Condensed pyridone compound as well as preparation method and application thereof

Abstract

The invention discloses a fused pyridone compound as well as a preparation method and application thereof, and particularly discloses a compound as shown in a formula (I-B), an optical isomer and pharmacologically acceptable salt thereof, and application of the compound as a KRAS inhibitor. # imgabs0 #

Description

[0001] The present invention claims the following priority:

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

[0003] CN201911129688.2, filed on November 18, 2019,

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

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

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

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

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

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

[0010] CN202010967317.8, application date is September 15, 2020.

[0011] This application is a divisional case of the Chinese invention patent with application date of September 21, 2020, application number 202080078771.6 (PCT / CN2020 / 116510), and name “Condensed pyridone compounds, preparation methods and applications thereof”. Technical Field

[0012] The present invention relates to a compound represented by formula (I-B), an optical isomer thereof and a pharmaceutically acceptable salt thereof, and use of the compound as a KRAS inhibitor. Background Art

[0013] About 30% of cancer patients have RAS gene mutations. In cancer gene research, scientists discovered more than 20 years ago that RAS 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, colorectal, and lung cancer) also happen to be the three most common cancers with RAS mutations, accounting for 95%, 52%, and 31% of patients with these three cancers, respectively. KRAS mutations are the overwhelming majority in pancreatic, colorectal, and lung cancers, while NRAS mutations are more common in melanoma and acute myeloid leukemia, and HRAS mutations are more common in bladder and head and neck cancers.

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

[0016] In lung adenocarcinoma, the probability of KRAS gene positivity accounts for 1 / 5-1 / 4, second only to the probability of EGFR positive mutations. The lack of targeted inhibitors makes both treatment and prognosis very difficult for patients with KRAS-positive non-small cell lung cancer. 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 on whether to use EGFR-TKI targeted drugs as clinical treatment measures will be based on the test results. If the KRAS gene is mutated, EGFR-TKI molecular targeted therapy is not recommended for patients.

[0017] According to the Thomson Reuters Competitive Intelligence Drug Database (Cortellis For CI), there are currently 162 drugs directly linked to the RAS gene / protein (data query date August 18, 2016). Among them, there are 18 small molecule drugs targeting KRAS, including 10 KRAS GTPase inhibitors, 4 KRAS gene inhibitors, 2 KRAS GTPase modulators, and 2 KRAS gene modulators. One such drug is currently in clinical development. Furthermore, the first KRAS inhibitor, Antrogen, has entered Phase II clinical trials with the US FDA, and AstraZeneca's selumetinib, an inhibitor targeting the KRAS downstream pathway MEK, is also in Phase II clinical trials. KRAS mutations are the most important tumor driver gene. These mutations account for a significant proportion of cases in pancreatic cancer, lung cancer, and colorectal cancer. Currently, there are no specific targeted drugs for this target. Therefore, this project has significant medical research and clinical application value, and will provide even greater medical benefits to the Chinese people. Develop a small molecule drug for KRAS-G12C, whose molecular mechanism has been basically elucidated, and the drug's molecular structure and pharmacodynamic effects have been verified under existing experimental conditions. It has high activity characteristics and the possibility of becoming a drug. Summary of the Invention

[0018] In the first aspect of the present invention, the present invention provides a compound represented by formula (I-B), an optical isomer thereof and a pharmaceutically acceptable salt thereof,

[0019]

[0020] in,

[0021] R1 and R2 are independently selected from H, halogen and C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with 1, 2 or 3 R groups;

[0022] R3 is selected from H, halogen, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl-O- and C 3-6 Cycloalkyl-O-, the C 1-6 Alkyl, C 1-6 Heteroalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl-O- or C 3-6 Cycloalkyl-O- is optionally substituted with 1, 2 or 3 R;

[0023] R4 are independently selected from H, halogen, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-10 membered heteroaryl, phenyl and 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl and 5-6 membered heterocycloalkyl, the 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 is optionally substituted by 1, 2 or 3 R groups;

[0024] R5 is selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, 5- to 6-membered heterocycloalkyl-C 1-3 Alkyl-, 3-8 membered heterocycloalkyl, phenyl, naphthyl, 5-10 membered heteroaryl, phenyl-5-6 membered heterocycloalkyl and 5-6 membered heteroaryl-5-6 membered heterocycloalkyl, the C 1-6 Alkyl, C 3-6 Cycloalkyl, 5- to 6-membered heterocycloalkyl-C 1-3 Alkyl-, 3-8 membered heterocycloalkyl, phenyl, naphthyl, 5-10 membered heteroaryl, phenyl-5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl-5-6 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R groups;

[0025] L1 is selected from -C(=O)-, -S(=O)- and -S(=O)2-;

[0026] R6 is 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)-, 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;

[0027] R7 are 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 heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Heteroalkyl C 1-6 Alkyl-OC(=O)- or -C 1-6Alkyl-3- to 6-membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R;

[0028] T1 and T2 are independently selected from N and -C(R8)-;

[0029] R8 is selected from H, halogen, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R;

[0030] R9 is selected from H, halogen, OH, NH2, CN, C 1-6 Alkyl and C 1-6 heteroalkyl, the C 1-6 Alkyl or C 1-6 Heteroalkyl is optionally substituted with 1, 2, or 3 R;

[0031] R 10 Selected from H, halogen, 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 Alkylamino is optionally substituted with 1, 2 or 3 R;

[0032] R are independently selected from H, halogen, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Heterocycloalkane, C 3-6 Cycloalkyl, 5- to 6-membered heterocycloalkyl, C 3-6 Cycloalkyl-O- and 5- to 6-membered heterocycloalkyl-O-, the C 1-6 Alkyl, C 1-6 Heterocycloalkane, 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;

[0033] R' is selected from F, Cl, Br, I, OH, NH2 and CH3;

[0034] Ring A is independently selected from C 6-10 Aryl, 5-10 membered heteroaryl, phenyl and 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl and 5-6 membered heterocycloalkyl;

[0035] n is selected from 0, 1, 2, 3 or 4;

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

[0037] D1 is selected from O;

[0038] Y is selected from N, CH or C;

[0039] for or , and when for When R2, R 10 does not exist;

[0040] for or

[0041] when middle for When X1 and X2 are independently selected from -N=, -C(R7)= and -C(R7)2-C(R7)=;

[0042] when middle for When X1 and X2 are independently selected from a single bond, -O-, -S-, S(=O), S(=O)2, -N(R6)-, -C(=O)-, -C(R7)2- and -C(R7)2-C(R7)2-;

[0043] And, Y cannot connect two , when the bond between Y and R9 is When , R9 does not exist;

[0044] The above 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 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.

[0045] In another aspect of the present invention, the present invention also provides a compound represented by formula (I-A), its optical isomers and pharmaceutically acceptable salts thereof,

[0046]

[0047] in,

[0048] R1 and R2 are independently selected from H, halogen and C 1-6 Alkyl, the C 1-6The alkyl group is optionally substituted with 1, 2 or 3 R groups;

[0049] R3 is selected from H, halogen, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl-O- and C 3-6 Cycloalkyl-O-, the C 1-6 Alkyl, C 1-6 Heteroalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl-O- or C 3-6 Cycloalkyl-O- is optionally substituted with 1, 2 or 3 R;

[0050] R4 are independently selected from H, halogen, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-10 membered heteroaryl, phenyl and 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl and 5-6 membered heterocycloalkyl, the 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 is optionally substituted by 1, 2 or 3 R groups;

[0051] R5 is selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, 5- to 6-membered heterocycloalkyl-C 1-3 Alkyl-, 3-8 membered heterocycloalkyl, phenyl, naphthyl, 5-10 membered heteroaryl, phenyl-5-6 membered heterocycloalkyl and 5-6 membered heteroaryl-5-6 membered heterocycloalkyl, the C 1-6 Alkyl, C 3-6 Cycloalkyl, 5- to 6-membered heterocycloalkyl-C 1-3 Alkyl-, 3-8 membered heterocycloalkyl, phenyl, naphthyl, 5-10 membered heteroaryl, phenyl-5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl-5-6 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R groups;

[0052] L1 is selected from -C(=O)-, -S(=O)- and -S(=O)2-;

[0053] R6 is 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 3-6Cycloalkyl-C(=O)-, 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;

[0054] R7 are 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 heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Alkyl-OC(=O)- or -C 1-6 Alkyl-3- to 6-membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R;

[0055] T1 and T2 are independently selected from N and -C(R8)-;

[0056] R8 is selected from H, halogen, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R;

[0057] R are independently selected from H, halogen, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Heterocycloalkane, C 3-6 Cycloalkyl, 5- to 6-membered heterocycloalkyl, C 3-6 Cycloalkyl-O- and 5- to 6-membered heterocycloalkyl-O-, the C 1-6 Alkyl, C 1-6 Heterocycloalkane, 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'; R' is selected from F, Cl, Br, I, OH, NH2 and CH3;

[0058] Ring A is independently selected from C 6-10 Aryl, 5-10 membered heteroaryl, phenyl and 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl and 5-6 membered heterocycloalkyl;

[0059] n is selected from 0, 1, 2, 3 or 4;

[0060] for or , and when for When , R2 does not exist;

[0061] for or;

[0062] when middle for When X1 and X2 are independently selected from -N=, -C(R7)= and -C(R7)2-C(R7)=;

[0063] when middle for When X1 and X2 are independently selected from a single bond, -O-, -S-, S(=O), S(=O)2, -N(R6)-, -C(=O)-, -C(R7)2- and -C(R7)2-C(R7)2-;

[0064] The above 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 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.

[0065] In some embodiments of the present invention, the above-mentioned compound, its optical isomers and pharmaceutically acceptable salts thereof are selected from

[0066]

[0067] in,

[0068] X1 and X2 are independently selected from a single bond, -O-, -S-, S(=O), S(=O)2, -N(R6)-, -C(=O)-, -C(R7)2- and -C(R7)2-C(R7)2-, and R1, R2, R3, R4, R5, L1, R6, R7, T1, T2, ring A and n are as defined above.

[0069] In some embodiments of the present invention, the above R are independently selected from H, halogen, OH, NH2, CN, C 1-3 Alkyl, C 1-3 Alkoxy, C1-3 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-, 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 The cycloalkyl-O- or 5- to 6-membered heterocycloalkyl-O- is optionally substituted with 1, 2 or 3 R's, and the other variables are as defined herein.

[0070] In some embodiments of the present invention, the above R are independently selected from H, F, Cl, Br, I, OH, NH2, CN, Me, CH2CH3,

[0071]

[0072] Other variables are as defined in the present invention.

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

[0074] In some embodiments of the present invention, the above structural unit Selected from and , other variables are as defined in the present invention.

[0075] In some embodiments of the present invention, the above R3 is selected from H, halogen, OH, NH2, CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 1-3 Alkylthio, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl-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 heterocycloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl-O- or C 3-6 Cycloalkyl-O- is optionally substituted with 1, 2 or 3 R groups, and the other variables are as defined herein.

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

[0077] In some embodiments of the present invention, the above R4 are independently selected from H, halogen, OH, NH2, CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 1-3 Alkylthio, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, pyridyl, pyrimidinyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, benzofuranyl, benzothienyl and indolyl, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 1-3 Alkylthio, C 3-6 Cycloalkyl, 3-6 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, and other variables are as defined herein.

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

[0079] In some embodiments of the present invention, the 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, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, 1H-benzo[d]imidazolyl, benzopyrazolyl, purinyl, Quinolinyl, isoquinolinyl, isoquinolin-1(2H)-onyl, isoindolin-1-onyl, benzo[d]oxazol-2(H)-onyl, benzo[d]oxazol-2(3H)-onyl, H-benzo[d][1,2,3]triazolyl, 1H-pyrazolo[3,4-b]pyridinyl, benzo[d]thiazolyl and 1,3-dihydro-2H-benzo[d]imidazol-2-onyl, the phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, benzofuranyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, 1H-benzo[d]imidazolyl, benzopyrazolyl, purinyl, quinolinyl, isoquinolinyl, isoquinolin-1(2H)- Keto, isoindolin-1-onyl, benzo[d]oxazol-2(H)-onyl, benzo[d]oxazol-2(3H)-onyl, H-benzo[d][1,2,3]triazolyl, 1H-pyrazolo[3,4-b]pyridinyl, benzo[d]thiazolyl or 1,3-dihydro-2H-benzo[d]imidazol-2-onyl is optionally substituted with 1, 2 or 3 R, and the other variables are as defined herein.

[0080] In some embodiments of the present invention, the above structural unit Selected from

[0081] Other variables are as defined in the present invention.

[0082] In some embodiments of the present invention, the above R5 is selected from H, C 1-3 Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydro-2H-pyranyl, piperidinyl, piperazinyl, 5-6 membered heterocycloalkyl-C 1-3alkyl-, 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)-onyl, isoindolin-1-onyl, benzo[d]oxazol-2(H)-onyl and 1,3-dihydro-2H-benzo[d]imidazol-2-onyl, said C 1-3 Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydro-2H-pyranyl, piperidinyl, piperazinyl, 5-6 membered heterocycloalkyl-C 1-3 Alkyl-, phenyl, naphthyl, pyridinyl, 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)-onyl, isoindolin-1-onyl, benzo[d]oxazol-2(H)-onyl or 1,3-dihydro-2H-benzo[d]imidazol-2-onyl is optionally substituted with 1, 2 or 3 R, and the other variables are as defined herein.

[0083] In some embodiments of the present invention, the above R5 is selected from H, Me, Other variables are as defined in the present invention.

[0084] In some embodiments of the present invention, the above R7 are independently selected from H, halogen, OH, NH2, CN, 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 heterocycloalkyl, 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 heterocycloalkyl group is optionally substituted with 1, 2, or 3 R groups, and the other variables are as defined herein.

[0085] In some embodiments of the present invention, the above R7 are independently selected from H, F, Cl, Br, I, OH, NH2, CN, Me, CF3, Other variables are as defined in the present invention.

[0086] In some embodiments of the present invention, the above R6 are 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)-, 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 heterocyclic alkyl or C 3-6 Cycloalkyl-C(=O)- is optionally substituted with 1, 2 or 3 R groups, and the other variables are as defined herein.

[0087] In some embodiments of the present invention, the above R6 are independently selected from H, CN, Me, CF3, Other variables are as defined in the present invention.

[0088] In some embodiments of the present invention, X1 and X2 are independently selected from a single bond, CH2, CH2CH2, C(=O), O, S, NH, N(CH3), S(=O), S(=O)2, Other variables are as defined in the present invention.

[0089] In some embodiments of the present invention, the above R8 is selected from H, halogen, OH, NH2, CN, 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 is optionally substituted with 1, 2 or 3 R groups, and the other variables are as defined herein.

[0090] In some embodiments of the present invention, the above R8 is selected from H, F, Cl, Br, I, OH, NH2, CN, Me, CF3, Other variables are as defined in the present invention.

[0091] In some embodiments of the present invention, the above structural unit Selected from

[0092]

[0093] Other variables are as defined in the present invention.

[0094] In another aspect of the present invention, the present invention also provides the following compounds, their optical isomers and pharmaceutically acceptable salts:

[0095]

[0096]

[0097]

[0098]

[0099]

[0100]

[0101]

[0102]

[0103]

[0104]

[0105]

[0106]

[0107]

[0108]

[0109]

[0110]

[0111]

[0112]

[0113]

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120]

[0121]

[0122]

[0123]

[0124]

[0125] In another aspect of the present invention, the present invention also provides a pharmaceutical composition, which contains the compound as described above, its optical isomers and pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0126] In another aspect of the present invention, the present invention also provides the use of the aforementioned compound, its optical isomers and pharmaceutically acceptable salts thereof, or the aforementioned pharmaceutical composition in the preparation of a drug for preventing and / or treating KRAS-G12C-related diseases.

