Fused pyridone compound, and preparation method therefor and use thereof

Abstract

Disclosed in the present invention are a fused pyridone compound, and a preparation method therefor and a use thereof. Specifically, the present invention discloses a compound of formula (I-B), an optical isomer thereof and a pharmaceutically acceptable salt thereof, and the use of the compound as a KRAS inhibitor.

Description

Fused pyridinone compounds, their preparation methods and applications

[0001] This invention claims the following priority:

[0002] CN201910892032.X, application date: September 20, 2019.

[0003] CN201911129688.2, application date: November 18, 2019.

[0004] CN201911157939.8, application date: November 22, 2019.

[0005] CN202010054188.3, ​​application date: January 17, 2020.

[0006] CN202010102546.3, application date: February 19, 2020.

[0007] CN202010230303.8, application date: March 27, 2020.

[0008] CN202010306926.9, application date: April 17, 2020.

[0009] CN202010367694.8, application date: April 30, 2020.

[0010] CN202010967317.8, application date: September 15, 2020. Technical Field

[0011] This invention relates to the compound represented by formula (I-B), its optical isomers and pharmacologically acceptable salts thereof, and the use of the compound as a KRAS inhibitor. Background Technology

[0012] Cancer has been the leading cause of death in China for 31 consecutive years, with lung cancer being one of the most common cancers, accounting for over 80% of all cases. Lung cancer also has a high incidence rate and a wide variety of mutations. To enrich the company's R&D pipeline and focus on unmet medical needs, developing innovative drugs for cancer treatment is essential for the company's long-term development and has significant economic and social implications.

[0013] Approximately 30% of cancer patients have RAS gene mutations. In cancer gene research, scientists discovered more than 20 years ago that the RAS gene is a key gene in cancers including lung cancer, colorectal cancer, and pancreatic cancer.

[0014] In the United States, the three cancers with the highest mortality rates (pancreatic cancer, colorectal cancer, and lung cancer) are also the three cancers with the most common RAS mutations, accounting for 95%, 52%, and 31% of patients with these three cancers, respectively. In pancreatic cancer, colorectal cancer, and lung cancer, KRAS mutations are the vast majority, while NRAS mutations are more common in melanoma and acute myeloid leukemia, and HRAS mutations are more common in bladder cancer and head and neck cancer.

[0015] The KRAS gene mutation rate in Asian populations is 10–15%. KRAS is a major oncogene that mutates in many cancers. KRAS-mutant tumors are the most potentially targeted molecular subtype of non-small cell lung cancer (NSCLC), with a mutation rate of approximately 15%–25% in NSCLC. In NSCLC cases, KRAS mutations primarily occur at codons 12 and 13. The most common codon variation, accounting for approximately 39% of KRAS-mutant NSCLCs, is the KRAS-G12C mutation.

[0016] In lung adenocarcinoma, the KRAS gene positivity rate is 1 / 5 to 1 / 4, second only to EGFR positivity. The lack of targeted inhibitors makes treatment and prognosis extremely difficult for KRAS-positive non-small cell lung cancer patients. The 2013 NCCN Clinical Practice Guidelines for Non-Small Cell Lung Cancer clearly state that lung cancer patients must undergo KRAS gene testing before receiving EGFR-TKI treatment, and the decision to use EGFR-TKI targeted drugs as a clinical treatment measure is based on the test results. If the KRAS gene is mutated, molecular targeted therapy with EGFR-TKIs is not recommended.

[0017] According to the Thomson Reuters Competitive Intelligence Drug Database (Cortellis For CI), there are currently 162 drugs directly related to the RAS gene / protein (data retrieved on August 18, 2016), including 18 KRAS small molecule drugs, comprising 10 KRAS GTPase inhibitors, 4 KRAS gene inhibitors, 2 KRAS GTPase modulators, and 2 KRAS gene modulators; one such drug is currently in clinical trials. Furthermore, the first KRAS inhibitor developed by a Taiwanese company, Androgene, has entered Phase II clinical trials with the US FDA, and AstraZeneca's inhibitor selactinib, targeting the MEK pathway downstream of KRAS, is also undergoing Phase II clinical trials. KRAS mutations are among the most important tumor driver genes. These mutations account for a significant proportion of pancreatic cancer, lung cancer, and colorectal cancer. Currently, there are no specific targeted drugs acting on this target. Therefore, this project has significant medical research and clinical application value, and even greater medical value for the Chinese population. The molecular mechanism of KRAS-G12C small molecule drug has been basically elucidated. The drug's molecular structure and efficacy have been verified under existing experimental conditions, and it possesses high activity characteristics and the potential to become a drug.

[0018] Summary of the Invention

[0019] In a first aspect, the present invention provides compounds of formula (I-B), their optical isomers, and their pharmacologically acceptable salts.

[0020]

[0021] in,

[0022] R1 and R2 are independently selected from H, halogens, and C, respectively. 1-6 Alkyl, the C 1-6 Alkyl groups may be optionally substituted with 1, 2, or 3 Rs;

[0023] R3 is selected from H, halogens, OH, NH2, CN, and C. 1-6 Alkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic alkyl -O- and C 3-6 cycloalkyl-O-, the C 1-6 Alkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic alkyl -O- or C 3-6 The cycloalkyl-O- can be optionally substituted with 1, 2 or 3 Rs;

[0024] R4 is independently selected from H, halogen, OH, NH2, CN, and C, respectively. 1-6 Alkyl, C1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-10 membered heteroaryl, phenyl-5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl-5-6 membered heterocycloalkyl, wherein C 1-6 Alkyl, C 1- 6 heteroalkyl, C 3-6 Cycloalkyl, 3-6-membered heterocycloalkyl, phenyl, 5-10-membered heteroaryl, phenyl-5-6-membered heterocycloalkyl or 5-6-membered heteroaryl-5-6-membered heterocycloalkyl may be substituted by 1, 2 or 3 Rs;

[0025] R5 is selected from H and C. 1-6 Alkyl, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl-C 1-3 Alkyl-, 3- to 8-membered heterocyclic alkyl, phenyl, naphthyl, 5- to 10-membered heteroaryl, phenyl-5- to 6-membered heterocyclic alkyl, and 5- to 6-membered heteroaryl-5- to 6-membered heterocyclic alkyl, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl-C 1-3 Alkyl-, 3- to 8-membered heterocyclic alkyl, phenyl, naphthyl, 5- to 10-membered heteroaryl, phenyl-5- to 6-membered heterocyclic alkyl, or 5- to 6-membered heteroaryl-5- to 6-membered heterocyclic alkyl may be substituted with 1, 2 or 3 Rs;

[0026] L1 is selected from -C(=O)-, -S(=O)- and -S(=O)2-;

[0027] R6 is selected from H, CN, and C. 1-6 Alkyl, C 1-6 Alkyl-S(=O)2-, 3- to 6-membered heterocyclic alkyl, -C 1-6 Alkyl-3 to 6-membered heterocyclic alkyl groups and C 3-6 cycloalkyl-C(=O)-, wherein the C 1-6 Alkyl, C 1-6 Alkyl-S(=O)2-, 3- to 6-membered heterocyclic alkyl, -C 1-6 Alkyl-3 to 6-membered heterocyclic alkyl or C 3-6 The cycloalkyl-C(=O) group is optionally substituted with 1, 2 or 3 R groups;

[0028] R7 is independently selected from H, halogen, OH, NH2, CN, -C(=O)-OH, C 1-6 Alkyl-OC(=O)-, -C(=O)-NH2, C 1-6 Alkyl, C 1-6 Heteroalkyl and -C 1-6 Alkyl-3 to 6-membered heterocyclic alkyl, wherein the C 1-6 Alkyl, C 1-6 Heteroalkyl C 1-6Alkyl-OC (=O)- or -C 1-6 The alkyl-3 to 6-membered heterocyclic alkyl group may be substituted with 1, 2 or 3 Rs;

[0029] T1 and T2 are independently selected from N and -C(R8)-, respectively;

[0030] R8 is selected from H, halogens, OH, NH2, CN, and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl and 3- to 6-membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or 3- to 6-membered heterocycloalkyl groups may be optionally substituted with 1, 2, or 3 Rs;

[0031] R9 is selected from H, halogens, OH, NH2, CN, and C. 1-6 Alkyl and C 1-6 Heteroalkyl, the C 1-6 Alkyl or C 1-6 The heteroalkyl group may be optionally substituted with 1, 2 or 3 Rs;

[0032] R 10 Selected from H, halogens, CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Alkylamino, the C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 The alkylamino group may be substituted with 1, 2 or 3 R groups;

[0033] R is independently selected from H, halogen, OH, NH2, CN, etc. C 1-6 Alkyl, C 1-6 Heterocyclic alkanes, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, C 3-6 Cycloalkyl-O- and 5- to 6-membered heterocycloalkyl-O-, wherein the C 1-6 Alkyl, C 1-6 Heterocyclic alkanes, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, C 3-6 Cycloalkyl-O- or 5- to 6-membered heterocycloalkyl-O- may be substituted with 1, 2 or 3 R';

[0034] R' is selected from F, Cl, Br, I, OH, NH2 and CH3;

[0035] Ring A is independently selected from C 6-10 Aryl, 5-10-membered heteroaryl, phenyl-5-6-membered heterocyclic alkyl and 5-6-membered heteroaryl-5-6-membered heterocyclic alkyl;

[0036] n is selected from 0, 1, 2, 3 or 4;

[0037] m is selected from 0, 1, 2, 3 or 4;

[0038] D1 is selected from O;

[0039] Y is selected from N, CH, or C;

[0040] for And when for At that time, R2, R 10 It does not exist;

[0041] for

[0042] when middle for At that time, X1 and X2 are independently selected from -N=, -C(R7)= and -C(R7)2-C(R7)=, respectively;

[0043] when middle for X1 and X2 are independently selected from single bonds, -O-, -S-, S(=O), S(=O)2, -N(R6)-, -C(=O)-, -C(R7)2- and -C(R7)2-C(R7)2-, respectively;

[0044] Furthermore, Y cannot connect two nodes simultaneously. When the key between Y and R9 is At that time, R9 does not exist;

[0045] The above-mentioned 3-6 membered heterocyclic alkyl, 5-6 membered heteroaryl, 5-6 membered heterocyclic alkyl, 5-10 membered heteroaryl or C 1-6 Heteroalkyl groups contain one, two or three heteroatoms or heterogroups independently selected from -O-, -NH-, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2- and N.

[0046] In another aspect, the present invention also proposes the compound represented by formula (I-A), its optical isomers, and its pharmacologically acceptable salts.

[0047]

[0048] in,

[0049] R1 and R2 are independently selected from H, halogens, and C, respectively. 1-6 Alkyl, the C1-6 Alkyl groups may be optionally substituted with 1, 2, or 3 Rs;

[0050] R3 is selected from H, halogens, OH, NH2, CN, and C. 1-6 Alkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic alkyl -O- and C 3-6 cycloalkyl-O-, the C 1-6 Alkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic alkyl -O- or C 3-6 The cycloalkyl-O- can be optionally substituted with 1, 2 or 3 Rs;

[0051] R4 is independently selected from H, halogen, OH, NH2, CN, and C, respectively. 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-10 membered heteroaryl, phenyl-5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl-5-6 membered heterocycloalkyl, wherein C 1-6 Alkyl, C 1- 6 heteroalkyl, C 3-6 Cycloalkyl, 3-6-membered heterocycloalkyl, phenyl, 5-10-membered heteroaryl, phenyl-5-6-membered heterocycloalkyl or 5-6-membered heteroaryl-5-6-membered heterocycloalkyl may be substituted by 1, 2 or 3 Rs;

[0052] R5 is selected from H and C. 1-6 Alkyl, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl-C 1-3 Alkyl-, 3- to 8-membered heterocyclic alkyl, phenyl, naphthyl, 5- to 10-membered heteroaryl, phenyl-5- to 6-membered heterocyclic alkyl, and 5- to 6-membered heteroaryl-5- to 6-membered heterocyclic alkyl, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl-C 1-3 Alkyl-, 3- to 8-membered heterocyclic alkyl, phenyl, naphthyl, 5- to 10-membered heteroaryl, phenyl-5- to 6-membered heterocyclic alkyl, or 5- to 6-membered heteroaryl-5- to 6-membered heterocyclic alkyl may be substituted with 1, 2 or 3 Rs;

[0053] L1 is selected from -C(=O)-, -S(=O)- and -S(=O)2-;

[0054] R6 is selected from H, CN, and C. 1-6 Alkyl, C 1-6 Alkyl-S(=O)2-, 3- to 6-membered heterocyclic alkyl, -C 1-6 Alkyl-3 to 6-membered heterocyclic alkyl groups and C3-6 cycloalkyl-C(=O)-, wherein the C 1-6 Alkyl, C 1-6 Alkyl-S(=O)2-, 3- to 6-membered heterocyclic alkyl, -C 1-6 Alkyl-3 to 6-membered heterocyclic alkyl or C 3-6 The cycloalkyl-C(=O) group is optionally substituted with 1, 2 or 3 R groups;

[0055] R7 is independently selected from H, halogen, OH, NH2, CN, -C(=O)OH, C 1-6 Alkyl-OC(=O)-, -C(=O)-NH2, C 1-6 Alkyl, C 1-6 Heteroalkyl and -C 1-6 Alkyl-3 to 6-membered heterocyclic alkyl, wherein the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Alkyl-OC (=O)- or -C 1-6 The alkyl-3 to 6-membered heterocyclic alkyl group may be substituted with 1, 2 or 3 Rs;

[0056] T1 and T2 are independently selected from N and -C(R8)-, respectively;

[0057] R8 is selected from H, halogens, OH, NH2, CN, and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl and 3- to 6-membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or 3- to 6-membered heterocycloalkyl groups may be optionally substituted with 1, 2, or 3 Rs;

[0058] R is independently selected from H, halogen, OH, NH2, CN, etc. C 1-6 Alkyl, C 1-6 Heterocyclic alkanes, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, C 3-6 Cycloalkyl-O- and 5- to 6-membered heterocycloalkyl-O-, wherein the C 1-6 Alkyl, C 1-6 Heterocyclic alkanes, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, C 3-6 Cycloalkyl-O- or 5- to 6-membered heterocycloalkyl-O- may be substituted with 1, 2 or 3 R';

[0059] R' is selected from F, Cl, Br, I, OH, NH2 and CH3;

[0060] Ring A is independently selected from C 6-10Aryl, 5-10-membered heteroaryl, phenyl-5-6-membered heterocyclic alkyl and 5-6-membered heteroaryl-5-6-membered heterocyclic alkyl;

[0061] n is selected from 0, 1, 2, 3 or 4;

[0062] for And when for At that time, R2 does not exist;

[0063] for or;

[0064] when middle for At that time, X1 and X2 are independently selected from -N=, -C(R7)= and -C(R7)2-C(R7)=, respectively;

[0065] when middle for X1 and X2 are independently selected from single bonds, -O-, -S-, S(=O), S(=O)2, -N(R6)-, -C(=O)-, -C(R7)2- and -C(R7)2-C(R7)2-, respectively;

[0066] The above-mentioned 3-6 membered heterocyclic alkyl, 5-6 membered heteroaryl, 5-6 membered heterocyclic alkyl, 5-10 membered heteroaryl or C 1-6 Heteroalkyl groups contain one, two or three heteroatoms or heterogroups independently selected from -O-, -NH-, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2- and N.

[0067] In some embodiments of the present invention, the above-mentioned compound, its optical isomer, and its pharmacologically acceptable salt are selected from...

[0068]

[0069] in,

[0070] X1 and X2 are independently selected from single bonds, -O-, -S-, S(=O), S(=O)2, -N(R6)-, -C(=O)-, -C(R7)2- and -C(R7)2-C(R7)2-, respectively. R1, R2, R3, R4, R5, L1, R6, R7, T1, T2, ring A and n are as defined above.

[0071] In some embodiments of the present invention, the R mentioned above is independently selected from H, halogen, OH, NH2, CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, C 3-6 Cycloalkyl-O- and -5 to 6-membered heterocycloalkyl-O-, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, C 3-6 Cycloalkyl-O- or 5- to 6-membered heterocycloalkyl-O- may be substituted with 1, 2 or 3 R', and other variables are as defined in this invention.

[0072] In some embodiments of the present invention, the R mentioned above is independently selected from H, F, Cl, Br, I, OH, NH2, CN, Me, CH2CH3, Other variables are as defined in this invention.

[0073] In some embodiments of the present invention, R1 and R2 are independently selected from H, F, Me, CF3, Other variables are as defined in this invention.

[0074] In some embodiments of the present invention, the above-mentioned structural unit Selected from Other variables are as defined in this invention.

[0075] In some embodiments of the present invention, R3 is selected from H, halogens, OH, NH2, CN, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 1-3 Alkylthio, 3-6 membered heterocyclic alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic alkyl -O- and C 3-6 cycloalkyl-O-, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 1-3 Alkylthio, 3-6 membered heterocyclic alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic alkyl -O- or C 3-6 The cycloalkyl-O- can be optionally replaced by 1, 2 or 3 Rs, and other variables are as defined in this invention.

[0076] In some embodiments of the present invention, R3 is selected from H, F, Cl, Br, I, OH, NH2, CN, Me, CF3, Other variables are as defined in this invention.

[0077] In some embodiments of the present invention, R4 is independently selected from H, halogen, OH, NH2, CN, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 1-3 Alkylthio, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, pyridinyl, pyrimidinyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, benzofuranyl, benzothienyl, and indoleyl, wherein C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 1-3 Alkylthio, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic alkyl, phenyl, pyridinyl, pyrimidinyl, thiophene, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, benzofuranyl, benzothiopheneyl, or indoleyl may be substituted with 1, 2, or 3 Rs, and other variables are as defined in this invention.

[0078] In some embodiments of the present invention, R4 is selected from H, F, Cl, Br, I, OH, NH2, CN, Me, CF3, Other variables are as defined in this invention.

[0079] In some embodiments of the present invention, the ring A is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, thiophene, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazole, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, benzofuranyl, benzothiophene, indoleyl, inzolyl, benzimidazolyl, 1H-benzo[d]imidazolyl, benzopyrazolyl, purine, Quinolinyl, isoquinolinyl, isoquinolin-1(2H)-keto, isoindoline-1-keto, benzo[d]oxazol-2(H)-keto, benzo[d]oxazol-2(3H)-keto, H-benzo[d][1,2,3]triazolyl, 1H-pyrazolo[3,4-b]pyridyl, benzo[d]thiazolyl and 1,3-dihydro-2H-benzo[d]imidazol-2-keto, the phenyl, Naphthyl, pyridyl, pyrimidinyl, pyridazinyl, thiophene, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazole, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, benzofuranyl, benzothiophene, indoleyl, inazolyl, benzimidazolyl, 1H-benzo[d]imidazolyl, benzopyrazolyl, purine, quinolinyl, isoquinolinyl, isoquinolin-1(2H)- The ketone group, isoindoline-1-keto group, benzo[d]oxazol-2(H)-keto group, benzo[d]oxazol-2(3H)-keto group, H-benzo[d][1,2,3]triazolyl group, 1H-pyrazolo[3,4-b]pyridyl group, benzo[d]thiazolyl group, or 1,3-dihydro-2H-benzo[d]imidazol-2-keto group may be substituted with 1, 2, or 3 R groups, and other variables are as defined in this invention.

[0080] In some embodiments of the present invention, the above-mentioned structural unit Selected from Other variables are as defined in this invention.

[0081] In some embodiments of the present invention, R5 is selected from H and C. 1-3 Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydro-2H-pyranyl, piperidinyl, piperazineyl, 5- to 6-membered heterocyclic alkyl-C 1-3 Alkyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, thiophene, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazole, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, benzofuranyl, benzothiophene, indoleyl, benzimidazolyl, benzopyrazolyl, purine, quinolinyl, isoquinolinyl, isoquinolin-1(2H)-keto, isoindololin-1-keto, benzo[d]oxazol-2(H)-keto, and 1,3-dihydro-2H-benzo[d]imidazol-2-keto, the C 1-3Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydro-2H-pyranyl, piperidinyl, piperazineyl, 5- to 6-membered heterocyclic alkyl-C 1-3 Alkyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, thiophene, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazole, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, benzofuranyl, benzothiophene, indolyl, benzimidazolyl, benzopyrazolyl, purine, quinolinyl, isoquinolinyl, isoquinolin-1(2H)-keto, isoindololin-1-keto, benzo[d]oxazol-2(H)-keto, or 1,3-dihydro-2H-benzo[d]imidazol-2-keto may be substituted with 1, 2, or 3 Rs, and other variables are as defined in this invention.

[0082] In some embodiments of the present invention, R5 is selected from H, Me, Other variables are as defined in this invention.

[0083] In some embodiments of the present invention, R7 is independently selected from H, halogen, OH, NH2, CN, and C. 1-3 Alkyl, C 1-3 Alkyl-OC(=O)-, -C(=O)-NH2, C 1-3 Alkoxy, C 1-3 Alkylamino, C 1-3 alkylthio and -C 1-3 Alkyl-3 to 6-membered heterocyclic alkyl, wherein the C 1-3 Alkyl, C 1-3 Alkyl-OC(=O)-, -C(=O)-NH2, C 1-3 Alkoxy, C 1-3 Alkylamino, C 1-3 alkylthio or -C 1-3 The alkyl-3 to 6-membered heterocyclic alkyl group may be substituted with 1, 2 or 3 Rs, and other variables are as defined in this invention.

[0084] In some embodiments of the present invention, R7 is independently selected from H, F, Cl, Br, I, OH, NH2, CN, Me, CF3, Other variables are as defined in this invention.

[0085] In some embodiments of the present invention, R6 is independently selected from H, CN, and C. 1-3 Alkyl, C 1-3 Alkyl-S(=O)2-, 3- to 6-membered heterocyclic alkyl, -C 1-3 Alkyl-3 to 6-membered heterocyclic alkyl groups and C3-6 cycloalkyl-C(=O)-, wherein the C 1-3 Alkyl, C 1-3 Alkyl-S(=O)2-, 3- to 6-membered heterocyclic alkyl, -C 1-3 Alkyl 3-6 membered heterocyclic alkyl or C 3-6 The cycloalkyl-C(=O)- is optionally substituted with 1, 2 or 3 Rs, and other variables are as defined in this invention.

[0086] In some embodiments of the present invention, R6 is independently selected from H, CN, Me, CF3, Other variables are as defined in this invention.

[0087] In some embodiments of the present invention, X1 and X2 are independently selected from single bonds, CH2, CH2CH2, C(=O), O, S, NH, N(CH3), S(=O), S(=O)2, etc. Other variables are as defined in this invention.

[0088] In some embodiments of the present invention, R8 is selected from H, halogens, OH, NH2, CN, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino and C 1-3 Alkylthio, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino or C 1-3 The alkylthio group may be optionally substituted with 1, 2 or 3 R groups, and other variables are as defined in this invention.

[0089] In some embodiments of the present invention, R8 is selected from H, F, Cl, Br, I, OH, NH2, CN, Me, CF3, Other variables are as defined in this invention.

[0090] In some embodiments of the present invention, the above-mentioned structural unit Selected from Other variables are as defined in this invention.

[0091] In another aspect, the present invention also provides compounds of the following formula, their optical isomers, and their pharmacologically acceptable salts.

[0092] In another aspect of the invention, a pharmaceutical composition is also provided, the pharmaceutical composition comprising the compound as described above, its optical isomer and its pharmacologically acceptable salt, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0093] In another aspect of the invention, the invention also proposes the use of the foregoing compounds, their optical isomers, and their pharmacologically acceptable salts or the foregoing pharmaceutical compositions in the preparation of medicaments for the prevention and / or treatment of KRAS-G12C-related diseases.

[0094] In some embodiments of the present invention, the aforementioned KRAS-G12C-related diseases are selected from non-small cell lung cancer, colon cancer, and pancreatic cancer.

[0095] Definitions and Explanations

[0096] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0097] The term “pharmaceutically acceptable” as used herein refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0098] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of this invention, prepared by reacting a compound having specific substituents discovered in this invention with a relatively non-toxic acid or base. When the compounds of this invention contain relatively acidic functional groups, base addition salts can be obtained by contacting a neutral form of such compound 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 this invention contain relatively basic functional groups, acid addition salts can be obtained by contacting a neutral form of such compound with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; as well as salts of amino acids (such as arginine) and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups, and thus can be converted into either a base or an acid addition salt.

[0099] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture thereof.

[0100] A hyphen ("-") not between two letters or symbols indicates the connection site of a substituent. For example, C 1-6 Alkyl carbonyl group - refers to a carbonyl group connected to the rest of the molecule via a carbonyl group. 1-6 Alkyl groups. However, when the linking site of the substituent is obvious to those skilled in the art, such as halogen substituents, the "-" may be omitted.

[0101] When the group valence bond is marked with a dashed line At times, for example, in In the diagram, the wavy line indicates the connection point between the group and other parts of the molecule.

[0102] The compounds of this invention can exist in specific geometric or stereoisomeric or optical isomeric forms. This invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this invention.

[0103] Unless otherwise stated, the terms "enantiomer" or "optical isomer" refer to stereoisomers that are mirror images of each other.

[0104] Unless otherwise stated, the terms "cis-trans isomers" or "geometric isomers" arise because the single bonds of double bonds or cyclic carbon atoms cannot rotate freely.

[0105] Unless otherwise stated, the term "diastereomer" refers to a stereoisomer of a molecule having two or more chiral centers and being in a non-mirror relationship with each other.

[0106] Unless otherwise specified, use wedge-shaped solid line keys. and wedge-shaped dashed key It represents the absolute configuration of the center of a solid.

[0107] The compounds of this invention can exist in specific forms. Unless otherwise stated, the terms "tautomer" or "tautomer form" refer to isomers of different functional groups in dynamic equilibrium at room temperature, capable of rapidly interconverting into each other. If tautomerization is possible (e.g., in solution), chemical equilibrium of the tautomer can be achieved. For example, proton tautomers (also called prototropic tautomers) include interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions involving the rearrangement of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between the two tautomers, pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0108] The compounds of this invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium. 3 H), Iodine-125 125 I) or C-14 14C). For example, deuterium can be used to replace hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than that between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds of the present invention, regardless of radioactivity, are included within the scope of the present invention. "Optional" or "optionally" means that the events or conditions described below may occur but are not necessary, and the description includes both the occurrence of said events or conditions and the non-occurrence of said events or conditions.

[0109] Stereochemical definitions and conventions can be found in SP Parker, ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994. Many organic compounds exist in an optically active form, meaning they possess the ability to rotate the plane of polarized light. In describing optically active compounds, the prefixes D and L, or R and S, are used to indicate the absolute configuration of the molecule with respect to its chiral center. The prefixes d and l, or (+) and (-), are used to indicate the symbol for rotating the plane of polarized light, where (-) or l indicates that the compound is levorotatory. Compounds with the prefix (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers can also be called enantiomers, and mixtures of such isomers are often called enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur in chemical reactions or methods where there is no stereoselectivity or stereospecificity. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two optically inactive enantiomers.

[0110] Racemic mixtures can be used in their original form or resolved into individual isomers. Resolution yields stereochemically pure compounds or mixtures enriched with one or more isomers. Methods for isomer separation are well-known (see Allinger NL and Eliel EL, "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971), including physical methods such as chromatography using chiral adsorbents. Individual chiral isomers can be prepared from chiral precursors. Alternatively, a single isomer can be chemically separated from a mixture by forming a diastereomeric salt with a chiral acid (e.g., a single enantiomer of 10-camphorsulfonic acid, camphoric acid, α-bromocamphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, etc.), the salt is fractionally crystallized, and one or both of the separated bases are then released. This process can optionally be repeated to obtain one or two isomers that substantially do not contain the other isomer, i.e., the desired stereoisomers with an optical purity of, for example, at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% by weight. Alternatively, as is well known to those skilled in the art, a racemic compound can be covalently attached to a chiral compound (auxiliary compound) to obtain a diastereomeric isomer.

[0111] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which can include deuterium and hydrogen variants, provided that 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 or may not be substituted, unless otherwise specified, and the type and number of substituents can be arbitrary on a chemically feasible basis.

[0112] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Thus, for example, if a group is substituted by 0-2 Rs, the group can optionally be substituted by at most two Rs, and the Rs in each case have independent options. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound.

[0113] When one of the variables is selected as a single bond, it means that the two groups it connects to are directly connected, for example... When L3 represents a single bond, it means that the structure is actually

[0114] When the listed substituents do not specify which atom they are attached to the substituted group, such substituents can be bonded to any of their atoms. For example, a pyridinium substituent can be attached to the substituted group by any carbon atom on the pyridine ring.

[0115] When the listed linking groups do not specify their linking direction, the linking direction is arbitrary, for example, The linking group L is at this time The benzene ring and cyclohexane can be connected in the same direction as the reading order from left to right to form the structure. Alternatively, the benzene ring and cyclohexane can be connected in the reverse order of reading from left to right to form the benzene ring. The combination of linking groups, substituents, and / or their variants is permitted only if such a combination produces a stable compound.

[0116] Unless otherwise specified, the number of atoms in a ring is usually defined as the elemental number of the ring. For example, a “5-7 elemental ring” refers to a “ring” with 5-7 atoms arranged around it.

[0117] Unless otherwise specified, the term "C" 1-6 "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C 1-6 Alkyl groups include C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-4 C6 and C5 alkyl groups, etc.; they can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). 1-6 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, etc.

[0118] Unless otherwise specified, the term "C" 1-3 "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C 1-3 Alkyl groups include C 1-2 and C 2-3 Alkyl groups, etc.; they can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). C 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), etc.

[0119] The term "heteroalkyl" on its own or in combination with another term refers to a stable straight-chain or branched alkyl group or a combination thereof consisting of a certain number of carbon atoms and at least one heteroatom or heterogroup. In some embodiments, the heteroatom is selected from B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. In other embodiments, the heterogroup is selected from -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O)2-, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)-, and -S(=O)N(H)-. In some embodiments, the heteroalkyl group is C 1-6 Heteroalkyl; in other embodiments, the heteroalkyl group is C10. 1-3 Heteroalkyl. Heteroatoms or heteroatomic groups can be located in any internal position of a heteroalkyl group, including the position where the alkyl group is attached to the rest of the molecule, but the terms "alkoxy", "alkamino" and "alkthio" (or thioalkoxy) are conventional expressions referring to those alkyl groups that are attached to the rest of the molecule by an oxygen atom, an amino atom or a sulfur atom, respectively. Examples of heteroalkyl groups include, but are not limited to, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH2(CH3)2, -CH2-CH2-O-CH3, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)(CH2CH3), -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, -CH2-S-CH2-CH3, -CH2-CH2, -S(=O)-CH3, -CH2-CH2-S(=O)2-CH3, and. At most two heteroatoms can be consecutive, for example, -CH2-NH-OCH3.

[0120] Unless otherwise specified, the term "C" 1-6 "Alkoxy" refers to alkyl groups containing 1 to 6 carbon atoms that are attached to the rest of the molecule by an oxygen atom. The C 1-6 Alkoxy groups include C 1-4 C 1-3 C 1-2 C 2-6 C 2-4 C6, C5, C4, and C3 alkoxy groups, etc. 1- Examples of 6-alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), pentoxy (including n-pentoxy, isopentoxy and neopentoxy), hexoxy, etc.

[0121] Unless otherwise specified, the term "C" 1-3 "Alkoxy" refers to alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule by an oxygen atom. The C 1-3 Alkoxy groups include C 1-2 C 2-3 C3 and C2 alkoxy groups, etc. 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), etc.

[0122] Unless otherwise specified, the term "C" 1-6 "Alkylamino" refers to alkyl groups containing 1 to 6 carbon atoms that are attached to the rest of the molecule via an amino group. The C 1-6 Alkylamino groups include C 1-4 C 1-3 C 1-2 C 2-6 C 2-4 C6, C5, C4, C3, and C2 alkylamino groups, etc. 1-6 Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -N(CH2CH3)(CH2CH3), -NHCH2CH2CH3, -NHCH2(CH3)2, -NHCH2CH2CH2CH3, etc.

[0123] Unless otherwise specified, the term "C" 1-3 "Alkylamino" refers to alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule via an amino group. The C 1-3 Alkylamino groups include C 1-2 C3 and C2 alkylamino groups, etc. C 1-3 Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -NHCH2CH2CH3, -NHCH2(CH3)2, etc.

[0124] Unless otherwise specified, the term "C" 1-6 "Alkylthio" refers to alkyl groups containing 1 to 6 carbon atoms that are attached to the rest of the molecule via a sulfur atom. The C 1-6 Alkyl thio groups include C 1-4 C 1-3 C 1-2 C 2-6 C 2-4 C6, C5, C4, C3, and C2 alkylthio groups, etc. C 1-Examples of 6-alkylthio groups include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, etc.

[0125] Unless otherwise specified, the term "C" 1-3 "Alkylthio" refers to alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule via a sulfur atom. The C 1-3 Alkyl thio groups include C 1-3 C 1-2 And C3 alkylthio groups, etc. C 1-3 Examples of alkylthio groups include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, etc.

[0126] Unless otherwise specified, "C 3-6 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which can be monocyclic or bicyclic. 3-6 Cycloalkyl groups include C 3-5 C 4-5 and C 5-6 Cycloalkyl groups, etc.; they can be monovalent, divalent, or polyvalent. C 3-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0127] Unless otherwise specified, the term "3-8 membered heterocyclic alkyl" on its own or in combination with other terms refers to a saturated cyclic group consisting of 3 to 8 ring atoms, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)). p (where p is 1 or 2). It includes monocyclic, bicyclic, and tricyclic systems, with bicyclic systems including spirocyclic, fused, and bridged rings. Furthermore, regarding the "3-8 membered heterocyclic alkyl," the heteroatom can occupy the connection position between the heterocyclic alkyl group and the rest of the molecule. The 3-8 membered heterocyclic alkyl groups include 3-6, 3-5, 4-6, 5-6, 4, 5, and 6 membered heterocyclic alkyl groups, etc. Examples of 3-8 membered heterocyclic alkyl groups include, but are not limited to, azirrobutyl, oxacyclobutyl, thiocyclobutyl, pyrrolidinyl, pyrazolyl, imidazoalkyl, tetrahydrothiopheneyl (including tetrahydrothiophene-2-yl and tetrahydrothiophene-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperidinyl and 2-piperidinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxane, dithiaalkyl, isoxazolyl, isothiazolyl, 1,2-oxazinyl, 1,2-thiaazinyl, hexahydropyridazinyl, homopiperidinyl, homopiperidinyl, or dioxaneheptyl, etc.

[0128] Unless otherwise specified, the term "3-6 membered heterocyclic alkyl" on its own or in combination with other terms refers to a saturated cyclic group consisting of 3 to 6 ring atoms, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)). p (where p is 1 or 2). It includes monocyclic and bicyclic systems, with bicyclic systems including spirocyclic, fused, and bridged rings. Furthermore, regarding the "3-6 membered heterocyclic alkyl," the heteroatom can occupy the connection position between the heterocyclic alkyl and the rest of the molecule. The 3-6 membered heterocyclic alkyl includes 4-6, 5-6, 4, 5, and 6 membered heterocyclic alkyls, etc. Examples of 3-6 membered heterocyclic alkyl groups include, but are not limited to, azirrobutyl, oxacyclobutyl, thiocyclobutyl, pyrrolidinyl, pyrazolyl, imidazoalkyl, tetrahydrothiopheneyl (including tetrahydrothiophene-2-yl and tetrahydrothiophene-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperidinyl and 2-piperidinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxyl, dithiaalkyl, isoxazolyl, isothiazolyl, 1,2-oxazinyl, 1,2-thiaazinyl, hexahydropyridazinyl, homopiperidinyl or homopiperidinyl, etc.

[0129] Unless otherwise specified, the term "C" in this invention refers to... 6-10 "Aromatic ring" and "C" 6-10 "Aryl" can be used interchangeably; the term "C" is used interchangeably. 6-10 "Aromatic ring" or "C" 6-10 "Aryl" indicates a cyclic hydrocarbon group consisting of 6 to 10 carbon atoms with a conjugated π-electron system. It can be a monocyclic, fused bicyclic, or fused tricyclic system, where each ring is aromatic. It can be monovalent, divalent, or polyvalent. 6-10 Aryl groups include C 6-9 C9, C 10 And C6 aryl, etc. C 6-10 Examples of aryl groups include, but are not limited to, phenyl and naphthyl groups (including 1-naphthyl and 2-naphthyl groups).

[0130] Unless otherwise specified, the terms "5-10-membered heteroaryl" and "5-10-membered heteroaryl" are used interchangeably in this invention. 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 remainder 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 may optionally be oxidized (i.e., NO and S(O)).p (where p is 1 or 2). 5-10-membered heteroaryl groups can be attached to the rest of the molecule via heteroatoms or carbon atoms. These 5-10-membered heteroaryl groups include 5-8-membered, 5-7-membered, 5-6-membered, 5-membered, and 6-membered heteroaryl groups, etc. Examples of the 5-10 membered heteroaryl groups include, but are not limited to, pyrrole (including N-pyrrole, 2-pyrrole, and 3-pyrrole), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl), imidazole (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl), oxazolyl (including 2-oxazolyl, 4-oxazolyl, and 5-oxazolyl), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2,4-triazolyl), tetrazolyl, isoxazolyl (3-isooxazolyl, 4-isooxazolyl, and 5-isooxazolyl), and 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, indole (including 5-indole, etc.), isoquinolinyl (including 1-isoquinolinyl and 5-isoquinolinyl, etc.), quinoxalinyl (including 2-quinoxalinyl and 5-quinoxalinyl, etc.), or quinolinyl (including 3-quinolinyl and 6-quinolinyl, etc.).

[0131] Unless otherwise specified, the terms "5-6 membered heteroaryl" and "5-6 membered heteroaryl" are used interchangeably in this invention. The term "5-6 membered heteroaryl" refers to a monocyclic group with a conjugated π-electron system consisting of 5 to 6 ring atoms, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)). p(where p is 1 or 2). The 5-6 membered heteroaryl group can be attached to the rest of the molecule via a heteroatom or a carbon atom. The 5-6 membered heteroaryl group includes both 5-membered and 6-membered heteroaryl groups. Examples of the 5-6 membered heteroaryl group include, but are not limited to, pyrrole (including N-pyrrole, 2-pyrrole, and 3-pyrrole), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl), imidazole (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl), oxazolyl (including 2-oxazolyl, 4-oxazolyl, and 5-oxazolyl), and 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-isooxazolyl, 4-isooxazolyl and 5-isooxazolyl, 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 or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).

[0132] Unless otherwise specified, "benzo5-6-membered heterocyclic alkyl" refers to a bicyclic ring structure formed by the fusion of a phenyl group and a heterocycle and a 5-6-membered heterocyclic alkyl group, wherein the substituent can be linked to other structures via a benzene ring or a 5-6-membered heterocyclic alkyl ring. Examples of benzo5-6-membered heterocyclic alkyl groups include, but are not limited to, those described above. wait.

[0133] Unless otherwise specified, "5-6-membered heteroaryl-5-6-membered heterocyclic alkyl" refers to a bicyclic ring structure formed by the fusion of a 5-6-membered heteroaryl group and a heterocycle and a 5-6-membered heterocyclic alkyl group, wherein the substituent can be linked to other structures through a 5-6-membered heteroaryl group or a 5-6-membered heterocyclic alkyl ring. Examples of the benzo5-6-membered heterocyclic alkyl group include, but are not limited to, those described above. wait.

[0134] Unless otherwise specified, C n-n+m Or C n -C n+m This includes any specific case with n to n+m carbons, such as C 1-12 Including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 C 11 and C 12 It 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 C6-9 C 6-12 and C 9-12 Similarly, n-membered to n+m-membered rings represent the number of atoms in the ring from n to n+m. For example, 3-12-membered rings include 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, and 12-membered rings, and also any range from n to n+m. For example, 3-12-membered rings include 3-6-membered, 3-9-membered, 5-6-membered, 5-7-membered, 6-7-membered, 6-8-membered, and 6-10-membered rings, etc.

[0135] As used herein, the term "treatment" refers to the administration of one or more pharmaceutical substances, particularly compounds of formula (I) and / or pharmaceutically acceptable salts thereof, to an individual suffering from or exhibiting symptoms of a disease, for the purpose of curing, alleviating, reducing, altering, treating, improving, modifying, or influencing the disease or its symptoms. The term "prevention" as used herein refers to the administration of one or more pharmaceutical substances, particularly compounds of formula (I) and / or pharmaceutically acceptable salts thereof, to an individual with a predisposition to the disease, for the purpose of preventing the individual from contracting the disease. When a chemical reaction is involved, the terms "treatment," "contact," and "reaction" refer to the addition or mixing of two or more reagents under appropriate conditions to produce the indicated and / or desired product. It should be understood that the reaction producing the indicated and / or desired product may not necessarily originate directly from the combination of the two initially added reagents; that is, one or more intermediates may be present in the mixture that ultimately lead to the formation of the indicated and / or desired product.

[0136] As used herein, the term "effective amount" refers to an amount that is generally sufficient to produce a beneficial effect on an individual. The effective amount of the compounds of the present invention can be determined by conventional methods (e.g., modeling, dose escalation studies, or clinical trials) in combination with conventional influencing factors (e.g., route of administration, pharmacokinetics of the compound, severity and course of disease, individual medical history, individual health status, individual response to the drug, etc.).

[0137] The compounds of the present invention can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention.

[0138] The solvents used in this invention are commercially available. The following abbreviations are used in this invention: CDCl3 represents deuterated chloroform; CD3OD represents deuterated methanol; DMSO-d6 represents deuterated dimethyl sulfoxide; TBS represents tert-butyldimethylsilyl.

[0139] Compounds are named according to conventional naming principles in the field or using Software naming conventions are used; commercially available compounds use supplier catalog names. Attached Figure Description

[0140] Figure 1 is a graph showing the relationship between the number of days of NCI-H358 cell inoculation and body weight change after administration of compound 29B according to an embodiment of the present invention.

