5 with 2 mol / L hydrochloric acid. A white solid precipitated, and compound 010-14 was obtained by suction filtration. LCMS: (ESI) m / z=251.8 [M+H] + .

[0624] Step 4: Synthesis of Compound 010-15

[0625] 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 and reacted at 200°C for 4 hours. The reaction solution was cooled to room temperature, slurried with 200 mL of water, and filtered to obtain compound 010-15. LCMS: (ESI) m / z=276.9 [M+H] + .

[0626] Step 5: Synthesis of Compound 002-1

[0627] At 0°C, N,N-diisopropylethylamine (11.66 g, 90.25 mmol, 15.72 mL, 5 eq) was added dropwise to phosphorus oxychloride (82.50 g, 538.05 mmol, 50 mL, 29.81 eq), and then compound 010-15 (5 g, 18.05 mmol, 1 eq) was added in batches. After the addition, the mixture was refluxed at 80°C for 20 hours, the phosphorus oxychloride was evaporated, and the crude product was purified by silica gel column (gradient elution: petroleum ether: ethyl acetate = 20: 1-10: 1) to obtain compound 002-1. LCMS: (ESI) rm / z = 312.9 [M+H] + .

[0628] Step 6: Synthesis of Compound 010-17

[0629] Compound 010-16A (1.2 g, 3.82 mmol, 1 eq) was dissolved in N, N-dimethylformamide (2 mL), and 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, and the mixture was stirred at 25°C for 2 hours. The reaction solution was poured into 50 mL of water, and a solid was precipitated. The solid was washed with water (3*20 mL) to obtain compound 010-17. LCMS: (ESI) m / z=489.0 [M+H] + .

[0630] Step 7: Synthesis of Compound 010-7A

[0631] Compound 010-17 (1.6 g, 3.27 mmol, 1 eq) was dissolved in N, N-dimethylformamide (10 mL) and THF (10 mL), and then cesium carbonate (3.19 g, 9.80 mmol, 3 eq), compound 001-4A (780.17 mg, 4.90 mmol, 1.5 eq), triethylenediamine (36.65 mg, 326.70 μmol, 35.93 μL, 0.1 eq) were added, and the mixture was stirred at 25°C for 18 hours. After the reaction, the mixture was extracted with 40 mL of ethyl acetate, washed with water, and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column (gradient elution: petroleum ether: ethyl acetate = 20: 1-10: 1) to obtain compound 010-7A. LCMS: (ESI) m / z = 612.2 [M+H] + .

[0632] Step 8: Synthesis of Compound 022-1

[0633] Compound 010-7A (0.2 g, 408.38 μmol, 1 eq) and compound 022-1A (127.47 mg, 408.38 μmol, 1 eq) were dissolved in 1,4-dioxane (2 mL) and water (2 mL), and 1,1′-bis(di-tert-butylphosphino)ferrocenedichloropalladium (26.62 mg, 40.84 μmol, 0.1 eq) and potassium phosphate (130.03 mg, 612.57 μmol, 1.5 eq) were added. The mixture was reacted at 90° C. for 18 hours under nitrogen protection. After the reaction, the reaction solution was dried by rotary evaporation, and the crude product was purified by silica gel column (gradient elution: petroleum ether: ethyl acetate = 20: 1-10: 1) to obtain compound 022-1. LCMS: (ESI) m / z = 800.3 [M+H] + .

[0634] Step 9: Synthesis of compound 022

[0635] Compound 022-1 (25 mg, 31.25 μmol, 1 eq) was dissolved in acetonitrile (1 mL) and hydrochloric acid / 1,4-dioxane (1 rmL), and reacted at 25°C for 12 hours. After the reaction, the solvent was dried by spin drying, and the preparation and separation were performed: chromatographic column: Phenomenex C18 150*40mm*5μm; mobile phase: [water (0.2% formic acid)-acetonitrile]; acetonitrile%: 1%-30%, 10 min, to obtain the formate salt of compound 022. LCMS: (ESI) m / z=600.1[M+H] + .

[0636] Embodiment 23

[0637]

[0638] Step 1: Synthesis of compound 023-2

[0639] Compound 023-1 (15 g, 59.89 mmol, 1 eq) was added to a reaction flask, and then urea (60 g, 999.08 mmol, 53.57 mL, 16.68 eq) was added, heated to 200°C and refluxed for 4 hours, cooled to room temperature, and slurried with hot water to obtain compound 023-2. LCMS: (ESI) m / z=274.9 [M+H] + .

[0640] Step 2: Synthesis of compound 023-3

[0641] N, N-diisopropylethylamine (11.73 g, 90.75 mmol, 15.81 mL, 5 eq) was added to phosphorus oxychloride (82.50 g, 538.05 mmol, 50 mL, 29.64 eq) at 0°C, and 023-2 (5 g, 18.15 mmol, 1 eq) was added in batches after the addition was complete. The mixture was reacted at 100°C. After the reaction was completed, the reaction solution was evaporated to dryness to remove phosphorus trichloride. The crude product was purified by silica gel column (gradient elution: petroleum ether: ethyl acetate = 20: 1-10: 1) to obtain compound 023-3. 1 H NMR (400 MHz, DMSO-d 6 )δppm 8.50 (s, 1H) 8.58 (s, 1H).

[0642] Step 3: Synthesis of compound 023-4

[0643] 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, and stirred at 25°C for 4 hours. The reaction solution was poured into 200 mL of water, filtered to obtain a solid, and the solid was washed 3 times with 20 mL of water to obtain compound 023-4. LCMS: (ESI) m / z=487.0 [M+H] + .

[0644] Step 4: Synthesis of Compound 023-5

[0645] 023-4 (1.5 g, 3.07 mmol, 1 eq) was dissolved in N, N-dimethylformamide (10 mL) and THF (10 mL), and then cesium carbonate (3.00 g, 9.22 mmol, 3 eq), 001-4A (733.71 mg, 4.61 mmol, 1.5 eq), triethylenediamine (34.46 mg, 307.25 mol, 33.79 LL, 0.1 eq) were added, and the mixture was stirred at 25°C for 18 hours. After the reaction, the mixture was extracted with 50 mL of ethyl acetate, washed with water three times, and washed with saturated brine. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column (gradient elution: petroleum ether: ethyl acetate = 100: 1-20: 1) to obtain compound 023-5. LCMS: (ESI) m / z = 610.2 [M+H] + .

[0646] Step 5: Synthesis of Compound 023-6

[0647] 023-5 (0.4 g, 654.72 μmol, 1 eq) and 022-1A (204.36 mg, 654.72 μmol, 1 eq) were dissolved in 1,4-dioxane (6 mL) and water (6 mL), and 1,1′-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (42.67 mg, 65.47 μmol, 0.1 eq) and potassium phosphate (208.47 mg, 982.09 μmol, 1.5 eq) were added. The mixture was reacted at 90° C. for 18 hours under nitrogen protection. After the reaction, the reaction solution was dried by rotary evaporation, and the crude product was purified by silica gel column (gradient elution: dichloromethane: methanol = 100: 1-20: 1) to obtain compound 023-6. LCMS: (ESI) m / z = 798.3 [M+H] + .

[0648] Step 6: Synthesis of compound 023

[0649] 023-6 (0.1 g, 125.26 μmol, 1 eq) was dissolved in acetonitrile (2 mL), and hydrogen chloride / 1,4-dioxane (2 mL) was added. The mixture was reacted at 25°C for 15 hours. After the reaction, the reaction solution was evaporated to dryness and separated by preparative HPLC: chromatographic column: Phenomenex C18 150*40mm*5μm; mobile phase: [water (0.2% formic acid)-acetonitrile]; acetonitrile%: 7%-37%, and the formate salt of compound 023 was obtained in 10 min. 1HNMR (400 MHz, DMSO-d 6 )δppm1.67-1.95(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).