[0127] In some embodiments of the present invention, the KRAS-G12C-related disease is selected from non-small cell lung cancer, colon cancer and pancreatic cancer.

[0128] Definition and Description

[0129] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as indefinite or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0130] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0131] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, prepared by reacting the compounds of the present invention with relatively nontoxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts, or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in neat solution or in 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, bisulfate, hydroiodic acid, phosphorous acid, and the like; and organic acid salts such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; and salts of amino acids (such as arginine) and organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and can be converted into either base or acid addition salts.

[0132] Pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. 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 of the two.

[0133] A hyphen ("-") that is not between two letters or symbols indicates the site of attachment of a substituent. For example, C 1-6 Alkylcarbonyl - refers to a C-alkyl group attached to the rest of the molecule through a carbonyl group. 1-6 However, when the attachment point of the substituent is obvious to those skilled in the art, for example, a halogen substituent, the "-" may be omitted.

[0134] When the group valence bond is marked with a dotted line When, for example, In the example, the wavy line indicates the point of attachment of the group to the rest of the molecule.

[0135] The compounds of the present invention may exist in specific geometric or stereoisomer or optical isomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of the present invention.

[0136] Unless otherwise indicated, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of one another.

[0137] Unless otherwise indicated, the term "cis-trans isomers" or "geometric isomers" arises from the inability to rotate freely about double bonds or single bonds forming ring carbon atoms.

[0138] Unless otherwise indicated, the term "diastereomer" refers to stereoisomers that have two or more chiral centers and that are not mirror images of each other.

[0139] Unless otherwise specified, use a solid wedge key. and dotted wedge key Indicates the absolute configuration of a stereocenter.

[0140] The compounds of the present invention may exist in specific forms. Unless otherwise indicated, the term "tautomer" or "tautomeric form" refers to isomers with different functional groups that are in dynamic equilibrium at room temperature and can quickly convert into each other. If tautomerism is possible (such as in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions that occur through proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence isomers (valencetautomers) include interconversions that occur through the reorganization of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-ene-2-one.

[0141] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute 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, deuterated drugs can be formed by replacing hydrogen with heavy hydrogen. The bond between deuterium and carbon is stronger than that between ordinary hydrogen and carbon. Compared to undeuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, enhanced therapeutic efficacy, and prolonged biological half-life. All isotopic variations of the compounds of this invention, whether radioactive or not, are encompassed by this invention. "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs as well as instances where it does not.

[0142] Stereochemical definitions and conventions can be followed 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 optically active forms, that is, they have the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule about its chiral center. The prefixes d and l or (+) and (-) are used to indicate the sign of rotation of plane-polarized light by the compound, where (-) or l indicates that the compound is left-handed. Compounds with a prefix of (+) or d are right-handed. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often referred to as an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers that are optically inactive.

[0143] The racemic mixture can be used as such or resolved into its individual isomers. Resolution can yield a stereochemically pure compound or a mixture enriched in one or more isomers. Methods for separating isomers are well known (see Allinger N.L. and Eliel EL, "Topics in Stereochemistry," Vol. 6, Wiley Interscience, 1971), and include physical methods such as chromatography using chiral adsorbents. Individual isomers can be prepared in chiral form from chiral precursors. Alternatively, the individual isomers can be chemically separated from the mixture by forming diastereomeric salts with chiral acids (e.g., individual enantiomers of 10-camphorsulfonic acid, camphoric acid, α-bromocamphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, etc.), fractionally crystallizing the salts, then liberating one or both of the resolved bases, and optionally repeating this process to obtain one or both isomers substantially free of the other isomer, i.e., the desired stereoisomer having 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, the racemates can be covalently linked to chiral compounds (auxiliaries) to obtain diastereomers.

[0144] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may be substituted or unsubstituted, and unless otherwise specified, the type and number of substituents can be any on the basis of chemical achievable.

[0145] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, with each occurrence of R being an independent choice. Furthermore, combinations of substituents and / or their variants are permissible only if such combinations result in stable compounds.

[0146] When one of the variables is selected from a single bond, it means that the two groups it connects are directly connected, such as When L3 represents a single bond, it means that the structure is actually

[0147] When the substituents listed do not specify through which atom they are connected to the substituted group, such substituents can be bonded through any atom thereof. For example, a pyridyl substituent can be connected to the substituted group through any carbon atom on the pyridine ring.

[0148] When the linking group is listed without specifying its linking direction, its linking direction is arbitrary, for example, The connecting group L is at this time You can connect benzene rings and cyclohexane in the same direction as reading from left to right to form You can also connect benzene rings and cyclohexane in the opposite direction of reading from left to right to form Combinations of linkers, substituents, and / or variations thereof are permissible only if such combinations result in stable compounds.

[0149] Unless otherwise specified, the number of atoms in a ring is generally defined as the number of members of the ring, for example, a "5-7 membered ring" refers to a "ring" having 5-7 atoms arranged around it.

[0150] Unless otherwise specified, the term “C 1-6 "Alkyl" is used to represent a straight or branched chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms. 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, etc.; which can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as 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, and the like.

[0151] Unless otherwise specified, the term “C 1-3 "Alkyl" is used to represent a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms. 1-3 Alkyl groups include C 1-2 and C 2-3 Alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.

[0152] The term "heteroalkyl" by itself or in combination with another term refers to a stable straight or branched chain alkyl radical or combination thereof consisting of a certain number of carbon atoms and at least one heteroatom or heteroatom group. 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 heteroatom group 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 In other embodiments, the heteroalkyl group is C 1-3 Heteroalkyl. The heteroatom or heteroatom group may be placed at any interior position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule, but the terms "alkoxy," "alkylamino," and "alkylthio" (or thioalkoxy) are customary expressions and refer to those alkyl groups that are attached to the remainder of the molecule through an oxygen, amino, or sulfur atom, respectively. Examples of heteroalkyl groups include, but are not limited to, -OCH, -OCHCH, -OCHCHCH, -OCH(CH), -CH-CH-O-CH, -NHCH, -N(CH), -NHCHCH, -N(CH)(CHCH), -CH-CH-NH-CH, -CH-CH-N(CH)-CH, -SCH, -SCHCH, -SCHCHCH, -SCH(CH), -CH-S-CH-CH, -CH-CH, -S(=O)-CH, -CH-CH-S(=O)-CH, and -CH. Up to two heteroatoms may be consecutive, for example, -CH-NH-OCH.

[0153] Unless otherwise specified, the term “C 1-6 "Alkoxy" refers to an alkyl group containing 1 to 6 carbon atoms which is attached to the rest of the molecule via an oxygen atom. 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, etc. 1-6 Examples of 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), hexyloxy, and the like.

[0154] Unless otherwise specified, the term “C 1-3 "Alkoxy" refers to those alkyl groups containing 1 to 3 carbon atoms which are attached to the rest of the molecule via an oxygen atom. The C 1-3 Alkoxy groups include C 1-2 、C 2-3 , C3 and C2 alkoxy, etc. 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.

[0155] Unless otherwise specified, the term “C 1-6 "Alkylamino" means an alkyl group containing 1 to 6 carbon atoms which is attached to the rest of the molecule via an amino group. 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, 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, and the like.

[0156] Unless otherwise specified, the term “C 1-3 "Alkylamino" means an alkyl group containing 1 to 3 carbon atoms which is attached to the rest of the molecule via an amino group. 1-3 Alkylamino groups include C 1-2 , C3 and C2 alkylamino, etc. 1-3 Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -NHCH2CH2CH3, -NHCH2(CH3)2, and the like.

[0157] Unless otherwise specified, the term “C 1-6 "Alkylthio" refers to those alkyl groups containing 1 to 6 carbon atoms which are linked to the rest of the molecule via a sulfur atom. 1-6 Alkylthio includes C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 , C6, C5, C4, C3 and C2 alkylthio, etc. 1-6Examples of alkylthio groups include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, and the like.

[0158] Unless otherwise specified, the term “C 1-3 "Alkylthio" refers to those alkyl groups containing 1 to 3 carbon atoms which are linked to the rest of the molecule via a sulfur atom. 1-3 Alkylthio includes C 1-3 、C 1-2 and C3 alkylthio, etc. 1-3 Examples of alkylthio groups include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, etc.

[0159] Unless otherwise specified, “C 3-6 "Cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which is a monocyclic or bicyclic ring system. 3-6 Cycloalkyl groups include C 3-5 、C 4-5 and C 5-6 Cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. 3-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0160] Unless otherwise specified, the term "3-8 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 3 to 8 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). This includes monocyclic, bicyclic, and tricyclic ring systems, wherein bicyclic ring systems include spirocyclic, fused, and bridged rings. In addition, with respect to the term "3-8 membered heterocycloalkyl," a heteroatom may occupy the position at which the heterocycloalkyl is attached to the rest of the molecule. The term "3-8 membered heterocycloalkyl" includes 3-6 membered, 3-5 membered, 4-6 membered, 5-6 membered, 4 membered, 5 membered, and 6 membered heterocycloalkyls, and the like. Examples of 3-8 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl or dioxepanyl, etc.

[0161] Unless otherwise specified, the term "3-6 membered heterocycloalkyl" by itself or in combination with other terms means a saturated cyclic group consisting of 3 to 6 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)). p , p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spirocyclic, fused and bridged rings. In addition, with respect to the "3-6 membered heterocycloalkyl", a heteroatom may occupy the position at which the heterocycloalkyl is connected to the rest of the molecule. The 3-6 membered heterocycloalkyl includes 4-6 membered, 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyls, etc. Examples of 3-6 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl or homopiperidinyl, etc.

[0162] Unless otherwise specified, the term "C 6-10 Aromatic ring" and "C 6-10 Aryl" can be used interchangeably, the term "C 6-10 Aromatic ring" or "C 6-10 "Aryl" means a cyclic hydrocarbon group consisting of 6 to 10 carbon atoms with a conjugated π electron system, which can be a monocyclic, fused bicyclic or fused tricyclic ring system, wherein each ring is aromatic. It can be monovalent, divalent or polyvalent, C 6-10 Aryl groups include C 6-9 、C9、C 10 and C6 aryl, etc. 6-10 Examples of aryl groups include, but are not limited to, phenyl, naphthyl (including 1-naphthyl and 2-naphthyl, etc.).

[0163] Unless otherwise specified, the terms "5-10 membered heteroaromatic ring" and "5-10 membered heteroaryl" are used interchangeably. The term "5-10 membered heteroaryl" refers to a cyclic group consisting of 5 to 10 ring atoms with a conjugated π electron system, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. It can be a monocyclic, fused bicyclic or fused tricyclic ring system, wherein each ring is aromatic. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)p , p is 1 or 2). The 5-10 membered heteroaryl group may be attached to the rest of the molecule via a heteroatom or carbon atom. The 5-10 membered heteroaryl group includes 5-8 membered, 5-7 membered, 5-6 membered, 5 membered, and 6 membered heteroaryl groups. Examples of the 5-10 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl), imidazolyl (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-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl), thiazolyl (including 2-thiazolyl, 4- thiazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl, pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.), benzothiazolyl (including 5-benzothiazolyl, etc.), purinyl, benzimidazolyl (including 2-benzimidazolyl, etc.), benzoxazolyl, indolyl (including 5-indolyl, etc.), isoquinolyl (including 1-isoquinolyl and 5-isoquinolyl, etc.), quinoxalinyl (including 2-quinoxalinyl and 5-quinoxalinyl, etc.) or quinolyl (including 3-quinolyl and 6-quinolyl, etc.).

[0164] Unless otherwise specified, the terms "5-6 membered heteroaromatic ring" and "5-6 membered heteroaryl" are used interchangeably in the present 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 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p, p is 1 or 2). 5-6 membered heteroaryl can be connected to the rest of the molecule through a heteroatom or a carbon atom. The 5-6 membered heteroaryl includes 5-membered and 6-membered heteroaryl. Examples of the 5-6 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl) and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, 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.).

[0165] Unless otherwise specified, "benzo 5-6 membered heterocycloalkyl" means a bicyclic structure formed by combining a phenyl group, a heterocycle and a 5-6 membered heterocycloalkyl group, wherein the substituent can be connected to other structures through a phenyl ring or a 5-6 membered heterocycloalkyl ring. Examples of the benzo 5-6 membered heterocycloalkyl group include but are not limited to

[0166] Unless otherwise specified, "5-6 membered heteroaryl and 5-6 membered heterocycloalkyl" means a bicyclic structure formed by the combination of a 5-6 membered heteroaryl, a heterocycle and a 5-6 membered heterocycloalkyl. The substituent can be connected to other structures through a 5-6 membered heteroaryl or a 5-6 membered heterocycloalkyl ring. Examples of the benzo 5-6 membered heterocycloalkyl include but are not limited to

[0167] Unless otherwise specified, C n-n+m or C n -C n+m Any specific case including n to n+m carbons, such as C 1-12 Including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 , and C 12 , also includes any range from n to n+m, such as C 1-12 Including C 1-3 、C 1-6 、C 1-9 、C 3-6 、C 3-9 、C 3-12 、C 6-9 、C6-12 , and C 9-12 Similarly, n-membered to n+m-membered means that the number of atoms in the ring is n to n+m, for example, a 3-12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, an 11-membered ring, and a 12-membered ring, and also includes any range from n to n+m, for example, a 3-12-membered ring includes a 3-6-membered ring, a 3-9-membered ring, a 5-6-membered ring, a 5-7-membered ring, a 6-7-membered ring, a 6-8-membered ring, and a 6-10-membered ring, etc.

[0168] As used herein, the term "treatment" refers to the administration of one or more pharmaceutical substances, particularly compounds of formula (I) as described herein and / or pharmaceutically acceptable salts thereof, to an individual suffering from a disease or symptoms of said disease, in order to cure, alleviate, mitigate, alter, cure, ameliorate, improve or affect said disease or symptoms of said disease. As used herein, the term "prevention" refers to the administration of one or more pharmaceutical substances, particularly compounds of formula (I) as described herein and / or pharmaceutically acceptable salts thereof, to an individual with a predisposition to said disease, in order to prevent said individual from developing said disease. When referring to a chemical reaction, the terms "treating," "contacting," and "reacting" 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 that produces the indicated and / or desired product may not necessarily result directly from the combination of the two reagents initially added, i.e., there may be one or more intermediates generated in the mixture that ultimately lead to the formation of the indicated and / or desired product.

[0169] The term "effective amount" as used herein refers to an amount that is generally sufficient to produce a beneficial effect on an individual. The effective amount of a compound 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 the disease, individual medical history, individual health status, individual response to the drug, etc.).

[0170] The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention.

[0171] The solvents used in the present invention can be obtained commercially. The present invention uses the following abbreviations: CDCl3 represents deuterated chloroform; CD3OD represents deuterated methanol; DMSO-d6 represents deuterated dimethyl sulfoxide; TBS represents tert-butyldimethylsilyl.

[0172] Compounds are named according to the conventional nomenclature in the art or using Software naming, commercially available compounds use supplier catalog names. BRIEF DESCRIPTION OF THE DRAWINGS

[0173] Figure 1 This is a graph showing the relationship between the number of days of NCI-H358 cell inoculation and body weight changes after administration of Example Compound 29B according to an example of the present invention.

[0174] Figure 2 This is a graph showing the relationship between the number of days after NCI-H358 cell inoculation and tumor volume after administration of Example Compound 29B according to an example of the present invention. DETAILED DESCRIPTION

[0175] The present application is described in detail below by way of examples, but this does not necessarily mean that there are 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 embodiments of the present application without departing from the spirit and scope of the present application.