[0141] Figure 2 is a graph showing the relationship between the number of days of NCI-H358 cell inoculation and tumor volume after administration of compound 29B according to an embodiment of the present invention. Detailed Implementation

[0142] The present application is described in detail below with reference to embodiments, but this does not imply any adverse limitations on the present application. The present application has been described in detail herein, and specific embodiments thereof have been disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific implementations of the present application without departing from the spirit and scope thereof.

[0143] Example 1: Preparation of Compound 1

[0144] Step 1: Preparation of compounds 1-2

[0145]

[0146] Raw material 1-1 (2.00 g, 9.57 mmol) was dissolved in thionyl chloride (10 mL) and heated to 80 °C for 16 h. The system was concentrated to obtain a crude product, which was then dissolved in dioxane (10 mL). At 0 °C, a mixed solution of dioxane (5 mL) and ethanol (5 mL) was added dropwise. After the addition was complete, the system was stirred at room temperature (20 °C) for 1 h. The system was dissolved in ethyl acetate (20 mL), washed with saturated potassium carbonate solution, allowed to stand for separation, dried over anhydrous sodium sulfate, and concentrated to obtain a yellow oily compound 1-2.

[0147] Step 2: Preparation of compounds 1-3

[0148]

[0149] Compounds 1-2 (1.5 g, 6.32 mmol) were dissolved in methanol (15 mL). A methanol solution of sodium methoxide (1.25 g, 6.96 mmol, 30% by weight) was added dropwise at 0 °C. After the addition was complete, the system was stirred at 0 °C for 15 min, then heated to room temperature (20 °C) and stirred for 1 h. The system was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (20 mL), washed with saturated ammonium chloride solution, allowed to stand for separation, dried over anhydrous sodium sulfate, and concentrated to obtain crude compounds 1-3, which were used directly in the next reaction without further purification.

[0150] 1 H NMR (400MHz, CDCl3) 7.94 (d, 1H, J = 12Hz), 4.09 (s, 3H), 3.93 (s, 3H).

[0151] Step 3: Preparation of compounds 1-5

[0152]

[0153] Compounds 1-3 (1.05 g, 4.79 mmol), 1-4 (0.776 g, 5.75 mmol), palladium acetate (107 mg, 0.479 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (275 mg, 0.479 mmol), and cesium carbonate (3.142 g, 9.58 mmol) were dissolved in anhydrous dioxane (15 mL) at room temperature (20 °C). The system was heated to 100 °C and stirred for 3 h under a nitrogen atmosphere. The system was cooled to room temperature, concentrated, diluted with water (100 mL), extracted with ethyl acetate (3 x 20 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–10%) to give compound 1-5 as a white solid.

[0154] MS(ESI)m / z(M+H) + =319.2.

[0155] Step 4: Preparation of compounds 1-6

[0156]

[0157] Compounds 1-5 (200 mg, 0.629 mmol) and acetyl chloride (3 mL) were added to a 5 mL microwave tube. The system was heated to 150 °C and reacted for 3 h under microwave conditions. The system was cooled to room temperature and concentrated to obtain a crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–50%) to obtain a reddish-brown oily compound 1-6.

[0158] MS(ESI)m / z(M+H) + =361.2.

[0159] Step 5: Preparation of compounds 1-7

[0160]

[0161] Compounds 1-6 (360 mg, 1 mmol) and potassium tert-butoxide (336 mg, 3 mmol) were dissolved in toluene (5 mL) at room temperature (20 °C). The system was heated to 100 °C and stirred for 3 h under a nitrogen atmosphere. After cooling to room temperature, the system was quenched with dilute hydrochloric acid (1 N, 10 mL), extracted with ethyl acetate (2 x 10 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–50%) to give compound 1-7 as a yellow solid.

[0162] MS(ESI)m / z(M+H) + =329.2.

[0163] Step 6: Preparation of compounds 1-8

[0164]

[0165] Compounds 1-7 (200 mg, 0.61 mmol) were dissolved in acetic acid (3 mL). Concentrated nitric acid (0.3 mL) was added dropwise at room temperature. After the addition was complete, the system was stirred at room temperature (20 °C) for 30 min. The system was then poured into ice water (100 mL), precipitating a yellow solid. This solid was filtered, and the filter cake was dried under vacuum until it no longer lost weight, yielding the yellow solid compound 1-8.

[0166] MS(ESI)m / z(M+H) + =374.2.

[0167] Step 7: Preparation of compounds 1-9

[0168]

[0169] Compounds 1-8 (200 mg, 0.54 mmol) were dissolved in acetic acid (2 mL). Hydrobromic acid (48%, 1 mL) was added to the solution at room temperature, and the mixture was heated to 100 °C and stirred for 3 h. The reaction solution was concentrated to obtain crude compounds 1-9, which were used directly in the next reaction without further purification.

[0170] MS(ESI)m / z(M+H) + =360.3.

[0171] Step 8: Preparation of compounds 1-10

[0172]

[0173] Compounds 1-9 (360 mg, 1 mmol) were added to N,N-diisopropylethylamine (2 mL). At room temperature, phosphorus oxychloride (1 mL) was added, and the reaction mixture turned black. The system was then heated to 90 °C and stirred for 1 h. The system was concentrated, and the crude product was dissolved in ethyl acetate (10 mL), washed with water, allowed to stand for separation, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–10%) to give a yellow solid compound 1-10.

[0174] MS(ESI)m / z(M+H) + =396.0.

[0175] Step 9: Preparation of compounds 1-12

[0176]

[0177] Compounds 1-10 (147 mg, 0.372 mmol), 1-11 (102 mg, 0.446 mmol), cuprous iodide (71.0 mg, 0.372 mmol), and cesium carbonate (244 mg, 0.744 mmol) were dissolved in dioxane (4 mL). The system was heated to 100 °C and stirred for 2 h under a nitrogen atmosphere. The system was filtered through diatomaceous earth, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–30%) to give a yellow solid compound 1-12.

[0178] MS(ESI)m / z(M+H) + =590.2.

[0179] Step 10: Preparation of compounds 1-14

[0180]

[0181] Compounds 1-12 (100 mg, 0.169 mmol), 1-13 (34.6 mg, 0.203 mmol), 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (12.3 mg, 0.0169 mmol), and potassium carbonate (46.6 mg, 0.338 mmol) were dissolved in a mixed solution of tetrahydrofuran (3 mL) and water (0.3 mL). The system was heated to 80 °C and stirred for 1 h under a nitrogen atmosphere. The system was concentrated, and the residue was dissolved in ethyl acetate (10 mL), washed with water, allowed to stand for separation, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–50%) to obtain compound 1-14.

[0182] MS(ESI)m / z(M+H) + =680.2.

[0183] Step 11: Preparation of compounds 1-15

[0184]

[0185] Compound 1-14 (30 mg, 0.044 mmol) was dissolved in N,N-dimethylacetamide (1 mL). At room temperature, a 24% tetrahydrofuran solution of LiHMDS (0.1 mL) was added. Under a nitrogen atmosphere, the system was heated to 160 °C and stirred for 4 h. The system was cooled to room temperature and concentrated. The residue was dissolved in ethyl acetate (3 mL), washed with water, allowed to stand for separation, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–40%) to obtain compound 1-15.

[0186] MS(ESI)m / z(M+H) + =633.4.

[0187] Step 12: Preparation of compounds 1A and 1B

[0188]

[0189] Compound 1-15 (8 mg, 0.0126 mmol) was dissolved in dichloromethane (1 mL). Trifluoroacetic acid (1 mL) was added at room temperature, and the mixture was stirred for 1 h at room temperature (20 °C). The system was concentrated, and the residue was dissolved in dichloromethane (1 mL). The system was cooled to 0 °C, and triethylamine (2.52 mg, 0.0252 mmol) and acryloyl chloride (2.27 mg, 0.0252 mmol) were added dropwise. After the addition was complete, the system was allowed to react at room temperature (20 °C) for 30 min. The reaction solution was washed with water (5 mL), extracted with dichloromethane (3 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by high-performance liquid chromatography (separation conditions: Welch Ultimate XB-C18 column 10*250mm, 5μm, aqueous phase 0.15TFA, organic phase acetonitrile, gradient 52%-70%, time 12min) to obtain compound 1A and compound 1B.

[0190] Compound 1A:

[0191] 1 H NMR(400MHz,MeOD-d4)7.83(d,1H,J=8Hz),7.38-7.07(m,3H),6.93-6.86(m, 1H),6.80-6.54(m,3H),6.20(d,1H,J=8Hz),5.75-5.67(m,2H),4.40-4.27(m ,2H),4.21-4.08(m,1H),4.02-3.82(m,3H),3.81-3.69(m,2H),3.58(d,3H), 2.44-2.32(m,1H),1.08-0.98(m,3H),0.92-0.85(m,3H),0.84-0.76(m,3H).

[0192] MS(ESI)m / z(M+H) + =587.42.

[0193] Separation conditions: Column: Waters Xselect CSH C18 3.5μm, 100*4.6mm; Column temperature: 60℃; Mobile phase: Water (0.01% trifluoroacetic acid solution) - acetonitrile (0.01% trifluoroacetic acid solution); Acetonitrile: 5%-95% for 7 min, 95% for 8 min; Flow rate: 1.2 mL / min. Retention time: 6.175 min.

[0194] Compound 1B:

[0195] 1H NMR(400MHz,MeOD-d4)7.83(d,1H,J=8Hz),7.38-7.21(m,3H),7.20-7.12(m, 1H),7.0-6.89(m,1H),6.80-6.57(m,3H),6.20-6.11(m,1H),5.73(d,1H,J=8 .0Hz),4.38-4.21(m,4H),4.20-4.08(m,2H),4.07-3.93(m,2H),3.58(d,3H) ,2.35-2.25(m,1H),1.06-0.99(m,3H),0.92-0.83(m,3H),0.82-0.79(m,3H).

[0196] MS(ESI)m / z(M+H) + =587.4.

[0197] Separation conditions: Column: Waters Xselect CSH C18 3.5μm, 100*4.6mm; Column temperature: 60℃; Mobile phase: water (0.01% trifluoroacetic acid solution) - acetonitrile (0.01% trifluoroacetic acid solution); Acetonitrile: 5%-95% for 7 min, 95% for 8 min; Flow rate: 1.2 mL / min. Retention time: 6.327 min.

[0198] Example 2: Preparation of Compound 2

[0199] Step 1: Preparation of compound 2-2

[0200]

[0201] Compound 2-1 (2.87 g, 15 mmol) was dissolved in anhydrous N,N-dimethylacetamide (10 mL). Sodium hydride (60%, 660 mg, 16.5 mol) was added in portions at 0 °C. After the addition was complete, the system was heated to room temperature and stirred for 10 min. Chloromethyl ether (2.4 g, 30 mmol) was then added dropwise. After the addition was complete, the system was stirred at room temperature for 10 min. The system was quenched in ice water (50 mL), and extracted with methyl tert-butyl ether (3 x 50 mL). The organic phases were combined, washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–10%) to give a pale yellow viscous compound 2-2.

[0202] 1H NMR (400MHz, CDCl3-d1)7.24-7.18(m,1H),6.95-6.93(m,1H),6.83-6.79(m,1H),5.26(s,2H),3.52(s,3H).

[0203] Step 2: Preparation of compounds 2-3

[0204]

[0205] Compounds 1-2 (650 mg, 2.77 mmol) were dissolved in anhydrous tetrahydrofuran (5 mL). At -78 °C, n-butyllithium (2.5 N, 1.22 mL, 3.05 mmol) was added dropwise, and the mixture was stirred at -78 °C for 30 min. Then, isopropyl pinacol borate (567 mg, 3.05 mmol) was added dropwise, and the mixture was stirred at -78 °C for 30 min. The mixture was brought to room temperature, the reaction was quenched with water, and the mixture was extracted with ethyl acetate (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–20%) to give a colorless oily substance 2-3.

[0206] Step 3: Preparation of compounds 2-4

[0207]

[0208] Compounds 1-12 (50 mg, 0.0848 mmol), 2-3 (28.7 mg, 0.10 mmol), 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (6.2 mg, 0.00848 mmol), and potassium carbonate (23.4 mg, 0.169 mmol) were dissolved in a mixed solution of tetrahydrofuran (2 mL) and water (0.2 mL). The system was heated to 80 °C and stirred for 2 h under a nitrogen atmosphere. The system was concentrated to obtain a crude product, which was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–50%) to give a yellow solid, compound 2-4.

[0209] MS(ESI)m / z(M+H) + =710.2.

[0210] Step 4: Preparation of compounds 2-5

[0211]

[0212] Compound 2-4 (30 mg, 0.0423 mmol) was dissolved in N,N-dimethylacetamide (1 mL) under a nitrogen atmosphere, and a tetrahydrofuran solution (24%, 0.1 mL) of lithium bis(trimethylsilylamino)amine was added dropwise. The system was heated to 160 °C and reacted for 4 h. The system was cooled to room temperature and concentrated to obtain a crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–50%) to give a pale yellow solid compound 2-5.

[0213] MS(ESI)m / z(M+H) + =663.2.

[0214] Step 5: Preparation of compounds 2-6

[0215]

[0216] Compound 2-5 (6 mg, 0.009 mmol), hydrochloric acid (6 N, 0.5 mL), and a mixed solution of methanol (0.45 mL) and tetrahydrofuran (0.05 mL) were added. The system was heated to 55 °C and reacted for 15 min. The system was concentrated to obtain crude product 2-6, which was used directly in the next reaction without further purification.

[0217] MS(ESI)m / z(M+H) + =519.2.

[0218] Step 6: Preparation of Products 2A and 2B

[0219]

[0220] Compounds 2-6 (5 mg, 0.0096 mmol) were dissolved in dichloromethane (1.0 mL), and the system was cooled to 0 °C. Triethylamine (1.95 mg, 0.0193 mmol) and acryloyl chloride (1.73 mg, 0.0193 mmol) were added dropwise, and the system was reacted at 0 °C for 1 h. The system was concentrated to obtain a crude product, which was purified by high-performance liquid chromatography (HPLC) (separation conditions: Welch Ultimate XB-C18 column 10*250 mm, 5 μm, aqueous phase 10 mmol / L ammonium acetate, organic phase acetonitrile, gradient 38%-65%, time 15 min) to obtain compounds 2A and 2B.

[0221] Compound 2A:

[0222] MS(ESI)m / z(M+H) + =573.4.

[0223] Separation conditions: Column: Waters Xbridge C18 3.5μm, 100*4.6mm; Column temperature: 40℃; Mobile phase: water (10mM ammonium bicarbonate aqueous solution)-acetonitrile; Acetonitrile: 5%-95% for 7 min, 95% for 8 min; Flow rate: 1.2 mL / min. Retention time: 5.743 min.

[0224] Compound 2B:

[0225] MS(ESI)m / z(M+H) + =573.4.

[0226] Separation conditions: Column: Waters Xbridge C18 3.5μm, 100*4.6mm; Column temperature: 40℃; Mobile phase: water (10mM ammonium bicarbonate aqueous solution)-acetonitrile; Acetonitrile: 5%-95% for 7 min, 95% for 8 min; Flow rate: 1.2 mL / min. Retention time: 5.879 min.

[0227] Example 3: Preparation of Compound 3

[0228] Step 1: Preparation of compound 3-2

[0229]

[0230] Chloral hydrate (19.08 g, 115.38 mmol, 15.03 mL) and sodium sulfate (122.92 g, 865.37 mmol) were dissolved in water (360 mL). The system was heated to 35 °C, and an aqueous solution of 3-1 (20 g, 96.15 mmol) in 120 mL, hydrochloric acid (12 M, 10.82 mL), and hydroxylamine hydrochloride (21.38 g, 307.69 mmol) were added sequentially. After the addition was complete, the system was heated to 90 °C and reacted for 16 h. A gray precipitate appeared. The system was cooled to room temperature, filtered to obtain a filter cake, washed with water, and dried under vacuum to obtain compound 3-2, which was used directly in the next reaction without further purification.

[0231] 1 H NMR (400MHz, DMSO-d6) δ12.34(s,1H),10.01(s,1H),7.78-7.74(m,1H),7.70(s,1H),7.31-7.26(m,1H).

[0232] Step 2: Preparation of compound 3-3

[0233]

[0234] Compound 3-2 (35 g, 125.43 mmol) was added to concentrated sulfuric acid (368.00 g, 3.75 mol, 200 mL) at 60 °C. After addition, the system was heated to 90 °C and stirred for 3 h. The system was cooled to room temperature and poured into ice water, resulting in the precipitation of a black precipitate. The precipitate was filtered to obtain a filter cake, which was then dried to obtain crude product A. The filtrate was extracted with ethyl acetate (500 mL x 2), and the organic phases were combined and washed with saturated brine (500 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain crude product B. Crude products A and B were combined to obtain compound 3-3, which was used directly in the next reaction without further purification.

[0235] Step 3: Preparation of compounds 3-4

[0236]

[0237] Compound 3-3 (29 g, 110.68 mmol) was dissolved in an aqueous sodium hydroxide solution (2 M, 290.00 mL). Hydrogen peroxide (70.80 g, 624.44 mmol, 60 mL, 30% purity) was added dropwise at 0 °C. After the addition was complete, the system was stirred at 0 °C for 0.5 h, then raised to room temperature (20 °C) and stirred for 16 h. The system was then poured into ice water (300 mL), and the pH was adjusted to 6 with concentrated hydrochloric acid. A precipitate formed, which was filtered to obtain a filter cake. The filter cake was dried to obtain compound 3-4, which was used directly in the next reaction without further purification.

[0238] Step 4: Preparation of compounds 3-5

[0239]

[0240] Compound 3-4 (28 g, 111.11 mmol) was dissolved in methanol (300 mL), and concentrated sulfuric acid (18.40 g, 187.60 mmol, 10 mL) was added. The system was heated to 75 °C and reacted for 16 h under a nitrogen atmosphere. The system was concentrated, and the crude product was extracted separately with ethyl acetate (200 mL) and water (300 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–20%) to obtain compound 3-5.

[0241] 1 H NMR (400MHz, CDCl3) δ7.46 (d, J = 8.6Hz, 1H), 5.73 (br s, 2H), 3.90 (br d, J = 2.0Hz, 3H)

[0242] Step 5: Preparation of compounds 3-6

[0243]

[0244] Compounds 3-5 (2.3 g, 8.65 mmol), compounds 1-13 (2.20 g, 12.97 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (723 mg, 864.53 μmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (403 mg, 864.53 μmol), and potassium carbonate (3.58 g, 25.94 mmol) were dissolved in a mixed solution of dioxane (25 mL) and water (5 mL). The system was heated to 100 °C and stirred for 16 h under a nitrogen atmosphere. The system was concentrated and dissolved in ethyl acetate (50 mL), filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0-20%) to obtain compounds 3-6.

[0245] 1 H NMR (400MHz, CDCl3) δ7.48 (dd, J=2.0, 9.9Hz, 1H), 7.42-7.36 (m, 1H), 6.87-6.78 (m, 2H), 5.67 (br s, 2H), 3.92 (s, 3H), 3.82 (s, 3H).

[0246] Step 6: Preparation of compounds 3-7

[0247]

[0248] Compounds 3-6 (2 g, 6.43 mmol), cuprous iodide (1.24 g, 6.51 mmol), and potassium iodide (2.16 g, 13.01 mmol) were dissolved in acetonitrile (30 mL). Tert-butyl nitrite (1.39 g, 13.45 mmol, 1.60 mL) was added at 0 °C. The system was heated to 80 °C and stirred for 2 h under a nitrogen atmosphere. The system was filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–10%) to obtain compound 3-7.

[0249] 1 H NMR (400MHz, CDCl3) δ7.50 (dd, J = 1.5, 9.0Hz, 1H), 7.45-7.37 (m, 1H), 6.87-6.78 (m, 2H), 3.98 (s, 3H), 3.86-3.77 (s, 3H).

[0250] Step 7: Preparation of compounds 3-8

[0251]

[0252] Compounds 3-7 (1.6 g, 3.79 mmol), 3-9 (640 mg, 4.26 mmol), tris(dibenzylacetone)dipalladium (350 mg, 382.21 μmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (221 mg, 381.94 μmol), and cesium carbonate (3.7 g, 11.37 mmol) were dissolved in toluene (30 mL) at room temperature (20 °C). The system was heated to 110 °C and stirred for 16 h under a nitrogen atmosphere. The system was then cooled to room temperature and concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–20%) to obtain compound 3-8.

[0253] 1 H NMR (400MHz, CDCl3) δ8.90(d,J=3.1Hz,1H),8.29(d,J=4.9Hz,1H),7.64(dd,J=1.9,9.6Hz,1H),7.39-7.29(m,1H),6.94(t,J=5.1Hz ,1H),6.79-6.60(m,2H),3.97(s,3H),3.74(d,J=15.7Hz,3H),3.55-3.37(m,1H),2.20(s,3H),1.33-1.14(m,6H).MS(ESI)m / z(M+H) + =445.0.

[0254] Step 8: Preparation of compounds 3-10

[0255]

[0256] Compound 3-8 (1.26 g, 2.83 mmol) was dissolved in N,N-dimethylformamide (15 mL) at room temperature (20 °C). Sodium hydride (454 mg, 11.35 mmol, 60% purity) was added in portions. After the addition was complete, acetyl chloride (888.59 mg, 11.32 mmol, 807.81 μL) was added dropwise. After the addition was complete, the system was heated to 100 °C and reacted for 8 h under a nitrogen atmosphere. The reaction was quenched by adding saturated ammonium chloride aqueous solution (5 mL), followed by the addition of 30 mL of water. The mixture was extracted with ethyl acetate (30 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–30%) to obtain compound 3-10.

[0257] MS(ESI)m / z(M+H) + =487.2.

[0258] Step 9: Preparation of compound 3-11

[0259]

[0260] Compound 3-10 (800 mg, 1.64 mmol) was dissolved in toluene (15 mL) at room temperature (20 °C), and potassium tert-butoxide (1 M, 5.33 mL) was added. After the addition was complete, the system was reacted at room temperature (20 °C) for 0.5 h under a nitrogen atmosphere. The reaction was quenched by adding water (20 mL), the pH was adjusted to neutral with 1 N hydrochloric acid, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 3-11, which was used directly in the next reaction without further purification.

[0261] 1 H NMR (400MHz, CDCl3) δ8.55 (t, J = 4.5Hz, 1H), 7.64 (br d,J=8.6Hz,1H),7.39-7.27(m,1H),7.19-7.06(m,1H),6.79-6.65(m,2H),6.41(s,1H),3. 72(s,1.5H),3.66(s,1.5H),2.85-2.78(m,1H),2.08(d,J=5.7Hz,3H),1.31-1.07(m,6H).

[0262] MS(ESI)m / z(M+H) + =455.1.

[0263] Step 10: Preparation of compound 3-12

[0264]

[0265] Compound 3-11 (1 g, 2.20 mmol) was dissolved in glacial acetic acid (20 mL). Nitric acid (2.55 g, 40.40 mmol, 1.82 mL) was added dropwise to the system at room temperature (20 °C). After the addition was complete, the system was heated to 80 °C and stirred for 2 h. The system was then cooled to room temperature, and most of the glacial acetic acid was removed by concentration. The remainder was poured into ice water (50 mL), and a precipitate formed. This precipitate was filtered, washed with water, and dried to obtain compound 3-12, which was used directly in the next step without further purification.

[0266] 1H NMR(400MHz, DMSO-d6)δ8.72(d,J=5.8Hz,1H),7.97-7.74(m,2H),7.48(q,J=8.1Hz,1H),7.06-6.83 (m,2H),3.74(s,1.5H),3.67(s,1.5H),3.18-3.05(m,1H),2.25(d,J=7.5Hz,3H),1.30-1.09(m,6H).

[0267] MS(ESI)m / z(M+H) + =500.5.

[0268] Step 11: Preparation of compound 3-13

[0269]

[0270] Compound 3-12 (900 mg, 1.80 mmol) and N,N-diisopropylethylamine (1.40 g, 10.81 mmol, 1.88 mL) were dissolved in acetonitrile (10 mL). Phosphorus oxychloride (828.92 mg, 5.41 mmol, 502.38 μL) was added at room temperature. After the addition was complete, the system was heated to 80 °C and stirred for 2 h. The system was concentrated to obtain a crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–50%) to give compound 3-13.

[0271] 1 H NMR (400MHz, CDCl3) δ8.54(t,J=4.3Hz,1H),7.87-7.84(m,1H),7.42-7.36(m,1H),7.10(t,J=4.3Hz,1H),6.85-6 .67(m,2H),3.76(s,1.5H),3.70(s,1.5H),2.79-2.66(m,1H),2.13(s,1.5H),2.11(s,1.5H),1.28-1.15(m,6H).

[0272] Step 12: Preparation of compounds 3-14

[0273]

[0274] Compounds 3-13 (700 mg, 1.35 mmol), 1-11 (467 mg, 2.03 mmol), and N,N-diisopropylethylamine (873.44 mg, 6.76 mmol, 1.18 mL) were dissolved in acetonitrile (10 mL). Under a nitrogen atmosphere, the system was heated to 80 °C and stirred for 1 h. The system was concentrated to obtain a crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–60%) to obtain compound 3-14.

[0275] 1 H NMR(400MHz,MeOD)δ8.57-8.36(m,1H),7.77(br d,J=7.8Hz,1H),7.59-7.41(m,1H),7.33-7.21(m,1H),7.07-6.89(m,1H),6.85-6.75(m,1H),4.45(br s,1H),4.02-3.91(m,2H),3.82-3.65(m,6H),3.16-3.29(m,1H),2.96- 2.72(m,1H),2.27-2.07(m,3H),1.60-1.36(m,12H),1.30-1.02(m,6H).

[0276] MS(ESI)m / z(M+H) + =712.3.

[0277] Step 13: Preparation of Compounds 3-15

[0278]

[0279] Compound 3-14 (700 mg, 983.52 μmol) and Molecular sieve (1 g) was dissolved in N-methylpyrrolidone (10 mL), and a tetrahydrofuran solution (1 M, 2.10 mL) of lithium bis(trimethylsilylamino)amine was added at room temperature. After the addition was complete, the system was heated to 130 °C and stirred for 24 h under a nitrogen atmosphere. The system was cooled to room temperature, and water (50 mL) was added. The mixture was extracted with ethyl acetate (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–60%) to give compound 3-15.

[0280] 1H NMR (400MHz, MeOD) δ8.42(d,J=5.1Hz,1H),7.53(d,J=9.7Hz,1H),7.46-7.34(m,1H),7.24(br d,J=5.1Hz,1H),6.94-6.85(m,1H),6.79(t,J=9.0Hz,1H),4.67-4.44(m,3H),4.50-4.35(m,1H),4.21-4.07(m ,1H),3.82-3.64(m,3H),3.57-3.39(m,2H),3.14-3.08(m,1H),2.75-2.61(m,1H),2.12-1.98(m,3H),1.64(br d,J=6.8Hz,3H),1.51(s,9H),1.23-1.04(m,6H).

[0281] MS(ESI)m / z(M+H) + =665.3.

[0282] Step 14: Preparation of Compounds 3-16

[0283]

[0284] Compound 3-15 (180 mg, 270.79 μmol) was dissolved in anhydrous dichloromethane (3 mL). At 0 °C, a dichloromethane solution of boron tribromide (339.20 mg, 1.35 mmol, 130.46 μL) was added. After the addition was complete, the system was heated to room temperature (20 °C) and stirred for 2 h under a nitrogen atmosphere. Methanol (10 mL) was then added and stirred for 10 min. The system was concentrated and lyophilized to obtain compound 3-16 (hydrobromide), which was used directly in the next step without further purification.

[0285] MS(ESI)m / z(M+H) + =551.3.

[0286] Step 15: Preparation of compounds 3A, 3B, 3C, and 3D

[0287]

[0288] Compound 3-16 (180 mg, 285.04 μmol, hydrobromide) was dissolved in tetrahydrofuran (5 mL) and saturated sodium bicarbonate aqueous solution (2.62 mL). Acrylic anhydride (43.59 mg, 345.68 μmol) was added at room temperature (20 °C). After addition, the system was stirred at room temperature (20 °C) for 2 h. Methanol (3 mL) and an aqueous solution of lithium hydroxide (21.80 mg, 910.16 μmol) were added to the system, and stirring was continued at room temperature (20 °C) for another 2 h. The pH of the system was adjusted to neutral with 1 N hydrochloric acid, and the mixture was extracted with ethyl acetate (10 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by high-performance liquid chromatography (separation conditions: column: Phenomenex Gemini-NX 80*30mm*3μm; mobile phase: [water (10mM ammonium bicarbonate solution)-acetonitrile]; acetonitrile %: 41%-51% 9.5min) to obtain compounds 3A and 3B.

[0289] Compound 3A

[0290] 1 H NMR(400MHz,MeOD)δ8.42(d,J=4.9Hz,1H),7.54(br d,J=9.0Hz,1H),7.31-7.16(m,2H),6.86-6.79(m,1H),6.73-6.59(m,2H),6.27(dd,J=2.0,16.8 Hz,1H),5.81(d,J=9.7Hz,1H),4.72-4.34(m,3H),4.32-4.09(m,1H),3.82-3.41(m,3H),3.13(br s,1H),2.81-2.60(m,1H),2.20-1.99(m,3H),1.87-1.63(m,3H),1.17-1.04(m,6H).

[0291] MS(ESI)m / z(M+H) + =605.3.

[0292] HPLC purity 98.77%; retention time 3.72 min.

[0293] Separation conditions: Column: Ultimate C18 3.0*50mm, 3μm; Column temperature: 40℃; Mobile phase: water (0.0688% trifluoroacetic acid solution) - acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10%-80% for 6 min, 80% for 2 min; Flow rate: 1.2 mL / min.

[0294] Compound 3B

[0295] 1 H NMR(400MHz,MeOD)δ8.42(d,J=5.1Hz,1H),7.54(d,J=7.9Hz,1H),7.33-7.14(m,2H),6.83(dd,J=10.7,16.6Hz,1H),6.70-6.53 (m,2H),6.27(dd,J=2.0,16.8Hz,1H),5.82(d,J=10.4Hz,1H),4.74-4.33(m,3H),4.31-4.04(m,1H),3.84-3.36(m,3H),3.15(br s,1H),2.87-2.56(m,1H),2.05(d,J=4.0Hz,3H),1.88-1.59(m,3H),1.23-0.97(m,6H).

[0296] MS(ESI)m / z(M+H) + =605.3.

[0297] HPLC purity 98.77%; retention time 3.59 min.

[0298] Separation conditions: Column: Ultimate C18 3.0*50mm, 3μm; Column temperature: 40℃; Mobile phase: water (0.0688% trifluoroacetic acid solution) - acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10%-80% for 6 min, 80% for 2 min; Flow rate: 1.2 mL / min.

[0299] Step 16: Resolution of the 3A isomer of compound

[0300]

[0301] The diastereomer compound 3A was purified by SFC (separation conditions: column: DAICEL CHIRALCEL OJ-H (250mm*30mm, 5μm); mobile phase: [0.1% ammonia solution-ethanol]; ethanol %: 30%-30%; flow rate: 60mL / min). After concentration, compounds 3A-1 and 3A-2 were obtained.

[0302] Compound 3A-1

[0303] 1H NMR(400MHz,MeOD)δ8.42(d,J=5.1Hz,1H),7.54(d,J=9.0Hz,1H),7.37-7.10(m,2H),6.82(dd,J=10.7 ,16.6Hz,1H),6.68(d,J=8.2Hz,1H),6.62(t,J=8.8Hz,1H),6.27(dd,J=1.8,16.8Hz,1H),5.81(d,J=1 0.4Hz,1H),4.68-4.54(m,2H),4.50-4.38(m,1H),4.31-4.05(m,1H),3.81-3.37(m,3H),3.17-3.08(m ,1H),2.69-2.62(m,1H),2.05(s,3H),1.86-1.52(m,3H),1.15(d,J=6.8Hz,3H),1.06(d,J=6.8Hz,3H).

[0304] MS(ESI)m / z(M+H) + =605.3.

[0305] HPLC purity 97.74%; retention time 3.606 min.

[0306] Separation conditions: Column: Xbridge C18, 5μm, 2.1*50mm; Column temperature: 50℃; Mobile phase: water (0.02% ammonia solution) - acetonitrile; Acetonitrile: 10%-80% for 6 min, 80% for 2 min; Flow rate: 0.8 mL / min.

[0307] SFC 100%ee. Retention time 3.864 min.

[0308] Compound 3A-2

[0309] 1 H NMR(400MHz,MeOD)δ8.42(d,J=4.9Hz,1H),7.54(br d,J=7.9Hz,1H),7.33-7.14(m,2H),6.82(dd,J=10.6,16.8Hz,1H),6.71-6.56(m,2H),6.27(dd,J=1.8,16.8Hz,1H),5.81(br d,J=10.8Hz,1H),4.61(br s,2H),4.53-4.09(m,2H),3.81-3.40(m,3H),3.14(br s,1H),2.80-2.66(m,1H),2.03(s,3H),1.80-1.66(m,3H),1.15-1.10(m,6H).

[0310] MS(ESI)m / z(M+H) + =605.3.

[0311] HPLC purity 95.13%; retention time 3.674 min.

[0312] Separation conditions: Column: Xbridge C18, 5μm, 2.1*50mm; Column temperature: 50℃; Mobile phase: water (0.02% ammonia solution) - acetonitrile; Acetonitrile: 10%-80% for 6 min, 80% for 2 min; Flow rate: 0.8 mL / min.

[0313] SFC 98.88%ee. Retention time 4.332min.

[0314] Step 17: Resolution of the 3B isomer of compound

[0315]

[0316] The diastereomer compound 3B was purified by SFC (separation conditions: column: DAICEL CHIRALCEL OJ-H (250mm*30mm, 5μm); mobile phase: [0.1% ammonia solution-ethanol]; ethanol %: 30%-30%; flow rate: 60mL / min). After concentration, compounds 3B-1 and 3B-2 were obtained.

[0317] Compound 3B-1

[0318] 1 H NMR (400MHz, MeOD) δ8.42 (d, J = 5.1Hz, 1H), 7.54 (br d,J=9.0Hz,1H),7.34-7.12(m,2H),6.82(dd,J=10.7,16.6Hz,1H),6.75-6.51(m,2H),6.27(dd,J=1.8,16.8Hz,1H),5.81(br d,J=10.1Hz,1H),4.74-4.57(m,2H),4.45(d,J=10.1Hz,1H),4.31-4.09(m,1H),3.74(br d,J=9.7Hz,1H),3.63-3.43(m,2H),3.15-3.08(m,1H),2.69-2.62(m,1H),2.05(s,3H),1.86-1.61(m,3H),1.13(dd,J=6.7,13.1Hz,6H).

[0319] MS(ESI)m / z(M+H) + =605.3.

[0320] HPLC purity 95.70%; retention time 3.669 min.

[0321] Separation conditions: Column: Xbridge C18, 5μm, 2.1*50mm; Column temperature: 50℃; Mobile phase: water (0.02% ammonia solution) - acetonitrile; Acetonitrile: 10%-80% for 6 min, 80% for 2 min; Flow rate: 0.8 mL / min.

[0322] SFC 100%ee. Retention time 3.978min.

[0323] Compound 3B-2

[0324] 1 H NMR(400MHz,MeOD)δ8.42(d,J=4.9Hz,1H),7.54(br d,J=8.8Hz,1H),7.31-7.14(m,2H),6.82(dd,J=10.8,16.8Hz,1H),6.68(d,J=8.4Hz,1H),6.62(t,J=8.7Hz,1H),6.27(br dd,J=1.8,16.8Hz,1H),5.81(br d,J=10.6Hz,1H),4.65(br d,J=13.2Hz,1H),4.56-4.34(m,2H),4.27-4.07(m,1H),3.83-3.43(m,3H),3.15(br s,1H),2.76-2.63(m,1H),2.04(s,3H),1.86-1.59(m,3H),1.15(d,J=6.6Hz,3H),1.07(d,J=6.8Hz,3H).

[0325] MS(ESI)m / z(M+H) + =605.3.

[0326] HPLC purity 98.65%; retention time 3.581 min.

[0327] Separation conditions: Column: Xbridge C18, 5μm, 2.1*50mm; Column temperature: 50℃; Mobile phase: water (0.02% ammonia solution) - acetonitrile; Acetonitrile: 10%-80% for 6 min, 80% for 2 min; Flow rate: 0.8 mL / min.

[0328] SFC 100%ee. Retention time 4.607 min.

[0329] Example 4: Preparation of Compound 4

[0330] Step 1: Preparation of compound 4-2

[0331]

[0332] Chloral hydrate (22 g, 133.01 mmol, 17.32 mL) and sodium sulfate (168.20 g, 1.18 mol, 120.14 mL) were dissolved in water (360 mL). The system was heated to 35 °C, and an aqueous solution of 4-1 (25 g, 131.57 mmol) (120 mL), hydrochloric acid (12 M, 14.80 mL), and hydroxylamine hydrochloride (29.26 g, 421.02 mmol) were added sequentially. After the addition was complete, the system was heated to 90 °C and reacted for 16 h. A yellow precipitate appeared. The system was cooled to room temperature, filtered to obtain a filter cake, washed with water, dissolved in ethyl acetate (300 mL), filtered, and the filtrate was concentrated to obtain compound 4-2, which was used directly in the next reaction without further purification. MS (ESI) m / z (M+H) + =262.9.

[0333] Step 2: Preparation of compound 4-3

[0334]

[0335] Compound 4-2 (30.8 g, 117.99 mmol) was added to concentrated sulfuric acid (460.00 g, 4.60 mol, 250 mL, purity 98%) at 60 °C. After the addition was complete, the system was heated to 90 °C and stirred for 3 h. The system was cooled to room temperature and poured into ice water, resulting in the precipitation of a yellow precipitate. The precipitate was filtered to obtain a filter cake, which was then dried to obtain a yellow solid 4-3, which was used directly in the next reaction without further purification.

[0336] Step 3: Preparation of compound 4-4

[0337]

[0338] Compound 4-3 (22 g, 90.16 mmol) was dissolved in an aqueous sodium hydroxide solution (2 M, 225.39 mL). Hydrogen peroxide (51.11 g, 450.79 mmol, 43.31 mL, 30% purity) was added dropwise at 0 °C. After the addition was complete, the system was stirred at 0 °C for 0.5 h, then raised to room temperature (20 °C) and stirred for 16 h. The system was then poured into ice water (400 mL), and the pH was adjusted to 6 with concentrated hydrochloric acid. A precipitate formed, which was filtered to obtain a filter cake. The filter cake was dried to obtain compound 3-4, which was used directly in the next reaction without further purification.

[0339] Step 4: Preparation of compounds 4-5

[0340]

[0341] Compound 4-4 (20.5 g, 87.60 mmol) was dissolved in N,N-dimethylformamide (100 mL), and N-chlorosuccinimide (11.70 g, 87.60 mmol) was added at room temperature (20 °C). After the addition was complete, the system was heated to 70 °C and stirred for 16 h under a nitrogen atmosphere. After cooling the system to room temperature, it was poured into ice water, and a precipitate formed. The precipitate was filtered to obtain a filter cake, which was washed with water and dried to obtain compound 4-5, which was used directly in the next reaction without further purification.

[0342] Step 5: Preparation of compounds 4-6

[0343]

[0344] Compound 4-5 (15 g, 55.87 mmol) was dissolved in methanol (100 mL), and thionyl chloride (67.50 g, 567.37 mmol, 41.16 mL) was added dropwise. Under a nitrogen atmosphere, the system was heated to 75 °C and stirred for 16 h. The system was concentrated, and the crude product was dissolved in ethyl acetate (200 mL). The organic phase was washed successively with saturated sodium bicarbonate aqueous solution (80 mL) and saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–10%) to obtain compound 4-6.

[0345] 1 H NMR (400MHz, DMSO-d6) δ7.68 (d, J = 2.0Hz, 1H), 6.86 (s, 2H), 3.83 (s, 3H).

[0346] MS(ESI)m / z(M+H) + =283.8.

[0347] Step 6: Preparation of compounds 4-8

[0348]

[0349] Compounds 4-6 (6 g, 21.24 mmol), 4-7 (10 g, 43.10 mmol), tris(dibenzylacetone)dipalladium (840 mg, 1.46 mmol), 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (2.03 g, 4.25 mmol), and potassium carbonate (7.34 g, 53.10 mmol) were dissolved in a mixed solution of dioxane (100 mL) and water (20 mL). The system was heated to 100 °C and stirred for 16 h under a nitrogen atmosphere. After concentration, the system was extracted separately with ethyl acetate (50 mL x 2) and water (80 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–10%) to obtain compound 4-8.

[0350] 1 H NMR (400MHz, DMSO-d6) δ7.83-7.77(m,1H),7.67(d,J=1.7Hz,1H),7.03(d,J=8.5Hz,1H),6.96(t,J=8.7Hz,1H),6.73(s,2H),3.86(s,3H),3.77(s,3H).

[0351] MS(ESI)m / z(M+H) + =328.0.

[0352] Step 7: Preparation of compounds 4-9

[0353]

[0354] Compound 4-8 (4.8 g, 14.65 mmol) was dissolved in glacial acetic acid (50 mL). Acetic anhydride (4.49 g, 43.94 mmol, 4.12 mL) was added dropwise at 0 °C. The system was then heated to room temperature (20 °C) and reacted for 36 h. The system was concentrated to obtain a crude product, which was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–100%) to obtain compound 4-9.

[0355] 1 H NMR (400MHz, DMSO-d6) δ10.05 (s, 1H), 7.71 (s, 1H), 7.54 (q, J = 8.1Hz, 1H), 7.06 (d,J=8.5Hz,1H),6.99(t,J=8.7Hz,1H),3.79(s,3H),3.77(s,3H),2.03(s,3H).

[0356] MS(ESI)m / z(M+H) + =370.0.

[0357] Step 8: Preparation of compounds 4-10

[0358]

[0359] Compound 4-9 (4 g, 10.82 mmol) and potassium carbonate (4.49 g, 32.45 mmol) were dissolved in N,N-dimethylformamide (40 mL), and iodomethane (4.61 g, 32.45 mmol, 2.02 mL) was added. The system was stirred at room temperature (20 °C) for 16 h. The system was filtered, and the filtrate was poured into water (100 mL) and extracted with ethyl acetate (100 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–50%) to give compound 4-10.