[0650] Embodiment 24

[0651]

[0652] Step 1: Synthesis of Compound 024-1

[0653] 020-3 (1.8 g, 3.68 mmol, 1 eq) and 024-1A (1.50 g, 3.68 mmol, 1 eq) were dissolved in 1,4-dioxane (2 mL) and water (2 mL), and 1,1′-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (479.09 mg, 735.08 μmol, 0.2 eq) and potassium phosphate (1.17 g, 5.51 mmol, 1.5 eq) were added. The mixture was protected by nitrogen and reacted at 90° C. for 18 hours. After the reaction, 30 mL of ethyl acetate was used for extraction twice. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column (gradient elution: dichloromethane: methanol = 100: 1-20: 1) to obtain compound 024-1. LCMS: (ESI) m / z = 774.3 [M+H] + .

[0654] Step 2: Synthesis of compound 024-2

[0655] 024-1 (1.3 g, 1.68 mmol, 1 eq) was dissolved in N, N-dimethylformamide (2 mL), N-iodosuccinimide (1.13 g, 5.04 mmol, 3 eq) was added, and the mixture was reacted at 25°C for 2 hours. After the reaction, the mixture was extracted twice with 30 mL of ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column (gradient elution: petroleum ether: ethyl acetate = 100: 1-10: 1) to obtain compound 024-2. LCMS: (ESI) m / z = 900.2 [M+H] + .

[0656] Step 3: Synthesis of compound 024-3

[0657] 024-2 (100 mg, 111.09 μmol, 1 eq) was dissolved in N-methylpyrrolidone (2 mL), and then methyl fluorosulfonyl difluoroacetate (3.02 g, 15.72 mmol, 2 mL, 141.50 eq) and cuprous iodide (105.79 mg, 555.45 μmol, 5 eq) were added. Under nitrogen protection, hexamethylphosphoric triamide (99.54 mg, 555.45 μmol, 97.59 μL, 5 eq) was added, and the mixture was refluxed at 80°C for 18 hours. 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, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column (gradient elution: petroleum ether: ethyl acetate = 100: 1-10: 1) to obtain compound 024-3. LCMS: (ESI) m / z = 842.3 [M+H] + .

[0658] Step 4: Synthesis of compound 024-4

[0659] 024-3 (70 mg, 83.11 μmol, 1 eq) was dissolved in tetrahydrofuran (1 mL) and N,N-dimethylformamide (1 mL), and then cesium carbonate (27.08 mg, 83.11 μmol, 1 eq), 001-4A (15.88 mg, 99.73 μmol, 1.2 eq), triethylenediamine (932.23 μg, 8.31 μmol, 9.14e-1 μL, 0.1 eq) were added, and the mixture was reacted at 25°C for 18 hours. After the reaction, water was added, and the mixture was extracted with 100 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column (gradient elution: dichloromethane: methanol = 100: 1-20: 1) to obtain compound 024-4. LCMS: (ESI) m / z = 9814 [M+H] + .

[0660] Step 5: Synthesis of Compound 024

[0661] 024-4 (50 mg, 50.94 μmol, 1 eq) was dissolved in trifluoroacetic acid (5.81 mg, 50.94 μmol, 3.77 μL, 1 eq), stirred at 25°C for 2 hours, and the solvent was evaporated after the reaction. Preparation and separation: chromatographic column: Phenomenex C18 150*40mm*5μm; mobile phase: [water (0.2% formic acid)-acetonitrile]; acetonitrile%: 5%-35%, 10 min, to obtain the formate salt of compound 024. LCMS: (ESI) m / z=641.2[M+H] + .

[0662] Embodiment 25

[0663]

[0664] Step 1: Synthesis of compound 025-1

[0665] 021-1 (1.1 g, 2.42 mmol, 1 eq) and 024-1A (988.77 mg, 2.42 mmol, 1 eq) were dissolved in 1,4-dioxane (2 mL) and water (2 mL), 1,1′-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (314.93 mg, 483.20 μmol, 0.2 eq) and potassium phosphate (769.27 mg, 3.62 mmol, 1.5 eq) were added, nitrogen was protected, and the reaction was carried out at 90° C. for 18 hours. After the reaction, 30 mL of ethyl acetate was used for extraction twice, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column (gradient elution: petroleum ether / ethyl acetate=10:1-5:1) to obtain compound 025-1. LCMS: (ESI) m / z=740.3 [M+H] +

[0666] Step 2: Synthesis of compound 025-2

[0667] 025-1 (1.1 g, 1.49 mmol, 1 eq) was dissolved in N, N-dimethylformamide (2 mL), N-iodosuccinimide (501.77 mg, 2.23 mmol, 1.5 eq) was added, and the mixture was reacted at 25°C for 2 hours. After the reaction, the mixture was extracted twice with 30 mL of ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column (gradient elution: petroleum ether: ethyl acetate = 10: 1-5: 1) to obtain compound 025-2. LCMS: (ESI) m / z = 866.2 [M+H] + .

[0668] Step 3: Synthesis of Compound 025-3

[0669] 025-2 (1.1 g, 1.27 mmol, 1 eq) was dissolved in N, N-dimethylformamide (2 mL), and methyl fluorosulfonyl difluoroacetate (1.22 g, 6.35 mmol, 808.29 μL, 5 eq), hexamethylphosphoric triamide (1.14 g, 6.35 mmol, 1.12 mL, 5 eq), and cuprous iodide (483.98 mg, 2.54 mmol, 2 eq) were added. The mixture was protected by nitrogen and refluxed at 80°C for 18 hours. After the reaction, the mixture was extracted twice with 20 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column (gradient elution: petroleum ether: ethyl acetate = 10: 1-5: 1) to obtain compound 025-3. LCMS: (ESI) m / z = 866.2 [M+H] + .

[0670] Step 4: Synthesis of compound 025-4

[0671] 025-3 (118.24 mg, 742.74 μmol, 1 eq) was dissolved in tetrahydrofuran (2 mL) and N, N-dimethylformamide (2 mL), and cesium carbonate (242.00 mg, 742.74 μmol, 1 eq), triethylenediamine (8.33 mg, 74.27 μmol, 8.17 μL, 0.1 eq), 001-4A (0.6 g, 742.74 μmol, 1 eq) were added, and the mixture was reacted at 25°C for 18 hours. After the reaction, water was added, and the mixture was extracted with 100 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column (gradient elution: dichloromethane: methanol = 100: 1-20: 1) to obtain compound 025-4. LCMS: (ESI) m / z = 947.4 [M+H] + .

[0672] Step 5: Synthesis of Compound 025

[0673] 025-4 (60 mg, 63.36 μmol, 1 eq) was dissolved in trifluoroacetic acid (7.22 mg, 63.36 μmol, 4.69 μL, 1 eq), stirred at 25°C for 1 hour, and the solvent was dried after the reaction. The preparation and separation were as follows: chromatographic column: Phenomenex C18 150*40mm*5μm; mobile phase: [water (0.2% formic acid)-acetonitrile]; acetonitrile%: 5%-35%, 10 min to obtain the formate salt of compound 025. LCMS: (ESI) m / z=607.2[M+H] + ; 1 H NMR (400 MHz, DMSO-d 6)δppm 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).

[0674] Embodiment 26

[0675]

[0676] Step 1: Synthesis of compound 026-2

[0677] 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, stirred at 200°C for 2 hours, cooled to room temperature after the reaction, 200 mL of water was added, and filtered to obtain compound 026-2. LCMS: (ESI) m / z=274.9 [M+H] + .