[0176] Example 1: Preparation of Compound 1

[0177] Step 1: Preparation of compound 1-2

[0178]

[0179] 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 reaction mixture was concentrated to obtain a crude product, which was then dissolved in dioxane (10 mL). A mixture of dioxane (5 mL) and ethanol (5 mL) was added dropwise at 0°C. After the addition was complete, the mixture was stirred at room temperature (20°C) for 1 h. The mixture was dissolved in ethyl acetate (20 mL), washed with saturated potassium carbonate solution, and allowed to stand for separation. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain compound 1-2 as a yellow oil.

[0180] Step 2: Preparation of compound 1-3

[0181]

[0182] Compound 1-2 (1.5 g, 6.32 mmol) was 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 mixture was stirred at 0°C for 15 minutes, then warmed to room temperature (20°C) and stirred for 1 hour. The mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (20 mL), washed with saturated ammonium chloride solution, and allowed to stand for separation. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain crude compound 1-3, which was used directly in the next reaction without further purification.

[0183] 1 H NMR (400MHz, CDCl3) 7.94 (d, 1H, J = 12Hz), 4.09 (s, 3H), 3.93 (s, 3H).

[0184] Step 3: Preparation of compound 1-5

[0185]

[0186] At room temperature (20°C), compound 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(diphenylphosphino)-9,9-dimethylxanthene (275 mg, 0.479 mmol), and cesium carbonate (3.142 g, 9.58 mmol) were dissolved in anhydrous dioxane (15 mL). Under a nitrogen atmosphere, the mixture was heated to 100°C and stirred for 3 h. The mixture was cooled to room temperature, concentrated, diluted with water (100 mL), and extracted with ethyl acetate (3 x 20 mL). The organic phases were combined, 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 obtain compound 1-5 as a white solid. MS (ESI) m / z (M+H) + =319.2.

[0187] Step 4: Preparation of Compound 1-6

[0188]

[0189] Compound 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 under microwave conditions for 3 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 obtain compound 1-6 as a reddish-brown oil.

[0190] MS (ESI) m / z (M+H) + =361.2.

[0191] Step 5: Preparation of Compound 1-7

[0192]

[0193] At room temperature (20°C), compound 1-6 (360 mg, 1 mmol) and potassium tert-butoxide (336 mg, 3 mmol) were dissolved in toluene (5 mL). Under a nitrogen atmosphere, the mixture was heated to 100°C and stirred for 3 h. After cooling to room temperature, the mixture was quenched with dilute hydrochloric acid (1N, 10 mL) and extracted with ethyl acetate (2 x 10 mL). The organic phases were combined, 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 1-7 as a yellow solid.

[0194] MS (ESI) m / z (M+H) + =329.2.

[0195] Step 6: Preparation of Compound 1-8

[0196]

[0197] Compound 1-7 (200 mg, 0.61 mmol) was dissolved in acetic acid (3 mL). Concentrated nitric acid (0.3 mL) was added dropwise at room temperature. After the addition was complete, the mixture was stirred at room temperature (20°C) for 30 min. The mixture was poured into ice water (100 mL) to precipitate a yellow solid. The solid was filtered and the filter cake was dried under vacuum until no further weight loss occurred, yielding Compound 1-8 as a yellow solid.

[0198] MS (ESI) m / z (M+H) + =374.2.

[0199] Step 7: Preparation of Compound 1-9

[0200]

[0201] Compound 1-8 (200 mg, 0.54 mmol) was dissolved in acetic acid (2 mL). Hydrobromic acid (48%, 1 mL) was added at room temperature. The mixture was heated to 100°C and stirred for 3 h. The reaction mixture was concentrated to obtain crude compound 1-9, which was used directly in the next reaction without further purification.

[0202] MS (ESI) m / z (M+H) + =360.3.

[0203] Step 8: Preparation of Compound 1-10

[0204]

[0205] Compound 1-9 (360 mg, 1 mmol) was added to N,N-diisopropylethylamine (2 mL). Phosphorus oxychloride (1 mL) was added at room temperature. The reaction system turned dark. The temperature was raised to 90°C and stirred for 1 hour. The system was concentrated, and the crude product was dissolved in ethyl acetate (10 mL). The mixture was washed with water and allowed to stand for stratification. 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 1-10 as a yellow solid.

[0206] MS (ESI) m / z (M+H) + =396.0.

[0207] Step 9: Preparation of Compound 1-12

[0208]

[0209] Compound 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). Under a nitrogen atmosphere, the mixture was heated to 100°C and stirred for 2 h. The mixture was filtered through celite, 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 1-12 as a yellow solid.

[0210] MS (ESI) m / z (M+H) + =590.2.

[0211] Step 10: Preparation of Compound 1-14

[0212]

[0213] Compound 1-12 (100 mg, 0.169 mmol), 1-13 (34.6 mg, 0.203 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (12.3 mg, 0.0169 mmol), and potassium carbonate (46.6 mg, 0.338 mmol) were dissolved in a mixture of tetrahydrofuran (3 mL) and water (0.3 mL). Under a nitrogen atmosphere, the mixture was heated to 80°C and stirred for 1 h. The mixture was concentrated, and the residue was dissolved in ethyl acetate (10 mL), washed with water, and allowed to stand for separation. 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 compound 1-14.

[0214] MS (ESI) m / z (M+H) + =680.2.

[0215] Step 11: Preparation of Compound 1-15

[0216]

[0217] Compound 1-14 (30 mg, 0.044 mmol) was dissolved in N,N-dimethylacetamide (1 mL). A 24% solution of LiHMDS in tetrahydrofuran (0.1 mL) was added at room temperature. The mixture was heated to 160°C and stirred for 4 h under a nitrogen atmosphere. The mixture was cooled to room temperature and concentrated. The residue was dissolved in ethyl acetate (3 mL), washed with water, and allowed to stand for separation. 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 1-15.

[0218] MS (ESI) m / z (M+H) + =633.4.

[0219] Step 12: Preparation of Compounds 1A and 1B

[0220]

[0221] Compound 1-15 (8 mg, 0.0126 mmol) was dissolved in dichloromethane (1 mL). Trifluoroacetic acid (1 mL) was added at room temperature and stirred at room temperature (20°C) for 1 hour. 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 warmed to room temperature (20°C) and reacted for 30 minutes. The reaction solution was washed with water (5 mL) and extracted with dichloromethane (3 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: 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.

[0222] Compound 1A:

[0223] 1H 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).MS(ESI)m / z(M+H) + =587.42.

[0224] Separation conditions: Column: Waters Xselect CSH C18 3.5 μm, 100 x 4.6 mm; Column temperature: 60°C; Mobile phase: Water (0.01% trifluoroacetic acid solution)-Acetonitrile (0.01% trifluoroacetic acid solution); Acetonitrile: 5% to 95% over 7 minutes, 95% over 8 minutes; Flow rate: 1.2 mL / min. Retention time: 6.175 minutes.

[0225] Compound 1B:

[0226] 1 H 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).MS(ESI)m / z(M+H) + =587.4.

[0227] Separation conditions: Column: Waters Xselect CSH C18 3.5 μm, 100 x 4.6 mm; Column temperature: 60°C; Mobile phase: Water (0.01% trifluoroacetic acid solution)-Acetonitrile (0.01% trifluoroacetic acid solution); Acetonitrile: 5% to 95% over 7 minutes, then 95% over 8 minutes; Flow rate: 1.2 mL / min. Retention time: 6.327 minutes.

[0228] Example 2: Preparation of Compound 2

[0229] Step 1: Preparation of compound 2-2

[0230]

[0231] 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 portionwise at 0°C. After addition, the mixture was warmed to room temperature and stirred for 10 minutes. Chloromethyl methyl ether (2.4 g, 30 mmol) was added dropwise. After addition, the mixture was stirred at room temperature for 10 minutes. The mixture was quenched by pouring into ice water (50 mL) and extracted with methyl tert-butyl ether (3 x 50 mL). The organic phases were combined and washed once with saturated sodium chloride solution. The 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) = 0-10%) to obtain compound 2-2 as a light yellow viscous product.

[0232] 1 H 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).

[0233] Step 2: Preparation of compound 2-3

[0234]

[0235] Compound 1-2 (650 mg, 2.77 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL). At -78°C, n-butyllithium (2.5 N, 1.22 mL, 3.05 mmol) was added dropwise. The mixture was stirred at -78°C for 30 min. Isopropyl pinacol borate (567 mg, 3.05 mmol) was then added dropwise. The mixture was stirred at -78°C for 30 min. The mixture was warmed to room temperature, quenched with water, and extracted with ethyl acetate (10 mL). The organic phases were combined, 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) = 0-20%) to obtain 2-3 as a colorless oil.

[0236] Step 3: Preparation of compound 2-4

[0237]

[0238] Compound 1-12 (50 mg, 0.0848 mmol), compound 2-3 (28.7 mg, 0.10 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (6.2 mg, 0.00848 mmol), and potassium carbonate (23.4 mg, 0.169 mmol) were dissolved in a mixture of tetrahydrofuran (2 mL) and water (0.2 mL). Under a nitrogen atmosphere, the mixture was heated to 80°C and stirred for 2 h. The mixture 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 2-4 as a yellow solid.

[0239] MS (ESI) m / z (M+H) + =710.2.

[0240] Step 4: Preparation of compound 2-5

[0241]

[0242] Compound 2-4 (30 mg, 0.0423 mmol) was dissolved in N,N-dimethylacetamide (1 mL). Under a nitrogen atmosphere, a solution of lithium bistrimethylsilylamide in tetrahydrofuran (24%, 0.1 mL) was added dropwise. The reaction mixture was heated to 160°C and allowed to react for 4 h. The mixture 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 afford compound 2-5 as a pale yellow solid.

[0243] MS (ESI) m / z (M+H) + =663.2.

[0244] Step 5: Preparation of Compound 2-6

[0245]

[0246] Compound 2-5 (6 mg, 0.009 mmol) and hydrochloric acid (6N, 0.5 mL) were added to a mixture of methanol (0.45 mL) and tetrahydrofuran (0.05 mL). The mixture was heated to 55°C and reacted for 15 minutes. The mixture was concentrated to afford crude product 2-6, which was used directly in the next reaction without further purification.

[0247] MS (ESI) m / z (M+H) + =519.2.

[0248] Step 6: Preparation of Product 2A and Product 2B

[0249]

[0250] Compound 2-6 (5 mg, 0.0096 mmol) was dissolved in dichloromethane (1.0 mL). The mixture was cooled to 0°C, and triethylamine (1.95 mg, 0.0193 mmol) and acryloyl chloride (1.73 mg, 0.0193 mmol) were added dropwise. The reaction was continued at 0°C for 1 h. The mixture was concentrated to obtain a crude product, which was then purified by high-performance preparative liquid chromatography (HPLC) using a Welch Ultimate XB-C18 10*250 mm, 5 μm column, 10 mmol / L ammonium acetate in the aqueous phase and acetonitrile in the organic phase, using a gradient of 38% to 65% over 15 min, to afford compounds 2A and 2B.

[0251] Compound 2A:

[0252] MS (ESI) m / z (M+H) + =573.4.

[0253] Separation conditions: Column: Waters Xbridge C18 3.5 μm, 100 x 4.6 mm; Column temperature: 40°C; Mobile phase: Water (10 mM ammonium bicarbonate in water)-acetonitrile; Acetonitrile: 5% to 95% over 7 min, then 95% over 8 min; Flow rate: 1.2 mL / min. Retention time: 5.743 min.

[0254] Compound 2B:

[0255] MS (ESI) m / z (M+H) + =573.4.

[0256] Separation conditions: Column: Waters Xbridge C18 3.5 μm, 100 x 4.6 mm; Column temperature: 40°C; Mobile phase: Water (10 mM ammonium bicarbonate in water)-acetonitrile; Acetonitrile: 5% to 95% over 7 min, then 95% over 8 min; Flow rate: 1.2 mL / min. Retention time: 5.879 min.

[0257] Example 3: Preparation of Compound 3

[0258] Step 1: Preparation of compound 3-2

[0259]

[0260] Dissolve chloral hydrate (19.08 g, 115.38 mmol, 15.03 mL) and sodium sulfate (122.92 g, 865.37 mmol) in water (360 mL). Heat the mixture to 35°C. Add a 120 mL aqueous solution of 3-1 (20 g, 96.15 mmol), hydrochloric acid (12 M, 10.82 mL), and hydroxylamine hydrochloride (21.38 g, 307.69 mmol). After addition, heat the mixture to 90°C for 16 h. A gray precipitate forms. Cool the mixture to room temperature and filter to obtain a filter cake. Wash the filter cake with water and dry it in vacuo to obtain compound 3-2, which is used directly in the next step without further purification.

[0261] 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).

[0262] Step 2: Preparation of compound 3-3

[0263]

[0264] 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 mixture was heated to 90°C and stirred for 3 h. The mixture was cooled to room temperature and poured into ice water. A black precipitate precipitated, which was filtered to obtain a filter cake. The filter cake was dried to obtain crude product A. The filtrate was extracted with ethyl acetate (500 mL x 2). The organic phases were combined and washed with saturated brine (500 mL). The organic phases were 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.

[0265] Step 3: Preparation of compound 3-4

[0266]

[0267] Compound 3-3 (29 g, 110.68 mmol) was dissolved in a 2M aqueous sodium hydroxide solution (290.00 mL). Hydrogen peroxide (70.80 g, 624.44 mmol, 60 mL, 30% purity) was added dropwise at 0°C. After the addition, the mixture was stirred at 0°C for 0.5 h, then warmed to room temperature (20°C) and stirred for 16 h. The mixture was poured into ice water (300 mL) and the pH was adjusted to 6 with concentrated hydrochloric acid. A precipitate was precipitated and filtered to obtain a filter cake. The filter cake was dried to yield compound 3-4, which was used directly in the next reaction without further purification.

[0268] Step 4: Preparation of compound 3-5

[0269]

[0270] 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. Under a nitrogen atmosphere, the system was heated to 75°C and reacted for 16 h. The system was concentrated, and the resulting crude product was extracted 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.

[0271] 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)

[0272] Step 5: Preparation of Compound 3-6

[0273]

[0274] Compound 3-5 (2.3 g, 8.65 mmol), compound 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 mixture of dioxane (25 mL) and water (5 mL). Under a nitrogen atmosphere, the system was heated to 100°C and stirred for 16 hours. The system was concentrated and dissolved with ethyl acetate (50 mL), filtered, and the filtrate was concentrated to obtain a crude product, which was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0-20%) to obtain compound 3-6. 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 (brs, 2H), 3.92 (s, 3H), 3.82 (s, 3H).

[0275] Step 6: Preparation of Compound 3-7

[0276]

[0277] Compound 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. Under a nitrogen atmosphere, the mixture was heated to 80°C and stirred for 2 h. The mixture was filtered, and the filtrate was concentrated to obtain the crude product, which was then purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0-10%) to obtain compound 3-7.

[0278] 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).

[0279] Step 7: Preparation of Compound 3-8

[0280]

[0281] At room temperature (20°C), compound 3-7 (1.6 g, 3.79 mmol), compound 3-9 (640 mg, 4.26 mmol), tris(dibenzylideneacetone)dipalladium (350 mg, 382.21 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (221 mg, 381.94 μmol), and cesium carbonate (3.7 g, 11.37 mmol) were dissolved in toluene (30 mL). Under a nitrogen atmosphere, the mixture was heated to 110°C and stirred for 16 hours. The mixture 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 3-8.

[0282] 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.

[0283] Step 8: Preparation of compound 3-10

[0284]

[0285] At room temperature (20°C), compound 3-8 (1.26 g, 2.83 mmol) was dissolved in N,N-dimethylformamide (15 mL). Sodium hydride (454 mg, 11.35 mmol, 60% purity) was added portionwise. Acetyl chloride (888.59 mg, 11.32 mmol, 807.81 μL) was added dropwise. After addition, the system was heated to 100°C under a nitrogen atmosphere and reacted for 8 h. The reaction was quenched by adding saturated aqueous ammonium chloride (5 mL). 30 mL of water was then added, and 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.