[0360] MS(ESI)m / z(M+H) + =384.0.

[0361] Step 9: Preparation of Compound 4-11

[0362]

[0363] Compound 4-10 (4.1 g, 10.68 mmol) was dissolved in toluene (60 mL) at room temperature (20 °C), and potassium tert-butoxide (1 M, 21.37 mL) was added. After the addition was complete, the system was reacted at room temperature (20 °C) for 4 h under a nitrogen atmosphere. The reaction was quenched by adding 1 M hydrochloric acid, diluted with water (80 mL), and extracted with ethyl acetate (80 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was slurried with methanol to obtain compound 4-11, which was used directly in the next reaction without further purification.

[0364] 1 H NMR (400MHz, DMSO-d6) δ11.88(s,1H),7.84(s,1H),7.54(q,J=7.8Hz,1H),7.10-6.95(m,2H),5.98(s,1H),3.78(s,3H),3.65(d,J=9.3Hz,3H).

[0365] MS(ESI)m / z(M+H) + =351.9.

[0366] Step 10: Preparation of compound 4-12

[0367]

[0368] Compound 4-11 (1 g, 2.84 mmol) was dissolved in glacial acetic acid (20 mL). Nitric acid (2.80 g, 44.44 mmol, 2 mL) was added dropwise to the system at room temperature (20 °C). After the addition was complete, the system was heated to 80 °C and stirred for 1 h. The system was then cooled to room temperature, and most of the glacial acetic acid was removed by concentration. The residue was poured into ice water (25 mL) and extracted with ethyl acetate (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 4-12, which was used directly in the next step without further purification.

[0369] 1 H NMR (400MHz, CDCl3) δ13.53(br s,1H),8.21(d,J=1.8Hz,1H),7.47(t,J=6.8,8.4Hz,1H),6.91-6.83(m,2H),3.87(d,J=8.8Hz,3H),3.82(s,3H).

[0370] MS(ESI)m / z(M+H) + =397.0.

[0371] Step 11: Preparation of Compounds 4-13

[0372]

[0373] Compound 4-12 (1.1 g, 2.77 mmol) and N,N-diisopropylethylamine (1.43 g, 11.09 mmol, 1.93 mL) were dissolved in acetonitrile (10 mL). Phosphorus oxychloride (1.32 g, 8.61 mmol, 800 μL) was added at room temperature. After the addition was complete, the system was heated to 80 °C and stirred for 1 h. The system was cooled to room temperature and concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–10%) to give compound 4-13.

[0374] 1 H NMR (400MHz, CDCl3) δ8.07(d,J=1.8Hz,1H),7.48(t,J=6.8,8.4Hz,1H),6.91-6.83(m,2H),3.96(d,J=9.3Hz,3H),3.82(s,3H).

[0375] MS(ESI)m / z(M+H) + =414.9.

[0376] Step 12: Preparation of Compounds 4-14

[0377]

[0378] Compounds 4-13 (0.8 g, 1.93 mmol), 1-11 (621.28 mg, 2.70 mmol), and N,N-diisopropylethylamine (747.10 mg, 5.78 mmol, 1.01 mL) were dissolved in acetonitrile (10 mL). The system was heated to 80 °C and stirred for 3 h under a nitrogen atmosphere. The system was concentrated to obtain a crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–30%) to obtain compound 4-14.

[0379] 1 H NMR (400MHz, MeOD) δ7.91(s,1H),7.52(dt,J=6.8,8.4Hz,1H),7.00(d,J=8.3Hz,1H),6.89(t,J=8.7Hz,1H),4.38(br s,1H),4.16(br d,J=13.8Hz,1H),3.88-3.74(m,8H),3.72-3.52(m,3H),2.98(br d,J=12.3Hz,1H),1.50(s,9H),1.34(d,J=6.8Hz,3H).

[0380] MS(ESI)m / z(M+H) + =609.1.

[0381] Step 13: Preparation of compounds 4-15

[0382]

[0383] Compound 4-14 (0.86 g, 1.41 mmol) and Molecular sieve (0.5 g) was dissolved in N-methylpyrrolidone (10 mL). A tetrahydrofuran solution (1 M, 2.82 mL) of lithium bis(trimethylsilylamino)amine was added at room temperature. After the addition was complete, the system was heated to 140 °C and stirred for 5 h under a nitrogen atmosphere. The system was cooled to room temperature and filtered. The filtrate was diluted with ethyl acetate (80 mL) and washed successively with water (60 mL x 2) and saturated brine (60 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0-50%) to obtain the crude product. The crude product was then purified by high-performance preparative liquid chromatography (separation conditions: column: Phenomenex Gemini-NX 80*30mm*3μm; mobile phase: [water (10mM ammonium bicarbonate solution)-acetonitrile]; acetonitrile %: 60%-90% 9.5min) to obtain compound 4-15.

[0384] 1H NMR(400MHz,MeOD)δ7.76(s,1H),7.51-7.44(m,1H),6.97(d,J=8.5Hz,1H),6.86(t,J=8.5Hz,1H ),4.60(s,1H),4.51-4.39(m,2H),4.33(dd,J=2.8,10.8Hz,1H),4.10(d,J=14.8Hz,1H),3.92(br s,1H),3.88(d,J=9.0Hz,3H),3.80(s,3H),3.37(br d,J=12.5Hz,1H),3.00(br d,J=12.8Hz,1H),1.60(d,J=7.0Hz,3H),1.50(s,9H).

[0385] MS(ESI)m / z(M+H) + =562.1.

[0386] Step 14: Preparation of compounds 4-16

[0387]

[0388] Compound 4-15 (0.08 g, 142.35 μmol) was dissolved in anhydrous dichloromethane (1 mL). At 0 °C, a dichloromethane solution of boron tribromide (260 mg, 1.04 mmol, 0.1 mL) was added. After the addition was complete, the system was heated to room temperature (20 °C) and stirred for 2 h under a nitrogen atmosphere. Methanol (2 mL) was then added and stirred for 10 min. The system was concentrated to give compound 4-16 (hydrobromide), which was used directly in the next step without further purification.

[0389] Step 15: Preparation of compounds 4A and 4B

[0390]

[0391] Compound 3-17 (0.1 g, 189.12 μmol, hydrobromide) was dissolved in tetrahydrofuran (5 mL) and saturated sodium bicarbonate aqueous solution (2.82 mL). Acrylic anhydride (0.02 g, 158.59 μmol) was added at room temperature (20 °C). After addition, the system was stirred at room temperature (20 °C) for 2 h. Methanol (3 mL) and an aqueous solution of lithium hydroxide (31.74 mg, 756.47 μmol) were added to the system, and stirring was continued at room temperature (20 °C) for another 2 h. The pH of the system was adjusted to neutral with 1 N hydrochloric acid, and the mixture was extracted with ethyl acetate (10 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by high-performance liquid chromatography (separation conditions: column: Phenomenex Gemini-NX 80*30mm*3μm; mobile phase: [water (10mM ammonium bicarbonate solution)-acetonitrile]; acetonitrile %: 43%-73% 9.5min) to obtain compounds 4A and 4B.

[0392] Compound 4A

[0393] 1 H NMR(400MHz,MeOD)δ7.78(br s,1H),7.34-7.26(m,1H),6.87-6.66(m,3H),6.26(dd,J=1.8,16.8 Hz,1H),5.80(br d,J=9.5Hz,1H),4.67-4.03(m,4H),3.89(d,J=9.0Hz,3H),3.72(br s,1H),3.46(br d,J=14.6Hz,2H),3.03(br d,J=10.0Hz,1H),1.77-1.61(m,3H).

[0394] MS(ESI)m / z(M+H) + =502.2.

[0395] HPLC purity 96.17%; retention time 9.28 min.

[0396] Separation conditions: Column: YMC-Pack ODS-A 150*4.6mm, 5μm; Column temperature: 40℃; Mobile phase: water (0.0688% trifluoroacetic acid solution) - acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10%-80% for 10 min, 80% for 5 min; Flow rate: 1.5 mL / min.

[0397] Compound 4B

[0398] 1H NMR(400MHz,MeOD)δ7.78(br s,1H),7.35-7.25(m,1H),6.86-6.67(m,3H),6.26(dd,J=1.9,16.7Hz,1H),5.81(br s,1H),4.69-4.04(m,4H),3.89(d,J=9.0Hz,3H),3.70(br d,J=15.3Hz,1H),3.47(br d,J=11.8Hz,2H),3.03(br s,1H),1.78-1.62(m,3H).MS(ESI)m / z(M+H) + =502.2.

[0399] HPLC purity 97.7%; retention time 9.60 min.

[0400] Separation conditions: Column: YMC-Pack ODS-A 150*4.6mm, 5μm; Column temperature: 40℃; Mobile phase: water (0.0688% trifluoroacetic acid solution) - acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10%-80% for 10 min, 80% for 5 min; Flow rate: 1.5 mL / min.

[0401] Example 5: Preparation of Compound 5

[0402] Step 1: Preparation of compound 5-1

[0403]

[0404] Compounds 1-3 (29.57 g, 135.0 mmol, 1.0 eq), 3-9 (20.25 g, 135.0 mmol, 1.0 eq), palladium acetate (3.038 g, 13.5 mmol, 0.1 eq), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (7.817 g, 13.5 mmol, 0.1 eq), and cesium carbonate (88.02 g, 270.0 mmol, 2.0 eq) were dissolved in anhydrous dioxane (270 mL) at room temperature (20 °C). The system was heated to 120 °C and stirred for 3 h under a nitrogen atmosphere. The system was cooled to room temperature, the reaction was quenched with saturated ammonium chloride aqueous solution (1 L), extracted with ethyl acetate (3 x 500 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0-10%) to give compound 5-1.

[0405] MS(ESI)m / z(M+H) + =334.1.

[0406] Step 2: Preparation of compound 5-2

[0407]

[0408] Compound 5-1 (13.32 g, 40 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (150 mL). Sodium hydride (4.8 g, 120 mmol, 3.0 eq) was added in portions at room temperature (20 °C). After the addition was complete, the system was stirred at room temperature (20 °C) for 10 min, and acetyl chloride (7.02 g, 120 mmol, 3.0 eq) was added dropwise. After the addition was complete, the system was heated to 100 °C and stirred for 2 h. The system was cooled to room temperature, and the reaction was quenched by adding saturated ammonium chloride aqueous solution (50 mL). The solution was diluted with 1000 mL of water and extracted with ethyl acetate (3 x 500 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by reversed-phase medium-pressure column chromatography (acetonitrile / water (v / v) = 30–45%) to obtain compound 5-2.

[0409] MS(ESI)m / z(M+H) + =344.1.

[0410] Step 3: Preparation of compound 5-3

[0411]

[0412] Compound 5-2 (688 mg, 2 mmol) was dissolved in acetic acid (10 mL). Concentrated nitric acid (2 mL) was added dropwise at room temperature. After the addition was complete, the system was heated to 50 °C and stirred for 1 h. The system was cooled to room temperature and poured into ice water (100 mL). The pH was adjusted to neutral with 10 N sodium hydroxide. The mixture was extracted with ethyl acetate (4 x 100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 5-3, which was used directly in the next reaction without further purification.

[0413] MS(ESI)m / z(M+H) + =389.40.

[0414] Step 4: Preparation of compound 5-4

[0415]

[0416] Compound 5-3 (300 mg, 0.77 mmol) was dissolved in acetic acid (3 mL), and hydrobromic acid (48%, 1.5 mL) was added at room temperature. After the addition was complete, the system was heated to 100 °C and stirred for 16 h. The reaction solution was cooled to room temperature and concentrated to obtain compound 5-4, which was used directly in the next reaction without further purification.

[0417] MS(ESI)m / z(M+H) + =375.00.

[0418] Step 5: Preparation of compound 5-5

[0419]

[0420] Compound 5-4 (290 mg, 0.77 mmol) and N,N-diisopropylethylamine (0.77 mL, 4.64 mmol) were dissolved in acetonitrile (10 mL). Phosphorus oxychloride (0.44 mL) was added at room temperature, and the reaction mixture turned black. The system was heated to 80 °C and stirred for 1 h. The system was concentrated, and the crude product was dissolved in ethyl acetate (10 mL), washed with water, allowed to stand for separation, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–15%) to obtain compound 5-5.

[0421] MS(ESI)m / z(M+H) + =411.00.

[0422] Step 6: Preparation of compounds 5-6

[0423]

[0424] Compounds 5-5 (120 mg, 0.3 mmol), 1-11 (73 mg, 0.315 mmol), cuprous iodide (57.3 mg, 0.3 mmol), and cesium carbonate (197 mg, 0.6 mmol) were dissolved in dioxane (4 mL). The system was heated to 100 °C and stirred for 2 h under a nitrogen atmosphere. The system was filtered through diatomaceous earth, and the filtrate was concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–40%) to obtain compound 5-6.

[0425] MS(ESI)m / z(M+H) + =605.20.

[0426] Step 7: Preparation of compounds 5-7

[0427]

[0428] Compounds 5-6 (100 mg, 0.165 mmol), 2-13 (94 mg, 0.332 mmol), 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (12.3 mg, 0.0169 mmol), and potassium carbonate (46.6 mg, 0.338 mmol) were dissolved in a mixed solution of tetrahydrofuran (3 mL) and water (0.3 mL). The system was heated to 80 °C and stirred for 1 h under a nitrogen atmosphere. The system was concentrated, and the residue was dissolved in ethyl acetate (10 mL), washed with water, allowed to stand for separation, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–40%) to obtain compound 5-7.

[0429] MS(ESI)m / z(M+H) + =725.40.

[0430] Step 8: Preparation of compounds 5-8

[0431]

[0432] Compound 5-7 (25 mg, 0.034 mmol) was dissolved in N,N-dimethylacetamide (2 mL). At room temperature, a tetrahydrofuran solution of bis(trimethylsilylamino)lithium (24%, 0.5 mL) was added. Under a nitrogen atmosphere, the system was heated to 160 °C and stirred for 10 h. The system was cooled to room temperature and concentrated. The residue was dissolved in ethyl acetate (3 mL), washed with water, allowed to stand for separation, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–40%) to obtain compound 5-8.

[0433] MS(ESI)m / z(M+H) + =678.40.

[0434] Step 9: Preparation of compounds 5-9

[0435]

[0436] Compound 5-8 (13 mg, 0.0192 mmol) and hydrochloric acid (6 N, 1 mL) were added to a mixed solution of methanol (0.9 mL) and tetrahydrofuran (0.1 mL). The system was heated to 55 °C and reacted for 15 min. The system was concentrated to obtain crude compound 5-9, which was used directly in the next reaction without further purification.

[0437] MS(ESI)m / z(M+H) + =534.20.

[0438] Step 10: Preparation of compounds 5A and 5B

[0439]

[0440] Compound 5-9 (12 mg, 0.0192 mmol) was dissolved in dichloromethane (1 mL). Triethylamine (2.52 mg, 0.0252 mmol) and acryloyl chloride (2.27 mg, 0.0252 mmol) were added dropwise at 0 °C. After the addition was complete, the system was brought to room temperature (20 °C) and reacted for 30 min. The reaction solution was washed with water (5 mL), extracted with dichloromethane (3 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by high-performance liquid chromatography (HPLC) (separation conditions: Welch Xtimate C18 column 10*250 mm, 5 μm; column temperature 25 °C; mobile phase: water (10 mM / L ammonium bicarbonate aqueous solution)-acetonitrile; acetonitrile 32%-47% 16 min; flow rate 8 mL / min) to obtain compounds 5A and 5B.

[0441] Compound 5A:

[0442] 1 H NMR (400MHz, DMSO-d6) δ10.00(s,1H),8.36(d,J=4.9Hz,1H),7.79(d,J=8.9Hz,1 H),7.24–7.06(m,2H),6.87–6.71(m,1H),6.68–6.51(m,2H),6.10(d,J=16.7Hz,1 H),5.69(d,J=10.5Hz,1H),4.51–4.07(m,3H),3.67–3.42(m,4H),2.65–2.48(m,2 H),1.73(s,3H),1.55–1.48(m,3H),0.98(d,J=6.7Hz,3H),0.84(d,J=6.8Hz,3H).

[0443] MS(ESI)m / z(M+H) + =588.20.

[0444] HPLC 100% purity; retention time 4.917 min.

[0445] Separation conditions: Column: Waters Xbridge C18 3.5μm, 100*4.6mm; Column temperature: 40℃; Mobile phase: water (10mM ammonium bicarbonate aqueous solution)-acetonitrile; Acetonitrile: 5%-95% for 7 min, 95% for 8 min; Flow rate: 1.2mL / min.

[0446] Compound 5B:

[0447] 1 H NMR (400MHz, DMSO-d6) δ10.38(brs,1H),8.44(d,J=4.9Hz,1H),7.92(d,J=8.5Hz,1H),7 .37–7.18(m,2H),6.97–6.80(m,1H),6.79–6.62(m,2H),6.21(dd,J=16.7,2.1Hz,1H),5. 82(d,J=10.6Hz,1H),4.51–4.07(m,3H),3.67–3.42(m,4H),2.65–2.48(m,1H),2.48–2. 42(m,1H),1.91(s,3H),1.72–1.53(m,3H),1.05(d,J=6.7Hz,3H),0.90(d,J=6.7Hz,3H).

[0448] MS(ESI)m / z(M+H) + =588.20.

[0449] HPLC 100% purity; retention time 4.975 min.

[0450] Separation conditions: Column: Waters Xbridge C18 3.5μm, 100*4.6mm; Column temperature: 40℃; Mobile phase: water (10mM ammonium bicarbonate aqueous solution)-acetonitrile; Acetonitrile: 5%-95% for 7 min, 95% for 8 min; Flow rate: 1.2mL / min.

[0451] Example 6: Preparation of Compound 6

[0452] Step 1: Preparation of compound 6-1

[0453]

[0454] Compounds 5-10 (90 mg, 0.15 mmol), 1-13 (51 mg, 0.30 mmol), 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (11 mg, 0.015 mmol), and potassium carbonate (41 mg, 0.3 mmol) were dissolved in a mixed solution of tetrahydrofuran (3 mL) and water (0.3 mL). The system was heated to 80 °C and stirred for 1 h under a nitrogen atmosphere. The system was concentrated, and the residue was dissolved in ethyl acetate (10 mL), washed with water, allowed to stand for separation, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–40%) to obtain compound 6-1.

[0455] MS(ESI)m / z(M+H) + =695.40.

[0456] Step 2: Preparation of compound 6-2

[0457]

[0458] Compound 6-1 (40 mg, 0.058 mmol) was dissolved in N,N-dimethylacetamide (2 mL). At room temperature, a tetrahydrofuran solution (24%, 0.5 mL) of lithium bis(trimethylsilylamino)amine was added. Under a nitrogen atmosphere, the system was heated to 160 °C and stirred for 10 h. The system was cooled to room temperature and concentrated. The residue was dissolved in ethyl acetate (3 mL), washed with water, allowed to stand for separation, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–40%) to obtain compound 6-2.

[0459] MS(ESI)m / z(M+H) + =648.40.

[0460] Step 3: Preparation of compounds 6A and 6B

[0461]

[0462] Compound 6-2 (14 mg, 0.022 mmol) was dissolved in dichloromethane (1 mL). Trifluoroacetic acid (1 mL) was added at room temperature, and the mixture was stirred for 1 h at room temperature (20 °C). The system was concentrated, and the residue was dissolved in dichloromethane (2 mL). The system was cooled to 0 °C, and triethylamine (0.014 mL, 0.1 mmol) and acryloyl chloride (4 mg, 0.04 mmol) were added dropwise. After the addition was complete, the system was allowed to react at room temperature (20 °C) for 30 min. The reaction solution was washed with water (5 mL), extracted with dichloromethane (3 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by high-performance liquid chromatography (separation conditions: Welch Xtimate C18 column 10*250mm, 5μm; column temperature 25℃; mobile phase: water (10mM ammonium bicarbonate aqueous solution)-acetonitrile; acetonitrile 28%-50% 19min; flow rate 8mL / min) to obtain compound 6A and compound 6B.

[0463] Compound 6A:

[0464] 1H NMR(400MHz, DMSO-d6)δ8.44–8.24(m,1H),7.80(d,J=9.0Hz,1H),7.51–7.31(m,1H), 7.15(dd,J=4.9,0.8Hz,1H),6.97–6.64(m,3H),6.10(d,J=16.6Hz,1H),5.70(d,J=15 .0Hz,1H),4.87–4.09(m,2H),3.59(d,J=3.5Hz,3H),3.55–3.45(m,5H),2.56–2.50(m ,2H),1.72(d,J=8.1Hz,3H),1.62–1.39(m,3H),1.09–0.94(m,3H),0.92–0.72(m,3H).

[0465] MS(ESI)m / z(M+H) + =602.20.

[0466] HPLC 100% purity; retention time 5.388 min.

[0467] Separation conditions: Column: Waters Xbridge C18 3.5μm, 100*4.6mm; Column temperature: 40℃; Mobile phase: water (10mM ammonium bicarbonate aqueous solution)-acetonitrile; Acetonitrile: 5%-95% for 7 min, 95% for 8 min; Flow rate: 1.2mL / min.

[0468] Compound 6B:

[0469] 1 H NMR(400MHz,Chloroform-d)δ8.67(s,1H),7.81(d,J=8.4Hz,1H),7.35(q,J=7.9Hz,1H),7.27–7 .14(m,1H),6.72(d,J=8.5Hz,2H),6.66–6.50(m,1H),6.40(d,J=16.4Hz,1H),5.83(d,J=10.3Hz, 1H),4.52–4.27(m,2H),3.78–3.58(m,5H),3.58–3.37(m,2H),3.10(d,J=12.6 Hz,1H),2.82–2.59(m,1H),2.13–1.98(m,1H),1.74(s,3H),1.31–0.96(m,9H).

[0470] MS(ESI)m / z(M+H) + =602.20.

[0471] HPLC 100% purity; retention time 5.455 min.

[0472] Separation conditions: Column: Waters Xbridge C18 3.5μm, 100*4.6mm; Column temperature: 40℃; Mobile phase: water (10mM ammonium bicarbonate aqueous solution)-acetonitrile; Acetonitrile: 5%-95% for 7 min, 95% for 8 min; Flow rate: 1.2mL / min.

[0473] Example 7: Preparation of Compound 7

[0474] Step 1: Preparation of compound 7-2

[0475]

[0476] Compounds 1-10 (2000 mg, 5.063 mmol), 7-1 (2000 mg, 7.751 mmol), cuprous iodide (470.0 mg, 2.46 mmol), and cesium carbonate (3280 mg, 10 mmol) were dissolved in dioxane (30 mL). The system was heated to 100 °C and stirred for 1 h under a nitrogen atmosphere. The system was filtered through diatomaceous earth, and the filtrate was concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–30%) to obtain compound 7-2.

[0477] MS(ESI)m / z(M+H) + =618.2.

[0478] Step 2: Preparation of compound 7-3

[0479]

[0480] Compound 7-2 (320 mg, 0.517 mmol) and iron powder (115 mg, 2.068 mmol) were dissolved in acetic acid (10 mL). The system was heated to 80 °C and stirred for 1 h under a nitrogen atmosphere. The system was filtered through diatomaceous earth, and the filtrate was concentrated to obtain crude compound 7-3. This crude compound was used directly in the next reaction without further purification.

[0481] MS(ESI)m / z(M+H) + =556.2.

[0482] Step 3: Preparation of compound 7-4

[0483]

[0484] Compound 7-3 (287 mg, 0.517 mmol) and potassium carbonate (276 mg, 2 mmol) were dissolved in acetone (20 mL). Iodomethane (284 mg, 2 mmol) was added at room temperature (20 °C). After the addition was complete, the system was heated to 45 °C and stirred for 3 h under a nitrogen atmosphere. The system was then cooled to room temperature and concentrated to obtain a crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–30%) to obtain compound 7-4.

[0485] MS(ESI)m / z(M+H) + =570.2.

[0486] Step 4: Preparation of Compounds 7-5

[0487]

[0488] Compound 7-4 (120 mg, 0.210 mmol), compound 2-3 (177 mg, 0.627 mmol), tetrakis(triphenylphosphine)palladium (240 mg, 0.207 mmol), and sodium carbonate (90 mg, 0.849 mmol) were dissolved in a mixed solution of dioxane (5 mL) and water (0.5 mL). The system was heated to 100 °C and stirred for 1 h under a nitrogen atmosphere. The system was concentrated to obtain a crude product, which was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–50%) to obtain compound 7-5.

[0489] MS(ESI)m / z(M+H) + =690.3.

[0490] Step 5: Preparation of compounds 7-6

[0491]

[0492] Compound 7-5 (180 mg, 0.261 mmol) and hydrochloric acid (6 N, 2 mL) were added to a mixed solution of methanol (10 mL) and tetrahydrofuran (1 mL). The system was heated to 55 °C and reacted for 1 h. The system was concentrated to obtain crude compound 7-6, which was used directly in the next reaction without further purification.

[0493] MS(ESI)m / z(M+H) + =546.2.

[0494] Step 6: Preparation of Compound 7

[0495]

[0496] Compound 7-6 (140 mg, 0.256 mmol) was dissolved in dichloromethane (5 mL), and the system was cooled to 0 °C. Triethylamine (78 mg, 0.771 mmol) and acryloyl chloride (46 mg, 0.514 mmol) were added dropwise, and the system was reacted at 0 °C for 0.5 h. The system was extracted separately with water (5 mL) and dichloromethane (3 mL), and the organic phase was concentrated to obtain the crude product. The crude product was dissolved in a mixed solvent of tetrahydrofuran (5 mL) and water (10 mL), and lithium hydroxide (40 mg) was added. After the addition was complete, the system was stirred at room temperature (20 °C) for 30 min. The system was extracted with ethyl acetate (50 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by high performance preparative liquid chromatography (separation conditions: Phenomenex Gemini-NX column 80*30mm*3μm, mobile phase: water (10mM ammonium bicarbonate aqueous solution)-acetonitrile; acetonitrile 51%-81% 9.5 min; flow rate 30 mL / min) to obtain compound 7.

[0497] Step 7: Preparation of compounds 7A and 7B

[0498]

[0499] The diastereomer compound 7 was purified by SFC (separation conditions: column: DAICEL CHIRALCEL OD (250mm*30mm, 10μm); mobile phase: [0.1% ammonia solution-ethanol]; ethanol %: 40%-40%; flow rate: 70mL / min). After concentration, compounds 7A and 7B were obtained.

[0500] Compound 7A

[0501] 1 H NMR(400MHz, Methanol-d4)δ8.20–7.90(m,1H),7.54–7.41(m,2H),7.34(t,J=7.4Hz,1H),7.20 (p,J=8.1Hz,1H),7.16–7.07(m,1H),6.71–6.48(m,2H),6.24(d,J=17.1Hz,1H),5.82(d,J=11.1 Hz,1H),4.75(d,J=14.3Hz,1H),4.65–4.46(m,1H),4.01–3.82(m,2H),3.48(s,3H),3.00–2.84 (m,1H),2.45–2.32(m,1H),1.67(d,J=6.8Hz,3H),1.12(d,J=6.8Hz,3H),0.96(d,J=6.8Hz,3H).

[0502] MS(ESI)m / z(M+H) + =600.0.

[0503] HPLC 100% purity; retention time 5.05 min.

[0504] Separation conditions: Column: Ultimate C18 3.0*50mm, 3μm; Column temperature: 40℃; Mobile phase: Water (0.0688% trifluoroacetic acid aqueous solution) - acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10%-80% for 6 min, 80% for 2 min; Flow rate: 1.2 mL / min.

[0505] SFC 100%ee. Retention time 3.939min.

[0506] Separation conditions: Column: Chiralcel OD-3 3μm, 100*4.6mm; Column temperature: 35℃; Mobile phase: CO2-ethanol (0.05% DEA); Ethanol: 5%-40% for 4 min, 40% for 2.5 min, 5% for 1.5 min; Flow rate: 2.8 mL / min.

[0507] Compound 7B

[0508] 1 H NMR(400MHz, Methanol-d4)δ8.06(d,J=8.9Hz,1H),7.58–7.40(m,2H),7.36–7.26(m,1H),7.25–7.16(m,1H) ,7.11(dd,J=16.9,10.7Hz,1H),7.06–6.95(m,1H),6.67–6.44(m,2H),6.22(dd,J=16.9,1.9Hz,1H),5.80(dd ,J=10.7,2.0Hz,1H),4.74(d,J=13.9Hz,1H),4.67–4.52(m,1H),3.99–3.81(m,2H),3.45(s,3H),2.93(dd,J= 12.4, 3.8Hz, 1H), 2.68 (p, J = 7.0Hz, 1H), 1.65 (d, J = 6.9Hz, 3H), 1.17 (d, J = 6.9Hz, 3H), 1.05 (d, J = 6.9Hz, 3H).

[0509] MS(ESI)m / z(M+H) + =600.0.

[0510] HPLC 100% purity; retention time 5.00 min.

[0511] Separation conditions: Column: Ultimate C18 3.0*50mm, 3μm; Column temperature: 40℃; Mobile phase: Water (0.0688% trifluoroacetic acid aqueous solution) - acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10%-80% for 6 min, 80% for 2 min; Flow rate: 1.2 mL / min.

[0512] SFC 100% ee. Retention time 4.329 min

[0513] Separation conditions: Column: Chiralcel OD-3 3μm, 100*4.6mm; Column temperature: 35℃; Mobile phase: CO2-ethanol (0.05% DEA); Ethanol: 5%-40% for 4 min, 40% for 2.5 min, 5% for 1.5 min; Flow rate: 2.8 mL / min.

[0514] Example 8: Preparation of Compound 8

[0515] Step 1: Preparation of compound 8-2

[0516]

[0517] Starting material 8-1 (10 g, 52.351 mmol) was dissolved in thionyl chloride (30 mL), and the system was heated to 85 °C and reacted for 16 h. The system was concentrated, and the residue was dissolved in 1,4-dioxane (30 mL). At 0 °C, this solution was slowly added to stirred methanol, and the system was heated to 70 °C and reacted for 2 h. The system was concentrated to give compound 8-2.

[0518] Step 2: Preparation of compound 8-3

[0519]

[0520] Compound 8-2 (4 g, 19.4 mmol) was dissolved in methanol (50 mL), and a methanol solution of sodium methoxide (4 mL, 21.3 mmol) was added dropwise. The system was reacted at room temperature (20 °C) for 3 h. The system was concentrated and poured into water (50 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give crude product 8-3.

[0521] MS(ESI)m / z(M+H) + =202.0.

[0522] Step 3: Preparation of compound 8-4

[0523]

[0524] Compound 8-3 (1.48 g, 7.36 mmol), compound 3-9 (1.11 g, 7.36 mmol), palladium acetate (165 mg, 0.736 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (425 mg, 0.735 mmol), and cesium carbonate (4.8 g, 14.73 mmol) were dissolved in dioxane (15 mL) under a nitrogen atmosphere. The system was heated to 110 °C and stirred for 4 h. The system was cooled to room temperature and concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–20%) to obtain compound 8-4.

[0525] MS(ESI)m / z(M+H) + =316.0.

[0526] Step 4: Preparation of Compound 8-5

[0527]

[0528] Compound 8-4 (1.58 g, 4.80 mmol) was dissolved in N,N-dimethylformamide (15 mL), and N-chlorosuccinimide (0.706 g, 5.28 mmol) was added. The system was heated to 80 °C and reacted for 5 h. The system was cooled to room temperature, poured into water (50 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–5%) to obtain compound 8-5.

[0529] MS(ESI)m / z(M+H) + =350.0

[0530] Step 5: Preparation of compounds 8-6

[0531]

[0532] Compound 8-5 (6.3 g, 7.82 mmol) was dissolved in N,N-dimethylformamide (30 mL) at room temperature (20 °C). Sodium hydride (2.17 g, 54.15 mmol) was added in portions at 0 °C. After the addition was complete, the system was reacted at 0 °C for 30 min, and then acetyl chloride (3.85 mL, 54.15 mmol) was added dropwise. Water (30 mL) and a saturated aqueous solution of potassium carbonate were added sequentially to the system, and the system was reacted at room temperature (20 °C) for 3 h. After extraction with EA (100 mL x 2), the aqueous phase was adjusted to pH 4–5 with hydrochloric acid (4N) and then extracted with ethyl acetate (100 mL x 4). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (methanol / dichloromethane (v / v) = 0–5%) to obtain compound 8-6.

[0533] MS(ESI)m / z(M+H) + =360.0.

[0534] Step 6: Preparation of compounds 8-7

[0535]

[0536] Compound 8-6 (1.86 g, 5.18 mmol) was dissolved in glacial acetic acid (30 mL), and nitric acid (15 mL) was added dropwise to the system at room temperature (20 °C). After the addition was complete, the system was stirred at room temperature (20 °C) for 2 h. The system was concentrated to remove most of the glacial acetic acid, and the remainder was poured into ice water (25 mL), the pH was adjusted to 5-6, filtered, and the filter cake was washed with water and dried to obtain compound 8-7.

[0537] MS(ESI)m / z(M+H) + =405.0.

[0538] Step 7: Preparation of compound 8-8

[0539]

[0540] Compound 8-7 (1 g, 2.47 mmol) was dissolved in a mixed solution of acetic acid (6 mL) and hydrobromic acid (8 mL). The system was heated to 100 °C and reacted for 16 h. The system was then evaporated to dryness to give compound 8-8.

[0541] MS(ESI)m / z(M+H) + =391.0.

[0542] Step 8: Preparation of compounds 8-9

[0543]

[0544] Compound 8-8 (2.0 g, 5.13 mmol) and N,N-diisopropylethylamine (5 mL, 30.7 mmol) were dissolved in acetonitrile (6 mL). Phosphorus oxychloride (7 mL, 77 mmol) was added at room temperature (20 °C). After the addition was complete, the system was heated to 80 °C and stirred for 2 h. The system was concentrated to obtain a crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–50%) to give compound 8-9.

[0545] MS(ESI)m / z(M+H) + =427.0.

[0546] Step 9: Preparation of compounds 8-10

[0547]

[0548] Compounds 8-9 (754 mg, 1.77 mmol), 1-11 (447 mg, 1.955 mmol), cesium carbonate (1.15 g, 3.54 mmol), and cuprous iodide (67 mg, 0.354 mmol) were dissolved in dioxane (5 mL). The system was heated to 100 °C and stirred for 3 h under a nitrogen atmosphere. The system was concentrated to obtain a crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–30%) to obtain compound 8-10.

[0549] MS(ESI)m / z(M+H) + =621.2.

[0550] Step 10: Preparation of compounds 8-11

[0551]

[0552] Compounds 8-10 (345 mg, 0.556 mmol), 2-3 (470 mg, 1.669 mmol), 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (23.4 mg, 0.032 mmol), and potassium carbonate (44 mg, 0.321 mmol) were dissolved in a mixed solution of dioxane (4 mL) and water (1 mL). The system was heated to 100 °C and stirred for 6 h under a nitrogen atmosphere. The system was concentrated, and the residue was dissolved in ethyl acetate (20 mL), washed with water, allowed to stand for separation, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–70%) to obtain compound 8-11.

[0553] MS(ESI)m / z(M+H) + =741.2.

[0554] Step 11: Preparation of compounds 8-12

[0555]

[0556] Compound 8-11 (230 mg, 0.311 mmol) was dissolved in anhydrous 1,2-dichloroethane (10 mL). Triphenylphosphine (244 mg, 0.932 mmol), imidazole (42 mg, 0.622 mmol), and carbon tetrachloride (143 mg, 0.932 mmol) were added at room temperature (20 °C). After the addition was complete, the system was heated to 80 °C and stirred for 2 h under a nitrogen atmosphere. The system was concentrated to obtain a crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–50%) to obtain compound 8-12.

[0557] Step 12: Preparation of compounds 8-13

[0558]

[0559] Compound 8-12 (150 mg, 0.198 mmol) was dissolved in glacial acetic acid (4 mL), and iron powder (112 mg, 1.98 mmol) was added. The system was reacted at room temperature (20 °C) for 1 h. The system was concentrated, and the residue was dissolved in ethyl acetate. The organic phase was washed with saturated sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound 8-13.

[0560] Step 13: Preparation of compounds 8-14

[0561]

[0562] Compound 8-13 (90 mg, 0.124 mmol) and N,N-diisopropylethylamine (48 mg, 0.371 mmol) were dissolved in N,N-dimethylformamide (2 mL), and the mixture was heated to 120 °C and reacted for 4 h. The mixture was then cooled to room temperature, and water (20 mL) was added. The mixture was extracted with ethyl acetate (15 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–50%) to obtain compound 8-14.

[0563] Step 14: Preparation of compounds 8-15

[0564]

[0565] Compound 8-14 (40 mg, 0.0578 mmol) was dissolved in tetrahydrofuran (2 mL). Sodium hydride (5 mg, 0.1156 mmol) was added at 0 °C. After the addition was complete, the system was heated to room temperature and stirred for 30 min. Iodomethane (12.3 mg, 0.086 mmol) was added to the system. After the addition was complete, the system was stirred at room temperature (20 °C) for 2 h. The reaction was quenched with water (5 mL), and the mixture was extracted with ethyl acetate (15 mL x 4). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–50%) to obtain compound 8-15.

[0566] Step 15: Preparation of compounds 8-16

[0567]

[0568] Compound 8-15 (16 mg, 0.02266 mmol), hydrochloric acid (6 N, 1 mL), and a mixed solution of methanol (0.9 mL) and tetrahydrofuran (0.1 mL) were added. The system was heated to 55 °C and reacted for 15 min. The system was then concentrated to give crude product 8-16.

[0569] Step 16: Preparation of Compound 8

[0570]

[0571] Compound 8-16 (13 mg) was dissolved in dichloromethane (2 mL). Triethylamine (11 mg, 0.112 mmol) and acryloyl chloride (7 mg, 0.084 mmol) were added at room temperature (20 °C). After addition, the system was stirred at room temperature (20 °C) for 2 h. Tetrahydrofuran (4 mL), water (1 mL), and an aqueous solution of lithium hydroxide (31.74 mg, 756.47 μmol) were added to the system, and stirring was continued at room temperature (20 °C) for another 2 h. The pH of the system was adjusted to neutral with 1 N hydrochloric acid, and the mixture was extracted with ethyl acetate (10 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by high-performance liquid chromatography (separation conditions: column: Agilent 10 Prep-C8 250×21.2mm; column temperature: 25℃; mobile phase: water (0.1% FA)-acetonitrile; acetonitrile ratio in the mobile phase 30%-50% in 16min; flow rate 30mL / min, to obtain compound 8).

[0572] Compound 8

[0573] 1 H NMR (400MHz, CDCl3)δ 1H NMR(400MHz, CDCl3)8.56(s,1H),8.08(s,1H),7.15(s,1H),6.57(s,3H),6.34(s,1H),5.73(s,1H),5.06(s,1H),4 .67(s,0.5H),4.30(s,0.5H),3.53(s,2H),3.37–2.84(m,7H),2.67(s,1H),1.93(s,3H),1.19(s,6H),1.05(s,3H).

[0574] MS(ESI)m / z(M+H) + =617.3.

[0575] HPLC purity 99%; retention time 5.46 min.

[0576] Separation conditions: Column: Waters X-bridge C18, 4.6*100mm, 3.5μm; Mobile phase: [water (10Mm ammonium bicarbonate aqueous solution)-acetonitrile]; Acetonitrile: 5%-95% for 7 min; Flow rate: 1.2 mL / min.

[0577] Example 9: Preparation of Compound 9

[0578] Step 1: Preparation of compound 9-1

[0579]

[0580] Compound 8-3 (6 g, 29.8 mmol) and an ethanol solution of methylamine (15 mL) were dissolved in ethanol (30 mL). Acetyl chloride (2.5 g, 2.36 mL, 31 mmol) was added dropwise. After the addition was complete, the system was heated to 100 °C and reacted for 2 h. The system was concentrated, and the residue was dissolved in ethyl acetate (200 mL). After washing with saturated brine (80 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–20%) to obtain compound 9-1.

[0581] Step 2: Preparation of compound 9-2

[0582]

[0583] Compound 9-1 (2.02 g, 10.3 mmol) was dissolved in N,N-dimethylformamide (10 mL), and N-chlorosuccinimide (1.5 g, 11.3 mmol) was added. The system was heated to 80 °C and reacted for 2 h. The system was cooled to room temperature, poured into water (50 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–5%) to obtain compound 9-2.

[0584] MS(ESI)m / z(M+H) + =231.0.

[0585] Step 3: Preparation of compound 9-3

[0586]

[0587] Compound 9-2 (1.8 g, 7.82 mmol) and triethylamine (4.8 g, 6.6 mL, 47 mmol) were dissolved in dichloromethane (30 mL), and acetyl chloride (2.5 g, 2.36 mL, 31 mmol) was added dropwise. After the addition was complete, the system was heated to 50 °C and reacted for 16 h. The system was concentrated, and the residue was dissolved in ethyl acetate (100 mL), washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–10%) to obtain compound 9-3.

[0588] MS(ESI)m / z(M+H) + =273.2.

[0589] Step 4: Preparation of compound 9-4

[0590]

[0591] Compound 9-3 (1.3 g, 1.91 mmol) was dissolved in toluene (20 mL) at room temperature (20 °C), and potassium tert-butoxide (1.28 g, 11.46 mmol) was added. After the addition was complete, the system was reacted at room temperature (20 °C) for 4 h under a nitrogen atmosphere. The reaction was quenched by adding 1 M hydrochloric acid, diluted with water (40 mL), and extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was then slurried with methanol to obtain compound 9-4.

[0592] MS(ESI)m / z(M+H) + =241.0.

[0593] Step 5: Preparation of compound 9-5

[0594]

[0595] Compound 9-4 (1 g, 2.84 mmol) was dissolved in glacial acetic acid (20 mL). Nitric acid (2.80 g, 44.44 mmol, 2 mL) was added dropwise to the system at room temperature (20 °C). After the addition was complete, the system was heated to 80 °C and stirred for 1 h. The system was then cooled to room temperature, and most of the glacial acetic acid was removed by concentration. The residue was poured into ice water (25 mL) and extracted with ethyl acetate (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 9-5.

[0596] MS(ESI)m / z(M+H) + =286.0.