[0678] Step 2: Synthesis of compound 026-3

[0679] At 0°C, N,N-diisopropylethylamine (11.13 g, 86.12 mmol, 15.00 mL, 11.86 eq) was added dropwise to phosphorus oxychloride (50 mL), and 026-2 (2 g, 7.26 mmol, 1 eq) was added in batches, and refluxed at 80°C for 20 hours. After the reaction was completed, the reaction solution was evaporated to dryness to remove phosphorus trichloride, and the crude product was purified by silica gel column (gradient elution: petroleum ether: ethyl acetate = 10: 1-3: 1) to separate compound 026-3. LCMS: (ESI) m / z = 310.8 [M+H] + Step 3: Synthesis of Compound 026-4

[0680] 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, and the mixture was stirred at 25°C for 2 hours. After the reaction, the reaction solution was poured into 200 mL of water to precipitate a solid, and the solid was washed with 60 mL of water to obtain compound 026-4. LCMS: (ESI) m / z=487.0 [M+H] + .

[0681] Step 4: Synthesis of Compound 026-5

[0682] 026-4 (1.3 g, 2.66 mmol, 1 eq) was dissolved in N, N-dimethylformamide (10 mL) and tetrahydrofuran (10 mL), and then cesium carbonate (867.60 mg, 2.66 mmol, 1 eq), 001-4A (635.88 mg, 3.99 mmol, 1.5 eq), triethylenediamine (29.87 mg, 266.28 μmol, 29.28 μ.L, 0.1 eq) were added, and the mixture was stirred at 25°C for 18 hours. After the reaction, the mixture was extracted with 50 mL of ethyl acetate, washed with saturated brine, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column (gradient elution: petroleum ether: ethyl acetate = 100: 1-20: 1) to obtain compound 026-5. LCMS: (ESI) m / z = 610.2 [M+H] + .

[0683] Step 5: Synthesis of Compound 026-6

[0684] 026-5 (0.2 g, 327.36 μmol, 1 eq) and compound 026-1A (91.03 mg, 327.36 μmol, 1 eq) were dissolved in 1,4-dioxane (1 mL) and water (0.2 mL), and [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (21.34 mg, 32.74 μmol, 0.1 eq) and potassium phosphate (104.23 mg, 491.04 μmol, 1.5 eq) were added. The mixture was protected by nitrogen and reacted at 90° C. for 18 hours. After the reaction was completed, the reaction solution was evaporated to dryness, and the crude product was purified by silica gel column (gradient elution: petroleum ether: ethyl acetate = 100: 1-20: 1) to obtain compound 026-6. LCMS: (ESI) m / z = 764.3 [M+H] + .

[0685] Step 6: Synthesis of Compound 026

[0686] 026-6 (100 mg, 130.84 μmol, 1 eq) was dissolved in hydrochloric acid / 1,4-dioxane (2 mL), acetonitrile (2 mL) was added, and the mixture was stirred at 25° C. for 15 hours. The reaction solution was spin-dried and separated by preparative HPLC: chromatographic column: Phenomenex C18 150*40mm*5μm; mobile phase: [water (0.2% formic acid)-acetonitrile]; acetonitrile%: 1%-30%, 10 min, to obtain the formate salt of compound 026. 1 H NMR (400 MHz, DMSO-d 6 )δppm 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 (b1 s, 1H).

[0687] Embodiment 27

[0688]

[0689] Step 1: Synthesis of Compound 027-1B

[0690] 027-1A (0.9 g, 4.03 mmol, 1 eq) was dissolved in N-methylpyrrolidone (5 mL), potassium carbonate (1.39 g, 10.09 mmol, 2.5 eq), potassium iodide (669.76 mg, 4.03 mmol, 1 eq) and p-methoxybenzyl chloride (1.58 g, 10.09 mmol, 1.37 mL, 2.5 eq) were added, and the mixture was reacted at 25°C for 15 hours. After the reaction, 20 mL of ethyl acetate was used for extraction twice, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column (gradient elution: petroleum ether: ethyl acetate = 100: 1-10: 1) to obtain compound 027-1B. LCMS: (ESI) m / z = 463.1 [M+H] + .

[0691] Step 2: Synthesis of Compound 027-1

[0692] 019-8 (0.6 g, 1.0) 1mmol, 1eq) was dissolved in 1,4-dioxane (10 mL), and bis(pinacol)diboron (384.44 mg, 1.51 mmol, 1.5 eq), bis(diphenylphosphino)ferrocenepalladium dichloride (73.85 mg, 100.93 μmol, 0.1 eq), potassium acetate (148.58 mg, 1.51 mmol, 1.5 eq) were added, and the mixture was refluxed at 105° C. for 15 hours. After the reaction was completed, the reaction solution was spin-dried and separated by preparative HPLC: chromatographic column: Phenomenex C18 150*40mm*5μm; mobile phase: [water (formic acid)-acetonitrile]; acetonitrile%: 10%-40%, and compound 027-1 (110 mg, 171.46 μmol, 16.99% yield) was obtained in 10 min. LCMS: (ESI)m / z=560.3[M-82+H] + .

[0693] Step 3: Synthesis of Compound 027-2

[0694] 027-1 (82.83 mg, 178.76 μmol, 1 eq) and 027-1B (100 mg, 178.76 μmol, 1 eq) were dissolved in 1,4-dioxane (2 mL) and water (0.4 mL), potassium phosphate (56.92 mg, 268.14 μmol, 1.5 eq) and 1,1-di(tert-butylphosphino)ferrocenepalladium chloride (11.65 mg, 17.88 μmol, 0.1 eq) were added, and the mixture was reacted at 80° C. for 15 hours under nitrogen protection. After the reaction, the reaction solution was directly evaporated to dryness, and the crude product was purified by silica gel column (gradient elution: petroleum ether: ethyl acetate = 100: 1-30: 1) to obtain compound 027-2. LCMS: (ESI) m / z = 898.4 [M+H] + .

[0695] Step 4: Synthesis of Compound 027

[0696] 027-2 (100 mg, 111.35 μmol, 1 eq) was dissolved in trifluoroacetic acid (2 mL), stirred at 25°C for 2 hours, and the solvent was dried after the reaction. The mixture was separated by preparative HPLC: chromatographic column: Phenomenex C18 150*40mm*5μm; flowability: [water (0.2% formic acid)-acetonitrile]; acetonitrile%: 55%-85%, and the formate salt of compound 027 was obtained in 10 min. LCMS: (ESI) m / z=558.3[M+H] + .

[0697] Embodiment 28

[0698]

[0699] Step 1: Synthesis of Compound 028-1

[0700] Compound 011-1A (0.30 g, 477.00 μmol, 1 eq) and 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), and the atmosphere was replaced with nitrogen three times. Chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) (37.53 mg, 47.70 μmol, 0.1 eq), replaced with nitrogen three times, reacted at 100 ° C for 16 hours, cooled to room temperature after the reaction, added 20 mL of water and 20 mL of ethyl acetate to the reaction solution, stirred for 5 min, then allowed to stand for separation, the aqueous phase was extracted once with 20 mL of ethyl acetate, the organic phases were combined, washed three times with 20 mL of saturated brine, then dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was purified by column chromatography (petroleum ether: ethyl acetate = 100: 0-0: 100) to obtain compound 028-1. LCMS: (ESI) m / z = 693.2 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 )δppm 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).