[0286] MS (ESI) m / z (M+H) + =487.2.

[0287] Step 9: Preparation of compound 3-11

[0288]

[0289] At room temperature (20°C), compound 3-10 (800 mg, 1.64 mmol) was dissolved in toluene (15 mL), and potassium tert-butoxide (1 M, 5.33 mL) was added. After addition, 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), and the pH was adjusted to neutral with 1N hydrochloric acid. 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.

[0290] 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).

[0291] MS (ESI) m / z (M+H) + =455.1.

[0292] Step 10: Preparation of compound 3-12

[0293]

[0294] 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 at room temperature (20°C). After the addition was complete, the system was heated to 80°C and stirred for 2 h. After cooling to room temperature, the system was concentrated to remove most of the glacial acetic acid. The residue was poured into ice water (50 mL) to separate the precipitate. The filter cake was washed with water and dried to obtain compound 3-12, which was used directly in the next step without further purification.

[0295] 1 H 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).

[0296] MS (ESI) m / z (M+H) + =500.5.

[0297] Step 11: Preparation of compound 3-13

[0298]

[0299] 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 addition, the mixture was heated to 80°C and stirred for 2 h. The mixture 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 3-13.

[0300] 1H 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).

[0301] Step 12: Preparation of Compound 3-14

[0302]

[0303] Compound 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 mixture was heated to 80°C and stirred for 1 hour. The mixture 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.

[0304] 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,1 H),2.27-2.07(m,3H),1.60-1.36(m,12H),1.30-1.02(m,6H).MS(ESI)m / z(M+H) + =712.3.

[0305] Step 13: Preparation of compound 3-15

[0306]

[0307] Compound 3-14 (700 mg, 983.52 μmol) and Molecular sieves (1 g) were dissolved in N-methylpyrrolidone (10 mL). A 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (2.10 mL) was added at room temperature. After addition, the system was heated to 130°C and stirred for 24 h under a nitrogen atmosphere. The system was cooled to room temperature, water (50 mL) was added, and 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 obtain compound 3-15.

[0308] 1 H 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(brd,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).

[0309] MS (ESI) m / z (M+H) + =665.3.

[0310] Step 14: Preparation of compound 3-16

[0311]

[0312] Compound 3-15 (180 mg, 270.79 μmol) was dissolved in anhydrous dichloromethane (3 mL). A dichloromethane solution of boron tribromide (339.20 mg, 1.35 mmol, 130.46 μL) was added at 0°C. After addition, the mixture was warmed to room temperature (20°C) and stirred under a nitrogen atmosphere for 2 hours. Methanol (10 mL) was added and stirred for 10 minutes. The mixture was concentrated and lyophilized to obtain compound 3-16 (hydrobromide salt), which was used directly in the next step without further purification.

[0313] MS (ESI) m / z (M+H) + =551.3.

[0314] Step 15: Preparation of compounds 3A, 3B, 3C, and 3D

[0315]

[0316] Compound 3-16 (180 mg, 285.04 μmol, hydrobromide salt) was dissolved in tetrahydrofuran (5 mL) and saturated aqueous sodium bicarbonate 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 2 h. The pH of the system was adjusted to neutral with 1N 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 preparative liquid chromatography (HPLC) (separation conditions: column: Phenomenex Gemini-NX 80*30mm*3μm; mobile phase: [water (10mM ammonium bicarbonate solution)-acetonitrile]; acetonitrile percentage: 41%-51% over 9.5min) to give compounds 3A and 3B.

[0317] Compound 3A

[0318] 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).

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

[0320] HPLC 98.77% purity; retention time 3.72 min.

[0321] Separation conditions: Chromatographic column: Ultimate C18 3.0*50 mm, 3 μm; column temperature: 40°C; 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.

[0322] Compound 3B

[0323] 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(brs ,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).

[0324] MS (ESI) m / z (M+H) + =605.3.

[0325] HPLC 98.77% purity; retention time 3.59 min.

[0326] Separation conditions: Chromatographic column: Ultimate C18 3.0*50 mm, 3 μm; column temperature: 40°C; 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.

[0327] Step 16: Separation of isomers of compound 3A

[0328]

[0329] The diastereoisomers of compound 3A were purified by SFC (separation conditions: column: DAICEL CHIRALCEL OJ-H (250 mm*30 mm, 5 μm); mobile phase: [0.1% ammonia solution-ethanol]; ethanol percentage: 30%-30%; flow rate: 60 mL / min). After concentration, compounds 3A-1 and 3A-2 were obtained.

[0330] Compound 3A-1

[0331] 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).

[0332] MS (ESI) m / z (M+H) + =605.3.

[0333] HPLC 97.74% purity; retention time 3.606 min.

[0334] Separation conditions: Chromatographic column: Xbridge C18, 5μm, 2.1*50mm; column temperature: 50°C; mobile phase: water (0.02% ammonia solution)-acetonitrile; acetonitrile: 10%-80% for 6 min, 80% for 2 min; flow rate: 0.8 mL / min.

[0335] SFC 100% ee. Retention time 3.864 min.

[0336] Compound 3A-2

[0337] 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).

[0338] MS (ESI) m / z (M+H) + =605.3.

[0339] HPLC 95.13% purity; retention time 3.674 min.

[0340] Separation conditions: Chromatographic column: Xbridge C18, 5μm, 2.1*50mm; column temperature: 50°C; mobile phase: water (0.02% ammonia solution)-acetonitrile; acetonitrile: 10%-80% for 6 min, 80% for 2 min; flow rate: 0.8 mL / min.

[0341] SFC 98.88% ee. Retention time 4.332 min.

[0342] Step 17: Separation of isomers of compound 3B

[0343]

[0344] The diastereoisomers of compound 3B were purified by SFC (separation conditions: column: DAICEL CHIRALCEL OJ-H (250 mm*30 mm, 5 μm); mobile phase: [0.1% ammonia solution-ethanol]; ethanol percentage: 30%-30%; flow rate: 60 mL / min). After concentration, compounds 3B-1 and 3B-2 were obtained.

[0345] Compound 3B-1

[0346] 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).

[0347] MS (ESI) m / z (M+H) + =605.3.

[0348] HPLC 95.70% purity; retention time 3.669 min.

[0349] Separation conditions: Chromatographic column: Xbridge C18, 5μm, 2.1*50mm; column temperature: 50°C; mobile phase: water (0.02% ammonia solution)-acetonitrile; acetonitrile: 10%-80% for 6 min, 80% for 2 min; flow rate: 0.8 mL / min.

[0350] SFC 100% ee. Retention time 3.978 min.

[0351] Compound 3B-2

[0352] 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).

[0353] MS (ESI) m / z (M+H) + =605.3.

[0354] HPLC 98.65% purity; retention time 3.581 min.

[0355] Separation conditions: Chromatographic column: Xbridge C18, 5μm, 2.1*50mm; column temperature: 50°C; mobile phase: water (0.02% ammonia solution)-acetonitrile; acetonitrile: 10%-80% for 6 min, 80% for 2 min; flow rate: 0.8 mL / min.

[0356] SFC 100% ee. Retention time 4.607 min.

[0357] Example 4: Preparation of Compound 4

[0358] Step 1: Preparation of compound 4-2

[0359]

[0360] The raw materials 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 (120 mL) of raw material 4-1 (25 g, 131.57 mmol), hydrochloric acid (12 M, 14.80 mL), and hydroxylamine hydrochloride (29.26 g, 421.02 mmol) were added sequentially. After the addition, the system was heated to 90°C and reacted for 16 hours. A yellow precipitate appeared in the system. The system was cooled to room temperature and filtered to obtain a filter cake. The filter cake was washed with water and then dissolved in ethyl acetate (300 mL). Filtered, 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.

[0361] Step 2: Preparation of compound 4-3

[0362]

[0363] At 60°C, compound 4-2 (30.8 g, 117.99 mmol) was added to concentrated sulfuric acid (460.00 g, 4.60 mol, 250 mL, 98% purity). After addition, the mixture was heated to 90°C and stirred for 3 h. The mixture was cooled to room temperature and poured into ice water to precipitate a yellow precipitate. The filter cake was filtered and dried to afford a yellow solid, 4-3, which was used directly in the next reaction without further purification.

[0364] Step 3: Preparation of compound 4-4

[0365]

[0366] Compound 4-3 (22 g, 90.16 mmol) was dissolved in a 2M aqueous sodium hydroxide solution (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 mixture was stirred at 0°C for 0.5 h, then warmed to room temperature (20°C) and stirred for 16 h. The mixture was poured into ice water (400 mL) and the pH was adjusted to 6 with concentrated hydrochloric acid. A precipitate was precipitated and filtered to obtain a filter cake. The filter cake was dried to yield compound 3-4, which was used directly in the next reaction without further purification.

[0367] Step 4: Preparation of compound 4-5

[0368]

[0369] 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 addition, the mixture was heated to 70°C and stirred for 16 h under a nitrogen atmosphere. After cooling to room temperature, the mixture was poured into ice water to precipitate. The filter cake was filtered, washed with water, and dried to obtain compound 4-5, which was used directly in the next reaction without further purification.

[0370] Step 5: Preparation of Compounds 4-6

[0371]

[0372] 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 resulting crude product was dissolved in ethyl acetate (200 mL). The organic phase was washed sequentially with saturated aqueous sodium bicarbonate (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.

[0373] 1 H NMR (400MHz, DMSO-d6) δ7.68 (d, J = 2.0Hz, 1H), 6.86 (s, 2H), 3.83 (s, 3H).

[0374] MS (ESI) m / z (M+H) + =283.8.

[0375] Step 6: Preparation of Compound 4-8

[0376]

[0377] Compound 4-6 (6 g, 21.24 mmol), compound 4-7 (10 g, 43.10 mmol), tris(dibenzylideneacetone)dipalladium (840 mg, 1.46 mmol), 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (2.03 g, 4.25 mmol), and potassium carbonate (7.34 g, 53.10 mmol) were dissolved in a mixture of dioxane (100 mL) and water (20 mL). Under a nitrogen atmosphere, the mixture was heated to 100°C and stirred for 16 h. The mixture was concentrated and extracted 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, which was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0-10%) to obtain compound 4-8.

[0378] 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).

[0379] MS (ESI) m / z (M+H) + =328.0.

[0380] Step 7: Preparation of Compound 4-9

[0381]

[0382] Compound 4-8 (4.8 g, 14.65 mmol) was dissolved in glacial acetic acid (50 mL) and acetic anhydride (4.49 g, 43.94 mmol, 4.12 mL) was added dropwise at 0°C. The mixture was warmed to room temperature (20°C) and reacted for 36 hours. The reaction mixture was concentrated to obtain a crude product, which was then purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0-100%) to obtain compound 4-9.

[0383] 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).

[0384] MS (ESI) m / z (M+H) + =370.0.

[0385] Step 8: Preparation of Compound 4-10

[0386]

[0387] 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 mixture was stirred at room temperature (20°C) for 16 h. The mixture was filtered, and the filtrate was poured into water (100 mL). The mixture was 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 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 4-10. MS (ESI) m / z (M+H) + =384.0.

[0388] Step 9: Preparation of Compound 4-11

[0389]

[0390] 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 addition, the system was reacted at room temperature (20°C) for 4 h under a nitrogen atmosphere. 1 M hydrochloric acid was added to quench the reaction, and the mixture was 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.

[0391] 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).

[0392] MS (ESI) m / z (M+H) + =351.9.

[0393] Step 10: Preparation of Compound 4-12

[0394]

[0395] 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 at room temperature (20°C). After the addition was complete, the mixture was heated to 80°C and stirred for 1 hour. After cooling to room temperature, the mixture was concentrated to remove most of the glacial acetic acid. 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.

[0396] 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).

[0397] MS (ESI) m / z (M+H) + =397.0.

[0398] Step 11: Preparation of Compound 4-13

[0399]

[0400] 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 addition, the mixture was heated to 80°C and stirred for 1 hour. The mixture 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 obtain compound 4-13.

[0401] 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).

[0402] MS (ESI) m / z (M+H) + =414.9.

[0403] Step 12: Preparation of Compound 4-14

[0404]

[0405] Compound 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). Under a nitrogen atmosphere, the mixture was heated to 80°C and stirred for 3 h. The mixture 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.

[0406] 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(brd,J=12.3Hz,1H),1.50(s,9H),1.34(d,J=6.8Hz,3H).

[0407] MS (ESI) m / z (M+H) + =609.1.

[0408] Step 13: Preparation of Compound 4-15

[0409]

[0410] Compound 4-14 (0.86 g, 1.41 mmol) and Molecular sieves (0.5 g) were dissolved in N-methylpyrrolidone (10 mL). A solution of lithium bis(trimethylsilylamide) in tetrahydrofuran (1 M, 2.82 mL) was added at room temperature. After addition, 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 sequentially 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 a crude product, which was then purified by high-performance preparative liquid chromatography (separation conditions: chromatographic 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.

[0411] 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).

[0412] MS (ESI) m / z (M+H) + =562.1.

[0413] Step 14: Preparation of Compound 4-16

[0414]

[0415] Compound 4-15 (0.08 g, 142.35 μmol) was dissolved in anhydrous dichloromethane (1 mL). A dichloromethane solution of boron tribromide (260 mg, 1.04 mmol, 0.1 mL) was added at 0°C. After addition, the mixture was warmed to room temperature (20°C) and stirred for 2 hours under a nitrogen atmosphere. Methanol (2 mL) was added and stirred for 10 minutes. The mixture was concentrated to afford compound 4-16 (hydrobromide salt), which was used directly in the next step without further purification.

[0416] Step 15: Preparation of compounds 4A and 4B

[0417]

[0418] Compound 3-17 (0.1 g, 189.12 μmol, hydrobromide salt) was dissolved in tetrahydrofuran (5 mL) and saturated aqueous sodium bicarbonate 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 2 h. The pH of the system was adjusted to neutral with 1N hydrochloric acid, and the system 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 preparative liquid chromatography (HPLC) (separation conditions: column: Phenomenex Gemini-NX 80*30mm*3μm; mobile phase: [water (10mM ammonium bicarbonate solution)-acetonitrile]; acetonitrile percentage: 43%-73% over 9.5min) to give compounds 4A and 4B.

[0419] Compound 4A

[0420] 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=1.8,16.8Hz,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).

[0421] MS (ESI) m / z (M+H) + =502.2.

[0422] HPLC 96.17% purity; retention time 9.28 min.

[0423] Separation conditions: Chromatographic column: YMC-Pack ODS-A 150*4.6mm, 5μm; column temperature: 40°C; 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.

[0424] Compound 4B

[0425] 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(brd,J=11.8Hz,2H),3.03(br s,1H),1.78-1.62(m,3H).MS(ESI)m / z(M+H) + =502.2.

[0426] HPLC 97.7% purity; retention time 9.60 min.

[0427] Separation conditions: Chromatographic column: YMC-Pack ODS-A 150*4.6mm, 5μm; column temperature: 40°C; 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.

[0428] Example 5: Preparation of Compound 5

[0429] Step 1: Preparation of compound 5-1

[0430]

[0431] At room temperature (20°C), 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(diphenylphosphino)-9,9-dimethylxanthene (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). Under a nitrogen atmosphere, the mixture was heated to 120°C and stirred for 3 h. The reaction mixture was cooled to room temperature and quenched with saturated aqueous ammonium chloride (1 L). The mixture was 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 obtain compound 5-1.

[0432] MS (ESI) m / z (M+H) + =334.1.

[0433] Step 2: Preparation of compound 5-2

[0434]

[0435] 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 portionwise at room temperature (20°C). After addition, 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, quenched with saturated aqueous ammonium chloride (50 mL), 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, which was purified by reverse-phase medium-pressure column chromatography (acetonitrile / water (v / v) = 30-45%) to obtain compound 5-2.