[0597] Step 6: Preparation of Compound 9-6

[0598]

[0599] Compound 9-5 (320 mg, 1.12 mmol) was dissolved in a mixed solution of glacial acetic acid (10 mL) and hydrobromic acid (5 mL), and the system was heated to 100 °C and reacted for 8 h. The system was then evaporated to dryness to obtain compound 9-6.

[0600] MS(ESI)m / z(M+H) + =272.0.

[0601] Step 7: Preparation of Compounds 9-7

[0602]

[0603] Compound 9-6 (300 g, 1.05 mmol) and N,N-diisopropylethylamine (781 mg, 6.06 mmol) were dissolved in acetonitrile (2 mL). Phosphorus oxychloride (2.46 g, 16.12 mmol) was added at room temperature. After the addition was complete, the system was heated to 80 °C and stirred for 1 h. The system was cooled to room temperature and concentrated to obtain a crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–20%) to give 150 mg of a yellow solid, compound 9-7.

[0604] MS(ESI)m / z(M+H) + =308.3.

[0605] Step 8: Preparation of compounds 9-8

[0606]

[0607] Compounds 9-7 (130 mg, 0.423 mmol), 1-11 (107 mg, 0.465 mmol), cesium carbonate (275 mg, 0.846 mmol), and cuprous iodide (16 mg, 0.0846 mmol) were dissolved in 1,4-dioxane (3 mL). The system was heated to 100 °C and stirred for 3 h under a nitrogen atmosphere. The system was concentrated to obtain a crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–30%) to obtain compound 9-8.

[0608] MS(ESI)m / z(M+H) + =502.2.

[0609] Step 9: Preparation of compound 9-9

[0610]

[0611] Compounds 9-8 (80 mg, 0.16 mmol), 2-3 (58.5 mg, 0.207 mmol), 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (23.4 mg, 0.032 mmol), and potassium carbonate (44 mg, 0.321 mmol) were dissolved in a mixed solution of dioxane (4 mL) and water (1 mL). The system was heated to 100 °C and reacted for 6 h under a nitrogen atmosphere. After concentration, the system was extracted separately with ethyl acetate (20 mL x 2) and water (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–70%) to obtain compound 9-9.

[0612] MS(ESI)m / z(M+H) + =622.2.

[0613] Step 10: Preparation of compounds 9-10

[0614]

[0615] Compound 9-9 (86 mg, 0.138 mmol) was dissolved in N,N-dimethylacetamide (3 mL). At room temperature, a tetrahydrofuran solution of bis(trimethylsilylamino)lithium (1 M, 0.8 mL) was added. After the addition was complete, the system was heated to 160 °C and stirred for 5 h under a nitrogen atmosphere. The system was cooled to room temperature and filtered. The filtrate was diluted with ethyl acetate (20 mL) and washed successively with water (10 mL x 2) and saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–40%) to obtain compound 9-10.

[0616] MS(ESI)m / z(M+H) + =575.2.

[0617] Step 11: Preparation of compounds 9-11

[0618]

[0619] Compound 9-10 (32 mg, 0.0577 mmol) and hydrochloric acid (6 N, 1 mL) were added to a mixed solution of methanol (0.9 mL) and tetrahydrofuran (0.1 mL). The system was heated to 55 °C and reacted for 15 min. The system was then concentrated to obtain crude product 9-11.

[0620] Step 12: Preparation of Compound 9

[0621]

[0622] Compound 9-11 (24 mg, 0.056 mmol) was dissolved in dichloromethane (2 mL). Triethylamine (11 mg, 0.112 mmol) and acryloyl chloride (7 mg, 0.084 mmol) were added at room temperature (20 °C). After addition, the system was stirred at room temperature (20 °C) for 2 h. Tetrahydrofuran (4 mL), water (1 mL), and an aqueous solution of lithium hydroxide (31.74 mg, 756.47 μmol) were added to the system, and stirring was continued at room temperature (20 °C) for another 2 h. The pH of the system was adjusted to neutral with 1 N hydrochloric acid, and the mixture was extracted with ethyl acetate (10 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by high-performance liquid chromatography (separation conditions: column: Agilent 10 Prep-C8 250×21.2mm; mobile phase: [water (0.1% FA)-acetonitrile]; acetonitrile %: 30%-50% 9min, flow rate 30mL / min) to obtain compound 9.

[0623] Compound 9

[0624] 1 H NMR (400MHz, CDCl3)δ 1H NMR (400MHz, CDCl3) δ8.11(s,1H),7.35(td,J=8.3,6.5Hz,1H),6.90(d,J=8.3Hz,1H),6.78(t,J=9.1Hz,1H),6.57(s,1H),6.38(d,J=17 .0Hz,1H),5.80(d,J=11.3Hz,1H),4.39(s,2H),3.82(s,3H),3.64(s,1H),3.38(d,J=13.4Hz,2H),2.99(d,J=13.0Hz,1H),1.72(s,3H).

[0625] MS(ESI)m / z(M+H) + =485.2.

[0626] HPLC purity 99%; retention time 5.27 min.

[0627] Separation conditions: Column: Waters XSelect CSH C18, 4.6*100mm, 3.5μm; Mobile phase: [water (0.01% trifluoroacetic acid) - acetonitrile (0.01% trifluoroacetic acid)]; Acetonitrile: 5%-95% for 7 min; Flow rate: 1.2 mL / min.

[0628] Example 10: Preparation of Compound 10

[0629] Step 1: Preparation of compound 10-1

[0630]

[0631] Compound 1-12 (470 mg, 0.798 mmol) and triphenylphosphine (630 mg, 2.4 mmol) were added to 20 mL of 1,2-dichloroethane under a nitrogen atmosphere, followed by the addition of carbon tetrachloride (370 mg, 2.4 mmol). After the addition was complete, the system was heated to 80 °C and reacted for 1 h. The system was concentrated to obtain a crude product, which was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–30%) to give compound 10-1.

[0632] MS(ESI)m / z(M+H) + =608.2.

[0633] Step 2: Preparation of compound 10-2

[0634]

[0635] Compound 10-1 (330 mg, 0.54 mmol) was dissolved in glacial acetic acid (10 mL), and iron powder (300 mg, 5.4 mmol) was added. The system was heated to 80 °C and reacted for 1 h. The system was concentrated, and the residue was dissolved in ethyl acetate and filtered through diatomaceous earth. The filtrate was concentrated under vacuum and purified by column chromatography (ethyl acetate / petroleum ether (v / v) = 0–40%) to give compound 10-2.

[0636] MS(ESI)m / z(M+H) + =578.2

[0637] Step 3: Preparation of compound 10-3

[0638]

[0639] Compound 10⁻² (200 mg, 0.347 mmol) and N,N-diisopropylethylamine (400 mg, 3.47 mmol) were dissolved in N,N-dimethylformamide (5 mL), and the mixture was heated to 150 °C and reacted for 3 h. The mixture was then cooled to room temperature, and water (20 mL) was added. The mixture was extracted with ethyl acetate (15 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–30%) to obtain compound 10⁻³.

[0640] MS(ESI)m / z(M+H) + =542.2.

[0641] Step 4: Preparation of compound 10-4

[0642]

[0643] Compound 10⁻³ (130 mg, 0.24 mmol), compound 2⁻³ (135 mg, 0.48 mmol), tetrakis(triphenylphosphine)palladium (138 mg, 0.12 mmol), and sodium carbonate (234 mg, 0.72 mmol) were dissolved in a mixed solution of dioxane (5 mL) and water (0.5 mL). The system was heated to 100 °C and stirred for 1 h under a nitrogen atmosphere. The system was concentrated, and the residue was dissolved in ethyl acetate (10 mL), washed with water, allowed to stand for separation, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–40%) to obtain compound 10⁻⁴.

[0644] MS(ESI)m / z(M+H) + =662.2.

[0645] Step 5: Preparation of compound 10-5

[0646]

[0647] Compound 10⁻⁴ (40 mg, 0.06 mmol) was dissolved in tetrahydrofuran (2 mL). Sodium hydride (7.2 mg, 0.18 mmol) was added at 0 °C. After the addition was complete, the system was heated to room temperature and stirred for 30 min. Iodomethane (17 mg, 0.12 mmol) was added to the system. After the addition was complete, the system was stirred at room temperature (20 °C) for 1 h. The reaction was quenched with water (5 mL), and the mixture was extracted with ethyl acetate (15 mL x 4). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–30%) to obtain compound 10⁻⁵.

[0648] MS(ESI)m / z(M+H) + =676.2.

[0649] Step 6: Preparation of compound 10-6

[0650]

[0651] Compound 10⁻⁵ (30 mg, 0.044 mmol) and hydrochloric acid (6 N, 2 mL) were added to a mixed solution of methanol (10 mL) and tetrahydrofuran (1 mL). The system was heated to 55 °C and reacted for 15 min. The system was then concentrated to obtain crude product 10⁻⁶.

[0652] MS(ESI)m / z(M+H) + =532.4.

[0653] Step 7: Preparation of Compound 10

[0654]

[0655] Compound 10-6 (15 mg, 0.060 mmol) was dissolved in dichloromethane (5 mL). The system was cooled to 0 °C, and triethylamine (10 mg, 0.100 mmol) and acryloyl chloride (5 mg, 0.055 mmol) were added dropwise. After the addition was complete, the system was brought to room temperature (20 °C) and reacted for 30 min. The reaction solution was washed with water (5 mL), extracted with dichloromethane (3 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by high-performance liquid chromatography (HPLC) (separation conditions: column: Welch Ultimate XB-C18 10×250 mm 5 μm; mobile phase: [water (0.1% FA)-acetonitrile]; acetonitrile %: 50%-60% 10 min, 60% 20 min; flow rate 8 mL / min). After concentration, compounds 10A and 10B were obtained.

[0656] MS(ESI)m / z(M+H) + =586.2.

[0657] Compound 10A:

[0658] 1 H NMR (400MHz, Methanol-d4) δ7.83(d,J=9.8Hz,1H),7.47–7.30(m,2H),7.23(td,J=7.5,1.7Hz,1H),7.10(td,J=8.3,6. 5Hz,1H),6.96(dd,J=7.9,1.3Hz,1H),6.74(dd,J=16.7,10.7Hz,1H),6.58–6.43(m,2H),6.18(dd,J=16.8,2.0Hz,1H), 5.72(d,J=10.6Hz,1H),5.24(td,J=4.5,2.2Hz,1H),4.41(m,2H),4.06(d,J=20.7Hz,1H),3.69–3.57(m,1H),3.48–3.3 5(m,2H),3.07(m,3H),3.073(m,1H),2.92(d,J=12.3Hz,1H),2.51–2.34(m,1H),1.63(m,3H),1.04(m,3H),0.89(m,3H).

[0659] HPLC purity 93%; retention time 6.397 min.

[0660] Separation conditions: Column: Waters X-bridge C18, 4.6*100mm, 3.5μm; Mobile phase: water (10mM ammonium bicarbonate solution)-acetonitrile; Acetonitrile: 5%-95% for 7 min; Flow rate: 1.2 mL / min.

[0661] Compound 10B:

[0662] 1 H NMR(400MHz, Methanol-d4)δ7.83(d,J=9.8Hz,1H),7.48–7.30(m,2H),7.22(td,J=7.5,1.7Hz,1H),7.09(td,J=8.3,6.5H z,1H),7.01(dd,J=7.9,1.3Hz,1H),6.74(dd,J=16.8,10.6Hz,1H),6.62–6.38(m,2H),6.18(dd,J=16.8,2.0Hz,1H),5.72( d,J=10.7Hz,1H),5.24(td,J=4.5,2.2Hz,1H),4.52(m,2H),4.06(d,J=19.0Hz,1H),3.72–3.57(m,1H),3.47–3.33(m,2H), 3.07(s,3H),3.05–3.00(m,1H),,2.51–2.34(m,1H),1.63(d,J=26.2Hz,3H),1.04(d,J=6.9Hz,3H),0.89(d,J=6.9Hz,3H).

[0663] HPLC purity 95%; retention time 6.580 min

[0664] Separation conditions: Column: Waters X-bridge C18, 4.6*100mm, 3.5μm; Mobile phase: water (10mM ammonium bicarbonate solution)-acetonitrile; Acetonitrile: 5%-95% for 7 min; Flow rate: 1.2 mL / min.

[0665] Example 11: Preparation of Compound 11

[0666] Step 1: Preparation of compound 11-1

[0667]

[0668] Compound 10⁻⁴ (40 mg, 0.06 mmol) and hydrochloric acid (6 N, 1 mL) were added to a mixed solution of methanol (3 mL) and tetrahydrofuran (0.5 mL). The system was heated to 55 °C and reacted for 15 min. The system was then concentrated to obtain crude product 11⁻⁴.

[0669] MS(ESI)m / z(M+H) + =518.2.

[0670] Step 2: Preparation of Compound 11

[0671]

[0672] Compound 11-1 (15 mg, 0.060 mmol) was dissolved in dichloromethane (5 mL), and the system was cooled to 0 °C. Triethylamine (10 mg, 0.100 mmol) and acryloyl chloride (5 mg, 0.055 mmol) were added dropwise. After the addition was complete, the system was brought to room temperature (20 °C) and reacted for 30 min. The reaction solution was washed with water (5 mL), extracted with dichloromethane (3 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by high-performance liquid chromatography (HPLC) (separation conditions: column: Welch Ultimate XB-C18 10×250 mm 5 μm; mobile phase: [water (0.1% FA)-acetonitrile]; acetonitrile %: 50%-60% 10 min, 60% 20 min; flow rate 8 mL / min) to obtain compounds 11A and 11B.

[0673] Compound 11A:

[0674] 1 H NMR (400MHz, Methanol-d4) δ7.85(dd,J=10.0,6.7Hz,1H),7.54–7.40(m,2H),7.33(td,J=7.5,1.8Hz,1H),7.17(td,J=8.3,6.5Hz,1 H),7.11–7.04(m,1H),6.83(dd,J=16.8,10.7Hz,2H),6.59(td,J=8.5,1.3Hz,2H),6.26(dd,J=16.8,2.0Hz,1H),5.80(ddd,J=10.7, 6.5,2.0Hz,1H),5.33(td,J=4.4,2.2Hz,1H),4.70–4.55(m,2H),4.24–4.05(m,1H),3.84–3.61(m,2H),3.53–3.31(m,2H),3.04(ddd ,J=16.8,12.4,3.7Hz,1H),2.47(td,J=6.9,2.6Hz,1H),1.73(dd,J=31.0,6.8Hz,3H),1.11(d,J=6.9Hz,3H),0.96(d,J=6.8Hz,3H).

[0675] MS(ESI)m / z(M+H) + =572.2.

[0676] HPLC purity 95%; retention time 6.180 min.

[0677] Separation conditions: Column: Waters X-bridge C18, 4.6*100mm, 3.5μm; Mobile phase: [water (10Mm ammonium bicarbonate aqueous solution)-acetonitrile]; Acetonitrile: 5%-95% for 7 min; Flow rate: 1.2 mL / min.

[0678] Compound 11B:

[0679] 1 H NMR(400MHz, Methanol-d4)δ7.75(dd,J=9.9,6.5Hz,1H),7.47–7.30(m,2H),7.23(td,J=7.5,1.7Hz,1H),7.16–6.95(m,1H), 6.74(ddd,J=16.8,10.6,2.6Hz,1H),6.55–6.41(m,2H),6.17(dd,J=16.8,1.9Hz,1H),5.71(ddd,J=10.7,6.5,2.0Hz,1H),5.2 4(td,J=4.5,2.2Hz,1H),4.59–4.48(m,1H),4.41(s,1H),4.14–3.92(m,1H),3.72–3.54(m,2H),3.46–3.28(m,2H),2.93(ddd ,J=16.6,12.5,3.7Hz,1H),2.30(q,J=6.9Hz,1H),1.64(dd,J=30.9,6.8Hz,3H),1.02(d,J=6.9Hz,3H),0.89(d,J=6.9Hz,3H).

[0680] MS(ESI)m / z(M+H) + =572.2.

[0681] HPLC purity 95%; retention time 6.328 min.

[0682] Separation conditions: Column: Waters X-bridge C18, 4.6*100mm, 3.5μm; Mobile phase: [water (10Mm ammonium bicarbonate aqueous solution)-acetonitrile]; Acetonitrile: 5%-95% for 7 min; Flow rate: 1.2 mL / min.

[0683] Example 12: Preparation of Compound 12

[0684] Step 1: Preparation of compound 12-2

[0685]

[0686] Compounds 1-10 (1.37 g, 3.46 mmol), 12-1 (900 mg, 4.16 mmol), cuprous iodide (395 mg, 0.5 mmol), and cesium carbonate (2.26 g, 6.92 mmol) were dissolved in dioxane (20.0 mL). Under a nitrogen atmosphere, the system was heated to 100 °C and stirred for 1 h. The system was filtered through diatomaceous earth, and the filtrate was concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–33%) to obtain compound 12-2.

[0687] MS(ESI)m / z(M+H) + =576.20.

[0688] Step 2: Preparation of compound 12-3

[0689]

[0690] Compound 12-2 (700 mg, 1.2 mmol), compound 2-3 (508 mg, 1.8 mmol), 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (176 mg, 0.24 mmol), and potassium carbonate (323 mg, 2.4 mmol) were dissolved in a mixed solution of dioxane (20 mL) and water (2 mL). The system was heated to 100 °C and stirred for 2 h under a nitrogen atmosphere. The system was concentrated, and the residue was dissolved in ethyl acetate (10 mL), washed with water, allowed to stand for separation, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–50%) to obtain compound 12-3.

[0691] MS(ESI)m / z(M+H) + =696.40.

[0692] Step 3: Preparation of compound 12-4

[0693]

[0694] Compound 12-3 (50 mg) was dissolved in N,N-dimethylacetamide (1 mL). At room temperature, a tetrahydrofuran solution (24%, 0.5 mL) of lithium bis(trimethylsilylamino)amine was added. Under a nitrogen atmosphere, the system was heated to 150 °C and stirred for 4 h. The system was cooled to room temperature and concentrated. The residue was dissolved in ethyl acetate (3 mL), washed with water, allowed to stand for separation, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–50%) to obtain compound 12-4.

[0695] MS(ESI)m / z(M+H)+ =649.40.

[0696] Step 4: Preparation of Compound 12-5

[0697]

[0698] Compound 12-4 (60.0 mg) and hydrochloric acid (6 N, 1 mL) were added to a mixed solution of methanol (0.9 mL) and tetrahydrofuran (0.1 mL). The system was heated to 55 °C and reacted for 15 min. The system was then concentrated to obtain crude product 12-5.

[0699] MS(ESI)m / z(M+H) + =505.20.

[0700] Step 5: Preparation of compounds 12A and 12B

[0701]

[0702] Compound 12-5 (45 mg, 0.09 mmol) was dissolved in dichloromethane (1 mL). Triethylamine (22 μL, 0.27 mmol) and acryloyl chloride (39 μL, 0.27 mmol) were added dropwise at 0 °C. After the addition was complete, the system was brought to room temperature (20 °C) and reacted for 30 min. The reaction solution was washed with water (5 mL), extracted with dichloromethane (3 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the intermediate. The intermediate was then dissolved in tetrahydrofuran (2.0 mL) and water (1.0 mL), and lithium hydroxide (18.9 mg, 0.45 mmol) was added. The mixture was stirred at room temperature for 30 min. The pH of the reaction solution was adjusted to 5–6 with dilute hydrochloric acid (3.0 N), and then extracted and concentrated with ethyl acetate to obtain the crude product. The crude product was purified by high-performance liquid chromatography (HPLC) (separation conditions: column: Agilent 10 Prep-C8 250×21.2mm; column temperature: 25℃; mobile phase: water (0.1% FA)-acetonitrile; acetonitrile ratio of 40%-52% in 12min, 52%-52% in 16min; flow rate: 30mL / min) to obtain compound 12A and compound 12B.

[0703] Compound 12A:

[0704] 1H NMR(400MHz,Chloroform-d)δ7.94(d,J=9.9Hz,1H),7.61–7.50(m,2H),7.47–7.34( m,1H),7.22(td,J=8.3,6.4Hz,1H),7.05(d,J=7.5Hz,1H),6.73–6.57(m,3H),6.41( dd,J=16.8,1.7Hz,1H),5.85(d,J=10.1Hz,1H),4.68–4.30(m,4H),3.81–3.35(m,4H ),3.16(s,1H),2.57(q,J=6.8Hz,1H),1.19(d,J=6.8Hz,3H),0.99(d,J=6.8Hz,3H).

[0705] MS(ESI)m / z(M+H) + =559.20.

[0706] HPLC 100% purity; retention time 5.483 min.

[0707] Separation conditions: Column: Waters X-bridge C18, 4.6*100mm, 3.5μm; Mobile phase: [water (10Mm ammonium bicarbonate aqueous solution)-acetonitrile]; Acetonitrile: 5%-95% for 7 min; Flow rate: 1.2 mL / min.

[0708] Compound 12B:

[0709] 1 H NMR(400MHz,Chloroform-d)δ7.93(d,J=9.9Hz,1H),7.63–7.48(m,2H),7.44–7.33(m,1 H),7.25–7.17(m,1H),7.13(d,J=7.8Hz,1H),6.70–6.56(m,3H),6.41(dd,J=16.7,1.7H z,1H),5.84(d,J=10.4Hz,1H),4.62–4.23(m,3H),4.07–4.00(m,1H),3.79–3.47(m,4H) ,3.21–3.03(m,1H),2.47(q,J=6.8Hz,1H),1.18(d,J=6.8Hz,3H),0.98(d,J=6.8Hz,3H).

[0710] MS(ESI)m / z(M+H) + =559.20.

[0711] HPLC 100% purity; retention time 5.555 min.

[0712] Separation conditions: Column: Waters X-bridge C18, 4.6*100mm, 3.5μm; Mobile phase: [water (10Mm ammonium bicarbonate aqueous solution)-acetonitrile]; Acetonitrile: 5%-95% for 7 min; Flow rate: 1.2 mL / min.

[0713] Example 13: Preparation of Compound 13

[0714] Step 1: Preparation of compound 13-2

[0715]

[0716] Compounds 1-12 (766 mg, 1.3 mmol), 13-1 (534 mg, 1.56 mmol), 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (96 mg, 0.13 mmol), and potassium carbonate (359 mg, 2.6 mmol) were dissolved in a mixed solution of tetrahydrofuran (20 mL) and water (2 mL). The system was heated to 80 °C and stirred for 2 h under a nitrogen atmosphere. The system was concentrated, and the residue was dissolved in ethyl acetate (10 mL), washed with water, allowed to stand for separation, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–33%) to obtain compound 13-2.

[0717] MS(ESI)m / z(M+H) + =770.20.

[0718] Step 2: Preparation of compound 13-3

[0719]

[0720] Compound 13-2 (300 mg) was dissolved in N,N-dimethylformamide (6 mL). At room temperature, a tetrahydrofuran solution (24%, 3.0 mL) of lithium bis(trimethylsilylamino)amine was added, and the system was heated to 150 °C and stirred for 16 h. The system was cooled to room temperature and concentrated. The residue was dissolved in ethyl acetate (3 mL), washed with water, allowed to stand for separation, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–50%) to obtain compound 13-3.

[0721] MS(ESI)m / z(M+H) + =723.30.

[0722] Step 3: Preparation of compound 13-4

[0723]

[0724] Compound 13-3 (214.0 mg), hydrochloric acid (6 N, 4.0 mL), and a mixed solution of methanol (3.6 mL) and tetrahydrofuran (0.4 mL) were added. The system was heated to 55 °C and reacted for 15 min. The system was then concentrated to obtain crude product 13-4.

[0725] MS(ESI)m / z(M+H) + =539.20

[0726] Step 4: Preparation of compounds 13A and 13B

[0727]

[0728] Compound 13-4 (159 mg, 0.29 mmol) was dissolved in N,N-dimethylformamide (5 mL). At room temperature, N,N-diisopropylethylamine (0.072 mL, 0.58 mmol), HATU (165.0 mg, 0.435 mmol), and acrylic acid (25.0 mg, 0.348 mmol) were added dropwise. After the addition was complete, the system was allowed to react at room temperature (20 °C) for 30 min. The reaction solution was washed with water (30 mL), extracted with ethyl acetate (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by high-performance liquid chromatography (HPLC) (column: Agilent 10 Prep-C8 250×21.2 mm; column temperature: 25℃; mobile phase: water (0.1% FA)-acetonitrile; acetonitrile ratio: 25%-40% in 9 min, 40%-45% in 12 min; flow rate: 30 mL / min) to obtain compounds 13A and 13B.

[0729] Compound 13A:

[0730] 1H NMR(400MHz,Chloroform-d)δ7.84(d,J=9.1Hz,1H),7.60(s,1H),7.45(d,J=8.6Hz,1H),7.40–7.33(m, 2H),7.33–7.26(m,2H),7.07(d,J=7.8Hz,1H),6.70–6.53(m,1H),6.40(d,J=16.3Hz,1H),5.87–5.76(m ,1H),5.19–4.70(m,1H),4.53–4.29(m,2H),4.19–3.91(m,1H),3.76–3.34(m,3H),3.16(d,J=12.2Hz,1 H),2.59(p,J=6.9Hz,1H),2.19(s,3H),1.89–1.63(m,3H),1.15(d,J=6.8Hz,3H),0.86(d,J=6.8Hz,3H).

[0731] HPLC 100% purity; retention time 5.069 min.

[0732] Separation conditions: Column: Waters X-bridge C18, 4.6*100mm, 3.5μm; Mobile phase: [water (10Mm ammonium bicarbonate aqueous solution)-acetonitrile]; Acetonitrile: 5%-95% for 7 min; Flow rate: 1.2 mL / min.

[0733] Compound 13B:

[0734] 1 H NMR(400MHz,Chloroform-d)δ7.84(d,J=9.1Hz,1H),7.57(s,1H),7.43–7.32(m,3H),7.26–7.16(m,2H ),7.11(d,J=7.7Hz,1H),6.73–6.55(m,1H),6.40(d,J=16.5Hz,1H),5.82(dd,J=10.5,1.7Hz,1H),5.15 –4.68(m,1H),4.42(d,J=26.9Hz,2H),4.23–3.93(m,1H),3.77–3.42(m,3H),3.12(d,J=12.2Hz,1H),2. 49(p,J=6.8Hz,1H),2.15(s,3H),1.75(d,J=23.3Hz,3H),1.15(d,J=6.8Hz,3H),0.84(d,J=6.8Hz,3H).

[0735] HPLC 100% purity; retention time 5.279 min.

[0736] Separation conditions: Column: Waters X-bridge C18, 4.6*100mm, 3.5μm; Mobile phase: [water (10Mm ammonium bicarbonate aqueous solution)-acetonitrile]; Acetonitrile: 5%-95% for 7 min; Flow rate: 1.2 mL / min.

[0737] Example 14: Preparation of Compound 14

[0738] Step 1: Preparation of compound 14-2

[0739]

[0740] Compound 5-10 (504 mg, 0.84 mmol), compound 14-1 (500 mg, 1.67 mmol), 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (62 mg, 0.084 mmol), and potassium carbonate (232 mg, 1.68 mmol) were dissolved in a mixed solution of tetrahydrofuran (20 mL) and water (2 mL). The system was heated to 80 °C and stirred for 6 h under a nitrogen atmosphere. The system was concentrated, and the residue was dissolved in ethyl acetate (10 mL), washed with water, allowed to stand for separation, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–60%) to obtain compound 14-2.

[0741] MS(ESI)m / z(M+H) + =746.20.

[0742] Step 2: Preparation of compound 14-3

[0743]

[0744] Compound 14-2 (200 mg, 0.268 mmol) and triphenylphosphine (213 mg, 0.8 mmol) were added to 1,2-dichloroethane (4 mL) under a nitrogen atmosphere, followed by the addition of carbon tetrachloride (130 mg, 0.8 mmol). After the addition was complete, the system was heated to 80 °C and reacted for 1 h. The system was concentrated to obtain a crude product, which was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–50%) to obtain compound 14-3.

[0745] MS(ESI)m / z(M+H) + =764.20.

[0746] Step 3: Preparation of compound 14-4

[0747]

[0748] Compound 14-3 (40 mg, 0.05 mmol) was dissolved in glacial acetic acid (3 mL), and iron powder (30.0 mg, 0.054 mmol) was added. The system was heated to 80 °C and reacted for 1 h. The system was concentrated, and the residue was dissolved in ethyl acetate and filtered through diatomaceous earth. The filtrate was concentrated under vacuum and purified by column chromatography (ethyl acetate / petroleum ether (v / v) = 0–50%) to give compound 14-4.

[0749] MS(ESI)m / z(M+H) + =734.20.

[0750] Step 4: Preparation of Compounds 14-5

[0751]

[0752] Compound 14-4 (60 mg, 0.082 mmol), N,N-diisopropylethylamine (0.4 mL), and potassium iodide (14 mg, 0.082 mmol) were dissolved in N,N-dimethylformamide (4 mL), and the mixture was heated to 120 °C and reacted for 7 h. The mixture was then cooled to room temperature, and water (20 mL) was added. The mixture was extracted with ethyl acetate (15 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–50%) to obtain compound 14-5.

[0753] MS(ESI)m / z(M+H) + =698.40.

[0754] Step 5: Preparation of compounds 14-6

[0755]

[0756] Compound 14-5 (33 mg, 0.047 mmol) was dissolved in tetrahydrofuran (2 mL). Sodium hydride (7.2 mg, 0.18 mmol) was added at 0 °C. After the addition was complete, the system was heated to room temperature and stirred for 30 min. Iodomethane (17 mg, 0.12 mmol) was added to the system. After the addition was complete, the system was stirred at room temperature (20 °C) for 1 h. The reaction was quenched with water (5 mL), and the mixture was extracted with ethyl acetate (15 mL x 4). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–50%) to obtain compound 14-6.

[0757] MS(ESI)m / z(M+H) + =712.50.

[0758] Step 6: Preparation of compounds 14-7

[0759]

[0760] Compound 14-6 (40 mg, 0.056 mmol), lithium chloride (10 mg, 0.25 mmol), and p-toluenesulfonic acid (45 mg, 0.25 mmol) were dissolved in N,N-dimethylformamide (1.5 mL). The system was heated to 120 °C and microwaved for 30 min. The system was concentrated, and the residue was dissolved in dichloromethane (4 mL). Trifluoroacetic acid (0.4 mL) was added, and the system was reacted at room temperature (20 °C) for 1 h. The system was then concentrated to give crude product 14-7.

[0761] MS(ESI)m / z(M+H) + =598.30.

[0762] Step 7: Preparation of Compound 14

[0763]

[0764] Compound 14-7 (30 mg, 0.05 mmol) was dissolved in dichloromethane (5 mL). Triethylamine (25.2 mg, 0.252 mmol) and acryloyl chloride (10 mg, 0.1 mmol) were added dropwise at 0 °C. After the addition was complete, the system was brought to room temperature (20 °C) and reacted for 30 min. The reaction solution was washed with water (5 mL), extracted with dichloromethane (3 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by high-performance liquid chromatography (HPLC) (separation conditions: column: ...). 5μm F5 LC Column 150 x 21.2 mm; Column temperature: 25 °C; Mobile phase: water (0.1% FA) - acetonitrile; Acetonitrile: 20%-35% in 10 min; Flow rate 30 mL / min) yielded compound 14.

[0765] 1H NMR (400MHz, DMSO-d6) δ11.37(s,1H),8.37(d,J=4.9Hz,1H),8.33(s,1H),7.82(d,J=10.4Hz,1H),7.78(d, J=9.9Hz,1H),7.46(d,J=6.7Hz,1H),7.18(d,J=4.9Hz,1H),7.11(t,J=6.2Hz,1H),6.90–6.75(m,1H),6.40 (d,J=7.2Hz,1H),6.11(d,J=16.7Hz,1H),5.78–5.64(m,1H),4.52–4.04(m,1H),3.29–4.00(m,6H),3.08(s ,3H),1.97–1.89(m,1H),1.76(s,3H),1.53(d,J=26.4Hz,3H),1.00(d,J=6.8Hz,3H),0.88(d,J=6.6Hz,3H).

[0766] MS(ESI)m / z(M+H) + =652.40.

[0767] Example 15: Preparation of Compound 15

[0768] Step 1: Preparation of Compound 15-1

[0769]

[0770] Compounds 5-6 (2000 mg, 5.063 mmol), 7-1 (2000 mg, 7.751 mmol), cuprous iodide (470.0 mg, 2.46 mmol), and cesium carbonate (3280 mg, 10 mmol) were dissolved in dioxane (30 mL). The system was heated to 100 °C and stirred for 1 h under a nitrogen atmosphere. The system was filtered through diatomaceous earth, and the filtrate was concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–30%) to obtain compound 15-1.

[0771] MS(ESI)m / z(M+H) + =633.2.

[0772] Step 2: Preparation of compound 15-2

[0773]

[0774] Compound 15-1 (320 mg, 0.517 mmol) and iron powder (115 mg, 2.068 mmol) were dissolved in acetic acid (10 mL). The system was heated to 80 °C and stirred for 1 h under a nitrogen atmosphere. The system was filtered through diatomaceous earth, and the filtrate was concentrated to obtain crude product 15-2.

[0775] MS(ESI)m / z(M+H) + =571.2.

[0776] Step 3: Preparation of compound 15-3

[0777]

[0778] Compound 15-2 (100 mg, 0.17 mmol), compound 2-3 (100 mg, 0.34 mmol), tetrakis(triphenylphosphine)palladium (50 mg, 0.04 mmol), and potassium carbonate (50 mg, 0.34 mmol) were dissolved in a mixed solution of dioxane (5 mL) and water (0.5 mL). The system was heated to 100 °C and stirred for 2 h under a nitrogen atmosphere. The system was concentrated to obtain a crude product, which was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–50%) to obtain compound 15-3.

[0779] MS(ESI)m / z(M+H) + =691.40.

[0780] Step 4: Preparation of compound 15-4

[0781]

[0782] Compound 15-3 (57 mg, 0.07 mmol) and potassium carbonate (30 mg, 0.2 mmol) were dissolved in N,N-dimethylformamide (2 mL). 1-fluoro-2-bromoethane (30 mg, 0.2 mmol) was added at room temperature (20 °C). After the addition was complete, the system was heated to 100 °C and stirred for 1 h under a nitrogen atmosphere. The system was then cooled to room temperature and concentrated to obtain a crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–50%) to give compound 15-4.

[0783] MS(ESI)m / z(M+H) + =737.5.

[0784] Step 5: Preparation of compound 15-5

[0785]

[0786] Compound 15-4 (25 mg, 0.035 mmol) and hydrochloric acid (6 N, 2 mL) were added to a mixed solution of methanol (2 mL) and tetrahydrofuran (0.2 mL). The system was heated to 55 °C and reacted for 1 h. The system was then concentrated to give crude compound 15-5.

[0787] MS(ESI)m / z(M+H) + =593.40.

[0788] Step 6: Preparation of Compound 15

[0789]

[0790] Compound 15-5 (25 mg, 0.04 mmol) was dissolved in dichloromethane (3 mL), and the system was cooled to 0 °C. Triethylamine (0.1 g) and acryloyl chloride (4.6 mg, 0.0514 mmol) were added dropwise, and the reaction was carried out at 0 °C for 0.5 h. The system was extracted separately with water (5 mL) and dichloromethane (3 mL), and the organic phase was concentrated to obtain the crude product. The crude product was purified by high-performance liquid chromatography (HPLC) (separation conditions: column...). 5μm F5 LC Column 150 x 21.2 mm; Column temperature: 25 °C; Mobile phase: water (0.1% FA) - acetonitrile; Acetonitrile: 15%-35% in 10 min, 35%-35% in 16 min; Flow rate 30 mL / min) to obtain compound 15.

[0791] 1 H NMR (400MHz, DMSO-d6) δ8.38(d,J=4.8Hz,1H),7.95(d,J=8.5Hz,1H),7.30–7.12(m,2H),6.95(dd,J=1 6.8,10.6Hz,1H),6.82–6.53(m,2H),6.08(dd,J=16.8,2.4Hz,1H),5.69(dd,J=10.5,2.5Hz,1H),4.58 –4.43(m,3H),3.96(dd,J=23.4,4.0Hz,1H),3.69(dd,J=14.2,4.3Hz,1H),3.50–3.32(m,3H),2.83–2. 71(m,1H),2.71–2.54(m,1H),1.81(d,J=55.9Hz,3H),1.48(dd,J=6.8,2.1Hz,3H),1.08–0.63(m,6H).

[0792] MS(ESI)m / z(M+H) + =647.4.

[0793] HPLC purity 90%; retention time 5.224 min.

[0794] Separation conditions: Column: Waters Xbridge C18 3.5μm, 100*4.6mm; Column temperature: 40℃; Mobile phase: water (10mM ammonium bicarbonate aqueous solution)-acetonitrile; Acetonitrile: 5%-95% for 7 min, 95% for 8 min; Flow rate: 1.2mL / min.

[0795] Example 16: Preparation of Compound 16

[0796] Step 1: Preparation of Compound 16-1

[0797]

[0798] Under nitrogen protection, compound 3-14 (100 mg, 140.50 μmol) was dissolved in 1,2-dichloroethane (3 mL), followed by the sequential addition of triphenylphosphine (112 mg, 427.01 μmol) and carbon tetrachloride (80 mg, 520.08 μmol, 0.05 mL). The mixture was heated to 80 °C and stirred for 16 h. The reaction solution was concentrated under reduced pressure, and the crude product was purified by preparative silica gel plate chromatography (ethyl acetate / petroleum ether (v / v) = 100%) to give compound 16-1.

[0799] MS(ESI)m / z(M+H) + =730.3.

[0800] Step 2: Preparation of compound 16-2

[0801]

[0802] Compound 16-1 (80 mg, 109.56 μmol) was dissolved in acetic acid (1 mL), and iron powder (31 mg, 555.11 μmol) was added. The mixture was heated to 80 °C and stirred for 1 h. The reaction solution was diluted with ethyl acetate (10 mL), filtered, and the filtrate was concentrated under reduced pressure. The crude product was dissolved in ethyl acetate (10 mL), washed with saturated sodium bicarbonate solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative silica gel plate chromatography (ethyl acetate / petroleum ether (v / v) = 100%) to give compound 16-2.

[0803] MS(ESI)m / z(M+H) + =700.2.

[0804] Step 3: Preparation of compound 16-3

[0805]

[0806] Compound 16-2 (60 mg, 85.69 μmol) was dissolved in N,N-dimethylformamide (1 mL), and diisopropylethylamine (37.10 mg, 287.06 μmol, 0.05 mL) was added. The reaction was carried out in a sealed tube and heated to 120 °C with stirring for 6 h. The reaction solution was concentrated under reduced pressure, and the crude product was purified by preparative silica gel plate chromatography (methanol / dichloromethane (v / v) = 1 / 15) to give compound 16-3.

[0807] MS(ESI)m / z(M+H) + =664.1.

[0808] Step 4: Preparation of compound 16-4

[0809]

[0810] Compound 16-3 (40 mg, 60.27 μmol) was dissolved in tetrahydrofuran (1 mL), and sodium hydride (5 mg, 125.01 μmol, 60%) and methyl iodide (10 mg, 70.45 μmol) were added sequentially. The reaction mixture was stirred at 25 °C for 1 h. The reaction solution was quenched with 2 drops of saturated ammonium chloride solution, diluted with ethyl acetate (20 mL), and washed sequentially with water (20 mL) and saturated sodium chloride solution (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude product 16-4.

[0811] MS(ESI)m / z(M+H) + =678.4.

[0812] Step 5: Preparation of compound 16-5

[0813]

[0814] Compound 16-4 (40 mg, 59.02 μmol) was dissolved in dichloromethane (1 mL), and boron tribromide (73.93 mg, 295.09 μmol, 28.43 μL) was added. The reaction mixture was stirred at 20 °C for 3 h. The reaction solution was quenched with methanol (10 mL), stirred for 10 min, and concentrated under reduced pressure to obtain crude product 16-5.

[0815] MS(ESI)m / z(M+H) + =564.0.

[0816] Step 6: Preparation of Compound 16

[0817]

[0818] Compound 16-5 (50 mg, 77.58 μmol) was dissolved in tetrahydrofuran (1 mL), and saturated sodium bicarbonate solution (2.16 g, 25.71 mmol, 1 mL) and acrylic anhydride (11 mg, 87.23 μmol) were added sequentially. The reaction mixture was stirred at 20 °C for 1 h. Methanol (1 mL) and potassium carbonate aqueous solution (2 M, 1 mL) were added, and stirring continued for 1.5 h. The reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (20 mL x 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by high-performance liquid chromatography (HPLC) (separation conditions: column: Phenomenex Gemini-NX 80*30 mm*3 μm; mobile phase: [water (10 mM ammonium bicarbonate)-acetonitrile]; acetonitrile %: 36%-66%, 9.5 min). Compound 16A (peak 1) and compound 16B (peak B) were obtained.

[0819] Compound 16A:

[0820] 1 H NMR (400MHz, MeOD) δ8.41 (d, J = 5.1Hz, 1H), 7.55 (br d,J=9.7Hz,1H),7.28-7.16(m,2H),6.84(dd,J=10.7,16.6Hz,1H),6.71-6.57(m,2H),6.28(dd,J=1.9,16.6Hz,1H),5.82(br d,J=10.8Hz,1H),5.04-4.91(m,2H),4.60-4.53(m,1H),4.13(br s,1H),3.74(br s,1H),3.59-3.43(m,2H),3.15(s,3H),3.02(br s,1H),2.81-2.57(m,1H),2.05(d,J=15.7Hz,3H),1.83-1.65(m,3H),1.18-1.06(m,6H).

[0821] MS(ESI)m / z(M+H) + =618.2.

[0822] HPLC 97% of purity; Retention time: 4.00min+4.051min.

[0823] Separation conditions: Column: Xbridge Shield RP-18, 5μm, 2.1*50mm; Column temperature: 50℃; Mobile phase: [water (0.02% ammonia solution) - acetonitrile]; Acetonitrile: 10%-80% for 6 min, 80% for 2 min; Flow rate: 0.8 mL / min.