[0701] Step 2: Synthesis of Compound 028-2

[0702] Compound 028-1 (110 mg, 158.60 μmol, 1 eq) was added to N, N-dimethylformamide (2 mL), and N-chlorosuccinimide (23.30 mg, 174.46 μmol, 1.1 eq) was added, and the mixture was reacted at 70°C for 3 hours. After the reaction, 10 mL of ethyl acetate and 5 mL of water were added to the reaction solution, and the mixture was stirred for 5 min, and then allowed to stand for separation. The aqueous phase was extracted once with 10 mL of ethyl acetate, and the organic phases were combined, washed twice with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by a silica gel column (dichloromethane: methanol (one thousandth of ammonia water was added dropwise) = 20: 1) to obtain compound 028-2. LCMS: (ESI) m / z = 727.1 [M+H] + .1HNMR (400MHz, CDCl 3 )δppm 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).

[0703] Step 3: Synthesis of Compound 028

[0704] Compound 028-2 (40 mg, 54.94 μmol, 1 eq) was added to anhydrous dichloromethane (2 mL), and trifluoroacetic acid (308.00 mg, 2.70 mmol, 200.00 μL, 49.16 eq) was added, and the mixture was reacted at 25° C. for 2 hours to precipitate a solid. After the reaction, the reaction solution was concentrated to dryness under reduced pressure, and the crude product was subjected to preparative separation and purification (chromatographic column: Phenomenex Luna 80*30mm*3μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile%: 15%-35%, 7 min) to obtain the hydrochloride of compound 028. 1 H NMR (400 MHz, CD 3OD)THANOL-d MHz,a 80*30mm*3.00J=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, 2 H), 3.84-4.04(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).

[0705] Embodiment 29

[0706]

[0707] Step 1: Synthesis of Compound 029-1

[0708] At 20°C, compound 001-1 (4 ((mg, 1.21mmol, 1eq) was dissolved in anhydrous N, N-dimethylformamide (10mL), and N, N-diisopropylethylamine (391.21mg, 3.03mmol, 527.24μL, 2.5eq) and 029-1A (257.03mg, 1.21mmol, 1eq) were added. The mixture was stirred for 0.5 hours. After the reaction was completed, the mixture was diluted with ethyl acetate (150mL), washed with saturated brine (30mL), dried over anhydrous sodium sulfate, and the dried organic phase was separated. The organic solvent was removed under reduced pressure to obtain a crude product 029-1. 1 HNMR (400 MHz, CDCl 3 )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).

[0709] Step 2: Synthesis of Compound 029-2

[0710] Compound 029-1 (600 mg, 1.19 mmol, 1 eq) was dissolved in tetrahydrofuran (3 mL) and N,N-dimethylformamide (3 mL). Under nitrogen protection, 001-4A (284.17 mg, 1.78 mmol, 1.5 eq), cesium carbonate (1.16 g, 3.57 mmol, 3 eq) and triethylenediamine (13.35 mg, 119.00 μmol, 13.09 μL, 0.1 eq) were added in sequence. The reaction solution was stirred at 20°C for 16 hours. After the reaction, 100 mL of ethyl acetate was added to the reaction solution, and the mixture was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, dried, and the organic solvent was removed under reduced pressure. The crude product was separated and purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 0-80%) to obtain compound 029-2. 1HNMR (400 MHz, CDCl 3 )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 (brd, 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).

[0711] Step 3: Synthesis of Compound 029-3

[0712] Under nitrogen protection, 029-2 (50 mg, 79.50 μmol, 1 eq), 029-3A (25.77 mg, 95.40 μmol, 1.2 eq) and sodium carbonate (25.28 mg, 238.50 μmol, 3 eq) were dissolved in 1,4-dioxane (2 mL) and water (1 mL), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (6.49 mg, 7.95 μmol, 0.1 eq) was added. After the addition, the mixture was reacted at 100° C. for 3 hours, cooled after the reaction, and the organic solvent was removed under reduced pressure. The crude product was separated and purified by preparative silica gel plate (developing solvent: dichloromethane: methanol = 10: 1) to obtain compound 029-3. LCMS: (ESI) m / z = 692.2 [M+H] + .

[0713] Step 4: Synthesis of Compound 029

[0714] At 20°C, compound 029-3 (40 mg, 57.79 μmol, 1 eq) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (770.00 mg, 6.75 mmol, 0.5 mL, 116.86 eq) was added, and the reaction solution was stirred for 1 hour. After the reaction was completed, the reaction solution was spin-dried, and the crude product was purified by preparative separation (chromatographic column: Phenomenex Synergi C18 150*30mm*4μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile%: 20%-50%, 9 min) to obtain the hydrochloride of compound 029. LCMS: (ESI) m / z=592.1[M+H] + .

[0715] Embodiment 30

[0716]

[0717] Step 1: Synthesis of Compound 030-1

[0718] At 20°C, compound 011-1A (500 mg, 794.99 mol, 1 eq) was dissolved in tetrahydrofuran (5 mL), and sodium methoxide (85.90 mg, 1.59 mmol, 2 eq) was added. The reaction solution was heated to 70°C and stirred for 48 hours. After the reaction, the solvent was dried and the crude product was separated and purified by preparative silica gel plate (developing solvent: ethyl acetate / petroleum ether = 0-100%) to obtain compound 030-1. 1 HNMR (400 MHz, CDCl 3 )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).

[0719] Step 2: Synthesis of compound 030-2

[0720] Under nitrogen protection, compound 030-1 (50 mg, 78.01 μmol, 1 eq), 029-3A (25.29 mg, 93.61 μmol, 1.2 eq) and cesium carbonate (76.25 mg, 234.02 μmol, 3 eq) were dissolved in 1,4-dioxane (5 mL) and water (1 mL), and Pd(PPh3)4 (9.01 mg, 7.80 μmol, 0.1 eq) was added. After the addition, the mixture was reacted at 100 ° C for 16 hours. After the reaction, the solvent was dried by spin drying. The crude product was separated and purified by preparative silica gel plate (developing solvent: dichloromethane: methanol = 10: 1) to obtain compound 030-2. LCMS: (ESI) m / z = 704.3 [M+H] + .

[0721] Step 3: Synthesis of Compound 030

[0722] At 20°C, compound 030-2 (20.00 mg, 28.40 μmol, 1 eq) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL, 475.58 eq) was added, and the reaction solution was stirred for 16 hours. After the reaction, the solvent was dried by spin drying, and the mixture was separated and purified by preparative separation (chromatographic column: Welch XtimateC18 100*40mm*3μm; mobile phase: [water (0.1% trifluoroacetic acid)-acetonitrile]; acetonitrile%: 15%-45%, 8 min) to obtain the trifluoroacetate salt of compound 030. LCMS: (ESI) m / z=604.5[M+H] + .

[0723] Embodiment 31

[0724]

[0725] Step 1: Synthesis of Compound 031-1

[0726] 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). After the temperature was lowered to 0°C, tert-butyldimethylsilyl chloride (162.79 mg, 1.08 mmol, 132.35 μL, 1.1 eq) was added dropwise. After nitrogen was replaced, the temperature was slowly raised to 20°C and stirred for 3 hours. After the reaction was completed, 5 ml of dichloromethane and 10 ml of water were added to the reaction system for dilution. After separation, the organic phase was collected, 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 obtain a crude product. The crude product was purified by column chromatography (gradient elution: petroleum ether: ethyl acetate = 10: 0-1: 10) to obtain compound 031-1. LCMS: (ESI) m / z=338.0 [M+H] +

[0727] Step 2: Synthesis of Compound 031-2

[0728] Compound 027-1 (0.2 g), compound 031-1 (43.54 mg, 128.71 μmol, 1.2 eq) and sodium carbonate (34.10 mg, 321.77 μmol, 3 eq) were added to 1,4-dioxane (4 mL) and water (0.8 mL), and the mixture was replaced with nitrogen three times. [1,1-)(bis(.phenylphosphino)ferrocene]palladium dichloride (7.85 mg, 10.73 μmol, 0.1 eq) was added under nitrogen protection, and the mixture was reacted at 100° C. for 2 hours. After the reaction, 5 mL of ethyl acetate was added to the reaction solution, and the mixture was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by high performance liquid preparative chromatography (chromatographic column: Phenomenex luna C1880*40mm*3μm; mobile phase A: water (0.05% HCl), mobile phase B: acetonitrile; running gradient: acetonitrile%: 40%-70%, running time: 7min), to obtain compound 031-2. LCMS: (ESI) m / z=773.3[M+H] + .