[0436] MS (ESI) m / z (M+H) + =344.1.

[0437] Step 3: Preparation of compound 5-3

[0438]

[0439] 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 mixture was heated to 50°C and stirred for 1 h. The mixture was cooled to room temperature and poured into ice water (100 mL). The pH was adjusted to neutral with 10N 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.

[0440] MS (ESI) m / z (M+H) + =389.40.

[0441] Step 4: Preparation of compound 5-4

[0442]

[0443] Compound 5-3 (300 mg, 0.77 mmol) was dissolved in acetic acid (3 mL). Hydrobromic acid (48%, 1.5 mL) was added at room temperature. After addition, the system was heated to 100°C and stirred for 16 hours. 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.

[0444] MS (ESI) m / z (M+H) + =375.00.

[0445] Step 5: Preparation of compound 5-5

[0446]

[0447] 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, causing the reaction system to turn dark. 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, and allowed to stand for stratification. 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) = 0-15%) to obtain compound 5-5.

[0448] MS (ESI) m / z (M+H) + =411.00.

[0449] Step 6: Preparation of compound 5-6

[0450]

[0451] Compound 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). Under a nitrogen atmosphere, the mixture was heated to 100°C and stirred for 2 h. The mixture was filtered through celite, 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.

[0452] MS (ESI) m / z (M+H) + =605.20.

[0453] Step 7: Preparation of compound 5-7

[0454]

[0455] Compound 5-6 (100 mg, 0.165 mmol), compound 2-13 (94 mg, 0.332 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (12.3 mg, 0.0169 mmol), and potassium carbonate (46.6 mg, 0.338 mmol) were dissolved in a mixture of tetrahydrofuran (3 mL) and water (0.3 mL). Under a nitrogen atmosphere, the mixture was heated to 80°C and stirred for 1 h. The mixture was concentrated, and the residue was dissolved in ethyl acetate (10 mL), washed with water, and allowed to stand for separation. 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 5-7.

[0456] MS (ESI) m / z (M+H) + =725.40.

[0457] Step 8: Preparation of compound 5-8

[0458]

[0459] Compound 5-7 (25 mg, 0.034 mmol) was dissolved in N,N-dimethylacetamide (2 mL). A solution of lithium bistrimethylsilylamide in tetrahydrofuran (24%, 0.5 mL) was added at room temperature. Under a nitrogen atmosphere, the mixture was heated to 160°C and stirred for 10 h. The mixture was cooled to room temperature and concentrated. The residue was dissolved in ethyl acetate (3 mL), washed with water, and allowed to stand for separation. 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 5-8.

[0460] MS (ESI) m / z (M+H) + =678.40.

[0461] Step 9: Preparation of compound 5-9

[0462]

[0463] Compound 5-8 (13 mg, 0.0192 mmol) and hydrochloric acid (6N, 1 mL) were added to a mixture of methanol (0.9 mL) and tetrahydrofuran (0.1 mL). The mixture was heated to 55°C and reacted for 15 minutes. The mixture was concentrated to afford crude compound 5-9, which was used directly in the next reaction without further purification.

[0464] MS (ESI) m / z (M+H) + =534.20.

[0465] Step 10: Preparation of compounds 5A and 5B

[0466]

[0467] 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 reaction mixture was warmed to room temperature (20°C) and allowed to react for 30 min. The reaction solution was washed with water (5 mL) and extracted with dichloromethane (3 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 (HPLC) (separation conditions: Welch Xtimate C18 column, 10 x 250 mm, 5 μm; column temperature, 25°C; mobile phase: water (10 mM / L aqueous ammonium bicarbonate)-acetonitrile; 32% to 47% acetonitrile over 16 min; flow rate, 8 mL / min) to obtain compounds 5A and 5B.

[0468] Compound 5A:

[0469] 1 H NMR (400MHz, DMSO-d6) δ10.00(s,1H),8.36(d,J=4.9Hz,1H),7.79(d,J=8.9Hz,1H),7.24–

[0470] 7.06(m,2H),6.87–6.71(m,1H),6.68–6.51(m,2H),6.10(d,J=16.7Hz,1H),5.69(d,J=10.5Hz,1H),4.51–4.07(m,3H) ,3.67–3.42(m,4H),2.65–2.48(m,2H),1.73(s,3H),1.55–1.48(m,3H),0.98(d,J=6.7Hz,3H),0.84(d,J=6.8Hz,3H).

[0471] MS (ESI) m / z (M+H) + =588.20.

[0472] HPLC 100% purity; retention time 4.917 min.

[0473] Separation conditions: Chromatographic column: Waters Xbridge C18 3.5μm, 100*4.6mm; column temperature: 40°C; mobile phase: water (10mM ammonium bicarbonate aqueous solution)-acetonitrile; acetonitrile: 5%-95% 7min, 95% 8min; flow rate: 1.2mL / min.

[0474] Compound 5B:

[0475] 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).

[0476] MS (ESI) m / z (M+H) + =588.20.

[0477] HPLC 100% purity; retention time 4.975 min.

[0478] Separation conditions: Chromatographic column: Waters Xbridge C18 3.5μm, 100*4.6mm; column temperature: 40°C; mobile phase: water (10mM ammonium bicarbonate aqueous solution)-acetonitrile; acetonitrile: 5%-95% 7min, 95% 8min; flow rate: 1.2mL / min.

[0479] Example 6: Preparation of Compound 6

[0480] Step 1: Preparation of compound 6-1

[0481]

[0482] Compound 5-10 (90 mg, 0.15 mmol), compound 1-13 (51 mg, 0.30 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (11 mg, 0.015 mmol), and potassium carbonate (41 mg, 0.3 mmol) were dissolved in a mixture of tetrahydrofuran (3 mL) and water (0.3 mL). Under a nitrogen atmosphere, the mixture was heated to 80°C and stirred for 1 hour. The mixture was concentrated, and the residue was dissolved in ethyl acetate (10 mL), washed with water, and allowed to stand for separation. 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 6-1.

[0483] MS (ESI) m / z (M+H) + =695.40.

[0484] Step 2: Preparation of compound 6-2

[0485]

[0486] Compound 6-1 (40 mg, 0.058 mmol) was dissolved in N,N-dimethylacetamide (2 mL). A solution of lithium bistrimethylsilylamide in tetrahydrofuran (24%, 0.5 mL) was added at room temperature. Under a nitrogen atmosphere, the mixture was heated to 160°C and stirred for 10 h. The mixture was cooled to room temperature and concentrated. The residue was dissolved in ethyl acetate (3 mL), washed with water, and allowed to stand for separation. 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 6-2.

[0487] MS (ESI) m / z (M+H) + =648.40.

[0488] Step 3: Preparation of compounds 6A and 6B

[0489]

[0490] Compound 6-2 (14 mg, 0.022 mmol) was dissolved in dichloromethane (1 mL). Trifluoroacetic acid (1 mL) was added at room temperature and stirred at room temperature (20°C) for 1 h. 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 warmed to room temperature (20°C) and reacted for 30 min. The reaction solution was washed with water (5 mL) and extracted with dichloromethane (3 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 (HPLC) (separation conditions: Welch Xtimate C18 10*250 mm, 5 μm column; column temperature 25°C; mobile phase: water (10 mM ammonium bicarbonate aqueous solution)-acetonitrile; acetonitrile 28%-50% over 19 min; flow rate 8 mL / min) to give Compound 6A and Compound 6B.

[0491] Compound 6A:

[0492] 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–

[0493] 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).

[0494] MS (ESI) m / z (M+H) + =602.20.

[0495] HPLC 100% purity; retention time 5.388 min.

[0496] Separation conditions: Chromatographic column: Waters Xbridge C18 3.5μm, 100*4.6mm; column temperature: 40°C; mobile phase: water (10mM ammonium bicarbonate aqueous solution)-acetonitrile; acetonitrile: 5%-95% 7min, 95% 8min; flow rate: 1.2mL / min.

[0497] Compound 6B:

[0498] 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=12.6Hz,1H),2.82–2.59(m,1H),2.13–1.98(m,1H),1.74(s,3H),1.31–0.96(m,9H).

[0499] MS (ESI) m / z (M+H) + =602.20.

[0500] HPLC 100% purity; retention time 5.455 min.

[0501] Separation conditions: Chromatographic column: Waters Xbridge C18 3.5μm, 100*4.6mm; column temperature: 40°C; mobile phase: water (10mM ammonium bicarbonate aqueous solution)-acetonitrile; acetonitrile: 5%-95% 7min, 95% 8min; flow rate: 1.2mL / min.

[0502] Example 7: Preparation of Compound 7

[0503] Step 1: Preparation of compound 7-2

[0504]

[0505] Compound 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). Under a nitrogen atmosphere, the mixture was heated to 100°C and stirred for 1 h. The mixture was filtered through celite, 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.

[0506] MS (ESI) m / z (M+H) + =618.2.

[0507] Step 2: Preparation of compound 7-3

[0508]

[0509] Compound 7-2 (320 mg, 0.517 mmol) and iron powder (115 mg, 2.068 mmol) were dissolved in acetic acid (10 mL). Under a nitrogen atmosphere, the mixture was heated to 80°C and stirred for 1 hour. The mixture was filtered through Celite, and the filtrate was concentrated to obtain crude compound 7-3. This was used directly in the next reaction without further purification.

[0510] MS (ESI) m / z (M+H) + =556.2.

[0511] Step 3: Preparation of compound 7-4

[0512]

[0513] Compound 7-3 (287 mg, 0.517 mmol) and potassium carbonate (276 mg, 2 mmol) were dissolved in acetone (20 mL). Methyl iodide (284 mg, 2 mmol) was added at room temperature (20°C). After addition, the mixture was heated to 45°C and stirred for 3 h under a nitrogen atmosphere. The mixture 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) = 0-30%) to obtain compound 7-4.

[0514] MS (ESI) m / z (M+H) + =570.2.

[0515] Step 4: Preparation of compound 7-5

[0516]

[0517] 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 mixture of dioxane (5 mL) and water (0.5 mL). Under a nitrogen atmosphere, the mixture was heated to 100°C and stirred for 1 hour. The mixture was concentrated to obtain a crude product, which was then purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0-50%) to obtain compound 7-5.

[0518] MS (ESI) m / z (M+H) + =690.3.

[0519] Step 5: Preparation of compound 7-6

[0520]

[0521] Compound 7-5 (180 mg, 0.261 mmol) and hydrochloric acid (6N, 2 mL) were added to a mixture of methanol (10 mL) and tetrahydrofuran (1 mL). The mixture was heated to 55°C and reacted for 1 h. The reaction mixture was concentrated to afford crude compound 7-6, which was used directly in the next reaction without further purification.

[0522] MS (ESI) m / z (M+H) + =546.2.

[0523] Step 6: Preparation of compound 7

[0524]

[0525] Compound 7-6 (140 mg, 0.256 mmol) was dissolved in dichloromethane (5 mL). The mixture was cooled to 0°C, and triethylamine (78 mg, 0.771 mmol) and acryloyl chloride (46 mg, 0.514 mmol) were added dropwise. The reaction was continued at 0°C for 0.5 h. The mixture was extracted with water (5 mL) and dichloromethane (3 mL), and the organic phase was concentrated to obtain a crude product. The crude product was dissolved in a mixture of tetrahydrofuran (5 mL) and water (10 mL), and lithium hydroxide (40 mg) was added. After addition, the mixture 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 a crude product, which was purified by high-performance preparative liquid chromatography (separation conditions: chromatographic column Phenomenex Gemini-NX 80*30mm*3μm, mobile phase: water (10mM ammonium bicarbonate aqueous solution)-acetonitrile; acetonitrile 51%-81% 9.5min; flow rate 30mL / min) to obtain compound 7.

[0526] Step 7: Preparation of compounds 7A and 7B

[0527]

[0528] The diastereoisomers of compound 7 were purified by SFC (separation conditions: column: DAICEL CHIRALCEL OD (250 mm*30 mm, 10 μm); mobile phase: [0.1% ammonia solution-ethanol]; ethanol percentage: 40%-40%; flow rate: 70 mL / min). After concentration, compound 7A and compound 7B were obtained.

[0529] Compound 7A

[0530] 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).

[0531] MS (ESI) m / z (M+H) + =600.0.

[0532] HPLC 100% purity; retention time 5.05 min.

[0533] Separation conditions: Chromatographic column: Ultimate C18 3.0*50 mm, 3 μm; column temperature: 40°C; mobile phase: water (0.0688% trifluoroacetic acid in water)-acetonitrile (0.0625% trifluoroacetic acid solution); acetonitrile: 10% to 80% for 6 min, 80% for 2 min; flow rate: 1.2 mL / min.

[0534] SFC 100% ee. Retention time 3.939 min.

[0535] Separation conditions: Chromatographic 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.

[0536] Compound 7B

[0537] 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=

[0538] 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–

[0539] 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).

[0540] MS (ESI) m / z (M+H) + =600.0.

[0541] HPLC 100% purity; retention time 5.00 min.

[0542] Separation conditions: Chromatographic column: Ultimate C18 3.0*50 mm, 3 μm; column temperature: 40°C; mobile phase: water (0.0688% trifluoroacetic acid in water)-acetonitrile (0.0625% trifluoroacetic acid solution); acetonitrile: 10% to 80% for 6 min, 80% for 2 min; flow rate: 1.2 mL / min.

[0543] SFC 100% ee. Retention time 4.329 min

[0544] Separation conditions: Chromatographic 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.

[0545] Example 8: Preparation of Compound 8

[0546] Step 1: Preparation of compound 8-2

[0547]

[0548] Dissolve raw material 8-1 (10 g, 52.351 mmol) in thionyl chloride (30 mL) and heat to 85°C for 16 h. Concentrate the mixture, and dissolve the residue in 1,4-dioxane (30 mL). Slowly add this solution to stirred methanol at 0°C, and heat to 70°C for 2 h. Concentrate the mixture to obtain compound 8-2.

[0549] Step 2: Preparation of compound 8-3

[0550]

[0551] 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 reaction was allowed to proceed at room temperature (20°C) for 3 h. The mixture was concentrated, 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 crude product 8-3.

[0552] MS (ESI) m / z (M+H) + =202.0.

[0553] Step 3: Preparation of compound 8-4

[0554]

[0555] At room temperature (20°C), 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(diphenylphosphino)-9,9-dimethylxanthene (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 mixture was heated to 110°C and stirred for 4 h. The mixture 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.

[0556] MS (ESI) m / z (M+H) + =316.0.

[0557] Step 4: Preparation of compound 8-5

[0558]

[0559] 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 a 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.

[0560] MS (ESI) m / z (M+H) + =350.0

[0561] Step 5: Preparation of compound 8-6

[0562]

[0563] 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 portionwise at 0°C. After addition, the mixture was allowed to react at 0°C for 30 min, and 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, and the mixture was allowed to react 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, which was purified by medium-pressure column chromatography (methanol / dichloromethane (v / v) = 0-5%) to yield compound 8-6.

[0564] MS (ESI) m / z (M+H) + =360.0.

[0565] Step 6: Preparation of compound 8-7

[0566]

[0567] Compound 8-6 (1.86 g, 5.18 mmol) was dissolved in glacial acetic acid (30 mL). Nitric acid (15 mL) was added dropwise at room temperature (20°C). After the addition was complete, the mixture was stirred at room temperature (20°C) for 2 h. The mixture was concentrated to remove most of the glacial acetic acid. The residue was poured into ice water (25 mL), the pH was adjusted to 5-6, and the mixture was filtered. The filter cake was washed with water and then dried to obtain compound 8-7.

[0568] MS (ESI) m / z (M+H) + =405.0.