[0824] Compound 16B:

[0825] 1 H NMR (400MHz, MeOD) δ8.41 (d, J = 5.1Hz, 1H), 7.54 (br d,J=9.0Hz,1H),7.30-7.14(m,2H),6.84(dd,J=10.9,16.6Hz,1H),6.71-6.55(m,2H),6.35-6.21(m,1H),5.81(br d,J=9.5Hz,1H),5.01-4.90(m,2H),4.66-4.50(m,1H),4.15(br d,J=15.4Hz,1H),3.71(br s,1H),3.62-3.42(m,2H),3.14(s,3H),3.01(br s,1H),2.81-2.56(m,1H),2.12-1.95(m,3H),1.83-1.61(m,3H),1.19-1.02(m,6H).

[0826] MS(ESI)m / z(M+H) + =618.3.

[0827] HPLC 94% of purity; Retention time: 4.082min.

[0828] Separation conditions: Column: Xbridge Shield RP-18, 5μm, 2.1*50mm; Column temperature: 50℃; Mobile phase: [water (0.02% ammonia solution) - acetonitrile]; Acetonitrile: 10%-80% for 6 min, 80% for 2 min; Flow rate: 0.8 mL / min.

[0829] Step 7: Preparation of compounds 16A-1 and 16A-2

[0830]

[0831] The diastereomer compound 16A was purified by SFC (separation conditions: column: DAICEL CHIRALPAK AD-H (250mm*30mm, 5μm); mobile phase: [CO2-isopropanol (0.1% ammonia)]; isopropanol %: 35%). After concentration, compounds 16A-1 and 16A-2 were obtained.

[0832] Compound 16A-1:

[0833] 1H NMR (400MHz, DMSO-d6) δ8.42(br d,J=4.9Hz,1H),7.40(br s,1H),7.29-7.07(m,2H),6.85(br d,J=10.3Hz,1H),6.75-6.53(m,2H),6.16(br d,J=9.0Hz,1H),5.74(br d,J=10.0Hz,1H),4.79(br s,1H),4.46(br d,J=14.4Hz,1H),4.16(br d,J=14.2Hz,1H),3.89(br d,J=14.7Hz,1H),3.51-3.36(m,2H),3.23-3.15(m,2H),3.08(s,2H),2.98-2.85(m,2H),2.66(br d,J=1.7Hz,1H),1.90(s,3H),1.72-1.47(m,3H),1.26-0.88(m,6H).

[0834] MS(ESI)m / z(M+H) + =618.3.

[0835] SFC retention time: 1.516 min.

[0836] Separation conditions: Column: Chiralpak AD-3 50 x 4.6 mm ID, 3 μm; Column temperature: 35℃; Mobile phase: CO2-isopropanol (0.05% DEA); Isopropanol: 5%-40% 2 min, 40% 1.2 min, 5% 0.8 min; Flow rate: 4 mL / min.

[0837] Compound 16A-2:

[0838] 1H NMR (400MHz, METHANOL-d4) δ8.41(br d,J=4.9Hz,1H),7.55(br d,J=11.0Hz,1H),7.30-7.10(m,2H),6.84(br dd,J=10.5,16.6Hz,1H),6.71-6.51(m,2H),6.27(br dd,J=1.8,16.8Hz,1H),5.82(br d,J=10.6Hz,1H),4.96-4.92(m,1H),4.61(br s,2H),4.26-4.13(m,1H),3.72(br s,1H),3.52-3.38(m,2H),3.14(s,3H),2.99(br s,1H),2.62(td,J=6.8,13.7Hz,1H),2.06(s,3H),1.85-1.59(m,3H),1.39-1.03(m,6H).

[0839] MS(ESI)m / z(M+H) + =618.3.

[0840] SFC retention time: 1.644 min.

[0841] Separation conditions: Column: Chiralpak AD-3 50 x 4.6 mm ID, 3 μm; Column temperature: 35℃; Mobile phase: CO2-isopropanol (0.05% DEA); Isopropanol: 5%-40% 2 min, 40% 1.2 min, 5% 0.8 min; Flow rate: 4 mL / min.

[0842] Step 8: Preparation of compounds 16B-1 and 16B-2

[0843]

[0844] The diastereomer compound 16B was purified by SFC (separation conditions: column: DAICEL CHIRALPAK AD-H (250mm*30mm, 5μm); mobile phase: [CO2-isopropanol (0.1% ammonia)]; isopropanol %: 35%). After concentration, compounds 16B-1 and 16B-2 were obtained.

[0845] Compound 16B-1:

[0846] 1H NMR (400MHz, DMSO-d6) δ8.43(br d,J=4.9Hz,1H),7.41(br s,1H),7.29-7.14(m,2H),6.86(br d,J=11.0Hz,1H),6.75-6.59(m,2H),6.19(br s,1H),5.75(br d,J=10.8Hz,1H),4.80(br s,1H),4.47(br d,J=14.4Hz,1H),4.15(br s,1H),3.90(br d,J=17.1Hz,1H),3.55-3.40(m,2H),3.21(br d,J=11.2Hz,2H),3.09(s,3H),2.97-2.81(m,2H),1.89(s,3H),1.68-1.51(m,3H),1.19-0.90(m,6H).

[0847] MS(ESI)m / z(M+H) + =618.3.

[0848] SFC retention time: 1.521 min.

[0849] Separation conditions: Column: Chiralpak AD-3 50 x 4.6 mm ID, 3 μm; Column temperature: 35℃; Mobile phase: CO2-isopropanol (0.05% DEA); Isopropanol: 5%-40% 2 min, 40% 1.2 min, 5% 0.8 min; Flow rate: 4 mL / min.

[0850] Compound 16B-2:

[0851] 1H NMR (400MHz, METHANOL-d4) δ8.41(br d,J=5.1Hz,1H),7.55(br d,J=10.4Hz,1H),7.34-7.13(m,2H),6.84(br dd,J=10.7,16.6Hz,1H),6.73-6.53(m,2H),6.28(br dd,J=1.8,16.8Hz,1H),5.81(br s,1H),4.98-4.93(m,1H),4.61(br s,2H),4.15(br s,1H),3.72(br s,1H),3.47(br d,J=13.9Hz,2H),3.15(s,3H),3.06-2.94(m,1H),2.68-2.57(m,1H),2.08(s,3H),1.87-1.63(m,3H),1.36-1.01(m,6H).

[0852] MS(ESI)m / z(M+H) + =618.3.

[0853] SFC retention time: 1.652 min.

[0854] Separation conditions: Column: Chiralpak AD-3 50 x 4.6 mm ID, 3 μm; Column temperature: 35℃; Mobile phase: CO2-isopropanol (0.05% DEA); Isopropanol: 5%-40% 2 min, 40% 1.2 min, 5% 0.8 min; Flow rate: 4 mL / min.

[0855] Example 17: Preparation of Compound 17

[0856] Step 1: Preparation of compound 17-2

[0857]

[0858] Compounds 1-12 (450 mg, 0.76 mmol), 17-1 (240 mg, 0.92 mmol), 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (65 mg, 0.076 mmol), and potassium carbonate (210 mg, 1.5 mmol) were dissolved in a mixed solution of dioxane (20 mL) and water (2 mL). The system was heated to 90 °C and stirred for 3 h under a nitrogen atmosphere. The system was concentrated, and the residue was dissolved in ethyl acetate (10 mL), washed with water, allowed to stand for separation, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–30%) to obtain compound 17-2.

[0859] MS(ESI)m / z:(M+H) + =770.1.

[0860] Step 2: Preparation of compound 17-3

[0861]

[0862] Compound 17-2 (50 mg, 0.065 mmol) was dissolved in N,N-dimethylacetamide (5 mL). At room temperature, a tetrahydrofuran solution of bis(trimethylsilylamino)lithium (24%, 0.65 mL) was added. Under a nitrogen atmosphere, the system was heated to 160 °C and stirred for 8 h. The system was cooled to room temperature and concentrated. The residue was dissolved in ethyl acetate (3 mL), washed with water, allowed to stand for separation, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–40%) to obtain compound 17-3.

[0863] MS(ESI)m / z:(M+H) + =723.3.

[0864] Step 3: Preparation of compound 17-4

[0865]

[0866] Compound 17-3 (30 mg, 0.041 mmol) was dissolved in methanol (3 mL), and concentrated hydrochloric acid (12 N, 2 mL) was added. After the addition was complete, the system was heated to 70 °C and reacted for 3 h. The system was concentrated to obtain a yellow oily substance 17-4, which was used directly in the next reaction without further purification.

[0867] MS(ESI)m / z(M+H) + =539.2.

[0868] Step 4: Preparation of compound 17-6

[0869]

[0870] Compound 17-5 (2 g, 15.2 mmol) was dissolved in trifluoroacetic acid (10 mL), and N-bromosuccinimide (3 g, 16.7 mmol) was added. After the addition was complete, the system was heated to 80 °C and stirred for 1 h under sealed conditions. The system was concentrated, and saturated sodium bicarbonate aqueous solution was added to adjust the pH to >7. The mixture was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to obtain the crude product, which was then purified by medium-pressure column chromatography (methanol / dichloromethane (v / v) = 0–10%) to obtain compound 17-6.

[0871] MS(ESI)m / z:(M+H) + =212.8.

[0872] Step 5: Preparation of compound 17-7

[0873]

[0874] Compound 17-6 (350 mg, 1.66 mmol) was dissolved in tetrahydrofuran (20 mL), and tetrahydropyran (420 mg, 5.0 mmol) and p-toluenesulfonic acid (65 mg, 0.33 mmol) were added. After the addition was complete, the system was heated to 80 °C and refluxed for 24 h. The system was concentrated to obtain a crude product, which was purified by medium-pressure column chromatography (methanol / dichloromethane (v / v) = 0–1%) to obtain compound 17-7.

[0875] MS(ESI)m / z:(M+H) + =297.0.

[0876] Step 6: Preparation of Compound 17-1

[0877]

[0878] Compound 17-7 (300 mg, 1.0 mmol), pinacol diborate (500 mg, 2.0 mmol), potassium acetate (300 mg, 3.0 mmol), and palladium dichloride dichloride (74 mg, 0.1 mmol) were dissolved in a mixed solvent of N,N-dimethylacetamide (10 mL) and water (1 mL). The system was heated to 155 °C and stirred for 2 h under a nitrogen atmosphere. After cooling to room temperature, the system was poured into water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 17-1, which was used directly in the next reaction without further purification.

[0879] MS(ESI)m / z:(M+H) + =261.0.

[0880] Step 7: Preparation of Compound 17

[0881]

[0882] Compound 17-4 (20 mg, 0.037 mmol) was dissolved in dichloromethane (1 mL). The system was cooled to 0 °C at room temperature, and triethylamine (10 mg, 0.1 mmol) and acryloyl chloride (5 mg, 0.05 mmol) were added dropwise. After the addition was complete, the system was brought to room temperature (20 °C) and reacted for 30 min. The reaction solution was washed with water (5 mL), extracted with dichloromethane (3 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by high-performance liquid chromatography (HPLC) (separation conditions: Agilent 10 Prep-C8 column 250 × 21.2 mm; column temperature: 25 °C; mobile phase: water (0.1% FA)-acetonitrile; acetonitrile: 20%-40% in 12 min; flow rate 30 mL / min) to obtain compound 17.

[0883] MS(ESI)m / z(M+H) + =593.3.

[0884] HPLC: 95%, 4.875min+5.087min.

[0885] Separation conditions: Column: Waters X-bridge C18, 4.6*100mm, 3.5μm; Mobile phase: [water (10mM ammonium bicarbonate aqueous solution)-acetonitrile]; Acetonitrile: 5%-95% for 7 min; Flow rate: 1.2 mL / min.

[0886] Example 18: Preparation of compounds 18A-1 / 18A-2 / 18B-1 and 18B-2

[0887] Step 1: Preparation of compound 18-1

[0888]

[0889] Compound 4-8 (8.6 g, 26.24 mmol) was dissolved in acetonitrile (40 mL) at 0 °C under nitrogen protection. Cuprous iodide (5.05 g, 26.51 mmol), potassium iodide (8.84 g, 53.27 mmol), and tert-butyl nitrite (5.66 g, 54.85 mmol, 6.52 mL) were added sequentially. The reaction mixture was heated to 80 °C and stirred for 2 h. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (80 mL), washed with saturated sodium thiosulfate solution (80 mL x 2), and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 0–2 / 3) to give compound 18-1.

[0890] 1H NMR (400MHz, CDCl3) δ7.77 (d, J = 1.5Hz, 1H), 7.46-7.38 (m, 1H), 6.87-6.77 (m, 2H), 3.98 (s, 3H), 3.80 (s, 3H).

[0891] Step 2: Preparation of compound 18-2

[0892]

[0893] Under nitrogen protection, compound 18-1 (6.5 g, 14.82 mmol) and 2-isopropyl-4-methylpyridin-3-amine (2.60 g, 17.31 mmol) were dissolved in toluene (10 mL), followed by the sequential addition of 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (950 mg, 1.64 mmol), tris(dibenzylacetone)dipalladium (1.5 g, 1.64 mmol), and cesium carbonate (14.49 g, 44.46 mmol). The reaction mixture was heated to 100 °C and stirred for 16 h. The reaction solution was diluted with ethyl acetate (100 mL), filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 0 to 2 / 3) to give compound 18-2.

[0894] MS(ESI)m / z(M+H) + =460.

[0895] 1 H NMR (400MHz, CDCl3) δ9.08 (br s,1H),8.29(d,J=4.9Hz,1H),8.04-7.92(m,1H),7.36-7.28(m,1H),6.94(t,J=5.4Hz,1H),6.78-6.68(m,2H), 3.98(s,3H),3.74(d,J=17.4Hz,3H),3.52-3.41(m,1H),2.20(s,3H),1.27-1.24(m,3H),1.21(d,J=6.6Hz,3H).

[0896] Step 9: Preparation of compound 18-3

[0897]

[0898] At 0 °C, compound 18-2 (3.2 g, 6.94 mmol) was dissolved in N,N-dimethylformamide (30 mL), sodium hydride (1.39 g, 34.71 mmol, 60%) was added, and the mixture was stirred for 20 min. Then, acetyl chloride (2.73 g, 34.71 mmol, 2.48 mL) was added, and the reaction was heated to 25 °C and stirred for 16 h. The reaction solution was quenched with water (100 mL), and saturated potassium carbonate solution (100 mL) was added. The mixture was stirred for 1 h, extracted with ethyl acetate (100 mL x 2), 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 chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 0 to 0 / 1) to give compound 18-3.

[0899] MS(ESI)m / z(M+H) + =503.1.

[0900] 1 H NMR (400MHz, CDCl3) δ8.49-8.43(m,1H),7.85(s,1H),7.37-7.30(m,1H),7.07-7.01(m,1H),6.80- 6.64(m,2H),4.04-3.89(m,3H),3.80-3.74(m,1H),3.74-3.42(m,4H),2.33(br d,J=3.1Hz,3H),1.97(br d,J=4.9Hz,3H),1.29(br d,J=6.4Hz,3H),0.88-0.71(m,3H).

[0901] Step 10: Preparation of compound 18-4

[0902]

[0903] Under nitrogen protection, compound 18-3 (580 mg, 1.15 mmol) was dissolved in toluene (10 mL), and potassium tert-butoxide (1.0 M tetrahydrofuran solution, 3.74 mL) was added. The reaction mixture was stirred at 25 °C for 30 min. The reaction solution was quenched with water (20 mL), and the pH was adjusted to 7.0 with 1.0 M hydrochloric acid. The mixture was extracted with ethyl acetate (30 mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product 18-4, which was used directly in the next reaction without further purification.

[0904] MS(ESI)m / z(M+H) + =471.2.

[0905] 1H NMR(400MHz,Chloroform-d)δ8.64-8.51(m,1H),8.01(s,1H),7.39-7.31(m,1H),7.13(t,J=4.1Hz,1H),6.79-6.70( m,2H),6.43(s,1H),3.75-3.66(m,3H),2.85-2.71(m,1H),2.12-2.07(m,3H),1.26-1.22(m,3H),1.17-1.11(m,3H).

[0906] Step 11: Preparation of compound 18-5

[0907]

[0908] Under nitrogen protection, compound 18-4 (500 mg, 1.06 mmol) was dissolved in acetic acid (10 mL), and concentrated nitric acid (1.23 g, 19.51 mmol, 878.20 μL) was added. The reaction mixture was heated to 80 °C and stirred for 2 h. The reaction solution was concentrated under reduced pressure to remove most of the acetic acid, cooled to 0 °C, and water (50 mL) was added. The mixture was filtered, and the filter cake was dried under vacuum to obtain crude product 18-5, which was used directly in the next reaction without further purification.

[0909] MS(ESI)m / z(M+H) + =516.2.

[0910] 1 H NMR(400MHz,DMSO-d6)δ8.57–8.55(m,1H),8.06(s,1H),7.67-7.38(m,2H),7.03 -6.77(m,2H),3.74-3.61(m,1H),3.58-3.50(m,3H),2.53-2.51(m,3H),2.15(br d,J=6.0Hz,1H),1.33-0.94(m,6H).

[0911] Step 12: Preparation of compound 18-6

[0912]

[0913] Under nitrogen protection, compound 18-5 (600 mg, 1.16 mmol) was dissolved in acetonitrile (10 mL), followed by the sequential addition of diisopropylethylamine (901.86 mg, 6.98 mmol, 1.22 mL) and phosphorus oxychloride (534.98 mg, 3.49 mmol, 324.23 μL). The reaction mixture was heated to 80 °C and stirred for 2 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 0 to 1 / 1) to give compound 18-6.

[0914] MS(ESI)m / z(M+H) + =534.

[0915] 1 H NMR(400MHz,Chloroform-d)δ8.57-8.51(m,1H),8.17(t,J=1.7Hz,1H),7.43-7.34(m,1H),7.09(t,J=4.2H z,1H),6.81-6.71(m,2H),3.81-3.65(m,4H),2.77-2.67(m,1H),2.13(d,J=6.0Hz,3H),1.35-1.17(m,6H).

[0916] Step 13: Preparation of compound 18-7

[0917]

[0918] Under nitrogen protection, compound 18-6 (320 mg, 598.87 μmol) was dissolved in acetonitrile (8 mL), and diisopropylethylamine (387.76 mg, 3.00 mmol, 522.59 μL) and compound 1-11 (206.88 mg, 898.31 μmol) were added sequentially. The reaction mixture was heated to 80 °C and stirred for 1 h. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 0 to 2 / 3) to give compound 18-7.

[0919] MS(ESI)m / z(M+H) + =728.2.

[0920] Step 14: Preparation of compound 18-8

[0921]

[0922] Under nitrogen protection, compound 18-7 (350 mg, 480.65 μmol) was dissolved in N-methylpyrrolidone (10 mL), followed by the addition of 4A molecular sieve (500 mg) and lithium bis(trimethylsilylamine) (1 M tetrahydrofuran solution, 1.44 mL). The reaction mixture was heated to 130 °C and stirred for 16 h. The solvent was removed by concentration under reduced pressure, and the solution was diluted with ethyl acetate (50 mL). The mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol (v / v) = 10 / 1) to give compound 18-8.

[0923] MS(ESI)m / z(M+H) + =681.3.

[0924] Step 15: Preparation of Compounds 18-9

[0925]

[0926] Under nitrogen protection, compound 18-8 (150 mg, 220.21 μmol) was dissolved in dichloromethane (3 mL), and boron tribromide (275.84 mg, 1.10 mmol, 106.09 μL) was added. The reaction mixture was stirred at 25 °C for 2 h. The reaction solution was quenched with methanol (10 mL), stirred for 10 min, and concentrated under reduced pressure to obtain crude product 18-9, which was used directly in the next reaction without further purification.

[0927] MS(ESI)m / z(M+H) + =567.1.

[0928] Step 16: Preparation of compounds 18A and 18B

[0929]

[0930] Compound 18-9 (128.49 mg, 226.60 μmol) was dissolved in tetrahydrofuran (5 mL), followed by the addition of sodium bicarbonate (3.79 g, 45.14 mmol, 1.76 mL) and acrylic anhydride (28.58 mg, 226.60 μmol). The reaction mixture was stirred at 25 °C for 30 min, then methanol (2 mL) and saturated potassium carbonate aqueous solution (2 mL) were added, and stirring was continued for 1 h. The reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL x 2), and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography (HPLC) (separation conditions: column: Phenomenex Gemini-NX 80*30 mm*3 μm; mobile phase: [water (10 mM ammonium bicarbonate solution) - acetonitrile]; acetonitrile %: 50%-80%, 9 min), yielding:

[0931] Compound 18A (HPLC retention times 3.747, 3.871 min).

[0932] Compound 18B (HPLC retention times 3.835, 3.916 min).

[0933] HPLC analysis conditions: Column: Xbridge Shield RP-18, 5μm, 2.1*50mm; Mobile phase: [water (0.02% ammonia solution v / v) - acetonitrile]; Acetonitrile %: 10%-80%; Column temperature: 50℃.

[0934] Compound 18A:

[0935] MS(ESI)m / z(M+H) + =621.2.

[0936] 1 H NMR (400MHz, Methanol-d4) δ8.42(d,J=4.9Hz,1H),7.89(br s,1H),7.26-7.17(m,2H),6.83(dd,J=10.6,16.8Hz,1H),6.69-6.58(m,2H),6.27(br d,J=16.8Hz,1H),5.82(br d,J=10.1Hz,1H),5.04-4.93(m,1H),4.72-4.10(m,4H),3.74(br s,1H),3.65-3.44(m,2H),3.14(br s,1H),2.66(td,J=6.6,13.8Hz,1H),2.12-2.01(m,3H),1.84-1.64(m,3H),1.19-1.03(m,6H).

[0937] Compound 18B:

[0938] MS(ESI)m / z(M+H) + =621.2.

[0939] 1H NMR (400MHz, Methanol-d4) δ8.42 (d, J = 4.9Hz, 1H), 7.89 (br s,1H),7.27-7.16(m,2H),6.83(dd,J=10.8,16.8Hz,1H),6.71-6.58(m,2H),6.27(dd,J=1.7,16.9Hz,1H),5.82(br d,J=10.6Hz,1H),5.04-4.92(m,1H),4.73-4.10(m,4H),3.74(br s,1H),3.66-3.47(m,2H),3.15(br d,J=10.4Hz,1H),2.77-2.58(m,1H),2.05(d,J=2.9Hz,3H),1.84-1.62(m,3H),1.17-1.02(m,6H).

[0940] Step 17: Separation of compounds 18A-1 and 18A-2

[0941]

[0942] Compound 18A was purified by SFC (separation conditions: column: REGIS(s,s)WHELK-O1 (250mm*30mm, 5μm); mobile phase: [supercritical carbon dioxide-ethanol]; ethanol %: 50%-50%), yielding:

[0943] Compound 18A-1 (HPLC retention time 8.29 min; ee: 99.24%).

[0944] Compound 18A-2 (HPLC retention time 8.37 min; ee: 99.38%).

[0945] HPLC analysis conditions: Column: WELCH Ultimate LP-C18 150*4.6mm, 5μm; Mobile phase: [water (0.06875% trifluoroacetic acid solution v / v) - acetonitrile (0.0625% trifluoroacetic acid solution v / v)]; Acetonitrile %: 10%-80%; Column temperature: 40℃.

[0946] SFC chiral analysis conditions: Column: (S,S)-Whelk-O1 100*4.6mm, 3μm; Mobile phase: [supercritical carbon dioxide-ethanol (0.05% diethylamine solution v / v)]; Ethanol %: 40%-40%; Column temperature: 35℃.

[0947] Compound 18A-1:

[0948] MS(ESI)m / z(M+H) +=621.3.

[0949] 1 H NMR (400MHz, Methanol-d4) δ8.42 (d, J = 5.1Hz, 1H), 7.89 (br s,1H),7.27-7.15(m,2H),6.83(dd,J=10.7,16.6Hz,1H),6.72-6.56(m,2H),6.28(dd,J=1.8,16.8Hz,1H),5.82(br d,J=10.1Hz,1H),5.05-4.94(m,1H),4.70-4.35(m,3H),3.83-3.68(m,1H),3.65-3.51(m, 2H),3.20-3.13(m,1H),2.79-2.66(m,1H),2.13-2.02(m,3H),1.83-1.65(m,3H),1.16(br d,J=6.6Hz,3H),1.11-1.00(m,3H).

[0950] Compound 18A-2:

[0951] MS(ESI)m / z(M+H) + =621.2.

[0952] 1 H NMR (400MHz, Methanol-d4) δ8.42 (d, J = 4.9Hz, 1H), 7.89 (br s,1H),7.28-7.17(m,2H),6.83(dd,J=10.6,16.8Hz,1H),6.69-6.58(m,2H),6.27(dd,J=1.8,16.8Hz,1H),5.82(br d,J=11.0Hz,1H),5.03-4.94(m,1H),4.70-4.34(m,3H),3.76(br d,J=11.5Hz,1H),3.64-3.48(m,2H),3.14(br d,J=9.3Hz,1H),2.66(td,J=6.8,13.6Hz,1H),2.06(s,3H),1.80-1.67(m,3H),1.14(d,J=6.8Hz,3H),1.11(d,J=6.8Hz,3H).

[0953] Step 18: Separation of compounds 18B-1 and 18B-2

[0954]

[0955] Compound 18B was purified by SFC (separation conditions: column: REGIS(s,s)WHELK-O1 (250mm*30mm, 5μm); mobile phase: [supercritical carbon dioxide-ethanol]; ethanol %: 50%-50%), yielding:

[0956] Compound 18B-1 (HPLC retention time 8.59 min; ee: 100%).

[0957] Compound 18B-2 (HPLC retention time 8.53 min; ee: 100%).

[0958] HPLC analysis conditions: Column: WELCH Ultimate LP-C18 150*4.6mm, 5μm; Mobile phase: [water (0.06875% trifluoroacetic acid solution v / v) - acetonitrile (0.0625% trifluoroacetic acid solution v / v)]; Acetonitrile %: 10%-80%; Column temperature: 40℃.

[0959] SFC chiral analysis conditions: Column: (S,S)-Whelk-O1 100*4.6mm, 3μm; Mobile phase: [supercritical carbon dioxide-ethanol (0.05% diethylamine solution v / v)]; Ethanol %: 40%-40%; Column temperature: 35℃.

[0960] 18B-1:

[0961] MS(ESI)m / z(M+H) + =621.2.

[0962] 1 H NMR (400MHz, Methanol-d4) δ8.42 (d, J = 5.1Hz, 1H), 7.88 (br s,1H),7.27-7.15(m,2H),6.83(dd,J=10.8,16.8Hz,1H),6.70-6.55(m,2H),6.27(dd,J=1.7,16.9Hz,1H),5.82(br d,J=9.9Hz,1H),5.04-4.93(m,1H),4.70-4.34(m,3H),3.75(br d,J=10.8Hz,1H),3.65-3.45(m,2H),3.17(br d,J=8.6Hz,1H),2.75-2.63(m,1H),2.09-1.99(m,3H),1.81-1.65(m,3H),1.14(br d,J=6.6Hz,3H),1.11-1.04(m,3H).

[0963] 18B-2:

[0964] MS(ESI)m / z(M+H) + =621.2.

[0965] 1 H NMR (400MHz, Methanol-d4) δ8.42(br d,J=5.1Hz,1H),7.89(br s,1H),7.29-7.17(m,2H),6.83(br dd,J=10.9,16.6Hz,1H),6.71-6.55(m,2H),6.27(br d,J=16.8Hz,1H),5.82(br d,J=9.5Hz,1H),5.03-4.92(m,1H),4.68-4.35(m,3H),3.75(br d,J=11.2Hz,1H),3.64-3.44(m,2H),3.14(br d,J=8.4Hz,1H),2.65(td,J=6.4,13.1Hz,1H),2.06(s,3H),1.84-1.66(m,3H),1.19-1.12(m,3H),1.11-0.97(m,3H).

[0966] Example 19: Preparation of Compound 19

[0967] Step 1: Preparation of compound 19-3

[0968]

[0969] Compound 19-1 (9.5 g, 57.93 mmol), compound 19-2 (29.20 g, 173.79 mmol), 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (3.39 g, 4.63 mmol), and potassium carbonate (24.02 g, 173.79 mmol) were dissolved in 1,4-dioxane (150 mL) and water (30 mL) at room temperature (20 °C). The system was heated to 100 °C and stirred for 12 h under a nitrogen atmosphere. After cooling the system to room temperature, most of the solvent was removed by concentration. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (80 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–50%) to obtain compound 19-3.

[0970] 1 H NMR (400MHz, DMSO-d6)8.39(s,1H),5.57-5.51(m,2H),5.42(s,2H),4.89(s,2H),2.06(s,6H).

[0971] MS(ESI)m / z(M+H) + =175.9.

[0972] Step 2: Preparation of compound 19-4

[0973]

[0974] Compound 19-3 (10.37 g, 59.18 mmol) was dissolved in methanol (50 mL) under a nitrogen atmosphere, and 10% palladium on carbon (1 g) was added. After the addition was complete, the system was purged with hydrogen. The system was stirred at room temperature (25 °C) for 12 h under a hydrogen atmosphere (15 psi). The system was filtered, and the filtrate was concentrated. The residue was dissolved in dichloromethane (100 mL), washed with 2 M hydrochloric acid aqueous solution (50 mL), the aqueous phase was adjusted to pH 9-10 with sodium hydroxide, and then extracted with dichloromethane (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound 19-4, which was used directly in the next reaction without further purification.

[0975] 1 H NMR (400MHz, DMSO-d6) 8.31 (s, 1H), 5.04 (s, 2H), 3.25-3.16 (m, 2H), 1.13 (d, J = 6.5Hz, 12H).

[0976] MS(ESI)m / z(M+H) + =180.0.

[0977] Step 3: Preparation of compound 19-5

[0978]

[0979] Compounds 3-8 (4.8 g, 11.37 mmol), 19-4 (2.65 g, 14.78 mmol), tris(dibenzylacetone)dipalladium (1.2 g, 1.31 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (750 mg, 1.30 mmol), and cesium carbonate (11.11 g, 34.11 mmol) were dissolved in toluene (40 mL) at room temperature (20 °C). The system was heated to 100 °C and stirred for 16 h under a nitrogen atmosphere. The system was cooled to room temperature, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–50%) to obtain compound 19-5.

[0980] 1H NMR (400MHz, Chloroform-d) δ8.97 (s, 1H), 8.90 (br d, J = 3.7Hz, 1H), 7.67 (br dd,J=2.0,9.5Hz,1H),7.39-7.30(m,1H),6.84-6.65(m,2H),3.99(s,3H),3.72(s,3H),3.45-3.31(m,2H),1.37-0.89(m,12H).MS(ESI)m / z(M+H) + =474.4.

[0981] Step 4: Preparation of compound 19-6

[0982]

[0983] Compound 19-5 (3.75 g, 7.92 mmol) was dissolved in N,N-dimethylformamide (40 mL). Sodium hydride (1.90 g, 47.52 mmol, 60% purity) was added in portions at 0 °C. After reacting at 0 °C for 20 min, acetyl chloride (3.73 g, 47.52 mmol, 3.39 mL) was added dropwise. After the addition was complete, the system was reacted at room temperature (25 °C) for 16 h under a nitrogen atmosphere. The reaction was quenched by adding water (20 mL), followed by the addition of a saturated potassium carbonate aqueous solution. After stirring at room temperature (25 °C) for 1 h, the mixture was extracted with ethyl acetate (100 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–100%) to obtain compound 19-6.

[0984] MS(ESI)m / z(M+H) + =516.3.

[0985] Step 5: Preparation of compound 19-7

[0986]

[0987] Compound 19-6 (1 g, 1.94 mmol) was dissolved in toluene (10 mL) at room temperature (20 °C), and potassium tert-butoxide (1 M, 6.28 mL) was added. After the addition was complete, the reaction was carried out at room temperature (25 °C) for 0.5 h under a nitrogen atmosphere. The reaction was quenched by adding water (20 mL), the pH was adjusted to neutral with 1 N hydrochloric acid, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 19-7, which was used directly in the next reaction without further purification.

[0988] 1H NMR(400MHz,Chloroform-d)δ11.25(br s,1H),9.48-9.16(m,1H),7.53(dd,J=1.4,8.5Hz,1H),7.36(dt,J=6.7,8.4Hz,1H),6.80-6.72(m,2H),6 .53(s,1H),3.72(s,3H),2.88-2.74(m,2H),1.23(dd,J=6.7,10.9Hz,6H),1.14(dd,J=6.7,11.6Hz,6H).

[0989] MS(ESI)m / z(M+H) + =484.0.

[0990] Step 6: Preparation of compound 19-8

[0991]

[0992] Compound 19-7 (1.3 g, 2.69 mmol) was dissolved in glacial acetic acid (15 mL). Nitric acid (3.11 g, 49.42 mmol, 2.22 mL) was added dropwise to the system at room temperature (20 °C). After the addition was complete, the system was heated to 80 °C and stirred for 2 h. The system was then cooled to room temperature, and most of the glacial acetic acid was removed by concentration. The remainder was poured into ice water (50 mL), and a precipitate formed. This precipitate was filtered, washed with water, and dried to obtain compound 19-8, which was used directly in the next step without further purification.

[0993] 1 H NMR(400MHz,DMSO-d6)δ9.02(s,1H),7.80(br d,J=9.0Hz,1H),7.51-7.40(m,1H),6.99-6.85(m,2H),3.73-3.63(m,3H),3.17(s,1H),2.91-2.75(m,2H),1.33-0.90(m,12H).

[0994] MS(ESI)m / z(M+H) + =529.0.

[0995] Step 7: Preparation of compound 19-9

[0996]

[0997] Compound 19-8 (800 mg, 1.51 mmol) and N,N-diisopropylethylamine (1.17 g, 9.08 mmol, 1.58 mL) were dissolved in acetonitrile (10 mL). Phosphorus oxychloride (696.32 mg, 4.54 mmol, 422.01 μL) was added at room temperature. After the addition was complete, the system was heated to 80 °C and stirred for 2 h. The system was concentrated to obtain a crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–100%) to give compound 19-9.

[0998] 1 H NMR(400MHz,Chloroform-d)δ9.18(s,1H),7.88(br d,J=8.6Hz,1H),7.48-7.34(m,1H),6.87-6.68(m,2H),3.82-3.66(m,3H),2.89-2.61(m,2H),1.39-1.07(m,12H).

[0999] MS(ESI)m / z(M+H) + =547.0.

[1000] Step 8: Preparation of compounds 19-10

[1001]

[1002] Compounds 19-9 (400 mg, 731.36 μmol), 1-11 (252.65 mg, 1.10 mmol), and N,N-diisopropylethylamine (473.56 mg, 3.66 mmol, 638.22 μL) were dissolved in acetonitrile (10 mL). The system was heated to 80 °C and stirred for 1 h under a nitrogen atmosphere. The system was concentrated to obtain a crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–100%) to give compound 19-10.

[1003] MS(ESI)m / z(M+H) + =741.1.

[1004] Step 9: Preparation of compounds 19-11

[1005]

[1006] Compound 19-10 (270 mg, 364.49 μmol) and Molecular sieve (1 g) was dissolved in N-methylpyrrolidone (8 mL). At room temperature, a tetrahydrofuran solution (1 M, 1.09 mL) of lithium bis(trimethylsilylamino)amine was added. After the addition was complete, the system was heated to 130 °C and stirred for 16 h under a nitrogen atmosphere. The system was cooled to room temperature, and water (20 mL) was added. Extraction was performed with ethyl acetate (20 mL x 2). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–100%) to give compound 19-11.

[1007] MS(ESI)m / z(M+H) + =694.1.

[1008] Step 10: Preparation of compounds 19-12

[1009]

[1010] Compound 19-11 (60 mg, 86.49 μmol) was dissolved in anhydrous dichloromethane (2 mL). Boron tribromide (108.33 mg, 432.43 μmol, 41.67 μL) was added at 0 °C. After the addition was complete, the system was heated to room temperature (25 °C) and stirred for 2 h under a nitrogen atmosphere. Methanol (5 mL) was added to the system and stirred for 10 min. The system was concentrated and lyophilized to obtain compound 19-12 (hydrobromide), which was used directly in the next step without further purification.

[1011] MS(ESI)m / z(M+H) + =580.1.

[1012] Step 11: Preparation of compounds 19A and 19B

[1013]

[1014] Compound 19-12 (70 mg, 120.77 μmol, hydrobromide) was dissolved in tetrahydrofuran (2 mL) and a saturated sodium bicarbonate aqueous solution (6.05 g, 71.99 mmol, 2.80 mL). Acrylic anhydride (15.23 mg, 120.77 μmol) was added at room temperature (25 °C). After addition, the system was stirred at room temperature (25 °C) for 30 min. Aqueous solutions of methanol (2 mL) and saturated potassium carbonate (2 mL) were added, and stirring continued at room temperature (25 °C) for 1 h. The system was diluted with water (10 mL), extracted with ethyl acetate (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified sequentially by medium-pressure column chromatography (methanol / dichloromethane (v / v) = 0–10%) and high-performance preparative liquid chromatography (separation conditions: column: Phenomenex Gemini-NX 150*30mm*5μm; mobile phase: [water (0.05% ammonia solution)-acetonitrile]; acetonitrile %: 42%–72% 7min) to obtain compounds 19A and 19B.

[1015] Compound 19A:

[1016] 1 H NMR(400MHz,Methanol-d4)δ9.06(s,1H),7.55(br d,J=8.4Hz,1H),7.29-7.15(m,1H),6.82(dd,J=10.4,16.8Hz,1H),6.72-6.58(m,2H),6.27(dd,J=2.0,16.8Hz,1H),5.81(br d,J=11.7Hz,1H),4.64-4.09(m,4H),3.83-3.41(m,3H),3.12(br s,1H),2.81-2.63(m,2H),1.84-1.63(m,3H),1.18-1.06(m,12H).

[1017] MS(ESI)m / z(M+H) + =634.3.

[1018] HPLC purity 91%; retention time 3.84 min.

[1019] Separation conditions: Column: Xbridge Shield RP-18, 5μm, 2.1*50mm; Column temperature: 50℃; Mobile phase: water (0.2mL / L ammonia solution)-acetonitrile; Acetonitrile: 10%-80% for 6min, 80% for 2min; Flow rate: 0.8mL / min.

[1020] Compound 19B:

[1021] 1 H NMR (400MHz, Methanol-d4) δ9.07 (s, 1H), 7.56 (br d, J = 8.8Hz, 1H), 7.30-7.16 (m, 1H), 6.82 (br dd,J=10.6,17.0Hz,1H),6.72-6.59(m,2H),6.27(dd,J=1.8,16.5Hz,1H),5.82(br d,J=10.1Hz,1H),4.67-4.09(m,4H),3.82-3.42(m,3H),3.13(br s,1H),2.82-2.63(m,2H),1.82-1.62(m,3H),1.17-1.04(m,12H).MS(ESI)m / z(M+H) + =634.3.

[1022] HPLC purity 91%; retention time 3.88 min.

[1023] Separation conditions: Column: Xbridge Shield RP-18, 5μm, 2.1*50mm; Column temperature: 50℃; Mobile phase: water (0.2mL / L ammonia solution)-acetonitrile; Acetonitrile: 10%-80% for 6min, 80% for 2min; Flow rate: 0.8mL / min.

[1024] Example 20: Preparation of Compound 20

[1025] Step 1: Preparation of compound 20-1

[1026]

[1027] Compounds 19-9 (390 mg, 713.08 μmol), 7-1 (276.30 mg, 1.07 mmol), and N,N-diisopropylethylamine (461.72 mg, 3.57 mmol, 622.27 μL) were dissolved in acetonitrile (10 mL). The system was heated to 80 °C and stirred for 12 h under a nitrogen atmosphere. The system was concentrated to obtain a crude product, which was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–100%) to give compound 20-1.

[1028] MS(ESI)m / z(M+H) + =769.1.

[1029] Step 2: Preparation of compound 20-2

[1030]

[1031] Compound 20-1 (400 mg, 520.31 μmol) and iron powder (116.52 mg, 2.09 mmol) were dissolved in acetic acid (7 mL). Under a nitrogen atmosphere, the system was heated to 80 °C and stirred for 45 min. The system was concentrated, diluted with dichloromethane (20 mL), filtered, and the filtrate was washed with saturated sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 20-2, which was used directly in the next reaction without further purification.

[1032] MS(ESI)m / z(M+H) + =707.2.

[1033] Step 3: Preparation of compound 20-3

[1034]

[1035] Compound 20-2 (100 mg, 141.49 μmol) and potassium carbonate (52.99 mg, 383.44 μmol) were dissolved in acetone (2 mL). Iodomethane (271.12 mg, 1.91 mmol, 118.91 μL) was added at room temperature (25 °C). After the addition was complete, the system was heated to 40 °C and stirred for 16 h under a nitrogen atmosphere. The system was concentrated, and dichloromethane (10 mL) and water (10 mL) were added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 20-3, which was used directly in the next reaction without further purification.

[1036] MS(ESI)m / z(M+H) + =721.3.

[1037] Step 4: Preparation of compound 20-4

[1038]

[1039] Compound 20-3 (100 mg, 138.74 μmol) was dissolved in dichloromethane (2 mL), and boron tribromide (1 M, 1 mL) was added. The reaction mixture was stirred at 20 °C for 16 h. The reaction solution was quenched with methanol (10 mL), stirred for 10 min, and concentrated under reduced pressure to obtain compound 20-4 (hydrobromide), which was used directly in the next reaction without further purification.

[1040] MS(ESI)m / z(M+H) + =607.1.

[1041] Step 5: Preparation of Compound 20

[1042]

[1043] Compound 20-4 (100 mg, 164.84 μmol, hydrobromide) was dissolved in tetrahydrofuran (2 mL) and a saturated sodium bicarbonate aqueous solution (13.85 mg, 164.84 μmol, 6.41 μL). Acrylic anhydride (20.79 mg, 164.84 μmol) was added at room temperature (25 °C). After addition, the system was stirred at room temperature (25 °C) for 30 min. A methanol solution (2 mL) and a saturated potassium carbonate solution (2 mL) were added to the system, and stirring continued at room temperature (25 °C) for 1 h. The system was diluted with water (10 mL), extracted with ethyl acetate (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by high-performance liquid chromatography (separation conditions: column: Phenomenex Gemini-NX 150*30mm*5μm; mobile phase: [water (10mM ammonium bicarbonate aqueous solution)-acetonitrile]; acetonitrile %: 50%-80% 9min) to obtain compounds 20A and 20B.