[0729] Step 3: Synthesis of Compound 031

[0730] Compound 031-2 (0.035 g, 45.28 μmol, 1 eq) was added to acetonitrile (2 mL), and hydrochloric acid / 1,4-dioxane (4 M, 226.39 μL, 20 eq) was added, and the mixture was reacted at 25° C. for 2 hours. After the reaction, the reaction solution was added to 5 mL of water and extracted with 3 mL of ethyl acetate twice, and the aqueous phase was concentrated to obtain compound 031. LCMS: (ESI) m / z=559.3 [M+H] + .1 H NMR (400 MHz, CD 3 OD)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), 4.3 3-4.17(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).

[0731] Embodiment 32

[0732]

[0733] Step 1: Synthesis of Compound 032-2

[0734] Ammonium thiocyanate (2.38 g, 31.25 mmol, 2.38 mL, 1.3 eq) was added to acetone (50 mL), and benzoyl chloride (3.38 g, 24.04 mmol, 2.79 mL, 1 eq) was added. The mixture was reacted at 70 ° C for 0.5 hours, cooled to 50 ° C, and a solution of compound 032-1 (5 g, 24.04 mmol, 1 eq) in acetone (7 mL) was added in batches. The mixture was reacted at 70 ° C for 0.5 hours, and sodium hydroxide (2M, 42.07 mL, 3.5 eq) was added. The mixture was refluxed for 0.5 hours. After the reaction, the reaction solution was cooled to room temperature, hydrochloric acid was added to pH 5, and the pH was adjusted to 8 with ammonia water. The mixture was stirred for 0.5 hours, extracted twice with 30 mL of ethyl acetate, and the organic phases were combined. The crude product was dried over anhydrous sodium sulfate and filtered, and then slurried and stirred with 30 mL of dichloromethane for 1 hour and filtered to obtain compound 032-2. LCMS: (ESI) m / z = 266.9 [M+H] + .

[0735] Step 2: Synthesis of Compound 032-3

[0736] Compound 032-2 (2 g, 7.49 mmol, 1 eq) was added to dichloroethane (20 mL), and a dichloroethane solution (2 mL) of bromine (2.39 g, 14.98 mmol, 772.04 μL, 2 eq) was added, and the mixture was reacted at 95° C. for 2 hours. After the reaction, the reaction solution was filtered, and the filter cake was washed with 20 mL of 1,2-dichloroethane to obtain compound 032-3. LCMS: (ESI) m / z=264.8 [M+H]+ .

[0737] Step 3: Synthesis of Compound 032-4

[0738] Compound 032-3 (1.0 g, 3.77 mmol, 1 eq) was added to anhydrous tetrahydrofuran (15 mL), and 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 under nitrogen protection, and the mixture was reacted at 20°C for 19 hours. After the reaction, 20 mL of water was added to the reaction solution, and 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, filtered, and concentrated. The crude product was slurried with 10 mL of dichloromethane for 1 hour, and then filtered to obtain compound 032-4. LCMS: (ESI) m / z=308.8 [M-55] + .

[0739] Step 4: Synthesis of Compound 032-5

[0740] Compound 027-1 (0.2 g), compound 032-4 (47.00 mg, 128.71 μmol, 1.2 eq) and sodium carbonate (34.10 mg, 321.77 μmol, 3 eq) were added to 1,4-dioxane (4 mL) and water (0.8 mL), and the mixture was replaced with nitrogen three times. [1,1-bis(monophenylphosphino)ferrocene]palladium dichloride (7.85 mg, 10.73 μmol, 0.1 eq) was added under nitrogen protection, and the mixture was reacted at 100° C. for 2 hours. After the reaction, 5 mL of ethyl acetate was added to the reaction solution, and the mixture was washed with 8 mL of water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by high performance liquid preparative chromatography (chromatographic column: Phenomenex lunaC18 80*40mm*3μm; mobile phase A: water (0.05% hydrochloric acid), mobile phase B: acetonitrile; running gradient: acetonitrile%: 40%-70%, running time: 7min) to obtain compound 032-5. LCMS: (ESI) m / z=800.3[M+H] + .

[0741] Step 5: Synthesis of Compound 032

[0742] Compound 032-5 (0.025 g, 31.25 μmol, 1 eq) was added to acetonitrile (1 mL), and hydrochloric acid / 1,4-dioxane (4 M, 156.27 μL, 20 eq) was added, and the reaction was carried out at 25° C. for 7 hours. After the reaction, the reaction solution was added to 5 mL of water, and extracted twice with 3 mL of ethyl acetate. The crude product was separated and purified by high performance liquid preparative chromatography (chromatographic column: Phenomenex luna C1880*40mm*3 μm; mobile phase A: water (0.05% hydrochloric acid), mobile phase B: acetonitrile; running gradient: acetonitrile%: 10%-35%, running time: 7 min) to obtain the hydrochloride of compound 032. LCMS: (ESI) m / z=600.2[M+H] + ; 1 H NMR (400 MHz, CD 3 OD)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).

[0743] Embodiment 33

[0744]

[0745] Step 1: Synthesis of Compound 033-2

[0746] Compound 033-1 (5 g, 21.27 mmol, 1 eq), N-chlorosuccinimide (4.26 g, 31.90 mmol, 1.5 eq), 4-nitro-2-(trifluoromethyl)phenol (1.32 g, 6.38 mmol, 0.3 eq) and 4-trifluoromethylaniline (342.71 mg, 2.13 mmol, 263.62 μL, 0.1 eq) were dissolved in dichloroethane (20 mL), and trifluoroethane was added under nitrogen protection. Acetic acid (24.25 g, 212.70 mmol, 15.75 mL, 10 eq) and palladium acetate (77.53 mg, 2.13 mmol, 0.1 eq) were reacted at 80°C for 16 hours. After the reaction was completed, the temperature was cooled to room temperature. 20 mL of water was added to the reaction solution, and the mixture was extracted twice with 20 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain compound 033-2. LCMS: (ESI) m / z = 268.9 [M+H] + .

[0747] Step 2: Synthesis of Compound 033-3

[0748] Compound 033-2 (3 g, 11.13 mmol, 1 eq) was added to dimethyl sulfoxide (10 mL), and then ammonium hydrochloride (1.55 g, 22.26 mmol, 2 eq) was added, and the mixture was reacted at 95° C. for 6 hours. After the reaction, 30 mL of water was added to the reaction solution, and 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 obtain compound 033-3. 1 H NMR (400 MHz, CD 3 OD) 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).

[0749] Step 3: Synthesis of Compound 033-4

[0750] p-Methoxybenzylamine (617.64 mg, 4.50 mmol, 582.68 μL, 1.2 eq) and compound 033-3 (1 g, 3.75 mmol, 1 eq) were added to N, N-dimethylformamide (5 mL), and potassium carbonate (1.04 g, 7.50 mmol, 2 eq) was added, and the mixture was reacted at 80°C for 16 hours. After the reaction, 30 mL of water was added to the reaction solution, and 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, and then dried and concentrated over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0-1:1) to obtain compound 033-4. 1HNMR (400 MHz, CD 3 OD)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).