[0569] Step 7: Preparation of compound 8-8

[0570]

[0571] Compound 8-7 (1 g, 2.47 mmol) was dissolved in a mixture of acetic acid (6 mL) and hydrobromic acid (8 mL). The mixture was heated to 100°C and reacted for 16 h. The mixture was then dried to obtain compound 8-8.

[0572] MS (ESI) m / z (M+H) + =391.0.

[0573] Step 8: Preparation of Compound 8-9

[0574]

[0575] 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 addition, the mixture was heated to 80°C and stirred for 2 h. The mixture 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 8-9.

[0576] MS (ESI) m / z (M+H) + =427.0.

[0577] Step 9: Preparation of compounds 8-10

[0578]

[0579] Compound 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). Under a nitrogen atmosphere, the mixture was heated to 100°C and stirred for 3 h. The mixture 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.

[0580] MS (ESI) m / z (M+H) + =621.2.

[0581] Step 10: Preparation of Compounds 8-11

[0582]

[0583] Compound 8-10 (345 mg, 0.556 mmol), compound 2-3 (470 mg, 1.669 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (23.4 mg, 0.032 mmol), and potassium carbonate (44 mg, 0.321 mmol) were dissolved in a mixture of dioxane (4 mL) and water (1 mL). Under a nitrogen atmosphere, the mixture was heated to 100°C and stirred for 6 h. The mixture was concentrated, and the residue was dissolved in ethyl acetate (20 mL), washed with water, and allowed to stand for separation. 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 8-11.

[0584] MS (ESI) m / z (M+H) + =741.2.

[0585] Step 11: Preparation of Compounds 8-12

[0586]

[0587] 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). The mixture was heated to 80°C and stirred for 2 h under a nitrogen atmosphere. The mixture 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.

[0588] Step 12: Preparation of Compounds 8-13

[0589]

[0590] 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 reaction was allowed to proceed at room temperature (20°C) for 1 h. The mixture 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 obtain compound 8-13.

[0591] Step 13: Preparation of Compounds 8-14

[0592]

[0593] 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). The reaction mixture was heated to 120°C and allowed to react for 4 hours. The mixture was cooled to room temperature, and water (20 mL) was added. The mixture was extracted with EA (15 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) = 0-50%) to obtain compound 8-14.

[0594] Step 14: Preparation of Compounds 8-15

[0595]

[0596] Compound 8-14 (40 mg, 0.0578 mmol) was dissolved in tetrahydrofuran (2 mL) and sodium hydride (5 mg, 0.1156 mmol) was added at 0°C. After addition, the mixture was warmed to room temperature and stirred for 30 minutes. Iodomethane (12.3 mg, 0.086 mmol) was added and stirred at room temperature (20°C) for 2 hours. Water (5 mL) was added to quench the reaction, 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.

[0597] Step 15: Preparation of Compounds 8-16

[0598]

[0599] Compound 8-15 (16 mg, 0.02266 mmol) and hydrochloric acid (6N, 1 mL) were added to a mixture of methanol (0.9 mL) and tetrahydrofuran (0.1 mL). The mixture was heated to 55°C and reacted for 15 minutes. The mixture was concentrated to obtain crude product 8-16.

[0600] Step 16: Preparation of Compound 8

[0601]

[0602] 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 2 h. The pH of the system was adjusted to neutral with 1N hydrochloric acid, and the system 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 preparative liquid chromatography (HPLC) (separation conditions: column: Agilent 10Prep-C8 250×21.2 mm; column temperature: 25° C.; mobile phase: water (0.1% FA)-acetonitrile; mobile phase acetonitrile ratio 30%-50% in 16 min; flow rate 30 mL / min) to obtain compound 8.

[0603] Compound 8

[0604] 1 H NMR (400 MHz, 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).

[0605] MS (ESI) m / z (M+H) + =617.3.

[0606] HPLC 99% purity; retention time 5.46 min.

[0607] Separation conditions: Chromatographic column: Waters X-bridge C18, 4.6*100 mm, 3.5 μm; mobile phase: [water (10 mM aqueous ammonium bicarbonate solution)-acetonitrile]; acetonitrile: 5%-95% 7 min; flow rate: 1.2 mL / min.

[0608] Example 9: Preparation of Compound 9

[0609] Step 1: Preparation of compound 9-1

[0610]

[0611] Compound 8-3 (6 g, 29.8 mmol) and an ethanolic 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 a 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.

[0612] Step 2: Preparation of compound 9-2

[0613]

[0614] 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 a 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.

[0615] MS (ESI) m / z (M+H) + =231.0.

[0616] Step 3: Preparation of compound 9-3

[0617]

[0618] 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). After washing with saturated brine (80 mL), the organic phase was dried over anhydrous sodium sulfate, 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 9-3. MS (ESI) m / z (M+H) + =273.2.

[0619] Step 4: Preparation of compound 9-4

[0620]

[0621] At room temperature (20°C), compound 9-3 (1.3 g, 1.91 mmol) was dissolved in toluene (20 mL), and potassium tert-butoxide (1.28 g, 11.46 mmol) was added. After addition, the system was reacted at room temperature (20°C) for 4 h under a nitrogen atmosphere. 1 M hydrochloric acid was added to the system to quench the reaction. After dilution with water (40 mL), the system was 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, which was then slurried with methanol to obtain compound 9-4.

[0622] MS (ESI) m / z (M+H) + =241.0.

[0623] Step 5: Preparation of compound 9-5

[0624]

[0625] 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 at room temperature (20°C). After the addition was complete, the mixture was heated to 80°C and stirred for 1 hour. After cooling to room temperature, the mixture was concentrated to remove most of the glacial acetic acid. 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.

[0626] MS (ESI) m / z (M+H) + =286.0.

[0627] Step 6: Preparation of compound 9-6

[0628]

[0629] 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 mixture was heated to 100° C. for 8 h. The mixture was then dried to obtain compound 9-6.

[0630] MS (ESI) m / z (M+H) + =272.0.

[0631] Step 7: Preparation of compound 9-7

[0632]

[0633] 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 addition, the mixture was heated to 80°C and stirred for 1 hour. The mixture 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 150 mg of compound 9-7 as a yellow solid.

[0634] MS (ESI) m / z (M+H) + =308.3.

[0635] Step 8: Preparation of compound 9-8

[0636]

[0637] Compound 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). Under a nitrogen atmosphere, the mixture was heated to 100°C and stirred for 3 h. The mixture 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. MS (ESI) m / z (M+H) + =502.2.

[0638] Step 9: Preparation of compound 9-9

[0639]

[0640] Compound 9-8 (80 mg, 0.16 mmol), compound 2-3 (58.5 mg, 0.207 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (23.4 mg, 0.032 mmol), and potassium carbonate (44 mg, 0.321 mmol) were dissolved in a mixture of dioxane (4 mL) and water (1 mL). Under a nitrogen atmosphere, the mixture was heated to 100°C and reacted for 6 h. The mixture was concentrated and extracted 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.

[0641] MS (ESI) m / z (M+H) + =622.2.

[0642] Step 10: Preparation of Compounds 9-10

[0643]

[0644] Compound 9-9 (86 mg, 0.138 mmol) was dissolved in N,N-dimethylacetamide (3 mL). A 1 M solution of lithium bistrimethylsilylamide in tetrahydrofuran (0.8 mL) was added at room temperature. After addition, the mixture was heated to 160°C and stirred for 5 h under a nitrogen atmosphere. The mixture was cooled to room temperature and filtered. The filtrate was diluted with ethyl acetate (20 mL) and washed sequentially 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.

[0645] MS (ESI) m / z (M+H) +=575.2.

[0646] Step 11: Preparation of Compounds 9-11

[0647]

[0648] Compound 9-10 (32 mg, 0.0577 mmol) and hydrochloric acid (6N, 1 mL) were added to a mixture of methanol (0.9 mL) and tetrahydrofuran (0.1 mL). The mixture was heated to 55°C and reacted for 15 minutes. The mixture was concentrated to obtain crude product 9-11.

[0649] Step 12: Preparation of compound 9

[0650]

[0651] 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 2 h. The pH of the system was adjusted to neutral with 1N hydrochloric acid, and the solution 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 preparative liquid chromatography (separation conditions: chromatographic column: Agilent 10Prep-C8 250×21.2 mm; mobile phase: [water (0.1% FA)-acetonitrile]; acetonitrile%: 30%-50% 9 min, flow rate 30 mL / min) to obtain compound 9.

[0652] Compound 9

[0653] 1 H NMR (400 MHz, CDCl3) δ 1 H 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).MS(ESI)m / z(M+H) +=485.2.

[0654] HPLC 99% purity; retention time 5.27 min.

[0655] Separation conditions: Chromatographic column: Waters XSelect CSH C18, 4.6*100 mm, 3.5 μm; mobile phase: [water (0.01% trifluoroacetic acid)-acetonitrile (0.01% trifluoroacetic acid)]; acetonitrile: 5%-95% 7 min; flow rate: 1.2 mL / min.

[0656] Example 10: Preparation of Compound 10

[0657] Step 1: Preparation of compound 10-1

[0658]

[0659] Compound 1-12 (470 mg, 0.798 mmol) and triphenylphosphine (630 mg, 2.4 mmol) were added to 1,2-dichloroethane (20 mL). Under a nitrogen atmosphere, carbon tetrachloride (370 mg, 2.4 mmol) was added. After addition, 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 obtain compound 10-1.

[0660] MS (ESI) m / z (M+H) + =608.2.

[0661] Step 2: Preparation of compound 10-2

[0662]

[0663] 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 mixture was heated to 80°C and reacted for 1 h. The mixture was concentrated, and the residue was dissolved in ethyl acetate and filtered through celite. The filtrate was concentrated under vacuum and purified by column chromatography (ethyl acetate / petroleum ether (v / v) = 0-40%) to obtain compound 10-2.

[0664] MS (ESI) m / z (M+H) + =578.2

[0665] Step 3: Preparation of compound 10-3

[0666]

[0667] 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). The temperature was raised to 150°C and the reaction was allowed to proceed for 3 hours. The mixture was cooled to room temperature, and water (20 mL) was added. The mixture was extracted with EA (15 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) = 0-30%) to obtain compound 10-3.

[0668] MS (ESI) m / z (M+H) + =542.2.

[0669] Step 4: Preparation of compound 10-4

[0670]

[0671] 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 mixture of dioxane (5 mL) and water (0.5 mL). Under a nitrogen atmosphere, the mixture was heated to 100°C and stirred for 1 h. The mixture was concentrated, and the residue was dissolved in ethyl acetate (10 mL), washed with water, and allowed to stand for separation. 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 10-4.

[0672] MS (ESI) m / z (M+H) + =662.2.

[0673] Step 5: Preparation of compound 10-5

[0674]

[0675] Compound 10-4 (40 mg, 0.06 mmol) was dissolved in tetrahydrofuran (2 mL) and sodium hydride (7.2 mg, 0.18 mmol) was added at 0°C. After addition, the mixture was warmed to room temperature and stirred for 30 minutes. Iodomethane (17 mg, 0.12 mmol) was added and stirred at room temperature (20°C) for 1 hour. Water (5 mL) was added to quench the reaction, 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.

[0676] MS (ESI) m / z (M+H) + =676.2.

[0677] Step 6: Preparation of compound 10-6

[0678]

[0679] Compound 10-5 (30 mg, 0.044 mmol) and hydrochloric acid (6N, 2 mL) were added to a mixture of methanol (10 mL) and tetrahydrofuran (1 mL). The mixture was heated to 55°C and reacted for 15 minutes. The mixture was concentrated to obtain the crude product 10-6.

[0680] MS (ESI) m / z (M+H) + =532.4.

[0681] Step 7: Preparation of compound 10

[0682]

[0683] Compound 10-6 (15 mg, 0.060 mmol) was dissolved in dichloromethane (5 mL). The mixture 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 mixture was warmed to room temperature (20°C) and reacted for 30 min. The reaction solution was washed with water (5 mL) and extracted with dichloromethane (3 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 (HPLC) (separation conditions: column: Welch Ultimate XB-C18 10×250 mm 5 μm; mobile phase: [water (0.1% FA)-acetonitrile]; acetonitrile percentage: 50%-60% for 10 min, 60% for 20 min; flow rate: 8 mL / min). After concentration, Compound 10A and Compound 10B were obtained.

[0684] MS (ESI) m / z (M+H) + =586.2.

[0685] Compound 10A:

[0686] 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–

[0687] 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),3.48–3.35(m,2H),3.07(m,3H),3.073(m,1H),2.92(d,J=1 2.3Hz,1H),2.51–2.34(m,1H),1.63(m,3H),1.04(m,3H),0.89(m,3H).

[0688] HPLC 93% purity; retention time 6.397 min.

[0689] Separation conditions: Chromatographic column: Waters X-bridge C18, 4.6*100 mm, 3.5 μm; mobile phase: water (10 mM ammonium bicarbonate solution)-acetonitrile; acetonitrile: 5%-95% 7 min; flow rate: 1.2 mL / min.

[0690] Compound 10B:

[0691] 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=8.3,6.5Hz,1H),7.01(dd,J=7.9,1.3Hz,1H),6.74(dd,J=16.8,10.6Hz,1H),6.62–

[0692] 6.38 (m, 2H), 6.18 (dd, J = 16.8, 2.0 Hz, 1H), 5.72 (d, J = 10.7 Hz, 1H), 5.24 (td, J = 4.5, 2.2 Hz, 1H), 4.52 (m, 2H), 4.06 (d, J = 19.0 Hz, 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 = 26.2 Hz, 3H), 1.04 (d, J = 6.9 Hz, 3H), 0.89 (d, J = 6.9 Hz, 3H). HPLC purity 95%; retention time 6.580 min

[0693] Separation conditions: Chromatographic column: Waters X-bridge C18, 4.6*100 mm, 3.5 μm; mobile phase: water (10 mM ammonium bicarbonate solution)-acetonitrile; acetonitrile: 5%-95% 7 min; flow rate: 1.2 mL / min.

[0694] Example 11: Preparation of Compound 11

[0695] Step 1: Preparation of compound 11-1

[0696]

[0697] Compound 10-4 (40 mg, 0.06 mmol) and hydrochloric acid (6N, 1 mL) were added to a mixture of methanol (3 mL) and tetrahydrofuran (0.5 mL). The mixture was heated to 55°C and reacted for 15 minutes. The mixture was concentrated to obtain crude product 11-1.

[0698] MS (ESI) m / z (M+H) + =518.2.

[0699] Step 2: Preparation of compound 11

[0700]

[0701] Compound 11-1 (15 mg, 0.060 mmol) was dissolved in dichloromethane (5 mL). The mixture 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 mixture was warmed to room temperature (20°C) and reacted for 30 min. The reaction solution was washed with water (5 mL) and extracted with dichloromethane (3 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 (HPLC) (separation conditions: column: Welch Ultimate XB-C18 10×250 mm 5 μm; mobile phase: [water (0.1% FA)-acetonitrile]; acetonitrile percentage: 50%-60% for 10 min, 60% for 20 min; flow rate: 8 mL / min) to obtain compounds 11A and 11B.

[0702] Compound 11A:

[0703] 1H 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).

[0704] MS (ESI) m / z (M+H) + =572.2.

[0705] HPLC 95% purity; retention time 6.180 min.

[0706] Separation conditions: Chromatographic column: Waters X-bridge C18, 4.6*100 mm, 3.5 μm; mobile phase: [water (10 mM aqueous ammonium bicarbonate solution)-acetonitrile]; acetonitrile: 5%-95% 7 min; flow rate: 1.2 mL / min.

[0707] Compound 11B:

[0708] 1H 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),5.24(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).MS(ESI)m / z(M+H) + =572.2.

[0709] HPLC 95% purity; retention time 6.328 min.