[1044] Compound 20A:

[1045] 1 H NMR(400MHz,Methanol-d4)δ9.08(s,1H),7.68(br d,J=9.1Hz,1H),7.29-7.20(m,1H),7.12(dd,J=11.0,16.8Hz,1H),6.71-6.57(m,2H),6.32-6.17(m,1H),5.86-5.74(m,1H),4.79-4.42(m ,3H),4.02-3.86(m,2H),3.42(s,3H),3.04-2.85(m,2H),2.68-2.52(m,1H),1.74-1.62(m,3H),1.21(d,J=6.8Hz,3H),1.17-1.07(m,9H).

[1046] MS(ESI)m / z(M+H) + =661.1.

[1047] HPLC purity 95%; retention time 10.49 min.

[1048] Separation conditions: Column: WELCHM Ultimate LP-C18 150*4.6mm, 5μm; Column temperature: 40℃; Mobile phase: Water (0.0688% trifluoroacetic acid solution) - acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10%-80% for 10 min, 80% for 5 min; Flow rate: 1.5 mL / min. Compound 20B:

[1049] 1 H NMR(400MHz,Methanol-d4)δ9.08(s,1H),7.68(br d,J=8.8Hz,1H),7.29-7.20(m,1H),7.12(dd,J=10.7,16.9Hz,1H),6.72-6.59(m,2H),6.32-6.17(m,1H),5.87-5.74(m,1H),4.86 -4.44(m,2H),4.04-3.86(m,2H),3.52-3.34(m,4H),3.05-2.85(m,2H),2.67-2.54(m,1H),1.76-1.63(m,3H),1.23-1.03(m,12H).

[1050] MS(ESI)m / z(M+H) + =661.1.

[1051] HPLC purity 94%; retention time 10.82 min.

[1052] Separation conditions: Column: WELCHM Ultimate LP-C18 150*4.6mm, 5μm; Column temperature: 40℃; Mobile phase: water (0.0688% trifluoroacetic acid solution) - acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10%-80% for 10 min, 80% for 5 min; Flow rate: 1.5 mL / min.

[1053] Example 21: Preparation of compound 21

[1054] Step 1: Preparation of compound 21-1

[1055]

[1056] Compounds 3-13 (500 mg, 965.47 μmol), 7-1 (374.09 mg, 1.45 mmol), and N,N-diisopropylethylamine (625.15 mg, 4.84 mmol, 842.52 μL) were dissolved in acetonitrile (10 mL). The system was heated to 80 °C and stirred for 12 h under a nitrogen atmosphere. The system was concentrated to obtain a crude product, which was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–100%) to give compound 21-1.

[1057] MS(ESI)m / z(M+H) + =740.2.

[1058] Step 2: Preparation of compound 21-2

[1059]

[1060] Compound 21-1 (500 mg, 675.92 μmol) and iron powder (151.36 mg, 2.71 mmol) were dissolved in acetic acid (8 mL). Under a nitrogen atmosphere, the system was heated to 80 °C and stirred for 45 min. The system was concentrated, diluted with dichloromethane (20 mL), filtered, and the filtrate was washed with saturated sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 21-2, which was used directly in the next reaction without further purification.

[1061] MS(ESI)m / z(M+H) + =678.1.

[1062] Step 3: Preparation of compound 21-3

[1063]

[1064] Compound 21-2 (120 mg, 177.07 μmol) and potassium carbonate (66.31 mg, 479.77 μmol) were dissolved in acetone (2 mL). Iodomethane (339.29 mg, 2.39 mmol, 148.81 μL) was added at room temperature (25 °C). After the addition was complete, the system was heated to 40 °C and stirred for 16 h under a nitrogen atmosphere. The system was concentrated, and dichloromethane (10 mL) and water (10 mL) were added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 21-3, which was used directly in the next reaction without further purification.

[1065] MS(ESI)m / z(M+H) + =692.2.

[1066] Step 4: Preparation of compound 21-4

[1067]

[1068] Compound 21-3 (100 mg, 144.56 μmol) was dissolved in dichloromethane (2 mL), and boron tribromide (181.08 mg, 722.82 μmol, 69.65 μL) was added. The reaction mixture was stirred at 25 °C for 2 h. The reaction solution was quenched with methanol (10 mL), stirred for 10 min, and concentrated under reduced pressure to obtain compound 21-4 (hydrobromide), which was used directly in the next reaction without further purification.

[1069] MS(ESI)m / z(M+H) + =578.1.

[1070] Step 5: Preparation of compounds 21A and 21B

[1071]

[1072] Compound 21-4 (100 mg, 151.86 μmol, hydrobromide) was dissolved in tetrahydrofuran (2 mL) and saturated sodium bicarbonate aqueous solution (4.62 g, 55.01 mmol, 2.14 mL). Acrylic anhydride (19.15 mg, 151.86 μmol) was added at room temperature (25 °C). After addition, the system was stirred at room temperature (25 °C) for 30 min. Methanol (2 mL) and potassium carbonate aqueous solution (2 mL) were added to the system, and stirring was continued at room temperature (25 °C) for 1 h. The system was diluted with water (10 mL), extracted with ethyl acetate (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by high-performance liquid chromatography (separation conditions: column: Phenomenex Gemini-NX 80*30mm*3μm; mobile phase: [water (10mM ammonium bicarbonate solution)-acetonitrile]; acetonitrile %: 38%-68% 9min) to obtain compounds 21A and 21B.

[1073] Compound 21A:

[1074] 1 H NMR (400MHz, Methanol-d4) δ8.45 (d, J=4.9Hz, 1H), 7.68 (br d,J=8.2Hz,1H),7.31-7.20(m,2H),7.12(dd,J=10.7,16.9Hz,1H),6.72-6. 60(m,2H),6.30-6.21(m,1H),5.84-5.74(m,1H),4.96-4.92(m,1H),4.75(br d,J=13.0Hz,1H),4.67-4.48(m,1H),3.91(br d,J=12.1Hz,2H),3.44(d,J=3.7Hz,3H),3.03-2.47(m,2H),2.29-1.90(m,3H),1.75-1.62(m,3H),1.26-1.06(m,6H).

[1075] MS(ESI)m / z(M+H) + =632.2.

[1076] Compound 21B:

[1077] 1H NMR (400MHz, Methanol-d4) δ8.45 (d, J = 4.9Hz, 1H), 7.67 (br d,J=8.8Hz,1H),7.30-7.20(m,2H),7.12(dd,J=10.8,17.0Hz,1H),6.72-6. 59(m,2H),6.31-6.20(m,1H),5.85-5.75(m,1H),4.96-4.92(m,1H),4.75(br d,J=13.0Hz,1H),4.66-4.44(m,1H),3.91(br d,J=11.9Hz,2H),3.44(d,J=4.0Hz,3H),3.03-2.49(m,2H),2.24-1.94(m,3H),1.75-1.63(m,3H),1.23-1.01(m,6H).

[1078] MS(ESI)m / z(M+H) + =632.3.

[1079] Step 6: Resolution of the 21A isomer of compound

[1080]

[1081] The diastereomer compound 21A was purified by SFC (separation conditions: column: Phenomenex-Cell μLose-2 (250mm*30mm, 10μm); mobile phase: [0.1% ammonia and methanol]; methanol %: 40%-40%). After concentration, compounds 21A-1 and 21A-2 were obtained.

[1082] Compound 21A-1:

[1083] 1 H NMR(400MHz, Methanol-d4)δ8.45(d,J=5.0Hz,1H),7.71-7.63(m,1H),7.31-7.19(m,2H) ,7.12(dd,J=10.7,16.9Hz,1H),6.72-6.57(m,2H),6.31-6.18(m,1H),5.86-5.74(m,1H) ,4.98-4.92(m,1H),4.80-4.45(m,2H),4.02-3.86(m,2H),3.53-3.41(m,3H),3.03-2.85 (m,1H),2.64-2.48(m,1H),2.20(s,3H),1.74-1.65(m,3H),1.10(dd,J=6.8,12.3Hz,6H).

[1084] MS(ESI)m / z(M+H) + =632.2.

[1085] HPLC purity 92%; retention time 8.18 min.

[1086] Separation conditions: Column: WELCH Ultimate LP-C18 150*4.6mm 5μm; Column temperature: 40℃; Mobile phase: Water (0.0688% trifluoroacetic acid solution) - acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10%-80% for 10 min, 80% for 5 min; Flow rate: 1.5 mL / min, SFC 90% ee. Retention time: 4.707 min.

[1087] Separation conditions: Column: Cellulose 2 100*4.6mm ID, 3μm; Column temperature: 35℃; Mobile phase: CO2-methanol (0.05% DEA); Methanol: 5%-40% for 4 min, 40% for 2.5 min, 5% for 1.5 min; Flow rate: 2.8 mL / min.

[1088] Compound 21A-2:

[1089] 1 H NMR (400MHz, Methanol-d4) δ8.44 (d, J = 5.0Hz, 1H), 7.68 (br d,J=8.9Hz,1H),7.29-7.19(m,2H),7.12(dd,J=10.7,17.0Hz,1H),6.72- 6.60(m,2H),6.31-6.19(m,1H),5.87-5.75(m,1H),4.99-4.94(m,1H),4. 80-4.30(m,2H),4.01-3.84(m,2H),3.44(s,3H),3.04-2.88(m,2H),1.99 (s,3H),1.72-1.65(m,3H),1.23(d,J=6.8Hz,3H),1.14(d,J=6.8Hz,3H).

[1090] MS(ESI)m / z(M+H) + =632.2.

[1091] HPLC purity 98%; retention time 8.17 min.

[1092] Separation conditions: Column: WELCH Ultimate LP-C18 150*4.6mm 5μm; Column temperature: 40℃; Mobile phase: Water (0.0688% trifluoroacetic acid solution) - acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10%-80% for 10 min, 80% for 5 min; Flow rate: 1.5 mL / min SFC 100% ee; Retention time: 5.145 min.

[1093] Separation conditions: Column: Cellulose 2 100*4.6mm ID, 3μm; Column temperature: 35℃; Mobile phase: CO2-methanol (0.05% DEA); Methanol: 5%-40% for 4 min, 40% for 2.5 min, 5% for 1.5 min; Flow rate: 2.8 mL / min.

[1094] Step 7: Resolution of the 21B isomer of compound

[1095]

[1096] The diastereomer compound 21B was purified by SFC (separation conditions: column: DAICEL CHIRALPAK AD-H (250mm*30mm, 5μm); mobile phase: [0.1% ammonia and ethanol]; ethanol %: 35%-35%). After concentration, compounds 21B-1 and 21B-2 were obtained.

[1097] Compound 21B-1:

[1098] 1 H NMR(400MHz, Methanol-d4)δ8.44(d,J=5.0Hz,1H),7.73-7.59(m,1H),7.29-7.19(m ,2H),7.12(dd,J=10.7,16.8Hz,1H),6.72-6.56(m,2H),6.32-6.17(m,1H),5.87-5. 73(m,1H),4.98-4.93(m,1H),4.80-4.38(m,2H),4.00-3.85(m,2H),3.52-3.40(m,3 H),3.03-2.87(m,2H),1.98(s,3H),1.75-1.63(m,3H),1.19(dd,J=6.7,20.0Hz,6H).

[1099] MS(ESI)m / z(M+H) + =632.1.

[1100] HPLC purity 99%; retention time 8.38 min.

[1101] Separation conditions: Column: WELCH Ultimate LP-C18 150*4.6mm 5μm; Column temperature: 40℃; Mobile phase: Water (0.0688% trifluoroacetic acid solution) - acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10%-80% for 10 min, 80% for 5 min; Flow rate: 1.5 mL / min, SFC 100% ee. Retention time: 4.041 min.

[1102] Separation conditions: Column: Chiralpak AD-3 150×4.6mm ID, 3μm; Column temperature: 35℃; Mobile phase: CO2-ethanol (0.05% DEA); Ethanol: 5%-40% for 5 min, 40% for 2.5 min, 5% for 2.5 min; Flow rate: 2.5 mL / min.

[1103] Compound 21B-2:

[1104] 1 H NMR(400MHz, Methanol-d4)δ8.45(d,J=5.0Hz,1H),7.71-7.63(m,1H),7.31-7.20(m,2H) ,7.12(dd,J=10.7,16.9Hz,1H),6.73-6.59(m,2H),6.30-6.19(m,1H),5.86-5.72(m,1H) ,4.98-4.92(m,1H),4.80-4.36(m,2H),4.02-3.85(m,2H),3.54-3.41(m,3H),3.02-2.85 (m,1H),2.54(td,J=6.6,13.4Hz,1H),2.20(s,3H),1.75-1.64(m,3H),1.16-1.00(m,6H).

[1105] MS(ESI)m / z(M+H) + =632.1.

[1106] HPLC purity 99%; retention time 8.30 min.

[1107] Separation conditions: Column: WELCH Ultimate LP-C18 150*4.6mm 5μm; Column temperature: 40℃; Mobile phase: Water (0.0688% trifluoroacetic acid solution) - acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10%-80% for 10 min, 80% for 5 min; Flow rate: 1.5 mL / min, SFC 100% ee; Retention time: 4.707 min.

[1108] Separation conditions: Column: Chiralpak AD-3 150×4.6mm ID, 3μm; Column temperature: 35℃; Mobile phase: CO2-ethanol (0.05% DEA); Ethanol: 5%-40% for 5 min, 40% for 2.5 min, 5% for 2.5 min; Flow rate: 2.5 mL / min.

[1109] Example 22: Preparation of compound 22

[1110] Step 1: Preparation of compound 22-1

[1111]

[1112] Compound 21-2 (80 mg, 118.04 μmol) was dissolved in dichloromethane (2 mL), and boron tribromide (147.86 mg, 590.22 μmol, 56.87 μL) was added. The reaction mixture was stirred at 25 °C for 2 h. The reaction solution was quenched with methanol (10 mL), stirred for 10 min, and concentrated under reduced pressure to obtain compound 22-1 (hydrobromide), which was used directly in the next reaction without further purification.

[1113] MS(ESI)m / z(M+H) + =564.1.

[1114] Step 2: Preparation of compounds 22A and 22B

[1115]

[1116] Compound 22-1 (80 mg, 124.13 μmol, hydrobromide) was dissolved in tetrahydrofuran (2 mL) and saturated sodium bicarbonate aqueous solution (3.78 g, 44.97 mmol, 1.75 mL). Acrylic anhydride (15.65 mg, 124.13 μmol) was added at room temperature (25 °C). After addition, the system was stirred at room temperature (25 °C) for 30 min. Methanol (2 mL) and potassium carbonate aqueous solution (2 mL) were added to the system, and stirring was continued at room temperature (25 °C) for 1 h. The system was diluted with water (10 mL), extracted with ethyl acetate (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by high-performance liquid chromatography (separation conditions: column: Phenomenex Gemini-NX 80*30mm*3μm; mobile phase: [water (10mM ammonium bicarbonate solution)-acetonitrile]; acetonitrile %: 37%-67% 9min) to obtain compounds 22A and 22B.

[1117] Compound 22A:

[1118] 1H NMR (400MHz, Methanol-d4) δ8.44(d,J=5.1Hz,1H),7.63(br d,J=9.0Hz,1H),7.32-7.17(m,2H),7.09(br dd,J=10.7,17.1Hz,1H),6.74-6.57(m,2H),6.29-6.18(m,1H),5.84-5.75(m,1H),4.82-4.46(m,3H),4.13- 3.72(m,2H),3.17-2.97(m,1H),2.80-2.67(m,1H),2.09-2.02(m,3H),1.76-1.58(m,3H),1.20-1.05(m,6H).

[1119] MS(ESI)m / z(M+H) + =618.2.

[1120] Compound 22B:

[1121] 1 H NMR (400MHz, Methanol-d4) δ8.44 (d, J = 5.1Hz, 1H), 7.63 (br d,J=9.0Hz,1H),7.31-7.21(m,2H),7.10(dd,J=10.8,16.8Hz,1H),6.73-6. 59(m,2H),6.31-6.18(m,1H),5.88-5.72(m,1H),5.01-4.93(m,1H),4.80(br d,J=13.9Hz,1H),4.71-4.39(m,1H),4.11-3.77(m,2H),3.03(br t,J=9.0Hz,1H),2.73(td,J=6.9,10.1Hz,1H),2.07(d,J=13.0Hz,3H),1.74-1.60(m,3H),1.19-1.05(m,6H).

[1122] MS(ESI)m / z(M+H) + =618.2&618.1.

[1123] Step 3: Resolution of the 22A isomer of compound

[1124]

[1125] The diastereomer compound 21A was purified by SFC (separation conditions: column: DAICEL CHIRALCEL OD-H (250mm*30mm, 5μm); mobile phase: [Neu-ethanol]; ethanol %: 50%-50%). After concentration, compounds 22A-1 and 22A-2 were obtained.

[1126] Compound 22A-1:

[1127] 1 H NMR (400MHz, Methanol-d4) δ8.44 (d, J = 5.1Hz, 1H), 7.63 (br d,J=9.0Hz,1H),7.30-7.20(m,2H),7.09(dd,J=10.8,17.0Hz,1H),6.73-6.60(m,2H),6.31-6.18(m,1H),5.87-5.72(m,1H),4.93(br s,1H),4.83-4.75(m,1H),4.66-4.46(m,1H),4.08-3.83(m,2H),3.17-3.00(m,1H),2.83- 2.68(m,1H),2.07(s,3H),1.74-1.63(m,3H),1.18(d,J=6.8Hz,3H),1.09(d,J=6.8Hz,3H).

[1128] MS(ESI)m / z(M+H) + =618.1.

[1129] HPLC 100% purity; retention time 7.85 min.

[1130] Separation conditions: Column: WELCH Ultimate LP-C18 150*4.6mm 5μm; Column temperature: 40℃; Mobile phase: Water (0.0688% trifluoroacetic acid solution) - acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10%-80% for 10 min, 80% for 5 min; Flow rate: 1.5 mL / min. SFC 100% ee. Retention time: 4.917 min.

[1131] Separation conditions: Column: Chiralcel OD-3 100*4.6mm ID, 3μm; Column temperature: 35℃; Mobile phase: CO2-ethanol (0.05% DEA); Ethanol: 5%-40% for 4 min, 40% for 2.5 min, 5% for 1.5 min; Flow rate: 2.8 mL / min.

[1132] Compound 22A-2:

[1133] 1 H NMR(400MHz, Methanol-d4)δ8.44(d,J=5.1Hz,1H),7.73-7.57(m,1H),7.33-7.19(m,2H),7.1 0(dd,J=10.7,17.1Hz,1H),6.71-6.57(m,2H),6.32-6.17(m,1H),5.88-5.73(m,1H),4.99(br s,1H),4.83-4.50(m,2H),4.10-3.84(m,2H),3.14-2.98(m,1H),2.78-2 .67(m,1H),2.09(s,3H),1.76-1.63(m,3H),1.14(dd,J=6.8,9.9Hz,6H).

[1134] MS(ESI)m / z(M+H) + =618.1.

[1135] HPLC purity 99.3%; retention time 7.91 min.

[1136] Separation conditions: Column: WELCHM Ultimate LP-C18 150*4.6mm 5μm; Column temperature: 40℃; Mobile phase: Water (0.0688% trifluoroacetic acid solution) - acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10%-80% for 10 min, 80% for 5 min; Flow rate: 1.5 mL / min, SFC 98.5% ee. Retention time: 5.3-10 min.

[1137] Separation conditions: Column: Chiralcel OD-3 100*4.6mm ID, 3μm; Column temperature: 35℃; Mobile phase: CO2-ethanol (0.05% DEA); Ethanol: 5%-40% for 4 min, 40% for 2.5 min, 5% for 1.5 min; Flow rate: 2.8 mL / min.

[1138] Step 4: Resolution of the 22B isomer of compound

[1139]

[1140] The diastereomer compound 21A was purified by SFC (separation conditions: column: DAICEL CHIRALCEL OD-H (250mm*30mm, 5μm); mobile phase: [Neu-methanol]; methanol %: 40%-40%). After concentration, compounds 22B-1 and 22B-2 were obtained.

[1141] Compound 22B-1:

[1142] 1 H NMR (400MHz, Methanol-d4) δ8.44 (d, J = 5.1Hz, 1H), 7.63 (br d,J=9.0Hz,1H),7.28-7.18(m,2H),7.09(dd,J=10.7,17.1Hz,1H),6.70-6. 61(m,2H),6.29-6.17(m,1H),5.83-5.74(m,1H),4.97-4.92(m,1H),4.78(br s,1H),4.64-4.48(m,1H),4.06-3.85(m,2H),3.14-2.98(m,1H),2.81-2. 64(m,1H),2.06(s,3H),1.74-1.65(m,3H),1.15(dd,J=6.8,18.3Hz,6H).

[1143] MS(ESI)m / z(M+H) + =618.1.

[1144] HPLC purity 93.6%; retention time 8.14 min.

[1145] Separation conditions: Column: WELCH Ultimate LP-C18 150*4.6mm 5μm; Column temperature: 40℃; Mobile phase: Water (0.0688% trifluoroacetic acid solution) - acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10%-80% for 10 min, 80% for 5 min; Flow rate: 1.5 mL / min. SFC 100% ee. Retention time: 3.589 min.

[1146] Separation conditions: Column: Chiralcel OD-3 100*4.6mm ID, 3μm; Column temperature: 35℃; Mobile phase: CO2-methanol (0.05% DEA); Methanol: 40%-40%; Flow rate: 2.8mL / min.

[1147] Compound 22B-2:

[1148] 1H NMR (400MHz, Methanol-d4) δ8.44 (d, J = 5.1Hz, 1H), 7.63 (br d,J=8.8Hz,1H),7.28-7.19(m,2H),7.09(dd,J=10.7,17.1Hz,1H),6.72-6. 58(m,2H),6.29-6.18(m,1H),5.83-5.73(m,1H),4.99-4.91(m,1H),4.78(br s,1H),4.67-4.42(m,1H),4.09-3.86(m,2H),3.14-2.97(m,1H),2.80-2.62(m,1H),2.19-2.05(m,3H),1.75-1.64(m,3H),1.16(br d,J=6.8Hz,3H),1.08(d,J=6.8Hz,3H).

[1149] MS(ESI)m / z(M+H) + =618.1.

[1150] HPLC purity 99.3%; retention time 8.12 min.

[1151] Separation conditions: Column: WELCH Ultimate LP-C18 150*4.6mm 5μm; Column temperature: 40℃; Mobile phase: water (0.0688% trifluoroacetic acid solution) - acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10%-80% for 10 min, 80% for 5 min; Flow rate: 1.5 mL / min; SFC 97.8% ee; Retention time: 4.079 min.

[1152] Separation conditions: Column: Chiralcel OD-3 100*4.6mm ID, 3μm; Column temperature: 35℃; Mobile phase: CO2-methanol (0.05% DEA); Methanol: 40%-40%; Flow rate: 2.8mL / min.

[1153] Example 23: Preparation of compound 23

[1154] Step 1: Preparation of compound 23-1

[1155]

[1156] Under nitrogen protection, compound 18-6 (450 mg, 842.16 μmol) was dissolved in acetonitrile (8 mL), followed by the sequential addition of diisopropylethylamine (545.29 mg, 4.22 mmol, 734.90 μL) and compound JMKX-1805-Inter 5A (326.31 mg, 1.26 mmol). The reaction mixture was heated to 80 °C and stirred for 12 h. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 0 to 0 / 1) to give compound 23-1.

[1157] MS(ESI)m / z(M+H) + =756.2.

[1158] Step 2: Preparation of compound 23-2

[1159]

[1160] Compound 23-1 (200 mg, 264.48 μmol) and iron powder (59.23 mg, 1.06 mmol) were dissolved in acetic acid (5 mL). Under a nitrogen atmosphere, the system was heated to 80 °C and stirred for 45 min. The system was concentrated, diluted with dichloromethane (20 mL), filtered, and the filtrate was washed with saturated sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 23-2, which was used directly in the next reaction without further purification.

[1161] MS(ESI)m / z(M+H) + =694.1.

[1162] Step 3: Preparation of compound 23-3

[1163]

[1164] Compound 23-2 (150 mg, 216.09 μmol) and potassium carbonate (80.94 mg, 585.60 μmol) were dissolved in acetone (2 mL). Iodomethane (414.06 mg, 2.92 mmol, 181.61 μL) was added at room temperature (25 °C). After the addition was complete, the system was heated to 40 °C and stirred for 16 h under a nitrogen atmosphere. The system was concentrated, and dichloromethane (10 mL) and water (10 mL) were added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 23-3, which was used directly in the next reaction without further purification.

[1165] MS(ESI)m / z(M+H) + =708.1.

[1166] Step 4: Preparation of compound 23-4

[1167]

[1168] Compound 23-3 (110 mg, 155.33 μmol) was dissolved in dichloromethane (2 mL), and boron tribromide (1 M, 776.63 μL) was added. The reaction mixture was stirred at 20 °C for 2 h. The reaction solution was quenched with methanol (5 mL), stirred for 10 min, and concentrated under reduced pressure to obtain compound 23-4 (hydrobromide), which was used directly in the next reaction without further purification.

[1169] MS(ESI)m / z(M+H) + =594.1.

[1170] Step 5: Preparation of compounds 23A and 23B

[1171]

[1172] Compound 23-4 (130 mg, 153.92 μmol, hydrobromide) was dissolved in tetrahydrofuran (5 mL) and a saturated sodium bicarbonate aqueous solution (4.32 g, 51.42 mmol, 2 mL). Acrylic anhydride (19.41 mg, 153.92 μmol) was added at room temperature (25 °C). After addition, the system was stirred at room temperature (25 °C) for 30 min. A methanol solution (2 mL) and a saturated potassium carbonate solution (2 mL) were added to the system, and stirring continued at room temperature (25 °C) for 1 h. The system was diluted with water (10 mL), extracted with ethyl acetate (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by high-performance liquid chromatography (separation conditions: column: Phenomenex Gemini-NX 80*30mm*3μm; mobile phase: [water (10mM ammonium bicarbonate aqueous solution)-acetonitrile]; acetonitrile %: 44%-74% 9min) to obtain compounds 23A and 23B.

[1173] Compound 23A:

[1174] 1H NMR(400MHz, Methanol-d4)δ8.44(d,J=4.8Hz,1H),8.02(s,1H),7.30-7.07(m,3H), 6.72-6.57(m,2H),6.32-6.19(m,1H),5.86-5.75(m,1H),4.98-4.94(m,1H),4.80-4 .48(m,2H),4.01-3.84(m,2H),3.44(d,J=3.8Hz,3H),3.02-2.89(m,1H),2.62-2.47 (m,1H),2.22-1.97(m,3H),1.77-1.62(m,3H),1.25-1.04(m,6H).MS(ESI)m / z(M+H) + =648.1.

[1175] Compound 23B:

[1176] 1 H NMR(400MHz, Methanol-d4)δ8.44(d,J=5.0Hz,1H),8.02(s,1H),7.31-7.06(m,3H), 6.74-6.57(m,2H),6.30-6.20(m,1H),5.86-5.76(m,1H),4.98-4.94(m,1H),4.76(br d,J=13.3Hz,2H),4.03-3.87(m,2H),3.44(d,J=3.8Hz,3H),3.00-2.88(m,1H),2.59-2 .49(m,1H),2.25-1.93(m,3H),1.75-1.64(m,3H),1.24-1.00(m,6H).MS(ESI)m / z(M+H) + =648.1.

[1177] Step 6: Resolution of the 23A isomer of compound

[1178]

[1179] The diastereomer compound 23A was purified by SFC (separation conditions: column: DAICEL CHIRALCEL OJ H (250mm*30mm, 5μm); mobile phase: [0.1% ammonia and isopropanol]; isopropanol %: 35%-35%). After concentration, compounds 23A-1 (2.46mg, yield 12.30%) and 23A-2 (4.07mg, yield 20.35%) were obtained.

[1180] Compound 23A-1:

[1181] 1 H NMR(400MHz, Acetonitrile-d3)δ8.45(d,J=4.9Hz,1H),8.01-7.96(m,1H),7.28(dt,J=6.9,8.3Hz,1H),7.18(d ,J=4.9Hz,1H),7.02(dd,J=10.6,16.9Hz,1H),6.77-6.69(m,2H),6.26-6.15(m,1H),5.79-5.67(m,1H),4.89(br s,1H),4.69-4.31(m,1H),3.90-3.74(m,2H),3.39(s,3H),3.20(br d,J=12.3Hz,1H),3.01-2.80(m,1H),2.59(td,J=6.6,13.3Hz,1H),2.14(s,3H),1.67-1.58(m,3H),1.06(d,J=6.7Hz,3H),1.01(d,J=6.8Hz,3H).

[1182] MS(ESI)m / z(M+H) + =648.2.

[1183] SFC retention time: 2.544 min

[1184] Separation conditions: Column: Chiralcel OJ-3 100mm x 4.6mm ID, 3μm; Column temperature: 35℃; Mobile phase: CO2-ethanol (0.05% DEA); Ethanol: 5%-40% for 4 min, 40% for 2.5 min, 5% for 1.5 min; Flow rate: 2.8 mL / min.

[1185] Compound 23A-2:

[1186] 1H NMR (400MHz, Methanol-d4) δ8.48(d,J=5.2Hz,1H),8.02(d,J=1.4Hz,1H),7.37(br d,J=5.1Hz,1H),7.23(dt,J=6.8,8.3Hz,1H),7.11(dd,J=10.8,17.0Hz,1H),6.7 3-6.59(m,2H),6.31-6.18(m,1H),5.86-5.73(m,1H),4.99-4.93(m,1H),4.75(br d,J=13.0Hz,2H),3.98-3.84(m,2H),3.43(s,3H),3.14-2.86(m,2H),2.0 4(s,3H),1.76-1.63(m,3H),1.25(d,J=6.8Hz,3H),1.15(d,J=6.8Hz,3H).

[1187] MS(ESI)m / z(M+H) + =648.2.

[1188] SFC retention time: 2.670 min.

[1189] Separation conditions: Column: Chiralcel OJ-3 100mm x 4.6mm ID, 3μm; Column temperature: 35℃; Mobile phase: CO2-ethanol (0.05% DEA); Ethanol: 5%-40% for 4 min, 40% for 2.5 min, 5% for 1.5 min; Flow rate: 2.8 mL / min.

[1190] Step 7: Resolution of the 23B isomer of compound

[1191]

[1192] The diastereomer compound 23B was purified by SFC (separation conditions: column: REGIS(s,s)WHELK-O1 (250mm*30mm, 5μm); mobile phase: [0.1% ammonia and ethanol]; ethanol %: 40%-40%). After concentration, compounds 23B-1 and 23B-2 were obtained.

[1193] Compound 23B-1:

[1194] 1H NMR(400MHz, Acetonitrile-d3)δ8.43(d,J=4.9Hz,1H),8.00-7.93(m,1H),7.31-7.22(m,1H),7.12(d,J=4 .9Hz,1H),7.01(dd,J=10.6,16.9Hz,1H),6.77-6.66(m,2H),6.25-6.13(m,1H),5.78-5.65(m,1H),4.87(br s,1H),4.67-4.31(m,1H),3.83-3.66(m,2H),3.40-3.32(m,3H),3.21(d,J=11.2Hz,1H),3.01-2.81(m,2H),2.10(br s,3H),1.66-1.54(m,3H),1.12(d,J=6.7Hz,3H),1.07(d,J=6.7Hz,3H).

[1195] MS(ESI)m / z(M+H) + =648.2.

[1196] SFC retention time: 5.051 min

[1197] Separation conditions: Column: (S,S)-Whelk-O1 100mm x 4.6mm ID, 3μm; Column temperature: 35℃; Mobile phase: CO2-ethanol (0.05% DEA); Ethanol: 5%-40% for 4 min, 40% for 2.5 min, 5% for 1.5 min; Flow rate: 2.8 mL / min.

[1198] Compound 23B-2:

[1199] 1H NMR(400MHz, Acetonitrile-d3)δ8.46(d,J=4.9Hz,1H),8.02-7.95(m,1H),7.34-7.24(m,1H),7.20(d,J=4.9Hz,1H),7 .02(dd,J=10.6,16.8Hz,1H),6.78(d,J=8.3Hz,1H),6.75-6.66(m,1H),6.27-6.14(m,1H),5.79-5.67(m,1H),4.89(br s,1H),4.65(d,J=13.6Hz,1H),3.90-3.74(m,2H),3.44-3.34(m,3H),3.20(br d,J=12.2Hz,1H),3.04-2.80(m,1H),2.57(td,J=6.6,13.3Hz,1H),2.16(s,3H),1.68-1.58(m,3H),1.06(d,J=6.7Hz,3H),0.97(d,J=6.7Hz,3H).

[1200] MS(ESI)m / z(M+H) + =648.2.

[1201] SFC retention time: 5.618 min

[1202] Separation conditions: Column: (S,S)-Whelk-O1 100mm x 4.6mm ID, 3μm; Column temperature: 35℃; Mobile phase: CO2-ethanol (0.05% DEA); Ethanol: 5%-40% for 4 min, 40% for 2.5 min, 5% for 1.5 min; Flow rate: 2.8 mL / min.

[1203] Example 24: Preparation of compound 24

[1204] Step 1: Preparation of compound 24-1

[1205]

[1206] Compound 21-2 (100 mg, 147.56 μmol) and potassium carbonate (123 mg, 889.98 μmol) were dissolved in N,N-dimethylformamide (3 mL). At room temperature (25 °C), 2-bromo-N,N-dimethylethylamine (100 mg, 429.29 μmol, HBr) and potassium iodide (25 mg, 150.60 μmol) were added. After the addition was complete, the system was heated to 100 °C and stirred for 16 h. The system was diluted with ethyl acetate (30 mL), washed successively with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 1 / 15) to obtain compound 24-1.

[1207] MS(ESI)m / z(M+H) + =749.4.

[1208] Step 2: Preparation of compound 24-2

[1209]

[1210] Compound 24-1 (45 mg, 60.09 μmol) was dissolved in dichloromethane (0.5 mL), and boron tribromide (1 M, 1 mL) was added. The reaction was carried out under a nitrogen atmosphere and stirred at room temperature (20 °C) for 8 h. The reaction solution was quenched with methanol (5 mL), stirred for 10 min, and concentrated under reduced pressure to obtain compound 24-2 (hydrobromide), which was used directly in the next reaction without further purification.

[1211] MS(ESI)m / z(M+H) + =635.2.

[1212] Step 3: Preparation of compounds 24A, 24B, 24C and 24D

[1213]

[1214] Compound 24-2 (45 mg, 62.88 μmol, hydrobromide) was dissolved in tetrahydrofuran (2 mL) and saturated sodium bicarbonate aqueous solution (2.16 g, 25.71 mmol, 1 mL). At room temperature (25 °C), a tetrahydrofuran solution of acrylic anhydride (15 mg, 118.94 μmol) (0.5 mL) was added. After the addition, the system was stirred at room temperature (25 °C) for 2 h. Methanol (1 mL) and saturated potassium carbonate aqueous solution (2 M, 1 mL) were added to the system, and stirring was continued at room temperature (25 °C) for 1.5 h. The system was diluted with water (10 mL), the pH was adjusted to approximately 7 with 1 N HCl, and the mixture was extracted with ethyl acetate (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by high-performance liquid chromatography (HPLC) (separation conditions: column: Phenomenex Gemini-NX 80*30mm*3μm; mobile phase: [water (10mM ammonium bicarbonate aqueous solution)-acetonitrile]; acetonitrile %: 40%-70% 9min), followed by SFC purification (separation conditions: column: DAICL CHIRALCEL OD (250mm*30mm, 10μm); mobile phase: [0.1% ammonia and isopropanol]; isopropanol %: 25%-25% and DAICL CHIRALPAK AD-H (250mm*30mm, 5μm); mobile phase: [0.1% ammonia and ethanol]; ethanol %: 25%-25%). After concentration, compounds 24A, 24B, 24C, and 24D were obtained.

[1215] Compound 24A:

[1216] 1 H NMR(400MHz, Methanol-d4)δ8.46(d,J=5.0Hz,1H),7.74-7.63(m,1H),7.32-7.21(m,2 H),7.11(dd,J=10.8,16.8Hz,1H),6.74-6.59(m,2H),6.24(d,J=15.1Hz,1H),5.81(br d,J=10.8Hz,1H),5.01-4.94(m,1H),4.75(d,J=12.5Hz,1H),4.64-4.46(m,1H),4.40-4.24(m,1H),4.13(br s,1H),4.05-3.88(m,2H), 3.37(s,2H),3.03(br d,J=14.6Hz,1H),2.83-2.49(m,7H),2.21(s,3H),1.78-1.67(m,3H),1.13(d,J=6.8Hz,3H),1.03(d,J=6.5Hz,3H).

[1217] MS(ESI)m / z(M+H) + =689.2.

[1218] SFC retention time: 3.949 min.

[1219] Separation conditions: Column: Chiralpak AD-3 150mm x 4.6mm ID, 3μm; Column temperature: 35℃; Mobile phase: CO2-isopropanol (0.05% DEA); Ethanol: 5%-40% for 5 min, 40%-5% for 0.5 min, 5% for 1.5 min; Flow rate: 2.5 mL / min.

[1220] Compound 24B:

[1221] 1 H NMR (400MHz, Methanol-d4) δ8.35 (d, J = 5.1Hz, 1H), 7.59 (br d,J=9.3Hz,1H),7.21-7.10(m,2H),7.03(dd,J=10.8,17.0Hz,1H),6.60-6.47(m,2H),6.21-6.06(m,1H),5.71(br d,J=11.0Hz,1H),4.88-4.85(m,1H),4.65(br d,J=13.9Hz,1H),4.51(s,1H),4.22(br dd,J=7.8,15.8Hz,2H),3.90-3.75(m,2H),3.04(br d,J=8.8Hz,1H),2.63-2.35(m,3H),2.20-2.06(m,9H),1.65-1.56(m,3H),1.00(dd,J=6.8,15.0Hz,6H).

[1222] MS(ESI)m / z(M+H) + =689.4.

[1223] SFC retention time: 3.389 min.

[1224] Separation conditions: Column: Chiralpak AD-3 150mm x 4.6mm ID, 3μm; Column temperature: 35℃; Mobile phase: CO2-isopropanol (0.05% DEA); Ethanol: 5%-40% for 5 min, 40%-5% for 0.5 min, 5% for 1.5 min; Flow rate: 2.5 mL / min.

[1225] Compound 24C:

[1226] 1H NMR (400MHz, Methanol-d4) δ8.45 (d, J = 5.0Hz, 1H), 7.70 (br d,J=9.3Hz,1H),7.30-7.21(m,2H),7.13(dd,J=10.7,16.9Hz,1H),6.75-6.60(m,2H),6.23(d,J=15.1Hz,1H),5.81(br d,J=12.3Hz,1H),4.95(br s,1H),4.74(br d,J=12.5Hz,1H),4.61(s,1H),4.30(br d,J=6.8Hz,2H),4.00-3.85(m,2H),3.24-3.12(m,1H),3.01-2.89(m,1H),2.71(br s,1H),2.60(br s,1H),2.40-2.24(m,6H),1.99(s,3H),1.74-1.66(m,3H),1.24(d,J=6.8Hz,3H),1.13(d,J=6.5Hz,3H).

[1227] MS(ESI)m / z(M+H) + =689.4.

[1228] SFC retention time: 3.917 min.

[1229] Separation conditions: Column: Chiralpak AD-3 150mm x 4.6mm ID, 3μm; Column temperature: 35℃; Mobile phase: CO2-isopropanol (0.05% DEA); Ethanol: 5%-40% for 5 min, 40%-5% for 0.5 min, 5% for 1.5 min; Flow rate: 2.5 mL / min.

[1230] Compound 24D:

[1231] 1H NMR (400MHz, Methanol-d4) δ8.43(d,J=4.9Hz,1H),7.68(br d,J=7.7Hz,1H),7.29-7.17(m,2H),7.11(br dd,J=10.5,16.9Hz,1H),6.71-6.58(m,2H),6.28-6.14(m,1H),5.79(br d,J=10.8Hz,1H),4.97-4.93(m,1H),4.72(br d,J=12.3Hz,1H),4.59(s,1H),4.28(br t,J=6.5Hz,2H),4.01-3.84(m,2H),3.21-3.08(m,1H),2.98-2.87(m,1H),2.64(br s,1H),2.52(br s,1H),2.35-2.14(m,6H),1.96(s,3H),1.72-1.62(m,3H),1.21(br d,J=6.8Hz,3H),1.14(br d,J=6.6Hz,3H).

[1232] MS(ESI)m / z(M+H) + =689.4.

[1233] SFC retention time: 4.278 min.

[1234] Separation conditions: Column: Chiralpak AD-3 150mm x 4.6mm ID, 3μm; Column temperature: 35℃; Mobile phase: CO2-isopropanol (0.05% DEA); Ethanol: 5%-40% for 5 min, 40%-5% for 0.5 min, 5% for 1.5 min; Flow rate: 2.5 mL / min.

[1235] Example 25: Preparation of compounds 25A and 25B

[1236] Step 1: Preparation of compound 25-1

[1237]

[1238] Compounds 8-9 (426 mg, 1.0 mmol), 7-1 (286 mg, 1.1 mmol), and N,N-diisopropylethylamine (0.2 mL) were dissolved in acetonitrile (10 mL), and the system was heated to 100 °C and stirred for 4 h. The system was concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–35%) to give compound 25-1.

[1239] MS(ESI)m / z(M+H) +=649.0.

[1240] Step 2: Preparation of compound 25-2

[1241]

[1242] Compound 25-1 (326 mg, 0.502 mmol) and iron powder (200 mg, 3.6 mmol) were dissolved in acetic acid (15 mL). The system was heated to 85 °C and stirred for 1 h under a nitrogen atmosphere. The system was filtered through diatomaceous earth, the filtrate was concentrated, the residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate, and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to give compound 25-2. This compound was used directly in the next reaction without further purification.