[0751] Step 4: Synthesis of Compound 033-5

[0752] Compound 033-4 (70.90 mg, 193.06 μmol, 1.2 eq) and sodium bicarbonate (27.03 mg, 321.77 μmol, 12.51 μL, 2 eq) were added to 1,4-dioxane (5 mL) and water (3 mL), and the mixture was replaced with nitrogen three times. [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (11.77 mg, 16.09 μmol, 0.1 eq) was added under nitrogen protection, the temperature was raised to 100°C, compound 027-1 (0.09 g, 160.88 μmol, 1 eq) was added, the mixture was replaced with nitrogen three times, and the mixture was reacted at 100°C for 1 hour under nitrogen protection. After the reaction, the reaction solution was poured into 30 mL of water, extracted three times with 20 mL of ethyl acetate, the organic phases were combined, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by high performance liquid chromatography (chromatographic column: Phenomenex luna C18 80*40mm*3μm; mobile phase A: water (0.05% hydrochloric acid), mobile phase B: acetonitrile; running gradient: acetonitrile%: 34%-54%, running time: 7min) to obtain compound 033-5. LCMS: (ESI) m / z=802.2[M+H] + .

[0753] Step 5: Synthesis of Compound 033

[0754] Compound 033-5 (0.002 g, 2.49 μmol, 1 eq) was added to anhydrous dichloromethane (0.25 mL) and trifluoroacetic acid (0.05 mL), and the mixture was reacted at 25° C. for 5 hours. After the reaction, the solvent was dried by spin drying. The crude product was separated and purified by high performance liquid preparative chromatography (chromatographic column: Phenomenex luna C18 80*40mm*3μm; mobile phase A: water (0.04% hydrochloric acid), mobile phase B: acetonitrile; running gradient: acetonitrile%: 10%-30%, running time: 8 min) to obtain the hydrochloride of compound 033. LCMS: (ESI) m / z=582.3[M+H] + .

[0755] Experimental Example 1: SOS1-mediated KRAS G12D Binding ability test with effector protein c-Raf

[0756] 1. Purpose

[0757] Through the TR-FRET method, the effective inhibitors of KRAS G12D Compounds that bind to c-Raf, a downstream effector protein in the MAPK pathway.

[0758] 2. Experimental Procedure

[0759] 2.1 Prepare 1x enzyme reaction buffer:

[0760] Table 1. Reaction buffer

[0761]

[0762] 2.2KRAS G12D enzyme preparation (2×):

[0763] Table 2. KRAS G12D enzymes

[0764]

[0765]

[0766] 2.3 Preparation of substrate and antibody mixture (2×):

[0767] Table 3. Substrate and antibody mixture

[0768]

[0769] 3. Compound screening:

[0770] 1) Compounds were serially diluted 5-fold with DMSO in a dilution plate, with a final starting concentration of 10 μM.

[0771] 2) Transfer the compound to a 384-well plate using Echo, 100 μL per well.

[0772] 3) Add 5 μL of KRAS G12D enzyme to each well of the reaction plate.

[0773] 4) Seal the plate with sealing film and centrifuge at 1000g for 30 seconds, and incubate at room temperature for 15 minutes.

[0774] 5) Prepare 2x cRaf / SOS1 / GTP / MAb Anti 6HIS-d2 / MAb AntiGST-Eu mixture with 1X enzyme reaction buffer and add 5 μL of the mixture to the reaction plate.

[0775] 6) Centrifuge at 1000 g for 30 seconds and react at room temperature for 2 hours.

[0776] 7) Use a BMG microplate reader to read the fluorescence signals at 615 nm (Cryptate) and 665 nm (XL665).

[0777] 8) Graphpad 7.0 software was used for data analysis to obtain IC 50 .

[0778] 4. Experimental Results

[0779] The results are shown in Table 4:

[0780] Table 4. Effects of Compounds on KRAS G12D Active IC 50 value

[0781]

[0782]

[0783] Experimental conclusion: The compounds of the present invention can significantly inhibit KRAS G12D active.

[0784] Experimental Example 2. Anti-cell proliferation effect of the compound in the tumor cell line AsPC-1

[0785] 1. Research objectives

[0786] This experiment studies the inhibitory effect of compounds on cell proliferation by detecting the effects of compounds on in vitro cell activity in the tumor cell line AsPC-1.

[0787] 2. Experimental Materials

[0788] Table 5. Cell lines

[0789] Cell lines Tumor type Growth characteristics Cultivation methods AsPC-1 Pancreatic cancer Adherent growth RPMI 1640 + 10% FBS

[0790] Ultra Low Cluster-96-well Plate (Coming-7007)

[0791] Greiner CELLSTAR 96-well Plate (#655090)

[0792] Promega CellTiter-Glo 3D Luminescent Cell Viability Assay Kit (Promega-G9683)

[0793] 2104-10 EnVision plate reader, PerkinElmer

[0794] RPMI 1640, DMEM, PBS (phosphate buffered saline), FBS (fetal bovine serum), Antibiotic-antimycotic (antibiotic-antifungal drug), L-glutamine (L-glutamine), DMSO (dimethyl sulfoxide)

[0795] 3. Experimental methods and steps

[0796] Cell culture

[0797] Tumor cell lines were cultured at 37°C and 5% CO 2 The cells were cultured in an incubator at 4 °C. The cells were subcultured regularly and the cells in the logarithmic growth phase were used for plating.

[0798] Cell plating

[0799] Cells were stained with trypan blue and viable cells were counted.

[0800] Adjust the cell concentration to an appropriate level.

[0801] Table 6. Cell lines

[0802] Cell lines Density (per well) AsPC-1 7000 cells

[0803] 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 the blank control well.

[0804] Immediately after plating, centrifuge the ULA plate at room temperature for 10 minutes at 1000 rpm. Note: After centrifugation, be careful not to cause unnecessary agitation during subsequent operations.

[0805] Incubate the plate at 37 °C, 5% CO 2 , and cultured in an incubator at 100% relative humidity overnight.

[0806] Preparation of 10X compound working solution and compound treatment of cells (Day 1)

[0807] After preparing the 10X compound working solution (DMSO 10X working solution), add 15 μL of the 10X compound working solution to the ULA culture plate, and add 15 μL of the DMSO-cell culture medium mixture to the vehicle control and blank control.

[0808] The 96-well cell plate was returned to the incubator for 120 hours.

[0809] The cell sphering was observed every day until the end of the experiment.

[0810] CellTiter-Glo luminescence cell activity assay (fifth day)

[0811] The following steps were performed according to the instructions of the Promega CellTiter-Glo 3D Luminescent Cell Viability Assay Kit (Promega #G9683).

[0812] Add 150 μL (equal to the volume of cell culture medium in each well) of CellTiter-Glo 3D reagent to each well. Wrap the cell plate with aluminum foil to protect it from light.

[0813] The plate was shaken on an orbital shaker for 5 minutes.

[0814] Carefully pipette up and down 10 times to mix the mixture. Make sure the spheroids are fully dissociated before proceeding to the next step.

[0815] The solution in the ULA culture plate was then transferred to a black bottom culture plate (#655090) and placed at room temperature for 25 minutes to stabilize the luminescent signal.

[0816] Luminescent signals were detected on a 2104 EnVision plate reader.

[0817] 4. Data Analysis

[0818] The inhibition rate (IR) of the test compound was calculated using the following formula: IR (%) = (1-(RLU compound-RLU blank control) / (RLU solvent control RLU blank control))*100%. The inhibition rates of different concentrations of the compound were calculated in Excel, and then the inhibition curves were plotted and related parameters were calculated using GraphPad Prism software, including the minimum inhibition rate, maximum inhibition rate and IC 50 .