[0710] Separation conditions: Chromatographic column: Waters X-bridge C18, 4.6*100 mm, 3.5 μm; mobile phase: [water (10 mM aqueous ammonium bicarbonate solution)-acetonitrile]; acetonitrile: 5%-95% 7 min; flow rate: 1.2 mL / min.

[0711] Example 12: Preparation of Compound 12

[0712] Step 1: Preparation of compound 12-2

[0713]

[0714] Compound 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 mixture was heated to 100°C and stirred for 1 h. The mixture was filtered through celite, 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.

[0715] MS (ESI) m / z (M+H)+ =576.20.

[0716] Step 2: Preparation of compound 12-3

[0717]

[0718] Compound 12-2 (700 mg, 1.2 mmol), compound 2-3 (508 mg, 1.8 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (176 mg, 0.24 mmol), and potassium carbonate (323 mg, 2.4 mmol) were dissolved in a mixture of dioxane (20 mL) and water (2 mL). Under a nitrogen atmosphere, the mixture was heated to 100°C and stirred for 2 h. The mixture was concentrated, and the residue was dissolved in ethyl acetate (10 mL), washed with water, and allowed to stand for separation. 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 compound 12-3.

[0719] MS (ESI) m / z (M+H) + =696.40.

[0720] Step 3: Preparation of compound 12-4

[0721]

[0722] Compound 12-3 (50 mg) was dissolved in N,N-dimethylacetamide (1 mL). A solution of lithium bistrimethylsilylamide in tetrahydrofuran (24%, 0.5 mL) was added at room temperature. Under a nitrogen atmosphere, the mixture was heated to 150°C and stirred for 4 hours. The mixture was cooled to room temperature and concentrated. The residue was dissolved in ethyl acetate (3 mL), washed with water, and allowed to stand for stratification. 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 compound 12-4.

[0723] MS (ESI) m / z (M+H) + =649.40.

[0724] Step 4: Preparation of compound 12-5

[0725]

[0726] Compound 12-4 (60.0 mg) and hydrochloric acid (6N, 1 mL) were added to a mixture of methanol (0.9 mL) and tetrahydrofuran (0.1 mL). The mixture was heated to 55°C and reacted for 15 minutes. The mixture was concentrated to obtain the crude product 12-5.

[0727] MS (ESI) m / z (M+H) + =505.20.

[0728] Step 5: Preparation of compounds 12A and 12B

[0729]

[0730] 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 mixture was warmed to room temperature (20°C) and allowed to react for 30 minutes. The reaction mixture was washed with water (5 mL) and extracted with dichloromethane (3 mL). The organic phase was 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 minutes. The pH of the reaction mixture was adjusted to 5-6 with dilute hydrochloric acid (3.0 N), and then extracted with ethyl acetate and concentrated to obtain the crude product. The crude product was purified by high-performance preparative liquid chromatography (HPLC) (separation conditions: chromatographic column: Agilent 10Prep-C8 250×21.2 mm; column temperature: 25°C; mobile phase: water (0.1% FA)-acetonitrile; mobile phase acetonitrile ratio 40%-52% in 12 min, 52%-52% in 16 min; flow rate 30 mL / min) to give compounds 12A and 12B.

[0731] Compound 12A:

[0732] 1 H 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).

[0733] MS (ESI) m / z (M+H) + =559.20.

[0734] HPLC 100% purity; retention time 5.483 min.

[0735] Separation conditions: Chromatographic column: Waters X-bridge C18, 4.6*100 mm, 3.5 μm; mobile phase: [water (10 mM aqueous ammonium bicarbonate solution)-acetonitrile]; acetonitrile: 5%-95% 7 min; flow rate: 1.2 mL / min.

[0736] Compound 12B:

[0737] 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).

[0738] MS (ESI) m / z (M+H) + =559.20.

[0739] HPLC 100% purity; retention time 5.555 min.

[0740] Separation conditions: Chromatographic column: Waters X-bridge C18, 4.6*100 mm, 3.5 μm; mobile phase: [water (10 mM aqueous ammonium bicarbonate solution)-acetonitrile]; acetonitrile: 5%-95% 7 min; flow rate: 1.2 mL / min.

[0741] Example 13: Preparation of Compound 13

[0742] Step 1: Preparation of compound 13-2

[0743]

[0744] Compound 1-12 (766 mg, 1.3 mmol), compound 13-1 (534 mg, 1.56 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (96 mg, 0.13 mmol), and potassium carbonate (359 mg, 2.6 mmol) were dissolved in a mixture of tetrahydrofuran (20 mL) and water (2 mL). Under a nitrogen atmosphere, the mixture was heated to 80°C and stirred for 2 h. The mixture was concentrated, and the residue was dissolved in ethyl acetate (10 mL), washed with water, and allowed to stand for separation. 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) = 0-33%) to obtain compound 13-2.

[0745] MS (ESI) m / z (M+H) + =770.20.

[0746] Step 2: Preparation of compound 13-3

[0747]

[0748] Compound 13-2 (300 mg) was dissolved in N,N-dimethylformamide (6 mL). A solution of lithium bistrimethylsilylamide in tetrahydrofuran (24%, 3.0 mL) was added at room temperature. The mixture was heated to 150°C and stirred for 16 hours. The mixture was cooled to room temperature and concentrated. The residue was dissolved in ethyl acetate (3 mL), washed with water, and allowed to stand for separation. 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 compound 13-3.

[0749] MS (ESI) m / z (M+H) + =723.30.

[0750] Step 3: Preparation of compound 13-4

[0751]

[0752] Compound 13-3 (214.0 mg) and hydrochloric acid (6N, 4.0 mL) were added to a mixture of methanol (3.6 mL) and tetrahydrofuran (0.4 mL). The mixture was heated to 55°C and reacted for 15 minutes. The mixture was concentrated to obtain the crude product 13-4.

[0753] MS (ESI) m / z (M+H) + =539.20

[0754] Step 4: Preparation of compounds 13A and 13B

[0755]

[0756] Compound 13-4 (159 mg, 0.29 mmol) was dissolved in N,N-dimethylformamide (5 mL). 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 at room temperature. After the addition was complete, the system was warmed to room temperature (20°C) and reacted for 30 minutes. The reaction solution was washed with water (30 mL) and extracted with ethyl acetate (30 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 (HPLC column: Agilent 10Prep-C8 250×21.2 mm; column temperature: 25°C; mobile phase: water (0.1% FA)-acetonitrile; mobile phase acetonitrile ratio 25%-40% in 9 min, 40%-45% in 12 min; flow rate 30 mL / min) to give compounds 13A and 13B.

[0757] Compound 13A:

[0758] 1 H 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).

[0759] HPLC 100% purity; retention time 5.069 min.

[0760] Separation conditions: Chromatographic column: Waters X-bridge C18, 4.6*100 mm, 3.5 μm; mobile phase: [water (10 mM aqueous ammonium bicarbonate solution)-acetonitrile]; acetonitrile: 5%-95% 7 min; flow rate: 1.2 mL / min.

[0761] Compound 13B:

[0762] 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).

[0763] HPLC 100% purity; retention time 5.279 min.

[0764] Separation conditions: Chromatographic column: Waters X-bridge C18, 4.6*100 mm, 3.5 μm; mobile phase: [water (10 mM aqueous ammonium bicarbonate solution)-acetonitrile]; acetonitrile: 5%-95% 7 min; flow rate: 1.2 mL / min.

[0765] Example 14: Preparation of Compound 14

[0766] Step 1: Preparation of compound 14-2

[0767]

[0768] Compound 5-10 (504 mg, 0.84 mmol), compound 14-1 (500 mg, 1.67 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (62 mg, 0.084 mmol), and potassium carbonate (232 mg, 1.68 mmol) were dissolved in a mixture of tetrahydrofuran (20 mL) and water (2 mL). Under a nitrogen atmosphere, the mixture was heated to 80°C and stirred for 6 h. The mixture was concentrated, and the residue was dissolved in ethyl acetate (10 mL), washed with water, and allowed to stand for separation. 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 obtain compound 14-2.

[0769] MS (ESI) m / z (M+H) + =746.20.

[0770] Step 2: Preparation of compound 14-3

[0771]

[0772] 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, carbon tetrachloride (130 mg, 0.8 mmol) was added. After addition, 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.

[0773] MS (ESI) m / z (M+H) + =764.20.

[0774] Step 3: Preparation of compound 14-4

[0775]

[0776] 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 mixture was heated to 80°C and reacted for 1 h. The mixture was concentrated, and the residue was dissolved in ethyl acetate and filtered through celite. The filtrate was concentrated under vacuum and purified by column chromatography (ethyl acetate / petroleum ether (v / v) = 0-50%) to obtain compound 14-4.

[0777] MS (ESI) m / z (M+H) + =734.20.

[0778] Step 4: Preparation of compound 14-5

[0779]

[0780] 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). The reaction mixture was heated to 120°C and allowed to react for 7 hours. The mixture was cooled to room temperature, and water (20 mL) was added. The mixture was extracted with EA (15 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) = 0-50%) to obtain compound 14-5.

[0781] MS (ESI) m / z (M+H) +=698.40.

[0782] Step 5: Preparation of compound 14-6

[0783]

[0784] Compound 14-5 (33 mg, 0.047 mmol) was dissolved in tetrahydrofuran (2 mL) and sodium hydride (7.2 mg, 0.18 mmol) was added at 0°C. After addition, the mixture was warmed to room temperature and stirred for 30 minutes. Iodomethane (17 mg, 0.12 mmol) was added and stirred at room temperature (20°C) for 1 hour. Water (5 mL) was added to quench the reaction, 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.

[0785] MS (ESI) m / z (M+H) + =712.50.

[0786] Step 6: Preparation of compound 14-7

[0787]

[0788] 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 reaction mixture was heated to 120°C and microwaved for 30 min. The mixture was concentrated, and the residue was dissolved in dichloromethane (4 mL). Trifluoroacetic acid (0.4 mL) was added, and the reaction mixture was allowed to react at room temperature (20°C) for 1 h. The reaction mixture was concentrated to obtain crude product 14-7.

[0789] MS (ESI) m / z (M+H) + =598.30.

[0790] Step 7: Preparation of compound 14

[0791]

[0792] 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 warmed to room temperature (20°C) and reacted for 30 minutes. The reaction solution was washed with water (5 mL) and extracted with dichloromethane (3 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by high-performance preparative liquid chromatography (separation conditions: chromatographic 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) to obtain compound 14.

[0793] 1 H 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).

[0794] MS (ESI) m / z (M+H) + =652.40.

[0795] Example 15: Preparation of Compound 15

[0796] Step 1: Preparation of compound 15-1

[0797]

[0798] Compound 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). Under a nitrogen atmosphere, the mixture was heated to 100°C and stirred for 1 h. The mixture was filtered through celite, 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.

[0799] MS (ESI) m / z (M+H) + =633.2.

[0800] Step 2: Preparation of compound 15-2

[0801]

[0802] Compound 15-1 (320 mg, 0.517 mmol) and iron powder (115 mg, 2.068 mmol) were dissolved in acetic acid (10 mL). Under a nitrogen atmosphere, the mixture was heated to 80°C and stirred for 1 h. The mixture was filtered through celite, and the filtrate was concentrated to obtain crude product 15-2.

[0803] MS (ESI) m / z (M+H) + =571.2.

[0804] Step 3: Preparation of compound 15-3

[0805]

[0806] 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 mixture of dioxane (5 mL) and water (0.5 mL). Under a nitrogen atmosphere, the mixture was heated to 100°C and stirred for 2 h. The reaction mixture was concentrated to obtain a crude product, which was then purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0-50%) to obtain compound 15-3.

[0807] MS (ESI) m / z (M+H) + =691.40.

[0808] Step 4: Preparation of compound 15-4

[0809]

[0810] 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 addition, the mixture was heated to 100°C and stirred for 1 hour under a nitrogen atmosphere. The mixture 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) = 0-50%) to obtain compound 15-4.

[0811] MS (ESI) m / z (M+H) + =737.5.

[0812] Step 5: Preparation of compound 15-5

[0813]

[0814] Compound 15-4 (25 mg, 0.035 mmol) and hydrochloric acid (6N, 2 mL) were added to a mixture of methanol (2 mL) and tetrahydrofuran (0.2 mL). The mixture was heated to 55°C and reacted for 1 h. The mixture was concentrated to obtain crude compound 15-5.

[0815] MS (ESI) m / z (M+H) + =593.40.

[0816] Step 6: Preparation of compound 15

[0817]

[0818] Compound 15-5 (25 mg, 0.04 mmol) was dissolved in dichloromethane (3 mL), the system was cooled to 0°C, triethylamine (0.1) and acryloyl chloride (4.6 mg, 0.0514 mmol) were added dropwise, and the system was reacted at 0°C for 0.5 h. The system was extracted with water (5 mL) and dichloromethane (3 mL), and the organic phase was concentrated to obtain a crude product. The crude product was purified by high-performance preparative liquid chromatography (separation conditions: chromatographic 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.

[0819] 1H 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).

[0820] MS (ESI) m / z (M+H) + =647.4.

[0821] HPLC 90% purity; retention time 5.224 min.

[0822] Separation conditions: Chromatographic column: Waters Xbridge C18 3.5μm, 100*4.6mm; column temperature: 40°C; mobile phase: water (10mM ammonium bicarbonate aqueous solution)-acetonitrile; acetonitrile: 5%-95% 7min, 95% 8min; flow rate: 1.2mL / min.

[0823] Example 16: Preparation of Compound 16

[0824] Step 1: Preparation of compound 16-1

[0825]

[0826] Under nitrogen, compound 3-14 (100 mg, 140.50 μmol) was dissolved in 1,2-dichloroethane (3 mL). Triphenylphosphine (112 mg, 427.01 μmol) and carbon tetrachloride (80 mg, 520.08 μmol, 0.05 mL) were added sequentially. The mixture was heated to 80°C and stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by preparative silica gel chromatography (ethyl acetate / petroleum ether (v / v) = 100%) to obtain compound 16-1.

[0827] MS (ESI) m / z (M+H) + =730.3.

[0828] Step 2: Preparation of compound 16-2

[0829]

[0830] 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 temperature was raised to 80°C with stirring 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 chromatography (ethyl acetate / petroleum ether (v / v) = 100%) to obtain compound 16-2.

[0831] MS (ESI) m / z (M+H) + =700.2.

[0832] Step 3: Preparation of compound 16-3

[0833]

[0834] 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 heated to 120°C in a sealed tube and stirred for 6 h. The reaction solution was concentrated under reduced pressure, and the crude product was purified by preparative silica gel chromatography (methanol / dichloromethane (v / v) = 1 / 15) to obtain compound 16-3.

[0835] MS (ESI) m / z (M+H) + =664.1.

[0836] Step 4: Preparation of compound 16-4

[0837]

[0838] Compound 16-3 (40 mg, 60.27 μmol) was dissolved in tetrahydrofuran (1 mL), and sodium hydride (5 mg, 125.01 μmol, 60%) and iodomethane (10 mg, 70.45 μmol) were added sequentially. The reaction 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 obtain crude product 16-4.

[0839] MS (ESI) m / z (M+H) + =678.4.

[0840] Step 5: Preparation of compound 16-5

[0841]

[0842] 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. MS (ESI) m / z (M+H) + =564.0.

[0843] Step 6: Preparation of compound 16

[0844]

[0845] 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 was stirred at 20°C for 1 hour. Methanol (1 mL) and aqueous potassium carbonate solution (2 M, 1 mL) were added, and stirring was continued for 1.5 hours. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 2). 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 preparative liquid chromatography (HPLC) (Separation conditions: Column: Phenomenex Gemini-NX 80*30 mm*3 μm; Mobile phase: [water (10 mM ammonium bicarbonate)-acetonitrile]; Acetonitrile percentage: 36%-66%; 9.5 min). Compound 16A (Peak 1) and Compound 16B (Peak B) were obtained.