[1243] MS(ESI)m / z(M+H) + =587.0.

[1244] Step 3: Preparation of compound 25-3

[1245]

[1246] Compound 25-2 (277 mg, 0.5 mmol), compound 2-3 (282 mg, 1 mmol), tetrakis(triphenylphosphine)palladium (150 mg, 0.125 mmol), and potassium carbonate (138 mg, 1 mmol) were dissolved in a mixed solution of dioxane (18 mL) and water (1.8 mL). The system was heated to 100 °C and stirred for 2 h under a nitrogen atmosphere. The system was concentrated to obtain a crude product, which was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–50%) to obtain compound 25-3.

[1247] MS(ESI)m / z(M+H) + =707.2.

[1248] Step 4: Preparation of compound 25-4

[1249]

[1250] Compound 25-3 (40 mg, 0.057 mmol) and potassium carbonate (21 mg, 0.15 mmol) were dissolved in acetone (3 mL). Iodomethane (21 mg, 0.15 mmol) was added at room temperature (20 °C). After the addition was complete, the system was heated to 60 °C and stirred for 3 h under a nitrogen atmosphere. The system was then cooled to room temperature and concentrated to obtain a crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–50%) to give compound 25-4.

[1251] MS(ESI)m / z(M+H)+ =721.2.

[1252] Step 5: Preparation of compound 25-5

[1253]

[1254] Compound 25-4 (50 mg, 0.069 mmol) and hydrochloric acid (6 N, 2 mL) were added to a mixed solution of methanol (2 mL) and tetrahydrofuran (0.2 mL). The system was heated to 55 °C and reacted for 10 min. The system was concentrated to obtain crude compound 25-5, which was used directly in the next step without further purification.

[1255] MS(ESI)m / z(M+H) + =577.2.

[1256] Step 6: Preparation of Compound 25

[1257]

[1258] Compound 25-5 (40 mg, 0.069 mmol) was dissolved in dichloromethane (5 mL). The system was cooled to 0 °C, and triethylamine (39 mg, 0.39 mmol) and acryloyl chloride (23 mg, 0.26 mmol) were added dropwise. The reaction was carried out at 0 °C for 0.5 h. The system was quenched with methanol and concentrated to obtain the crude product. The crude product was dissolved in methanol (5 mL), and potassium carbonate (140 mg) was added. After the addition was complete, the system was stirred at room temperature (20 °C) for 30 min. The pH of the system was adjusted to ~6 with hydrochloric acid, and the mixture was extracted separately with dichloromethane (10 mL) and water (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by high-performance liquid chromatography (HPLC) (separation conditions: column). 5μm F5 LC column 150 x 21.2 mm, mobile phase: water (0.1% FA) - acetonitrile; acetonitrile 22%-42% 9 min; flow rate 30 mL / min) to obtain compound 25.

[1259] MS(ESI)m / z(M+H) + =631.2.

[1260] Step 7: Preparation of compounds 25A and 25B

[1261]

[1262] The diastereomer compound 25 was purified by SFC (ChiralPak AD, 250×30mm ID, 10μm; mobile phase: [CO2-ethanol (0.1% ammonia)]; ethanol %: 35%; flow rate: 80 mL / min; column temperature: 38℃). After concentration, compounds 25A and 25B were obtained.

[1263] Compound 25A

[1264] 1 H NMR (400MHz, DMSO-d6) δ10.07(s,1H),8.44(d,J=4.9Hz,1H),8.24(s,1H),7.30–7.17(m,2H),7.03(dd,J=16.8,10. 6Hz,1H),6.76–6.63(m,2H),6.15(dd,J=16.8,2.5Hz,1H),5.77(dd,J=10.6,2.5Hz,1H),4.85–4.72(m,1H),4.62(d ,J=14.0Hz,1H),3.99–3.91(m,1H),3.76(dd,J=14.1,4.3Hz,1H),3.51–3.39(m,1H),2.91–2.83(m,1H),2.76(p,J= 6.8Hz,1H),1.81(d,J=9.0Hz,3H),1.53(d,J=6.8Hz,3H),1.24(s,3H),1.11(d,J=6.6Hz,3H),0.96(d,J=6.6Hz,3H).

[1265] MS(ESI)m / z(M+H) + =631.2.

[1266] SFC 100%ee. Retention time 4.102 min.

[1267] Separation conditions: Column: ChiralPak AD-3, 150×4.6mm ID, 3μm; Mobile phase: [CO2-ethanol (0.05% DEA)]; Ethanol %: 5%-40% 5 min, 40% 2.5 min, 5% 2.5 min; Flow rate: 2.5 mL / min; Column temperature: 35℃

[1268] Compound 25B

[1269] 1H NMR (400MHz, DMSO-d6) δ9.98(d,J=14.4Hz,1H),8.36(d,J=4.8Hz,1H),8.17(s,1H),7.16(d,J=8.5Hz,2H),6.96(dd, J=16.9,10.6Hz,1H),6.69–6.54(m,2H),6.08(dd,J=16.8,2.4Hz,1H),5.69(dd,J=10.5,2.4Hz,1H),4.74–4.63(m,1H ),4.54(d,J=14.1Hz,1H),4.05–3.87(m,1H),3.68(dd,J=14.1,4.3Hz,1H),3.37–3.26(m,1H),2.93–2.79(m,1H),2. 80–2.68(m,1H),1.92(d,J=3.2Hz,3H),1.46(d,J=6.8Hz,3H),1.17(s,3H),0.96(d,J=6.6Hz,3H),0.85–0.73(m,3H).

[1270] MS(ESI)m / z(M+H) + =631.2.

[1271] SFC 100%ee. Retention time 5.424 min.

[1272] Separation conditions: Column: ChiralPak AD-3, 150×4.6mm ID, 3μm; Mobile phase: [CO2-ethanol (0.05% DEA)]; Ethanol %: 5%-40% 5 min, 40% 2.5 min, 5% 2.5 min; Flow rate: 2.5 mL / min; Column temperature: 35℃

[1273] Example 26: Preparation of Compound 26

[1274] Step 1: Preparation of compound 26-2

[1275]

[1276] Compound 23-2 (400 mg, 576.23 μmol) and cesium carbonate (563.24 mg, 1.73 mmol) were dissolved in N,N-dimethylformamide (5 mL). Compound 26-2 (185.98 mg, 1.73 mmol) was added at room temperature (25 °C). After the addition was complete, the system was heated to 120 °C and stirred for 3 h under a nitrogen atmosphere. The system was concentrated, diluted with ethyl acetate (20 mL), filtered, and the filtrate was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 1 / 10) to obtain compound 26-2.

[1277] MS(ESI)m / z(M+H) + =765.5.

[1278] Step 2: Preparation of compound 26-3

[1279]

[1280] Compound 26-2 (230 mg, 345.78 μmol) was dissolved in dichloromethane (1 mL), and boron tribromide (1 M, 407.10 μL) was added. The reaction mixture was stirred at 20 °C for 16 h. The reaction solution was quenched with methanol (5 mL) and stirred for 10 min. Saturated sodium bicarbonate (30 mL) was added to the system, and the mixture was extracted with dichloromethane (30 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 26-3, which was used directly in the next reaction without further purification.

[1281] MS(ESI)m / z(M+H) + =651.3.

[1282] Step 3: Preparation of compounds 26A and 26B

[1283]

[1284] Compound 26-3 (280 mg, 430.01 μmol) was dissolved in tetrahydrofuran (3 mL) and saturated sodium bicarbonate aqueous solution (4.32 g, 51.42 mmol, 2 mL). Acrylic anhydride (108.46 mg, 860.02 μmol) was added at room temperature (25 °C). After addition, the system was stirred at room temperature (25 °C) for 30 min. The system was diluted with water (10 mL), extracted with ethyl acetate (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by high-performance preparative liquid chromatography (HPLC) (separation conditions: column: Phenomenex Gemini-NX 80*30mm*3μm; mobile phase: [water (10mM ammonium bicarbonate aqueous solution)-acetonitrile]; acetonitrile %: 55%-85% 9min), followed by SFC purification (separation conditions: column: DAICEL CHIRALPAK AD-H (250mm*30mm, 5μm); mobile phase: [CO2-(0.1% ammonia) isopropanol]; isopropanol %: 35%-35%). After concentration, compounds 26A, 26B, 26C, and 26D were obtained.

[1285] Compound 26A:

[1286] 1 H NMR (400MHz, Methanol-d4) δ8.44(d,J=5.0Hz,1H),8.04(s,1H),7.31-7.20(m,2H),7.13(dd,J=10.7,16.9Hz,1H ),6.69(d,J=8.3Hz,1H),6.63(t,J=8.8Hz,1H),6.30-6.19(m,1H),5.86-5.75(m,1H),4.99-4.94(m,1H),4.75(br d,J=13.8Hz,1H),4.67-4.44(m,1H),4.39-4.23(m,2H),4.03-3.85(m,2H),3.22-3.07(m,1H),2.66(br d,J=11.8Hz,1H),2.60-2.47(m,2H),2.32-2.09(m,9H),1.76-1.64(m,3H),1.12(d,J=6.8Hz,3H),1.02(d,J=6.8Hz,3H).

[1287] MS(ESI)m / z(M+H) + =705.3.

[1288] HPLC retention time: 6.9 min.

[1289] Separation conditions: Column: WELCH Ultimate LP-C18 150*4.6mm 5μm; Column temperature: 40℃; Mobile phase: water (0.0688% trifluoroacetic acid solution) - acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10%-80% for 10 min, 80% for 5 min; Flow rate: 1.5 mL / min. SFC retention time: 4.077 min.

[1290] Separation conditions: Column: Chiralpak AD-3 150 x 4.6 mm ID, 3 μm; Column temperature: 35℃; Mobile phase: CO2-isopropanol (0.05% DEA); Isopropanol: 5%-40% 5 min, 40% 2.5 min, 5% 2.5 min; Flow rate: 2.5 mL / min.

[1291] Compound 26B:

[1292] 1 H NMR(400MHz,Methanol-d4)δ8.52-8.34(m,1H),8.03(s,1H),7.31-7.19(m,2H),7.13(dd ,J=10.8,16.8Hz,1H),6.72-6.56(m,2H),6.32-6.16(m,1H),5.89-5.73(m,1H),4.95(br s,1H),4.81-4.68(m,1H),4.67-4.44(m,1H),4.39-4.20(m,2H),4.04-3.84(m,2H),3.14(dd,J=3.5, 12.0Hz,1H),2.72-2.42(m,3H),2.31-2.18(m,9H),1.76-1.64(m,3H),1.10(dd,J=6.8,15.1Hz,6H).

[1293] MS(ESI)m / z(M+H) + =705.3.

[1294] The HPLC retention time was 6.67 min.

[1295] Separation conditions: Column: WELCH Ultimate LP-C18 150*4.6mm 5μm; Column temperature: 40℃; Mobile phase: Water (0.0688% trifluoroacetic acid solution) - acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10%-80% for 10 min, 80% for 5 min; Flow rate: 1.5 mL / min; SFC retention time: 4.515 min.

[1296] Separation conditions: Column: Chiralpak AD-3 150 x 4.6 mm ID, 3 μm; Column temperature: 35℃; Mobile phase: CO2-isopropanol (0.05% DEA); Isopropanol: 5%-40% 5 min, 40% 2.5 min, 5% 2.5 min; Flow rate: 2.5 mL / min.

[1297] Compound 26C:

[1298] 1 H NMR(400MHz, Methanol-d4)δ8.44(d,J=5.0Hz,1H),8.04(s,1H),7.30-7.20(m,2H),7.13( dd,J=10.7,16.9Hz,1H),6.73-6.58(m,2H),6.32-6.16(m,1H),5.87-5.73(m,1H),4.95(br s,1H),4.74(br d,J=13.6Hz,1H),4.66-4.45(m,1H),4.37-4.20(m,2H),3.99-3.82(m,2H),3.20(br dd,J=3.4,12.4Hz,1H),2.94(td,J=6.7,13.5Hz,1H),2.67(br d,J=12.0Hz,1H),2.55(br d,J=5.3Hz,1H),2.34-2.15(m,6H),2.10-1.93(m,3H),1.77-1.61(m,3H),1.23(d,J=6.8Hz,3H),1.11(d,J=6.8Hz,3H).

[1299] MS(ESI)m / z(M+H) + =705.3.

[1300] The HPLC retention time was 6.67 min.

[1301] Separation conditions: Column: WELCH Ultimate LP-C18 150*4.6mm 5μm; Column temperature: 40℃; Mobile phase: Water (0.0688% trifluoroacetic acid solution) - acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10%-80% for 10 min, 80% for 5 min; Flow rate: 1.5 mL / min; SFC retention time: 4.826 min.

[1302] Separation conditions: Column: Chiralpak AD-3 150 x 4.6 mm ID, 3 μm; Column temperature: 35℃; Mobile phase: CO2-isopropanol (0.05% DEA); Isopropanol: 5%-40% 5 min, 40% 2.5 min, 5% 2.5 min; Flow rate: 2.5 mL / min.

[1303] Compound 26D:

[1304] 1 H NMR(400MHz, Methanol-d4)δ8.44(d,J=4.8Hz,1H),8.04(s,1H),7.34-7.20(m,2H),7.13( dd,J=10.7,16.9Hz,1H),6.72-6.53(m,2H),6.33-6.15(m,1H),5.92-5.65(m,1H),4.95(br s,1H),4.75(d,J=12.8Hz,1H),4.66-4.42(m,1H),4.30(br t,J=6.9Hz,2H),4.02-3.83(m,2H),3.26-3.13(m,1H),2.93(quin,J=6.8Hz,1H),2.74-2.59(m,1H),2.58-2 .45(m,1H),2.34-2.18(m,6H),1.99(s,3H),1.78-1.63(m,3H),1.22(d,J=6.8Hz,3H),1.15(d,J=6.8Hz,3H).

[1305] MS(ESI)m / z(M+H) + =705.3.

[1306] The HPLC retention time was 6.88 min.

[1307] Separation conditions: Column: WELCH Ultimate LP-C18 150*4.6mm 5μm; Column temperature: 40℃; Mobile phase: Water (0.0688% trifluoroacetic acid solution) - acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10%-80% for 10 min, 80% for 5 min; Flow rate: 1.5 mL / min; SFC retention time: 5.114 min.

[1308] Separation conditions: Column: Chiralpak AD-3 150 x 4.6 mm ID, 3 μm; Column temperature: 35℃; Mobile phase: CO2-isopropanol (0.05% DEA); Isopropanol: 5%-40% 5 min, 40% 2.5 min, 5% 2.5 min; Flow rate: 2.5 mL / min.

[1309] Example 27: Preparation of Compound 27

[1310] Step 1: Preparation of compound 27-1

[1311]

[1312] Compound 26-2 (600 mg, 784.02 μmol) was dissolved in dichloromethane (6 mL), and trifluoroacetic acid (1.83 g, 16.06 mmol, 1.19 mL) was added. The reaction mixture was stirred at 25 °C for 16 h. The reaction solution was concentrated to give compound 27-1, which was used directly in the next reaction without further purification.

[1313] MS(ESI)m / z(M+H) + =665.3.

[1314] Step 2: Preparation of Compound 27

[1315]

[1316] Compound 27-1 (200 mg, 300.67 μmol) was dissolved in tetrahydrofuran (2 mL) and saturated sodium bicarbonate aqueous solution (4.32 g, 51.42 mmol, 2 mL). Acrylic anhydride (75.84 mg, 601.35 μmol) was added at room temperature (25 °C). After addition, the system was stirred at room temperature (25 °C) for 30 min. The system was diluted with water (10 mL), extracted with ethyl acetate (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by high-performance liquid chromatography (HPLC) (separation conditions: column: Phenomenex Gemini-NX 80*30mm*3μm; mobile phase: [water (10mM ammonium bicarbonate aqueous solution)-acetonitrile]; acetonitrile %: 49%-79% 9min), followed by SFC purification (separation conditions: column: DAICEL CHIRALPAK AD-H (250mm*30mm, 5μm); mobile phase: [CO2-(0.1% ammonia water) ethanol]; ethanol %: 25%-25%). After concentration, compounds 27A, 27B, 27C, and 27D were obtained.

[1317] Compound 27A:

[1318] 1H NMR (400MHz, Methanol-d4) δ8.44(d,J=5.0Hz,1H),8.03(d,J=1.3Hz,1H),7.46-7.38(m,1H),7.27(d,J=5.0Hz,1H),7.1 3(dd,J=10.8,16.8Hz,1H),6.89(d,J=8.5Hz,1H),6.79(t,J=8.8Hz,1H),6.31-6.18(m,1H),5.87-5.75(m,1H),4.95(br s,1H),4.80-4.70(m,1H),4.68-4.42(m,1H),4.39-4.26(m,2H),4.02-3.87(m,2H),3.68(s,3H),3.25-3.12( m,1H),2.65-2.37(m,3H),2.23-2.14(m,9H),1.76-1.64(m,3H),1.13(d,J=6.8Hz,3H),1.05(d,J=6.8Hz,3H).

[1319] MS(ESI)m / z(M+H) + =719.3.

[1320] The HPLC retention time was 4.761 min.

[1321] Separation conditions: Column: Xbridge Shield RP-18, 5μm, 2.1*50mm; Column temperature: 50℃; Mobile phase: water (0.2mL / L ammonia solution)-acetonitrile; Acetonitrile: 10%-80% for 6min, 80% for 2min; Flow rate: 0.8mL / min.

[1322] SFC retention time: 4.329 min.

[1323] Separation conditions: Column: Chiralpak IG-3 100×4.6mm ID, 3μm; Column temperature: 35℃; Mobile phase: CO2-isopropanol (0.05% DEA); Isopropanol: 5%-40% for 4 min, 40% for 2.5 min, 5% for 1.5 min; Flow rate: 2.8 mL / min.

[1324] Compound 27B:

[1325] 1H NMR (400MHz, Methanol-d4) δ8.45(d,J=5.0Hz,1H),8.04(s,1H),7.48-7.37(m,1H),7.27(d,J=5.0Hz,1H),7.13(dd ,J=10.7,16.9Hz,1H),6.91(d,J=8.5Hz,1H),6.79(t,J=8.5Hz,1H),6.31-6.17(m,1H),5.87-5.75(m,1H),4.95(br s,1H),4.83-4.69(m,1H),4.67-4.49(m,1H),4.39-4.29(m,2H),4.05-3.85(m,2H),3.76(s,3H),3.27-3.13( m,1H),2.65-2.39(m,3H),2.24-2.13(m,9H),1.77-1.63(m,3H),1.12(d,J=6.8Hz,3H),1.02(d,J=6.8Hz,3H).

[1326] MS(ESI)m / z(M+H) + =719.3.

[1327] The HPLC retention time was 4.775 min.

[1328] Separation conditions: Column: Xbridge Shield RP-18, 5μm, 2.1*50mm; Column temperature: 50℃; Mobile phase: water (0.2mL / L ammonia solution)-acetonitrile; Acetonitrile: 10%-80% for 6min, 80% for 2min; Flow rate: 0.8mL / min.

[1329] SFC retention time: 4.523 min.

[1330] Separation conditions: Column: Chiralpak IG-3 100×4.6mm ID, 3μm; Column temperature: 35℃; Mobile phase: CO2-isopropanol (0.05% DEA); Isopropanol: 5%-40% for 4 min, 40% for 2.5 min, 5% for 1.5 min; Flow rate: 2.8 mL / min.

[1331] Compound 27C:

[1332] 1H NMR (400MHz, Methanol-d4) δ8.44(d,J=5.0Hz,1H),8.04(s,1H),7.50-7.37(m,1H),7.26(d,J=5.0Hz,1H),7.18-7.11( m,1H),6.91(d,J=8.3Hz,1H),6.80(t,J=8.7Hz,1H),6.31-6.17(m,1H),5.86-5.75(m,1H),4.99-4.93(m,1H),4.75(br d,J=12.8Hz,1H),4.65-4.40(m,1H),4.36-4.18(m,2H),4.02-3.85(m,2H),3.74(s,3H),3.16(br dd,J=3.5,12.3Hz,1H),2.96(td,J=6.9,13.6Hz,1H),2.86-2.67(m,2H),2.45-2.3 3(m,6H),1.99(s,3H),1.77-1.64(m,3H),1.23(d,J=6.8Hz,3H),1.14-1.09(m,3H).

[1333] MS(ESI)m / z(M+H) + =719.3.

[1334] The HPLC retention time was 4.732 min.

[1335] Separation conditions: Column: Xbridge Shield RP-18, 5μm, 2.1*50mm; Column temperature: 50℃; Mobile phase: water (0.2mL / L ammonia solution)-acetonitrile; Acetonitrile: 10%-80% for 6min, 80% for 2min; Flow rate: 0.8mL / min.

[1336] SFC retention time: 8.150 min.

[1337] Separation conditions: Column: ChiralPak IC-3 150×4.6mm ID, 3μm; Column temperature: 40℃; Mobile phase: CO2-ethanol (0.05% DEA); Isopropanol: 5%-40% 5.5min, 40% 3min, 5% 1.5min; Flow rate: 2.5mL / min.

[1338] Compound 27D:

[1339] 1H NMR (400MHz, Methanol-d4) δ8.45(d,J=4.8Hz,1H),8.05(s,1H),7.48-7.38(m,1H),7.25(d,J=5.3Hz,1H),7.13(dd ,J=10.8,17.1Hz,1H),6.90(d,J=8.5Hz,1H),6.80(t,J=8.5Hz,1H),6.32-6.16(m,1H),5.85-5.76(m,1H),4.96(br s,1H),4.75(br d,J=12.3Hz,1H),4.67-4.45(m,1H),4.36-4.20(m,2H),4.01-3.86(m,2H),3.71(s,3H),3.27-3.14(m,1H),2.94(td,J=6.8,13 .6Hz,1H),2.85-2.56(m,2H),2.39-2.24(m,6H),1.99(s,3H),1.76-1.65(m,3H),1.24(d,J=6.8Hz,3H),1.14(d,J=6.8Hz,3H).

[1340] MS(ESI)m / z(M+H) + =719.3.

[1341] The HPLC retention time was 4.716 min.

[1342] Separation conditions: Column: Xbridge Shield RP-18, 5μm, 2.1*50mm; Column temperature: 50℃; Mobile phase: water (0.2mL / L ammonia solution)-acetonitrile; Acetonitrile: 10%-80% for 6min, 80% for 2min; Flow rate: 0.8mL / min.

[1343] SFC retention time: 6.545 min.

[1344] Separation conditions: Column: ChiralPak IC-3 150×4.6mm ID, 3μm; Column temperature: 40℃; Mobile phase: CO2-ethanol (0.05% DEA); Isopropanol: 5%-40% 5.5min, 40% 3min, 5% 1.5min; Flow rate: 2.5mL / min.

[1345] Example 28: Preparation of compound 28

[1346] Step 1: Preparation of compound 28-2

[1347]

[1348] Compound 28-1 (1 g, 4.61 mmol), ammonium acetate (2.13 g, 27.65 mmol), diacetyliodobenzene (2.97 g, 9.22 mmol), and sodium dodecyl sulfate (265.74 mg, 921.51 μmol, 263.11 μL) were suspended in water (10 mL). The system was heated to 70 °C and reacted for 30 min. After cooling the system to room temperature (25 °C), saturated sodium thiosulfate (5 mL) was added. The system was stirred at room temperature (25 °C) for 15 min and then extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–5%) to obtain compound 28-2.

[1349] 1 H NMR (400MHz, CHLOROFORM-d) δ7.46 (dd, J=6.0, 8.6Hz, 1H), 7.11 (t, J=8.4Hz, 1H), 2.44 (s, 3H).

[1350] Step 2: Preparation of compound 28-3

[1351]

[1352] Compound 28-2 (760 mg, 3.55 mmol), pinacol diboronate (1.35 g, 5.33 mmol), 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (289.97 mg, 355.08 μmol), and potassium acetate (1.05 g, 10.65 mmol) were dissolved in 1,4-dioxane (5 mL) at room temperature (20 °C). The system was heated to 100 °C and stirred for 16 h under a nitrogen atmosphere. The system was then cooled to room temperature and concentrated to obtain a crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–5%) to obtain compound 28-3.

[1353] Step 3: Preparation of compound 28-5

[1354]

[1355] Compound 28-4 (210 mg, 348.80 μmol), compound 28-3 (136.61 mg, 523.19 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (29.17 mg, 34.88 μmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (16.28 mg, 34.88 μmol), and potassium carbonate (96.41 mg, 697.59 μmol) were dissolved in a mixed solution of dioxane (3 mL) and water (0.3 mL). Under a nitrogen atmosphere, the system was heated to 100 °C and stirred for 5 h. The system was filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0-50%) to give compound 28-5.

[1356] MS(ESI)m / z(M+H) + =701.1.

[1357] Step 4: Preparation of compound 28-6

[1358]

[1359] Compound 28-5 (150 mg, 214.06 μmol) was dissolved in ethanol (5 mL), and hydrazine hydrate (214.31 mg, 4.28 mmol, 208.07 μL) was added. The system was heated to 80 °C and reacted for 4 h. After cooling to room temperature (25 °C), the system was concentrated. The residue was dissolved in ethyl acetate (10 mL) and extracted with 1 N hydrochloric acid (20 mL x 3). The aqueous phases were combined, and the pH was adjusted to ~8 with 1 M sodium hydroxide. The mixture was then extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with water (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 28-6, which was used directly in the next reaction without further purification.

[1360] MS(ESI)m / z(M+H) + =713.4.

[1361] Step 5: Preparation of compound 28-7

[1362]

[1363] Compound 28-6 (60 mg, 84.18 μmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL) was added. The reaction mixture was stirred at 25 °C for 1 h. The reaction solution was concentrated to give compound 28-7, which was used directly in the next reaction without further purification.

[1364] MS(ESI)m / z(M+H) + =613.3.

[1365] Step 6: Preparation of Compound 28

[1366]

[1367] Compound 28-7 (50 mg, 81.61 μmol) was dissolved in tetrahydrofuran (3 mL) and saturated NaHCO3 aqueous solution (3 mL). Acrylic anhydride (11.32 mg, 89.77 μmol) was added at room temperature (25 °C). After the addition was complete, the system was stirred at room temperature (25 °C) for 2 h. The system was diluted with water (10 mL), extracted with ethyl acetate (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by high-performance liquid chromatography (HPLC) (separation conditions: column: Phenomenex Gemini-NX 80*30mm*3μm; mobile phase: [water (10mM ammonium bicarbonate aqueous solution)-acetonitrile]; acetonitrile %: 36%-66% 9min), followed by SFC purification (separation conditions: column: DAICL CHIRALPAK IG (250mm*30mm, 10μm); mobile phase: [CO2-(0.1% ammonia water) methanol]; methanol %: 55%-55%). After concentration, compounds 28A, 28B, and 28C were obtained.

[1368] Compound 28A:

[1369] 1 H NMR (400MHz, Methanol-d4) δ8.40 (d, J = 5.0Hz, 1H), 7.80 (br d,J=8.8Hz,1H),7.34-7.24(m,2H),7.23-7.19(m,1H),7.13(dd,J=10.7,16.9Hz,1H),6.25(dd,J=1.8,16.8Hz,1H),5.87-5.76(m,1H),4.95(br s,1H),4.77(br d,J=12.5Hz,1H),3.99-3.87(m,2H),3.46(s,3H),3.40(br d,J=12.3Hz,1H),3.03-2.92(m,2H),2.07(d,J=5.8Hz,6H),1.69(d,J=7.0Hz,3H),1.22(d,J=6.8Hz,3H),1.13(d,J=6.8Hz,3H).

[1370] MS(ESI)m / z(M+H)+ =667.3.

[1371] The HPLC retention time was 6.49 min.

[1372] Separation conditions: Column: WELCH Ultimate C18 150*4.6mm, 5μm; Column temperature: 40℃; Mobile phase: water (0.0688% trifluoroacetic acid solution) - acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10%-80% for 10 min, 80% for 5 min; Flow rate: 1.5 mL / min.

[1373] SFC retention time: 1.661 min.

[1374] Separation conditions: Column: Chiralpak IG-3 50*4.6mm ID, 3μm; Column temperature: 35℃; Mobile phase: CO2-methanol (0.05% DEA); Methanol: 40%-40%; Flow rate: 4mL / min.

[1375] Compound 28B:

[1376] 1 H NMR (400MHz, Methanol-d4) δ8.41 (d, J = 5.0Hz, 1H), 7.78 (br d,J=8.8Hz,1H),7.32-7.21(m,3H),7.14(dd,J=10.7,16.9Hz,1H),6.25(dd,J=1.8,16.8Hz,1H),5.88-5.76(m,1H),5.00-4.96(m,1H),4.77(br d,J=11.8Hz,1H),4.02-3.87(m,2H),3.49(br d,J=3.3Hz,1H),3.46(s,3H),3.12-2.93(m,2H),2.07(s,3H),1.97(s,3H),1. 75(s,1H),1.69(d,J=6.8Hz,2H),1.23(d,J=6.8Hz,3H),1.17(d,J=6.8Hz,3H).

[1377] MS(ESI)m / z(M+H) + =667.3.

[1378] The HPLC retention time was 6.66 min.

[1379] Separation conditions: Column: WELCH Ultimate C18 150*4.6mm, 5μm; Column temperature: 40℃; Mobile phase: water (0.0688% trifluoroacetic acid solution) - acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10%-80% for 10 min, 80% for 5 min; Flow rate: 1.5 mL / min.

[1380] SFC retention time: 4.234 min.

[1381] Separation conditions: Column: Chiralpak IG-3 50*4.6mm ID, 3μm; Column temperature: 35℃; Mobile phase: CO2-methanol (0.05% DEA); Methanol: 40%-40%; Flow rate: 4mL / min.

[1382] Compound 28C:

[1383] 1 H NMR (400MHz, Methanol-d4) δ8.40 (d, J = 5.0Hz, 1H), 7.77 (br d,J=9.0Hz,1H),7.32-7.22(m,3H),7.13(dd,J=10.7,16.9Hz,1H),6.31-6.20(m,1H),5.86-5.76(m,1H),4.94(br s,1H),4.77(br d,J=12.5Hz,1H),4.06-3.88(m,2H),3.46(s,4H),2.93(dd,J=3.5,12.3Hz,1H),2.64-2.54(m,1H ),2.25(s,3H),2.09(s,3H),1.69(d,J=6.8Hz,3H),1.13(d,J=6.8Hz,3H),1.01(d,J=6.8Hz,3H).

[1384] MS(ESI)m / z(M+H) + =667.3.

[1385] The HPLC retention time was 6.77 min.

[1386] Separation conditions: Column: WELCH Ultimate C18 150*4.6mm, 5μm; Column temperature: 40℃; Mobile phase: water (0.0688% trifluoroacetic acid solution) - acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10%-80% for 10 min, 80% for 5 min; Flow rate: 1.5 mL / min; SFC retention time: 2.725 min.

[1387] Separation conditions: Column: Chiralpak IG-3 50*4.6mm ID, 3μm; Column temperature: 35℃; Mobile phase: CO2-methanol (0.05% DEA); Methanol: 40%-40%; Flow rate: 4mL / min.

[1388] Example 29: Preparation of compound 29

[1389] Step 1: Preparation of compound 29-1

[1390]

[1391] Compound 25-3 (700 mg, 1 mmol) and cesium carbonate (977 mg, 3 mmol) were dissolved in N,N-dimethylformamide (20 mL). Compound 26-1 (432 mg, 3 mmol) was added at room temperature (25 °C). After the addition was complete, the system was heated to 120 °C and stirred for 2 h under a nitrogen atmosphere. The system was filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 1 / 10) to obtain compound 29-1.

[1392] MS(ESI)m / z(M+H) + =778.2.

[1393] Step 2: Preparation of compound 29-2

[1394]

[1395] Compound 29-1 (150 mg, 0.2 mmol) and hydrochloric acid (6 N, 7 mL) were added to a mixed solution of methanol (0.6 mL) and tetrahydrofuran (6 mL). The system was heated to 55 °C and reacted for 10 min. The system was concentrated to obtain crude compound 29-2, which was used directly in the next reaction without further purification.

[1396] MS(ESI)m / z(M+H) + =634.2.

[1397] Step 3: Preparation of Compound 29

[1398]

[1399] Compound 29-2 (140 mg, 0.2 mmol) was dissolved in dichloromethane (10 mL). The system was cooled to 0 °C, and triethylamine (0.3 mL, 2.1 mmol) and acryloyl chloride (27 mg, 0.3 mmol) were added dropwise. The reaction was carried out at 0 °C for 0.5 h. The system was quenched with methanol and concentrated to obtain the crude product. The crude product was dissolved in methanol (5 mL), and potassium carbonate (140 mg) was added. After the addition was complete, the system was stirred at room temperature (20 °C) for 30 min. The pH of the system was adjusted to ~6 with hydrochloric acid, and the mixture was extracted separately with dichloromethane (20 mL) and water (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by high-performance liquid chromatography (HPLC) (separation conditions: Welch column). C18 21.2×250mm, 10μm; column temperature: 25℃; mobile phase: water (10mM / L NH4HCO3)-acetonitrile; acetonitrile 40%-60% 9min; flow rate 30mL / min) yielded compound 29.

[1400] MS(ESI)m / z(M+H) + =688.2.

[1401] Step 4: Preparation of compounds 29A and 29B

[1402]

[1403] The diastereomer compound 29 was purified by SFC (ChiralPak AD, 250×30mm ID, 10μm; mobile phase: [CO2-ethanol (0.1% ammonia)]; ethanol %: 25%; flow rate: 60mL / min; column temperature: 38℃). After concentration, compounds 29A and 29B were obtained.

[1404] Compound 29A:

[1405] 1H NMR(400MHz, DMSO-d6)δ10.06(brs,1H),8.37(d,J=4.9Hz,1H),8.18(s,1H),7.29–7.05(m,2H),6.97(dd,J=16.8,10.6Hz,0.75H),6.79 (dd,J=16.7,10.7Hz,0.25H),6.69–6.46(m,2H),6.07(dd,J=16.8,2.5Hz,1H),5.68(dd,J=10.5,2.4Hz,1H),4.95(d,J=13.9Hz,0.25H), 4.82–4.66(m,0.75H),4.54(d,J=14.0Hz,1H),4.40–4.12(m,2H),3.94(dd,J=20.5,4.4Hz,1H),3.68(dd,J=14.2,4.4Hz,1H),3.14–2.90 (m,1H),2.43–2.34(m,2H),2.27–2.08(m,2H),1.97–1.82(m,9H),1.56–1.45(m,3H),0.97(dd,J=6.6,2.2Hz,3H),0.78(t,J=6.0Hz,3H).

[1406] MS(ESI)m / z(M+H) + =688.3.

[1407] SFC 100%ee. Retention time 3.559 min.

[1408] Separation conditions: Column: ChiralPak AD-3, 150×4.6mm ID, 3μm; Mobile phase: [CO2-ethanol (0.05% DEA)]; Ethanol %: 5%-40% 5 min, 40% 2.5 min, 5% 2.5 min; Flow rate: 2.5 mL / min; Column temperature: 35℃

[1409] Compound 29B:

[1410] 1H NMR(400MHz,DMSO-d6)δ10.18(brs,1H),8.45(d,J=4.9Hz,1H),8.26(s,1H),7.29–7.20(m,2H),7.04 (dd,J=16.8,10.4Hz,0.75H),6.86(dd,J=17.6,10.4Hz,0.25H),6.72–6.60(m,2H),6.14(d,J=16.4H z,1H),5.75(d,J=10.7Hz,1H),5.03(d,J=13.8Hz,0.25H),4.80(d,J=7.8Hz,0.75H),4.61(d,J=14.1 Hz,1H),4.43–4.30(m,1H),4.28–4.15(m,1H),4.04–3.89(m,1H),3.75(dd,J=14.5,4.4Hz,1H),3.28– 3.10(m,2H),2.75–2.65(m,1H),2.39–2.28(m,1H),2.28–2.17(m,1H),2.06–1.96(m,6H), 1.81(d,J=9.5Hz,3H), 1.53(d,J=6.8Hz,3H), 1.11(d,J=6.9Hz,3H), 0.95(d,J=6.6Hz,3H).

[1411] MS(ESI)m / z(M+H) + =688.3.

[1412] The HPLC retention time was 5.269 min.

[1413] Separation conditions: Column: Waters XBridge 4.6*100mm, 3.5μm; Column temperature: 40℃; Mobile phase: water (10mM ammonium bicarbonate)-acetonitrile; Acetonitrile: 5%-95% for 7 min; Flow rate: 1.2 mL / min; SFC 100% ee; Retention time: 4.349 min.

[1414] Separation conditions: Column: ChiralPak AD-3, 150×4.6mm ID, 3μm; Mobile phase: [CO2-ethanol (0.05% DEA)]; Ethanol %: 5%-40% 5min, 40% 2.5min, 5% 2.5min; Flow rate: 2.5mL / min; Column temperature: 35℃.

[1415] Example 30: Preparation of compound 30

[1416] Step 1: Preparation of compound 30-1

[1417]

[1418] Compound 25-2 (286 mg, 0.5 mmol), compound 1-13 (170 mg, 1 mmol), Pd(PPh3)4 (150 mg, 0.125 mmol), and potassium carbonate (138 mg, 1 mmol) were dissolved in a mixed solution of dioxane (18 mL) and water (1.8 mL). The system was heated to 100 °C and stirred for 2 h under a nitrogen atmosphere. The system was concentrated to obtain a crude product, which was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–50%) to give compound 30-1.

[1419] MS(ESI)m / z(M+H) + =677.2.

[1420] Step 2: Preparation of compound 30-2

[1421]

[1422] Compound 30-1 (700 mg, 1 mmol) and cesium carbonate (977 mg, 3 mmol) were dissolved in N,N-dimethylformamide (20 mL). Compound 26-1 (432 mg, 3 mmol) was added at room temperature (25 °C). After the addition was complete, the system was heated to 120 °C and stirred for 2 h under a nitrogen atmosphere. The system was filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 1 / 10) to obtain compound 30-2.

[1423] MS(ESI)m / z(M+H) + =748.2.

[1424] Step 3: Preparation of compound 30-3

[1425]

[1426] Compound 30-2 (80 mg, 0.107 μmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at 25 °C for 1 h. The reaction solution was concentrated to obtain compound 30-3, which was used directly in the next reaction without further purification.

[1427] MS(ESI)m / z(M+H) + =648.4.

[1428] Step 4: Preparation of Compound 30

[1429]

[1430] Compound 30-3 (70 mg, 0.107 mmol) was dissolved in dichloromethane (10 mL). The system was cooled to 0 °C, and triethylamine (0.1 mL, 0.7 mmol) and acryloyl chloride (14 mg, 0.2 mmol) were added dropwise. The reaction was carried out at 0 °C for 0.5 h. After quenching with water, the system was concentrated to obtain a crude product. The crude product was extracted separately with dichloromethane (10 mL) and water (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by high-performance liquid chromatography (HPLC) (separation conditions: Welch column). C18 21.2×250mm, 10μm; column temperature: 25℃; mobile phase: water (10mM / L NH4HCO3)-acetonitrile; acetonitrile 45%-75% 9min; flow rate 30mL / min) to obtain compound 30.

[1431] MS(ESI)m / z(M+H) + =702.2.

[1432] Step 5: Preparation of compounds 30A and 30B

[1433]

[1434] The diastereomer compound 30 was purified by SFC (ChiralPak AD, 250×30mm ID, 10μm; mobile phase: [CO2-ethanol (0.1% ammonia)]; ethanol %: 35%; flow rate: 80mL / min; column temperature: 38℃). After concentration, compounds 30A and 30B were obtained.

[1435] Compound 30A:

[1436] 1H NMR(400MHz,Chloroform-d)δ8.51(t,J=4.5Hz,1H),8.25(s,1H),7.45–7.27(m,1H),7.18–6.98(m,2H),6.88–6.61( m,2H),6.34(dd,J=16.9,1.9Hz,1H),5.79(dt,J=10.7,1.7Hz,1H),5.07(d,J=7.3Hz,1H),4.77(d,J=13.9Hz,1H),4. 64–4.37(m,1H),3.80(dt,J=14.1,4.7Hz,1H),3.68(d,J=26.8Hz,3H),3.34–3.02(m,2H),2.48(dt,J=13.7,7.1Hz,1 H),2.30–2.16(m,4H),2.02(d,J=1.7Hz,3H),1.75–1.46(m,9H),1.19(t,J=6.5Hz,3H),0.95(dd,J=12.9,6.7Hz,3H).

[1437] MS(ESI)m / z(M+H) + =702.3.

[1438] SFC 100%ee. Retention time 3.619 min.

[1439] Separation conditions: Column: ChiralPak AD-3, 150×4.6mm ID, 3μm; Mobile phase: [CO2-ethanol (0.05% DEA)]; Ethanol %: 5%-40% 5min, 40% 2.5min, 5% 2.5min; Flow rate: 2.5mL / min; Column temperature: 35℃.

[1440] Compound 30B:

[1441] 1H NMR(400MHz,Chloroform-d)δ8.51(dd,J=4.9,1.9Hz,1H),8.26(s,1H),7.32(td,J=8.4,6.6Hz,1H),7.15–6.98(m,2H ),6.83–6.66(m,2H),6.34(dd,J=16.9,2.0Hz,1H),5.79(dt,J=10.8,1.5Hz,1H),5.13–5.01(m,1H),4.77(d,J=14.0Hz ,1H),4.53–4.35(m,1H),3.79(dt,J=14.1,4.3Hz,1H),3.69(d,J=10.7Hz,3H),3.43–3.17(m,2H),2.70(h,J=6.7Hz,1 H),2.48–2.02(m,4H),1.97–1.83(m,3H),1.73–1.52(m,9H),1.21(dd,J=6.8,5.0Hz,3H),1.05(dd,J=8.0,6.7Hz,3H).

[1442] MS(ESI)m / z(M+H) + =702.3.

[1443] SFC 100%ee. Retention time 4.635min.