[0819] 4. Experimental Results

[0820] The results are shown in Table 7:

[0821] Table 7. Effects of Compounds on KRAS G12DAntiproliferative activity of mutant AsPC-1 cells

[0822] Compound No. <![CDATA[IC 50 (nM)]]> Compound 002A 17.7 Compound 013B 14.2 Compound 016B 14.2 Compound 017B 6.5

[0823] Experimental conclusion: The compound of the present invention KRAS G12D The mutant AsPC-1 cells had significant antiproliferative activity.

[0824] Experimental Example 3. Inhibitory effect of compounds on phospho-ERK in GP2D cells

[0825] 1. Research objectives

[0826] This experiment analyzes the effects of the test compounds on KRAS in human colon cancer GP2D cells. G12D Inhibitory effect on ERK protein phosphorylation downstream of the signaling pathway.

[0827] 2. Reagents, consumables and instruments

[0828] Table 8. Experimental materials

[0829]

[0830]

[0831] Table 9. Experimental instruments

[0832] instrument factory model <![CDATA[CO 2 Incubator]]> ESCO CLM-240B-8-CN Echo 655Liquid Handler Labcyte Echo 655 Odyssey CLx LI-COR Odyssey CLx Centrifuge Eppendorf 5810R Multi-channel pipettes Eppendorf / Sartorius / Apricot Tips (125uL) Apricot Designs 050-384-EZ-NS S2-PIPETTE Apricot Designs SP2-384-0125-03

[0833] 3. Experimental Procedure

[0834] 1. Cell Culture

[0835] 1) GP2D cells were cultured in a cell culture flask in DMEM medium (supplemented with 10% FBS and 1% P / S) at 37°C and 5% CO 2 nourish.

[0836] 2) After two days of culture, remove the culture medium and wash once with sterile PBS buffer.

[0837] 3) Add 3 mL of trypsin and digest in a 37°C incubator for 2 to 3 minutes until the cells are detached.

[0838] 4) Add 9 mL of fresh culture medium to neutralize the digestion, pipette into a centrifuge tube, and centrifuge at 1000 rpm for 5 minutes at room temperature.

[0839] 5) Remove the supernatant, add 3 mL of fresh culture medium to resuspend, and use cell counting technology.

[0840] 2. Compound Screening

[0841] 1) 7000 cells were plated per well in a 384 cell culture plate, 40 μL of culture medium was added, and cultured overnight in a 37°C and 5% CO2 incubator.

[0842] 2) Using the Ech0655 instrument, add 40 nL of serially diluted compounds (the starting concentration of the compound is 1000 nM, three-fold serial dilution. The final concentration of DMSO is 0.1%), and incubate in a 37°C and 5% CO2 incubator for 1 hour. Add EGF stimulator (final concentration is 0.1 ng / mL), and incubate in a 37°C and 5% CO2 incubator for 1 hour. 2 Incubate in the incubator for 15 minutes.

[0843] 3) Add 40 μL of 8% paraformaldehyde fixative and incubate at room temperature for 20 minutes.

[0844] 4) Wash twice with PBS buffer, add 40 μL of pre-cooled methanol, and incubate at room temperature for 20 minutes.

[0845] 5) Wash twice with PBS buffer, add 20 μL of blocking solution, and block at room temperature for 1 hour.

[0846] 6) Remove the blocking solution, add primary antibody mixture (phospho-p44 / 42 MAPK (T202 / Y204) Rabbit mAb diluted 1000 times, GAPDH (D4C6R) Mouse mAb diluted 2000 times), and incubate overnight in a 4°C refrigerator.

[0847] 7) Add PBST (0.05% Tween 20) buffer and wash three times, add secondary antibody mixture (IRDye 680RD Goat anti Mouse IgG (H+L) diluted 2000 times, IRDye 800CW Goat anti-Rabbit IgG (H+L) diluted 2000 times), and incubate at room temperature in the dark for 1 hour.

[0848] 8) Add PBST (0.05% Tween 20) buffer and wash three times, centrifuge at 1000 rpm for 1 minute, dry in the dark, and scan the plate with Odyssey CLx instrument.

[0849] 4. Data Analysis

[0850] 1) Data analysis:

[0851] Relative Signal=Signal Value(total channel 800) / Signal Value(total channel 700)

[0852] H=Ave(dimethyl sulfoxide), L=Ave(compound), SD(H)=STDEV(dimethyl sulfoxide); SD(L)=STDEV(compound)

[0853] CV%(H)=100*(SD_H / Ave_H), CV%(L)=100*SD_L / Ave_L

[0854] Z′=1-3*(SD_H+SD_L) / (Ave_H-Ave_L)

[0855] Inhibition=(Ave_H-Sample) / (Ave_H-Ave_L)*100

[0856] 2)Fit the cpd IC50 from non-linear regression equation:

[0857] Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope))

[0858] X: Log of cpd concentration, Y: Inhibition

[0859] Top and Bottom:Plateaus in same units as Y:logIC50:same log units asX:HillSlope:Slope factor or Hill slope

[0860] 5. Experimental Results

[0861] The results are shown in Table 10:

[0862] Table 10. Inhibitory effects of compounds on intracellular phospho-ERK

[0863] Compound No. <![CDATA[IC 50 (nM)]]> Compound 002A 0.15 Compound 013B 0.12 Compound 017B 0.069

[0864] Experimental conclusion: The compounds of the present invention have a significant inhibitory effect on phospho-ERK in GP2D cells.

[0865] Experimental Example 4. KRAS G12D Inhibitory activity test

[0866] 1. Purpose

[0867] Using the TR-FRET method, compounds that can effectively inhibit the binding of KRAS to GTP were screened.

[0868] 2. Consumables and instruments

[0869] Table 11. Consumables and instruments

[0870]

[0871]

[0872] 3. Reagent Preparation

[0873] a. Storage of reagents:

[0874] 1) KRAS Nucleotide Exchange Buffer

[0875] Take 20 mL 1000 mM HEPES, 20 mL 500 mM EDTA, 10 mL 5 M sodium chloride, 0.1 mL 100% Tween 20, and 949.9 mL water to prepare 1 L solution, sterilize by filtration, and store at 4°C.

[0876] 2) KRAS assay buffer

[0877] Take 20 mL 1000 mM HEPES, 10 mL 1000 mM magnesium chloride, 30 mL 5 M sodium chloride, 0.05 mL 100% Tween 20, 939.95 mL water, prepare 1 L solution, sterilize by filtration, and store at 4°C.

[0878] 3) KRAS / Bodipy GDP / Tb-SA mixture

[0879] Take 9.5 μL 95 μM KRAS G12D Protein was mixed with 440.5 μL KRAS nucleotide exchange buffer, incubated at room temperature for 1 hour, and then mixed with 8.4 μL 17.9 μM Tb-SA, 1.8 μL 5 mM Bodipy GDP, and 9539.8 μL KRAS experimental buffer to make a 1 L solution, which was allowed to stand at room temperature for 6 hours and stored at -80 °C.

[0880] b. Experimental reagents:

[0881] 1) KRAS enzyme solution

[0882] Take 73.3 μL of KRAS / Bodipy GDP / Tb-SA mixture and 2126.7 μL of KRAS assay buffer to prepare 2200 μL solution.

[0883] 2) SOS / GTP mixture

[0884] Take 1.59 μL 166 μM SOS protein, 198 μL 100 mM GTP, and 2000.41 μL KRAS assay buffer to prepare a 2200 μL solution.

[0885] 4. Experimental Procedure

[0886] 1) The concentration of the control compound stock solution is 1 mM, and the concentration of the test compound stock solution is 10 mM. Transfer 9 μL of the control compound and the test compound to the 384-LDV plate;

[0887] 2) Use Bravo to make 10-point 3-fold dilutions of the compounds on the LDV plate;

[0888] 3) Use ECHO to transfer 9 nL of the compound on the LDV plate to the experimental plate;

[0889] 4) Use the Dragonfly automatic sampler to add 3 μL of 3 nM Kras / 0.5 nM TB-SA / 30 nM BodipyGDP mixed solution and 3 μL of Ras buffer to each well of the experimental plate, and centrifuge the experimental plate at 1000 rpm / min for 1 minute;

[0890] 5) Incubate the experimental plate at room temperature for 1 hour;

[0891] 6) Use the Dragonfly automatic sampler to add 3 μL of 120 nM SOS / 9 mM GTP mixture to each well of the experimental plate, and centrifuge the experimental plate at 1000 rpm / min for 1 minute;

[0892] 7) Incubate the experimental plate at room temperature for 1 hour;

[0893] 8) Use Envision to read the plate and record the data;

[0894] 9) Use Excel and Xlfit to analyze data and calculate the IC of the tested compound 50 .

[0895] 5 Experimental results

[0896] The results are shown in Table 12.

[0897] Table 12 Effects of Compounds on KRAS G12D IC of enzyme inhibition 50 value

[0898] Compound No. <![CDATA[KRAS G12D IC 50 (nM)]]> Formate salt of compound 022 6.6 Hydrochloride of compound 029 38.6

[0899] Experimental conclusion: The compounds of the present invention have significant KRAS G12D Enzyme inhibition.

[0900] Experimental Example 5. GP2D cell p-ERK inhibition test

[0901] 1. Purpose

[0902] Using the HTRF method, we screened out compounds that can effectively inhibit p-ERK in GP2D cells.

[0903] 2. Experimental Procedure

[0904] 1). GP2D cells were seeded in a transparent 96-well cell culture plate, with 80 μL of cell suspension per well, and each well contained 8,000 cells. The cell plate was placed in a carbon dioxide incubator and incubated at 37 degrees overnight;

[0905] 2). Take 2 μL of compound and add it to 78 μL of cell culture medium. After mixing, take 20 μL of compound solution and add it to the corresponding well of the cell plate. Put the cell plate back into the carbon dioxide incubator and continue to incubate for 1 hour.

[0906] 3). After the incubation, discard the cell supernatant and add 50 μL 1X cell lysis buffer to each well, and incubate at room temperature with shaking for 30 minutes;

[0907] 4). Use detection buffer to dilute Phospho-ERK1 / 2 Eu Cryptate antibody and Phospho-ERK1 / 2 d2 antibody 20 times;

[0908] 5). Take 16μL of cell lysate supernatant per well into a new 384-well white microplate, add 2μL of Phospho-ERK1 / 2 Eu Cryptate antibody dilution and 2μL of Phospho-ERK1 / 2 d2 antibody dilution, and incubate at room temperature for at least 4 hours;

[0909] 6). After incubation, use a multi-label analyzer to read HTRF excitation: 320nm, emission: 615nm, 665nm;

[0910] 7). Calculate the IC of the compound to be tested 50 .

[0911] 3. Experimental results

[0912] The results are shown in Table 13.

[0913] Table 13 IC of compounds for inhibition of p-ERK in GP2D cells 50 value

[0914]

[0915]

[0916] Experimental conclusion: The compounds of the present invention have significant inhibitory effects on p-ERK in GP2D cells.

[0917] Experimental Example 6. GP2D cell proliferation inhibition test

[0918] 1. Experimental purpose:

[0919] This experiment aims to verify the inhibitory effect of the compounds of the present invention on the proliferation of GP2D human pancreatic cancer cells with KRAS G12D mutation.

[0920] 2. Experimental Materials:

[0921] Cell line GP2D, DMEM medium, penicillin / streptomycin antibiotics were purchased from Vicente, and fetal bovine serum was purchased from Biosera. 3D Cell Viability Assay (3D cell viability chemiluminescence detection reagent) reagent was purchased from Promega.

[0922] 3. Experimental methods:

[0923] GP2D cells were seeded in a 96-well U-bottom cell culture plate, with 80 μL of cell suspension per well, containing 2000 GP2D cells. The cell plate was placed in a carbon dioxide incubator for overnight culture. The compound to be tested was diluted 5 times to the 8th concentration, i.e., from 200 μM to 2.56 nM, using a dispenser, and a double-well experiment was set up. 78 μL of culture medium was added to the middle plate, and then 2 μL of the gradient dilution compound per well was transferred to the middle plate according to the corresponding position, and 20 μL of each well was transferred to the cell plate after mixing. The concentration range of the compound transferred to the cell plate was 1 μM to 0.0128 nM. The cell plate was placed in a carbon dioxide incubator for 5 days. After the cell plate with the compound added was incubated, 100 μL of cell viability chemiluminescent detection reagent was added to the cell plate per well, and the luminescent signal was stabilized at room temperature for 10 minutes. The reading was read using a multi-label analyzer.

[0924] 4. Data Analysis:

[0925] The raw data were converted into inhibition rate using the equation (Sample-Min) / (Max-Min)*100%, and the IC50 value was obtained by four-parameter curve fitting ("log (inhibitor) vs. response--Variable slope" mode in GraphPad Prism).

[0926] 5. Experimental Results

[0927] The results are shown in Table 14.

[0928] Table 14. IC of compounds against GP2D cell proliferation inhibition 50 value

[0929] Compound No. <![CDATA[GP2D IC 50 (nM)]]> Formate salt of compound 026 16

[0930] Experimental conclusion: The compound of the present invention has a significant inhibitory effect on GP2D cell proliferation.

[0931] Experimental Example 7: In vivo pharmacokinetic study

[0932] Compound 002A was prepared for intravenous injection by mixing with 5% dimethyl sulfoxide / 95% (10% hydroxypropyl-β-cyclodextrin aqueous solution) solution to a clear solution of 0.40 mg / mL. For oral solvent preparation, the test compound was mixed with 5% dimethyl sulfoxide / 95% (10% hydroxypropyl-β-cyclodextrin aqueous solution) solution, stirred until visually uniform, and then diluted to 3 mg / mL. Compound 013B and Compound 017B were prepared for intravenous injection by mixing with 5% dimethyl sulfoxide / 10% polyethylene glycol-15 hydroxystearate / 85% water to a clear solution of 0.4 mg / mL, stirred until clear. For oral solvent preparation, the test compound was mixed with 5% dimethyl sulfoxide / 95% (10% hydroxypropyl-β-cyclodextrin aqueous solution) solution, stirred until visually uniform, and then diluted to 5 mg / mL. Male C57BL / 6J mice aged 7 to 10 weeks were selected and the candidate compound solution was intravenously injected or orally. Whole blood was collected for a certain period of time to prepare plasma, and the drug concentration was analyzed by LC-MS / MS method, and the pharmacokinetic parameters were calculated using CertaraWinNonlin software (Certara, USA). The experimental results are shown in Table 15:

[0933] Table 15. Pharmacokinetic results of the tested compounds

[0934]

[0935]

[0936] Experimental conclusion: PK studies showed that each compound had good plasma exposure and oral bioavailability in mice.

Claims

1. The following compounds or their pharmaceutically acceptable salts, wherein the compound is selected from 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

3. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from 4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 8. The compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof for use in the preparation of a method for treating KRAS G12D Application of drugs in mutation-related tumors.

9. The use according to claim 8, wherein the tumor is colorectal cancer or pancreatic cancer.

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