[1444] Separation conditions: Column: ChiralPak AD-3, 150×4.6mm ID, 3μm; Mobile phase: [CO2-ethanol (0.05% DEA)]; Ethanol %: 5%-40% 5 min, 40% 2.5 min, 5% 2.5 min; Flow rate: 2.5 mL / min; Column temperature: 35℃

[1445] Example 31: Preparation of compound 31

[1446] Step 1: Preparation of compound 31-2

[1447]

[1448] Potassium nitrate (10.49 g, 103.72 mmol) was dissolved in concentrated sulfuric acid (80 mL). The system was stirred at room temperature (20 °C) for 1 h. Compound 31-1 (10 g, 57.62 mmol) was added in portions. After the addition was complete, the system was heated to (80 °C) and stirred for 2 h. The system was quenched with ice water (200 mL) and filtered. The filter cake was washed with water (20 mL x 2) and dried to obtain compound 31-2.

[1449] Step 2: Preparation of compound 31-3

[1450]

[1451] Compound 31-2 (12.6 g, 57.65 mmol) was dissolved in 20% sulfuric acid aqueous solution (200 mL), and the system was heated to (85 °C) and stirred for 16 h. After cooling the system to room temperature (20 °C), it was diluted with water (1 L), extracted with ethyl acetate (2 x 500 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound 31-3.

[1452] 1 H NMR (400MHz, DMSO-d6) δ = 7.77 (d, J = 7.8Hz, 1H).

[1453] Step 3: Preparation of compound 31-4

[1454]

[1455] Compound 31-3 (13 g, 54.73 mmol) was dissolved in methanol (120 mL), and thionyl chloride (26.04 g, 218.91 mmol, 15.88 mL) was added. After the addition was complete, the system was heated to 70 °C and stirred for 16 h. The system was then cooled to room temperature (20 °C) and concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–10%) to obtain compound 31-4.

[1456] Step 4: Preparation of Compounds 31-5

[1457]

[1458] Compound 31-4 (6 g, 23.85 mmol) was dissolved in a mixed solvent of ethyl acetate (50 mL) and dichloromethane (50 mL), and stannous chloride dihydrate (26.91 g, 119.25 mmol) was added. After the addition was complete, the system was stirred at room temperature (20 °C) for 16 h. The system was filtered, and the filtrate was concentrated to give compound 31-5.

[1459] 1 H NMR (400MHz, CHLOROFORM-d) δ = 7.50 (dd, J = 2.3, 9.8Hz, 1H), 5.74 (br s, 2H), 3.92 (s, 3H).

[1460] Step 5: Preparation of compounds 31-6

[1461]

[1462] Compound 31-5 (8 g, 36.10 mmol), cuprous iodide (6.88 g, 36.10 mmol), and potassium iodide (11.99 g, 72.21 mmol) were dissolved in acetonitrile (100 mL). At 0 °C, tert-butyl nitrite (11.17 g, 108.31 mmol, 12.88 mL) was added. The system was heated to 80 °C and stirred for 2 h under a nitrogen atmosphere. After cooling to room temperature (20 °C), the system was quenched with an aqueous sodium thiosulfate solution (100 mL), diluted with water (100 mL), and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–7%) to obtain compound 31-6.

[1463] 1 H NMR (400MHz, DMSO-d6) δ = 7.82-7.74 (m, 1H), 3.89 (s, 3H).

[1464] Step 6: Preparation of compounds 31-7

[1465]

[1466] Compounds 31-6 (7 g, 21.05 mmol), 3-9 (3.51 g, 23.37 mmol), Pd2(dba)3 (1.93 g, 2.11 mmol), Xantphos (1.22 g, 2.11 mmol), and cesium carbonate (13.72 g, 42.11 mmol) were dissolved in toluene (100 mL) at room temperature (20 °C). The system was heated to 100 °C and stirred for 16 h under a nitrogen atmosphere. The system was cooled to room temperature and concentrated. The residue was extracted separately with water (50 mL) and ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–7%) to obtain compound 31-7.

[1467] 1 H NMR(400MHz, DMSO-d6)δ=8.74-8.72(m,1H),8.28-8.26(m,1H),7.72-7.68(m,1H), 7.11-7.08(m,1H),3.84(s,3H),3.26-3.21(m,1H),2.08(s,3H),1.12-1.04(m,6H).

[1468] Step 7: Preparation of compounds 31-8

[1469]

[1470] Compound 31-7 (3 g, 8.46 mmol) was dissolved in N,N-dimethylformamide (30 mL) at 0 °C. NaH (2.03 g, 50.74 mmol, 60% purity) was added in portions. After the addition was complete, the system was stirred at 0 °C for 30 min. Acetyl chloride (3.98 g, 50.74 mmol, 3.62 mL) was added dropwise to the system at 0 °C. After the addition was complete, the system was heated to room temperature (20 °C) under a nitrogen atmosphere and reacted for 16 h. The reaction was quenched with water (300 mL), and the mixture was extracted with ethyl acetate (50 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–100%) to obtain compound 31-8.

[1471] MS(ESI)m / z(M+H) + =397.0.

[1472] Step 8: Preparation of compounds 31-9

[1473]

[1474] Compound 31-8 (1.5 g, 3.78 mmol) was dissolved in toluene (40 mL) at room temperature (20 °C), and potassium tert-butoxide (1 M, 11.34 mL) was added. After the addition was complete, the system was reacted at room temperature (20 °C) for 20 min under a nitrogen atmosphere. The reaction was quenched by adding water (10 mL), the pH was adjusted to neutral with 1 N hydrochloric acid, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 31-9, which was used directly in the next reaction without further purification.

[1475] MS(ESI)m / z(M+H) + =364.9.

[1476] Step 9: Preparation of compounds 31-10

[1477]

[1478] Compound 31-9 (1.2 g, 3.29 mmol) was dissolved in glacial acetic acid (15 mL). Nitric acid (2.49 g, 39.48 mmol, 1.78 mL) was added dropwise to the system at room temperature (20 °C). After the addition was complete, the system was heated to 80 °C and stirred for 2 h. The system was then cooled to room temperature, and most of the glacial acetic acid was removed by concentration. The remainder was poured into ice water (10 mL), and a precipitate formed. This precipitate was filtered, washed with water, and dried to obtain compound 31-10, which was used directly in the next step without further purification.

[1479] MS(ESI)m / z(M+H) + =409.9.

[1480] Step 10: Preparation of compounds 31-11

[1481]

[1482] Compound 31-10 (0.9 g, 2.20 mmol) and N,N-diisopropylethylamine (851.59 mg, 6.59 mmol, 1.15 mL) were dissolved in acetonitrile (10 mL). Phosphorus oxychloride (1.01 g, 6.59 mmol, 612.31 μL) was added at room temperature (20 °C). After the addition was complete, the system was heated to 80 °C and stirred for 2 h. The system was cooled to room temperature (20 °C) and poured into water (20 mL), then extracted with ethyl acetate (3 x 10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound 31-11, which was used directly in the next step without further purification.

[1483] 1 H NMR(400MHz,CHLOROFORM-d)δ=8.64(d,J=5.0Hz,1H),7.89(dd,J=2.0,8.5Hz, 1H), 7.18 (d, J = 4.8Hz, 1H), 2.69-2.58 (m, 1H), 2.12 (s, 3H), 1.26-1.12 (m, 6H).

[1484] Step 11: Preparation of compounds 31-12

[1485]

[1486] Compound 31-11 (0.8 g, 1.87 mmol), 7-1 (579.10 mg, 2.24 mmol), and N,N-diisopropylethylamine (362.17 mg, 2.80 mmol, 488.10 μL) were dissolved in tetrahydrofuran (10 mL), and the system was heated to 70 °C and stirred for 20 h. The system was concentrated to obtain a crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–40%) to obtain compound 31-12.

[1487] MS(ESI)m / z(M+H) + =650.1.

[1488] 1 H NMR (400MHz, CHLOROFORM-d) δ = 8.60 (dd, J = 2.1, 4.9Hz, 1H), 8.15-7.76 (m, 1H), 7.15 (dd, J = 5.1, 6.7Hz, 1H), 4.60-4.41 (m, 2H), 4.31 (br s, 1H), 4.00 (br s,1H),3.81(d,J=1.0Hz,3H),3.63-3.48(m,1H),3.24-3.07(m,1H),2.77-2.55(m,1H ),2.10-2.02(m,3H),1.51(d,J=1.3Hz,9H),1.35(t,J=6.0Hz,3H),1.25-1.13(m,6H)

[1489] Step 12: Preparation of compounds 31-13

[1490]

[1491] Compound 31-12 (0.9 g, 1.38 mmol) and iron powder (231.95 mg, 4.15 mmol) were dissolved in acetic acid (15 mL). The system was heated to 85 °C and stirred for 1 h under a nitrogen atmosphere. The system was filtered through diatomaceous earth, the filtrate was concentrated, the residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate, and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to give compound 31-13. This compound was used directly in the next reaction without further purification.

[1492] MS(ESI)m / z(M+H) + =588.1.

[1493] Step 13: Preparation of compound 28-4

[1494]

[1495] Compound 31-13 (800 mg, 1.36 mmol) and potassium carbonate (376.04 mg, 2.72 mmol) were dissolved in acetone (10 mL). Iodomethane (1.93 g, 13.60 mmol, 846.92 μL) was added at room temperature (20 °C). After the addition was complete, the system was heated to 40 °C and stirred for 16 h under a nitrogen atmosphere. The system was then cooled to room temperature, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–50%) to give compound 28-4.

[1496] 1 H NMR (400MHz, CHLOROFORM-d) δ = 8.62 (d, J = 5.0Hz, 1H), 7.59 (br d, J = 9.0Hz, 1H), 7.17 (dd, J = 4.8, 15.8Hz, 1H), 4.90 (br d,J=12.3Hz,1H),4.64-4.29(m,1H),3.55-3.38(m,4H),3.14-2.92(m,2H),2 .88-2.35(m,1H),2.21-2.00(m,3H),1.45-1.59(m,12H),1.26-1.01(m,6H).

[1497] Step 14: Preparation of compounds 31-14

[1498]

[1499] Compound 28-4 (100 mg, 166.09 μmol), o-fluorophenylboronic acid (46.48 mg, 332.19 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (13.89 mg, 16.61 μmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (7.75 mg, 16.61 μmol), and potassium carbonate (45.91 mg, 332.19 μmol) were dissolved in a mixed solution of dioxane (1 mL) and water (0.1 mL). The system was heated to 100 °C and stirred for 5 h under a nitrogen atmosphere. The system was concentrated to obtain a crude product, which was then purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–40%) to obtain compound 31-14.

[1500] MS(ESI)m / z(M+H) + =662.6.

[1501] Step 15: Preparation of compounds 31-15

[1502]

[1503] Compound 31-14 (100 mg, 151.12 μmol) was dissolved in dichloromethane (1 mL), and dioxane hydrochloride solution (5 M, 5 mL) was added. After the addition was complete, the system was stirred at room temperature (25 °C) for 2 h. The system was concentrated to obtain compound 31-15, which was used directly in the next reaction without further purification.

[1504] MS(ESI)m / z(M+H) + =562.1.

[1505] Step 16: Preparation of Compound 31

[1506]

[1507] Compound 31-15 (90 mg, 150.49 μmol, hydrochloride) was dissolved in an aqueous solution (5 mL) of tetrahydrofuran (5 mL) and sodium bicarbonate (63.21 mg, 752.44 μmol), and a tetrahydrofuran solution of acrylic anhydride (0.5 M, 361.17 μL) was added dropwise. After the addition was complete, the system was reacted at room temperature (20 °C) for 1 h. The system was quenched with methanol (0.1 mL), extracted with ethyl acetate (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by high-performance liquid chromatography (HPLC) (separation conditions: Phenomenex Gemini-NX column 80*30 mm*3 μm, mobile phase: water (10 mM ammonium bicarbonate)-acetonitrile; acetonitrile 46%-76% 9 min) to obtain compound 31.

[1508] MS(ESI)m / z(M+H) + =616.4.

[1509] Step 17: Preparation of compounds 31A and 31B

[1510]

[1511] The diastereomer compound 31 was purified by SFC (Phenomenex-Cellulose-2 (250mm*30mm, 10μm); mobile phase: [CO2-methanol (0.1% ammonia)]; methanol %: 50%). After concentration, compounds 31A and 31B were obtained.

[1512] Compound 31A:

[1513] 1H NMR (400MHz, METHANOL-d4) δ = 8.48 (d, J = 4.8Hz, 1H), 7.74 (d, J = 8.5Hz, 1H), 7.49 (s, 1H), 7.41-7.12 (m, 5H), 6.33-6.18 (m, 1H), 5.90-5.74 (m, 1H) ),4.78(m,2H),4.04-3.85(m,2H),3.52-3.45(m,4H),3.04-2.87(m,1H) ,2.58-2.52(m,1H),2.23(s,3H),1.77-1.63(m,3H),1.20-1.03(m,6H).

[1514] MS(ESI)m / z(M+H) + =616.2

[1515] The HPLC retention time was 4.12 min.

[1516] Separation conditions: Column: WELCH Ultimate LP-C18 150*4.6mm, 5μm; Column temperature: 40℃; Mobile phase: Water (0.0688% trifluoroacetic acid solution) - acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10%-80% for 10 min, 80% for 5 min; Flow rate: 1.5 mL / min

[1517] SFC retention time: 5.115 min.

[1518] Separation conditions: Column: Cellulose 2 150*4.6mm ID, 5μm; Column temperature: 35℃; Mobile phase: CO2-methanol (0.05% DEA); Methanol: 40%-40%; Flow rate: 2.5mL / min.

[1519] Compound 31B:

[1520] 1 H NMR (400MHz, METHANOL-d4) δ = 8.47 (d, J = 4.8Hz, 1H), 7.75 (d, J = 9.5Hz, 1H), 7.56-7.47 (m, 1H), 7.42-7.03 (m, 5H), 6.33-6.22 (m, 1H), 5.88-5.77 ( m,1H),4.82-4.50(m,2H),4.01-3.85(m,2H),3.53-4.35(m,4H),3.09-2 .89(m,2H),2.00(d,J=6.0Hz,3H),1.76-1.64(m,3H),1.29-1.13(m,6H).

[1521] MS(ESI)m / z(M+H) + =616.2.

[1522] HPLC retention time: 4.11 min.

[1523] Separation conditions: Column: WELCH Ultimate LP-C18 150*4.6mm, 5μm; Column temperature: 40℃; Mobile phase: Water (0.0688% trifluoroacetic acid solution) - acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10%-80% for 10 min, 80% for 5 min; Flow rate: 1.5 mL / min

[1524] SFC retention time: 7.223 min

[1525] Separation conditions: Column: Cellulose 2 150*4.6mm ID, 5μm; Column temperature: 35℃; Mobile phase: CO2-methanol (0.05% DEA); Methanol: 40%-40%; Flow rate: 2.5mL / min.

[1526] Example 32: Preparation of compound 32

[1527] Step 1: Preparation of compound 32-2

[1528]

[1529] Compound 28-4 (120 mg, 199.31 μmol), compound 32-1 (70.15 mg, 398.62 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (16.67 mg, 19.93 μmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (9.30 mg, 19.93 μmol), and potassium carbonate (55.09 mg, 398.62 μmol) were dissolved in a mixed solution of dioxane (1 mL) and water (0.1 mL). The system was heated to 100 °C and stirred for 5 h under a nitrogen atmosphere. The system was concentrated to obtain a crude product, which was then purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–60%) to obtain compound 32-2.

[1530] MS(ESI)m / z(M+H) + =698.3.

[1531] Step 2: Preparation of compound 32-3

[1532]

[1533] Compound 32-2 (102 mg, 146.18 μmol) was dissolved in dichloromethane (1 mL), and dioxane hydrochloride solution (5 M, 5 mL) was added. After the addition was complete, the system was stirred at room temperature (25 °C) for 2 h. The system was concentrated to obtain compound 32-3, which was used directly in the next reaction without further purification.

[1534] MS(ESI)m / z(M+H) + =598.1.

[1535] Step 3: Preparation of compound 32

[1536]

[1537] Compound 32-3 (92 mg, 145.08 μmol, hydrochloride) was dissolved in an aqueous solution (5 mL) of tetrahydrofuran (5 mL) and sodium bicarbonate (121.88 mg, 1.45 mmol) (5 mL). A tetrahydrofuran solution of acrylic anhydride (0.5 M, 377.21 μL) was then added dropwise. After the addition was complete, the system was reacted at room temperature (20 °C) for 2 h. The system was quenched with methanol (0.1 mL), extracted with ethyl acetate (5 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by high-performance liquid chromatography (HPLC) (separation conditions: Phenomenex Gemini-NX column 80*30 mm*3 μm, mobile phase: water (10 mM ammonium bicarbonate)-acetonitrile; acetonitrile 39%-69% 9 min) to obtain compounds 32A, 32B, 32C, and 32D.

[1538] Compound 32A:

[1539] 1 H NMR (400MHz, METHANOL-d4) δ = 8.41 (d, J = 5.0Hz, 1H), 7.82 (d, J = 8.0Hz, 1H), 7.55 (d, J = 9.0 Hz,1H),7.46(s,1H),7.37(d,J=8.5Hz,1H),7.28(d,J=5.3Hz,1H),7.20-6.74(m,1H),6.2 7(d,J=18.8Hz,1H),5.90-5.74(m,1H),4.82-4.50(m,2H),4.07-3.91(m,2H),3.52-3.45( m,4H),2.99-2.60(m,2H),2.23(s,1H),2.18(s,3H),1.78-1.65(m,3H),1.20-0.97(m,6H).

[1540] MS(ESI)m / z(M+H) + =652.2.

[1541] The HPLC retention time was 3.49 min.

[1542] Separation conditions: Column: WELCH Ultimate LP-C18 150*4.6mm, 5μm; Column temperature: 40℃; Mobile phase: Water (0.0688% trifluoroacetic acid solution) - acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10%-80% for 10 min, 80% for 5 min; Flow rate: 1.5 mL / min

[1543] Compound 32B:

[1544] 1 H NMR (400MHz, METHANOL-d4) δ = 8.42 (d, J = 4.8Hz, 1H), 7.82 (d, J = 8.0Hz, 1H), 7.55 (d, J = 8. 8Hz,1H),7.48(s,1H),7.37(d,J=8.5Hz,1H),7.23(d,J=4.8Hz,1H),7.20-6.80(m,1H),6 .33-6.24(m,1H),5.88-5.79(m,1H),4.82-4.50(m,2H),4.04-3.85(m,2H),3.54-3.37(m ,4H),3.10-2.90(m,2H),2.19(s,3H),2.05(s,3H),1.77-1.66(m,3H),1.27-1.12(m,6H).

[1545] MS(ESI)m / z(M+H) + =652.2.

[1546] HPLC retention time: 3.53 min.

[1547] Separation conditions: Column: WELCH Ultimate LP-C18 150*4.6mm, 5μm; Column temperature: 40℃; Mobile phase: Water (0.0688% trifluoroacetic acid solution) - acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10%-80% for 10 min, 80% for 5 min; Flow rate: 1.5 mL / min.

[1548] Compound 32C:

[1549] 1H NMR (400MHz, METHANOL-d4) δ = 8.43 (d, J = 5.0Hz, 1H), 7.80 (d, J = 9.5Hz, 1H), 7.59-7. 48(m,2H),7.38(d,J=8.5Hz,1H),7.25(d,J=5.3Hz,1H),7.21-6.83(m,1H),6.29-6.2 5(m,1H),5.88-5.78(m,1H),4.82-4.50(m,2H),4.03-3.86(m,2H),3.54-3.39(m,4H) ,3.15-2.90(m,2H),2.18(s,3H),2.01(s,3H),1.77-1.66(m,3H),1.30-1.07(m,6H).

[1550] MS(ESI)m / z(M+H) + =652.2.

[1551] The HPLC retention time was 3.66 min.

[1552] Separation conditions: Column: WELCH Ultimate LP-C18 150*4.6mm, 5μm; Column temperature: 40℃; Mobile phase: Water (0.0688% trifluoroacetic acid solution) - acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10%-80% for 10 min, 80% for 5 min; Flow rate: 1.5 mL / min.

[1553] Compound 32D:

[1554] 1 H NMR (400MHz, METHANOL-d4) δ = 8.42 (d, J = 5.0Hz, 1H), 7.80 (d, J = 10.0Hz, 1H), 7.58-7.50 (m ,2H),7.37(d,J=8.5Hz,1H),7.26(d,J=4.8Hz,1H),7.18-7.12(m,1H),6.35-6.21(m,1H), 5.91-5.75(m,1H),4.82-4.50(m,2H),4.07-3.87(m,2H),3.50-3.38(m,4H),2.99-2.87(m ,1H),2.72-2.51(m,1H),2.26(s,3H),2.18(s,3H),1.79-1.65(m,3H),1.19-0.96(m,6H).

[1555] MS(ESI)m / z(M+H) + =652.2.

[1556] HPLC retention time: 3.70 min

[1557] Separation conditions: Column: WELCH Ultimate LP-C18 150*4.6mm, 5μm; Column temperature: 40℃; Mobile phase: Water (0.0688% trifluoroacetic acid solution) - acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10%-80% for 10 min, 80% for 5 min; Flow rate: 1.5 mL / min.

[1558] Example 33: Preparation of compound 33

[1559] Step 1: Preparation of compound 33-2

[1560]

[1561] Compound 28-4 (100 mg, 166.09 μmol), compound 33-1 (68.15 mg, 249.14 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (13.89 mg, 16.61 μmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (7.75 mg, 16.61 μmol), and potassium carbonate (68.86 mg, 498.27 μmol) were dissolved in a mixed solution of dioxane (2 mL) and water (0.2 mL). The system was heated to 100 °C and stirred for 5 h under a nitrogen atmosphere. The system was concentrated to obtain a crude product, which was then purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0–30%) to obtain compound 33-2.

[1562] MS(ESI)m / z(M+H) + =677.3.

[1563] Step 2: Preparation of compound 33-3

[1564]

[1565] Compound 33-2 (95 mg, 140.38 μmol) was dissolved in dichloromethane (1 mL), and dioxane hydrochloride solution (5 M, 5 mL) was added. After the addition was complete, the system was stirred at room temperature (25 °C) for 2 h. The system was concentrated to obtain compound 33-3, which was used directly in the next reaction without further purification.

[1566] MS(ESI)m / z(M+H) + =577.2.

[1567] Step 3: Preparation of compound 33

[1568]

[1569] Compound 33-3 (90 mg, 146.80 μmol, hydrochloride) was dissolved in an aqueous solution (5 mL) of tetrahydrofuran and sodium bicarbonate (12.33 mg, 146.80 μmol), and a tetrahydrofuran solution of acrylic anhydride (0.5 M, 352.32 μL) was added dropwise. After the addition was complete, the system was reacted at room temperature (20 °C) for 2 h. The system was quenched with methanol (0.1 mL), extracted with ethyl acetate (5 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by high-performance liquid chromatography (HPLC) (separation conditions: Phenomenex Gemini-NX column 80*30 mm*3 μm, mobile phase: water ...

Claims

1. The compound represented by formula (I-B), its optical isomers and pharmaceutically acceptable salts thereof, wherein, R 1 、R 2 are each independently selected from H, halogen, and C 1-6 alkyl, where the C 1-6 alkyl is optionally substituted with 1, 2, or 3 R; R 3 Selected from H, halogen, OH, NH 2 , CN, C 1-6 alkyl, C 1-6 heteroalkyl, 3- to 6-membered heterocycloalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl-O- and C 3-6 cycloalkyl-O-, said C 1-6 alkyl, C 1-6 heteroalkyl, 3- to 6-membered heterocycloalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl-O- or C 3-6 cycloalkyl-O- is optionally substituted by 1, 2 or 3 R; R 4 are each independently selected from H, halogen, OH, NH 2 , CN, C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl, 3- to 6-membered hetero cycloalkyl, phenyl, 5- to 10-membered heteroaryl, phenyl-fused 5- to 6-membered hetero cycloalkyl, and 5- to 6-membered heteroaryl-fused 5- to 6-membered hetero cycloalkyl, wherein the C 1-6 alkyl, C 1- 6 heteroalkyl, C 3-6 cycloalkyl, 3- to 6-membered hetero cycloalkyl, phenyl, 5- to 10-membered heteroaryl, phenyl-fused 5- to 6-membered hetero cycloalkyl or 5- to 6-membered heteroaryl-fused 5- to 6-membered hetero cycloalkyl is optionally substituted with 1, 2 or 3 R's; R 5 selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, 5- to 6-membered heterocycloalkyl-C 1-3 alkyl-, 3- to 8-membered heterocycloalkyl, phenyl, naphthyl, 5- to 10-membered heteroaryl, phenyl-fused 5- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl-fused 5- to 6-membered heterocycloalkyl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, 5- to 6-membered heterocycloalkyl-C 1-3 alkyl-, 3- to 8-membered heterocycloalkyl, phenyl, naphthyl, 5- to 10-membered heteroaryl, phenyl-fused 5- to 6-membered heterocycloalkyl or 5- to 6-membered heteroaryl-fused 5- to 6-membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R; L 1 Selected from -C(=O)-, -S(=O)- and -S(=O) 2 -; R 6 selected from H, CN, C 1-6 alkyl, C 1-6 alkyl-S(=O) 2 -, 3- to 6-membered heterocycloalkyl, -C 1-6 alkyl-3- to 6-membered heterocycloalkyl and C 3-6 cycloalkyl-C(=O)-, wherein the C 1-6 alkyl, C 1-6 alkyl-S(=O) 2 -, 3- to 6-membered heterocycloalkyl, -C 1-6 alkyl-3- to 6-membered heterocycloalkyl or C 3-6 cycloalkyl-C(=O)- is optionally substituted with 1, 2 or 3 R; R 7 each independently selected from H, halogen, OH, NH 2 , CN, -C(=O)-OH, C 1-6 alkyl-O-C(=O)--, -C(=O)-NH 2 , C 1-6 alkyl, C 1-6 heteroalkyl and -C 1-6 alkyl-3- to 6-membered heteroalkyl, wherein the C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 alkyl-O-C(=O)- or -C 1-6 alkyl-3- to 6-membered heteroalkyl is optionally substituted by 1, 2 or 3 R; T 1 and T 2 are each independently selected from N and -C(R 8 ); R 8 selected from H, halogen, OH, NH 2 , CN, C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl and 3- to 6-membered hetero cycloalkyl, wherein the C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl or 3- to 6-membered hetero cycloalkyl is optionally substituted by 1, 2 or 3 R; R 9 Selected from H, halogen, OH, NH 2 , CN, C 1-6 alkyl, and C 1-6 heteroalkyl, wherein the C 1-6 alkyl or C 1-6 heteroalkyl is optionally substituted by 1, 2 or 3 R; R 10 Selected from H, halogen, CN, C 1-6 alkyl, C 1-6 alkoxy and C 1-6 alkylamino, wherein the C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkylamino is optionally is optionally substituted by 1, 2 or 3 R; R is independently selected from H, halogen, OH, NH 2 , CN, C 1-6 alkyl, C 1- 6 heteroalkane, C 3-6 cycloalkyl, 5- to 6-membered heteroalkyl, C 3-6 cycloalkyl-O- and 5- to 6-membered heteroalkyl-O-, wherein the C 1-6 alkyl, C 1-6 heteroalkane, C 3-6 cycloalkyl, 5- to 6-membered heteroalkyl, C 3-6 cycloalkyl-O- or 5- to 6-membered heteroalkyl-O- is optionally substituted by 1, 2 or 3 R's; R’ is selected from F, Cl, Br, I, OH, NH 2 and CH 3 ; Ring A is independently selected from C 6-10 aryl, 5- to 10-membered heteroaryl, phenyl-fused 5- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl-fused 5- to 6-membered heterocycloalkyl; n is selected from 0, 1, 2, 3 or 4; m is selected from 0, 1, 2, 3 or 4; D 1 selected from O; Y is selected from N, CH or C; For And when For When R 2 and R 10 do not exist; For When China For When, X 1 , X 2 are each independently selected from -N=, -C(R 7 )= and -C(R 7 ) 2 -C(R 7 )=; When China For When X 1 and X 2 are each independently selected from a single bond, -O-, -S-, S(=O), S(=O) 2 , -N(R 6 ), -, -C(=O)-, -C(R 7 ), 2 -, and -C(R 7 ), 2 -C(R 7 ), 2 -; Moreover, Y cannot be connected to two at the same time When Y and R 9 the key between them is When R 9 does not exist; The above-mentioned 3- to 6-membered heteroalkyl group, 5- to 6-membered heteroaryl group, 5- to 6-membered heteroalkyl group, 5- to 10-membered heteroaryl group or C 1-6 The heteroalkyl group contains 1, 2 or 3 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=O) 2 - and N.

2. The compound represented by formula (I-A), its optical isomers and pharmaceutically acceptable salts thereof, wherein, R 1 and R 2 are each independently selected from H, halogen, and C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1, 2, or 3 R; R 3 selected from H, halogen, OH, NH 2 , CN, C 1-6 alkyl, C 1-6 heteroalkyl, 3- to 6-membered heterocycloalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl-O-, and C 3-6 cycloalkyl-O-, wherein the C 1-6 alkyl, C 1-6 heteroalkyl, 3- to 6-membered heterocycloalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl-O-, or C 3-6 cycloalkyl-O- is optionally substituted with 1, 2, or 3 R; R 4 each independently selected from H, halogen, OH, NH 2 , CN, C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl, 3- to 6-membered heteroalkyl, phenyl, 5- to 10-membered heteroaryl, phenyl-fused 5- to 6-membered heteroalkyl, and 5- to 6-membered heteroaryl-fused 5- to 6-membered heteroalkyl, wherein the C 1-6 alkyl, C 1- 6 heteroalkyl, C 3-6 cycloalkyl, 3- to 6-membered heteroalkyl, phenyl, 5- to 10-membered heteroaryl, phenyl-fused 5- to 6-membered heteroalkyl or 5- to 6-membered heteroaryl-fused 5- to 6-membered heteroalkyl is optionally substituted with 1, 2 or 3 R's; R 5 selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, 5- to 6-membered heteroalkyl-C 1-3 alkyl-, 3- to 8-membered heteroalkyl, phenyl, naphthyl, 5- to 10-membered heteroaryl, phenyl-fused 5- to 6-membered heteroalkyl, and 5- to 6-membered heteroaryl-fused 5- to 6-membered heteroalkyl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, 5- to 6-membered heteroalkyl-C 1-3 alkyl-, 3- to 8-membered heteroalkyl, phenyl, naphthyl, 5- to 10-membered heteroaryl, phenyl-fused 5- to 6-membered heteroalkyl or 5- to 6-membered heteroaryl-fused 5- to 6-membered heteroalkyl is optionally substituted with 1, 2 or 3 R; L 1 Selected from -C(=O)-, -S(=O)-, and -S(=O) 2 -; R 6 selected from H, CN, C 1-6 alkyl, C 1-6 alkyl-S(=O) 2 -, 3- to 6-membered heterocycloalkyl, -C 1-6 alkyl-3- to 6-membered heterocycloalkyl and C 3-6 cycloalkyl-C(=O)-, wherein the C 1-6 alkyl, C 1-6 alkyl-S(=O) 2 -, 3- to 6-membered heterocycloalkyl, -C 1-6 alkyl-3- to 6-membered heterocycloalkyl or C 3-6 cycloalkyl-C(=O)- is optionally substituted with 1, 2 or 3 R; R 7 each independently selected from H, halogen, OH, NH 2 , CN, -C(=O)OH, C 1-6 alkyl-O-C(=O)-, -C(=O)-NH 2 , C 1-6 alkyl, C 1-6 heteroalkyl and -C 1-6 alkyl-3- to 6-membered heteroalkyl, wherein the C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 alkyl-O-C(=O)- or -C 1-6 alkyl-3- to 6-membered heteroalkyl is optionally substituted by 1, 2 or 3 R; T 1 and T 2 are each independently selected from N and -C(R 8 )-; R 8 selected from H, halogen, OH, NH 2 , CN, C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl and 3- to 6-membered heteroalkyl, wherein the C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl or 3- to 6-membered heteroalkyl is optionally substituted by 1, 2 or 3 R; R is independently selected from H, halogen, OH, NH 2 , CN, C 1-6 alkyl, C 1-6 heterocycle, C 3-6 cycloalkyl, 5- to 6-membered heterocycloalkyl, C 3-6 cycloalkyl-O- and 5- to 6-membered heterocycloalkyl-O-, wherein the C 1-6 alkyl, C 1-6 heterocycle, C 3-6 cycloalkyl, 5- to 6-membered heterocycloalkyl, C 3-6 cycloalkyl-O- or 5- to 6-membered heterocycloalkyl-O- is optionally substituted by 1, 2 or 3 R's; R’ is selected from F, Cl, Br, I, OH, NH 2 and CH 3 ; Ring A is independently selected from C 6-10 aryl, 5- to 10-membered heteroaryl, phenyl-fused 5- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl-fused 5- to 6-membered heterocycloalkyl; n is selected from 0, 1, 2, 3 or 4; For And when For When R 2 does not exist; For When China For When X 1 and X 2 are each independently selected from -N=, -C(R 7 )= and -C(R 7 ) 2 -C(R 7 )=; When China For When X 1 and X 2 are each independently selected from a single bond, -O-, -S-, S(=O), S(=O) 2 , -N(R 6 ), -, -C(=O)-, -C(R 7 ), 2 - and -C(R 7 ), 2 -C(R 7 ), 2 -; The above-mentioned 3- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, 5- to 6-membered heterocycloalkyl, 5- to 10-membered heteroaryl or C 1-6 The heterocycloalkyl contains 1, 2 or 3 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=O) 2 - and N.

3. The compound, its optical isomers and pharmaceutically acceptable salts thereof according to claim 1 or 2, which are selected from wherein, X 1 and X 2 are each independently selected from a single bond, -O-, -S-, S(=O), S(=O) 2 (R 6 ), -N(R 7 ), -C(=O)-, -C(R 2 )(R 7 ), -C(R 2 )(R 7 )(R 2 ), where R 1 , R 2 , R 3 , R 4 , R 5 , L 1 , R 6 , R 7 , T 1 , T 2 , ring A and n are as defined in claim 1 or 2.

4. The compound, its optical isomers and pharmaceutically acceptable salts thereof according to claim 3, wherein, R is independently selected from H, halogen, OH, NH 2 , CN, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 alkylamino, C 3-6 cycloalkyl, 5- to 6-membered heterocycloalkyl, C 3-6 cycloalkyl-O- and -5- to 6-membered heterocycloalkyl-O-, wherein the C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 alkylamino, C 3-6 cycloalkyl, 5- to 6-membered heterocycloalkyl, C 3-6 cycloalkyl-O- or 5- to 6-membered heterocycloalkyl-O- is optionally substituted by 1, 2 or 3 R'.

5. The compound, its optical isomers and pharmaceutically acceptable salts thereof according to claim 4, wherein, R is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, Me, CH 2 CH 3 , 6. The compound, its optical isomers and pharmaceutically acceptable salts thereof according to claim 1 or 2, wherein, R 1 、R 2 are each independently selected from H, F, Me, CF 3 , 7. The compound, its optical isomers and pharmaceutically acceptable salts thereof according to claim 6, wherein, Structural unit 8. The compound, its optical isomers and pharmaceutically acceptable salts thereof according to claim 1 or 2, wherein, R 3 selected from H, halogen, OH, NH 2 , CN, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, C 1-3 alkylthio, 3- to 6-membered heterocycloalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl-O-, and C 3-6 cycloalkyl-O-, wherein the C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, C 1-3 alkylthio, 3- to 6-membered heterocycloalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl-O-, or C 3-6 cycloalkyl-O- is optionally substituted with 1, 2 or 3 R.

9. The compound, its optical isomers and pharmaceutically acceptable salts thereof according to claim 8, wherein, R 3 selected from H, F, Cl, Br, I, OH, NH 2 , CN, Me, CF 3 , 10. The compound, its optical isomers and pharmaceutically acceptable salts thereof according to claim 1 or 2, wherein, R 4 each independently selected from H, halogen, OH, NH 2 , CN, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, C 1-3 alkylthio, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, pyridyl, pyrimidinyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, benzofuranyl, benzothienyl and indolyl, and the C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, C 1-3 alkylthio, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, pyridyl, pyrimidinyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, benzofuranyl, benzothienyl or indolyl is optionally substituted with 1, 2 or 3 R groups.

11. The compound, its optical isomers and pharmaceutically acceptable salts thereof according to claim 10, wherein, R 4 Selected from H, F, Cl, Br, I, OH, NH 2 , CN, Me, CF 3 , 12. The compound, its optical isomers and pharmaceutically acceptable salts thereof according to claim 1 or 2, wherein, Ring A is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, benzofuranyl, benzothienyl, indolyl, indazolyl, benzimidazolyl, 1H-benzo[d]imidazolyl, benzopyrazolyl, purinyl, quinolinyl, isoquinolinyl, isoquinolin-1(2H)-one, isoindolin-1-one, benzo[d]oxazol-2(H)-one, benzo[d]oxazol-2(3H)-one, H-benzo[d][1,2,3]triazolyl, 1H-pyrazolo[3,4-b]pyridyl, benzo[d]thiazolyl and 1,3-dihydro-2H-benzo[d]imidazol-2-one, and the phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, benzofuranyl, benzothienyl, indolyl, indazolyl, benzimidazolyl, 1H-benzo[d]imidazolyl, benzopyrazolyl, purinyl, quinolinyl, isoquinolinyl, isoquinolin-1(2H)-one, isoindolin-1-one, benzo[d]oxazol-2(H)-one, benzo[d]oxazol-2(3H)-one, H-benzo[d][1,2,3]triazolyl, 1H-pyrazolo[3,4-b]pyridyl, benzo[d]thiazolyl or 1,3-dihydro-2H-benzo[d]imidazol-2-one is optionally substituted by 1, 2 or 3 R groups.

13. The compound according to claim 12, its optical isomers and its pharmaceutically acceptable salts, wherein, Structural unit selected from 14. The compound according to claim 1 or 2, its optical isomers and its pharmaceutically acceptable salts, wherein, R 5 selected from H, C 1-3 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydro-2H-pyranyl, piperidinyl, piperazinyl, 5- to 6-membered heterocycloalkyl-C 1-3 alkyl-, phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, benzofuranyl, benzothienyl, indolyl, benzimidazolyl, benzopyrazolyl, purinyl, quinolinyl, isoquinolinyl, isoquinolin-1(2H)-one, isoindolin-1-one, benzo[d]oxazol-2(H)-one and 1,3-dihydro-2H-benzo[d]imidazol-2-one, wherein the C 1-3 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydro-2H-pyranyl, piperidinyl, piperazinyl, 5- to 6-membered heterocycloalkyl-C 1-3 alkyl-, phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, benzofuranyl, benzothienyl, indolyl, benzimidazolyl, benzopyrazolyl, purinyl, quinolinyl, isoquinolinyl, isoquinolin-1(2H)-one, isoindolin-1-one, benzo[d]oxazol-2(H)-one or 1,3-dihydro-2H-benzo[d]imidazol-2-one is optionally substituted by 1, 2 or 3 R.

15. The compound according to claim 14, its optical isomers and its pharmaceutically acceptable salts, wherein, R 5 selected from H, Me, 16. The compound according to claim 1 or 2, its optical isomers and its pharmaceutically acceptable salts, wherein, R 7 each independently selected from H, halogen, OH, NH 2 , CN, C 1-3 alkyl, C 1-3 alkyl-O-C(=O)-, -C(=O)-NH 2 , C 1-3 alkoxy, C 1-3 alkylamino, C 1- 3 alkylthio and -C 1-3 alkyl-3- to 6-membered heterocycloalkyl, wherein the C 1-3 alkyl, C 1-3 alkyl-O-C(=O)-, -C(=O)-NH 2 , C 1-3 alkoxy, C 1-3 alkylamino, C 1-3 alkylthio or -C 1-3 alkyl-3- to 6-membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R.

17. The compound according to claim 16, its optical isomers and its pharmaceutically acceptable salts, wherein, R 7 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, Me, CF 3 , 18. The compound according to claim 1 or 2, its optical isomers and its pharmaceutically acceptable salts, wherein, R 6 each independently selected from H, CN, C 1-3 alkyl, C 1-3 alkyl-S(=O) 2 -, 3- to 6-membered heterocycloalkyl, -C 1-3 alkyl-3- to 6-membered heterocycloalkyl and C 3-6 cycloalkyl-C(=O)-, wherein the C 1-3 alkyl, C 1-3 alkyl-S(=O) 2 -, 3- to 6-membered heterocycloalkyl, -C 1-3 alkyl 3- to 6-membered heterocycloalkyl or C 3-6 cycloalkyl-C(=O)- is optionally substituted by 1, 2 or 3 R.

19. The compound according to claim 18, its optical isomers and its pharmaceutically acceptable salts, wherein, R 6 each independently selected from H, 20. The compound according to claim 18, its optical isomers and its pharmaceutically acceptable salts, wherein, X 1 and X 2 are each independently selected from a single bond, CH 2 , CH 2 CH 2 , C(=O), O, S, NH, N(CH 3 ), S(=O), S(=O) 2 , 21. The compound according to claim 1 or 2, its optical isomers and its pharmaceutically acceptable salts, wherein, R 8 Selected from H, halogen, OH, NH 2 , CN, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino and C 1-3 alkylthio, wherein the C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino or C 1-3 alkylthio is optionally substituted by 1, 2 or 3 R groups.

22. The compound according to claim 21, its optical isomers and its pharmaceutically acceptable salts, wherein, R 8 selected from H, F, Cl, Br, I, OH, NH 2 , CN, Me, CF 3 , 23. The compound according to claim 1, its optical isomers and its pharmaceutically acceptable salts, wherein, Structural unit 24. The compound of the following formula, its optical isomers and its pharmaceutically acceptable salts, 25. A pharmaceutical composition, said pharmaceutical composition comprising a compound as described in any one of claims 1 to 24, its optical isomers and pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

26. Use of a compound as described in any one of claims 1 to 24, its optical isomers and pharmaceutically acceptable salts thereof or a pharmaceutical composition as described in claim 25 for the preparation of a medicament for preventing and / or treating a disease related to KRAS-G12C.

27. Use according to claim 26, wherein the disease related to KRAS-G12C is selected from non-small cell lung cancer, colon cancer and pancreatic cancer.