[0846] Compound 16A:

[0847] 1H 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).MS(ESI)m / z(M+H) + =618.2.

[0848] HPLC 97% of purity; Retention time: 4.00min+4.051min.

[0849] Separation conditions: Chromatographic column: Xbridge Shield RP-18, 5μm, 2.1*50mm; column temperature: 50°C; mobile phase: [water (0.02% ammonia solution)-acetonitrile]; acetonitrile: 10%-80% for 6 min, 80% for 2 min; flow rate: 0.8 mL / min.

[0850] Compound 16B:

[0851] 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(brd,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).

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

[0853] HPLC 94% of purity; Retention time: 4.082min.

[0854] Separation conditions: Chromatographic column: Xbridge Shield RP-18, 5μm, 2.1*50mm; column temperature: 50°C; mobile phase: [water (0.02% ammonia solution)-acetonitrile]; acetonitrile: 10%-80% for 6 min, 80% for 2 min; flow rate: 0.8 mL / min.

[0855] Step 7: Preparation of compounds 16A-1 and 16A-2

[0856]

[0857] The diastereoisomers of compound 16A were purified by SFC (separation conditions: column: DAICEL CHIRALPAK AD-H (250 mm*30 mm, 5 μm); mobile phase: [CO2-isopropanol (0.1% aqueous ammonia)]; isopropanol percentage: 35%). After concentration, compounds 16A-1 and 16A-2 were obtained.

[0858] Compound 16A-1:

[0859] 1 H 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(brd,J=10.0Hz,1H),4.79(brs,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).

[0860] MS (ESI) m / z (M+H) + =618.3.

[0861] SFC retention time: 1.516 min.

[0862] Separation conditions: Column: Chiralpak AD-3 50x 4.6mm ID, 3μm; column temperature: 35°C; mobile phase: CO2-isopropanol (0.05% DEA); isopropanol: 5%-40% 2min, 40% 1.2min, 5% 0.8min; flow rate: 4mL / min.

[0863] Compound 16A-2:

[0864] 1 H 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).

[0865] MS (ESI) m / z (M+H) + =618.3.

[0866] SFC retention time: 1.644 min.

[0867] Separation conditions: Column: Chiralpak AD-3 50x 4.6mm ID, 3μm; column temperature: 35°C; mobile phase: CO2-isopropanol (0.05% DEA); isopropanol: 5%-40% 2min, 40% 1.2min, 5% 0.8min; flow rate: 4mL / min.

[0868] Step 8: Preparation of compounds 16B-1 and 16B-2

[0869]

[0870] The diastereoisomers of compound 16B were purified by SFC (separation conditions: column: DAICEL CHIRALPAK AD-H (250 mm*30 mm, 5 μm); mobile phase: [CO2-isopropanol (0.1% aqueous ammonia)]; isopropanol percentage: 35%). After concentration, compound 16B-1 and compound 16B-2 were obtained.

[0871] Compound 16B-1:

[0872] 1 H 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).

[0873] MS (ESI) m / z (M+H) + =618.3.

[0874] SFC retention time: 1.521 min.

[0875] Separation conditions: Column: Chiralpak AD-3 50x 4.6mm ID, 3μm; column temperature: 35°C; mobile phase: CO2-isopropanol (0.05% DEA); isopropanol: 5%-40% 2min, 40% 1.2min, 5% 0.8min; flow rate: 4mL / min.

[0876] Compound 16B-2:

[0877] 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).

[0878] MS (ESI) m / z (M+H) + =618.3.

[0879] SFC retention time: 1.652 min.

[0880] Separation conditions: Column: Chiralpak AD-3 50x 4.6mm ID, 3μm; column temperature: 35°C; mobile phase: CO2-isopropanol (0.05% DEA); isopropanol: 5%-40% 2min, 40% 1.2min, 5% 0.8min; flow rate: 4mL / min.

[0881] Example 17: Preparation of Compound 17

[0882] Step 1: Preparation of compound 17-2

[0883]

[0884] Compound 1-12 (450 mg, 0.76 mmol), 17-1 (240 mg, 0.92 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (65 mg, 0.076 mmol), and potassium carbonate (210 mg, 1.5 mmol) were dissolved in a mixture of dioxane (20 mL) and water (2 mL). Under a nitrogen atmosphere, the mixture was heated to 90°C and stirred for 3 h. The mixture was concentrated, and the residue was dissolved in ethyl acetate (10 mL), washed with water, and allowed to stand for separation. 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 17-2.

[0885] MS (ESI) m / z: (M+H) + =770.1.

[0886] Step 2: Preparation of compound 17-3

[0887]

[0888] Compound 17-2 (50 mg, 0.065 mmol) was dissolved in N,N-dimethylacetamide (5 mL). A solution of lithium bistrimethylsilylamide in tetrahydrofuran (24%, 0.65 mL) was added at room temperature. Under a nitrogen atmosphere, the mixture was heated to 160°C and stirred for 8 hours. The mixture was cooled to room temperature and concentrated. The residue was dissolved in ethyl acetate (3 mL), washed with water, and allowed to stand for stratification. 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 17-3.

[0889] MS (ESI) m / z: (M+H) + =723.3.

[0890] Step 3: Preparation of compound 17-4

[0891]

[0892] Compound 17-3 (30 mg, 0.041 mmol) was dissolved in methanol (3 mL) and concentrated hydrochloric acid (12N, 2 mL) was added. After addition, the system was heated to 70°C and reacted for 3 h. The system was concentrated to obtain a yellow oil 17-4, which was used directly in the next reaction without further purification. MS (ESI) m / z (M+H) + =539.2.

[0893] Step 4: Preparation of compound 17-6

[0894]

[0895] 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, the system was heated to 80°C and stirred for 1 h under sealed conditions. The system was concentrated, and saturated aqueous sodium bicarbonate solution was added to adjust the pH to >7. The system was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to obtain a crude product, which was purified by medium-pressure column chromatography (methanol / dichloromethane (v / v) = 0-10%) to obtain compound 17-6.

[0896] MS (ESI) m / z: (M+H)+ =212.8.

[0897] Step 5: Preparation of compound 17-7

[0898]

[0899] 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, the mixture was heated to 80°C and refluxed for 24 h. The mixture 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.

[0900] MS (ESI) m / z: (M+H) + =297.0.

[0901] Step 6: Preparation of compound 17-1

[0902]

[0903] Compound 17-7 (300 mg, 1.0 mmol), pinacol diboronate (500 mg, 2.0 mmol), potassium acetate (300 mg, 3.0 mmol), and ditricyclohexylphosphine palladium dichloride (74 mg, 0.1 mmol) were dissolved in a mixture of N,N-dimethylacetamide (10 mL) and water (1 mL). Under a nitrogen atmosphere, the mixture was heated to 155°C and stirred for 2 h. After cooling to room temperature, the mixture 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.

[0904] MS (ESI) m / z: (M+H) + =261.0.

[0905] Step 7: Preparation of compound 17

[0906]

[0907] Compound 17-4 (20 mg, 0.037 mmol) was dissolved in dichloromethane (1 mL). The mixture 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 mixture was warmed to room temperature (20°C) and reacted for 30 min. The reaction solution was washed with water (5 mL) and extracted with dichloromethane (3 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 (HPLC) (separation conditions: Agilent 10Prep-C8 250 × 21.2 mm column; 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.

[0908] MS (ESI) m / z (M+H) + =593.3.

[0909] HPLC: 95%, 4.875min+5.087min.

[0910] Separation conditions: Chromatographic column: Waters X-bridge C18, 4.6*100 mm, 3.5 μm; mobile phase: [water (10 mM ammonium bicarbonate aqueous solution)-acetonitrile]; acetonitrile: 5%-95% 7 min; flow rate: 1.2 mL / min.

[0911] Example 18: Preparation of Compounds 18A-1 / 18A-2 / 18B-1 and 18B-2

[0912] Step 1: Preparation of compound 18-1

[0913]

[0914] At 0°C under nitrogen, compound 4-8 (8.6 g, 26.24 mmol) was dissolved in acetonitrile (40 mL). 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) and washed with saturated sodium thiosulfate solution (80 mL x 2). The organic phases were combined, 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 to 2 / 3) to obtain compound 18-1.

[0915] 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).

[0916] Step 2: Preparation of compound 18-2

[0917]

[0918] Under nitrogen, compound 18-1 (6.5 g, 14.82 mmol) and 2-isopropyl-4-methyl-pyridin-3-amine (2.60 g, 17.31 mmol) were dissolved in toluene (10 mL). 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (950 mg, 1.64 mmol), tris(dibenzylideneacetone)dipalladium (1.5 g, 1.64 mmol), and cesium carbonate (14.49 g, 44.46 mmol) were added sequentially. The reaction mixture was heated to 100°C and stirred for 16 hours. 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 obtain compound 18-2.

[0919] MS (ESI) m / z (M+H) + =460.

[0920] 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).

[0921] Step 9: Preparation of compound 18-3

[0922]

[0923] 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 stirred for 20 min. Acetyl chloride (2.73 g, 34.71 mmol, 2.48 mL) was then added. The reaction mixture was warmed to 25°C and stirred for 16 h. The reaction mixture was quenched with water (100 mL), saturated potassium carbonate solution (100 mL) was added, stirred for 1 h, 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. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 0 to 0 / 1) to obtain compound 18-3.

[0924] MS (ESI) m / z (M+H) + =503.1.

[0925] 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,1 H),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).

[0926] Step 10: Preparation of compound 18-4

[0927]

[0928] Under nitrogen, compound 18-3 (580 mg, 1.15 mmol) was dissolved in toluene (10 mL), and potassium tert-butoxide (1.0 M in tetrahydrofuran, 3.74 mL) was added. The reaction was stirred at 25°C for 30 min. The reaction mixture was quenched with water (20 mL), and the pH was adjusted to 7.0 by adding 1.0 M hydrochloric acid. The mixture was extracted with ethyl acetate (30 mL x 3). 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.

[0929] MS (ESI) m / z (M+H) + =471.2.

[0930] 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).

[0931] Step 11: Preparation of compound 18-5

[0932]

[0933] Under nitrogen, compound 18-4 (500 mg, 1.06 mmol) was dissolved in acetic acid (10 mL). Concentrated nitric acid (1.23 g, 19.51 mmol, 878.20 μL) was added, and the reaction mixture was heated to 80°C and stirred for 2 h. The reaction mixture 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 step without further purification.

[0934] MS (ESI) m / z (M+H) + =516.2.

[0935] 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).

[0936] Step 12: Preparation of compound 18-6

[0937]

[0938] Under nitrogen, compound 18-5 (600 mg, 1.16 mmol) was dissolved in acetonitrile (10 mL). Diisopropylethylamine (901.86 mg, 6.98 mmol, 1.22 mL) and phosphorus oxychloride (534.98 mg, 3.49 mmol, 324.23 μL) were added sequentially. The reaction mixture was heated to 80°C and stirred for 2 h. The reaction mixture 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 obtain compound 18-6.

[0939] MS (ESI) m / z (M+H) + =534.

[0940] 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).

[0941] Step 13: Preparation of compound 18-7

[0942]

[0943] 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 temperature was raised to 80°C and stirred for 1 hour. 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 obtain compound 18-7. MS (ESI) m / z (M+H) + =728.2.

[0944] Step 14: Preparation of compound 18-8

[0945]

[0946] Under nitrogen, compound 18-7 (350 mg, 480.65 μmol) was dissolved in N-methylpyrrolidone (10 mL). 4A molecular sieves (500 mg) and lithium bistrimethylsilylamide (1 M in tetrahydrofuran, 1.44 mL) were added sequentially. The reaction mixture was heated to 130°C and stirred for 16 hours. The solvent was removed by concentration under reduced pressure, and the mixture was diluted with ethyl acetate (50 mL). The mixture was filtered and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol (v / v) = 10 / 1) to afford compound 18-8.

[0947] MS (ESI) m / z (M+H) + =681.3.

[0948] Step 15: Preparation of compound 18-9

[0949]

[0950] Under nitrogen, 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 by adding 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.

[0951] MS (ESI) m / z (M+H) + =567.1.

[0952] Step 16: Preparation of compounds 18A and 18B

[0953]

[0954] Compound 18-9 (128.49 mg, 226.60 μmol) was dissolved in tetrahydrofuran (5 mL), and sodium bicarbonate (3.79 g, 45.14 mmol, 1.76 mL) and acrylic anhydride (28.58 mg, 226.60 μmol) were added sequentially. The reaction was stirred at 25°C for 30 min, and methanol (2 mL) and saturated aqueous potassium carbonate solution (2 mL) were added, and stirring was continued for 1 h. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by high-performance preparative liquid phase separation (separation conditions: chromatographic column: Phenomenex Gemini-NX 80*30 mm*3 μm; mobile phase: [water (10 mM ammonium bicarbonate solution)-acetonitrile]; acetonitrile %: 50%-80%, 9 min) to obtain:

[0955] Compound 18A (HPLC retention time 3.747, 3.871 min).

[0956] Compound 18B (HPLC retention time 3.835, 3.916 min).

[0957] HPLC analysis conditions: chromatographic column: Xbridge Shield RP-18, 5 μm, 2.1*50 mm; mobile phase: [water (0.02% ammonia solution v / v)-acetonitrile]; acetonitrile%: 10%-80%, column temperature: 50°C.

[0958] Compound 18A:

[0959] MS (ESI) m / z (M+H) + =621.2.

[0960] 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).

[0961] Compound 18B:

[0962] MS (ESI) m / z (M+H) + =621.2.

[0963] 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).

[0964] Step 17: Separation of compounds 18A-1 and 18A-2

[0965]

[0966] Compound 18A was separated and purified by SFC (separation conditions: chromatographic column: REGIS (s, s) WHELK-O1 (250 mm * 30 mm, 5 μm); mobile phase: [supercritical carbon dioxide-ethanol]; ethanol%: 50%-50%) to obtain:

[0967] Compound 18A-1 (HPLC retention time 8.29 min; ee: 99.24%).

[0968] Compound 18A-2 (HPLC retention time 8.37 min; ee: 99.38%).

[0969] HPLC analysis conditions: chromatographic 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°C.

[0970] SFC chiral analysis conditions: chromatographic column: (S,S)-Whelk-O1 100*4.6 mm, 3 μm; mobile phase: [supercritical carbon dioxide-ethanol (0.05% diethylamine solution v / v)]; ethanol%: 40%-40%, column temperature: 35°C.

[0971] Compound 18A-1:

[0972] MS (ESI) m / z (M+H) +=621.3.

[0973] 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).

[0974] Compound 18A-2:

[0975] MS (ESI) m / z (M+H) + =621.2.

[0976] 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).

[0977] Step 18: Isolation of compounds 18B-1 and 18B-2

[0978]

[0979] Compound 18B was separated and purified by SFC (separation conditions: chromatographic column: REGIS (s, s) WHELK-O1 (250 mm * 30 mm, 5 μm); mobile phase: [supercritical carbon dioxide-ethanol]; ethanol%: 50%-50%) to obtain:

[0980] Compound 18B-1 (HPLC retention time 8.59 min; ee: 100%).

[0981] Compound 18B-2 (HPLC retention time 8.53 min; ee: 100%).

[0982] HPLC analysis conditions: chromatographic 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°C.

[0983] SFC chiral analysis conditions: chromatographic column: (S,S)-Whelk-O1 100*4.6 mm, 3 μm; mobile phase: [supercritical carbon dioxide-ethanol (0.05% diethylamine solution v / v)]; ethanol%: 40%-40%, column temperature: 35°C.

[0984] 18B-1:

[0985] MS (ESI) m / z (M+H) + =621.2.

[0986] 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).

[0987] 18B-2:

[0988] MS (ESI) m / z (M+H) + =621.2.

[0989] 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(brdd,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).

[0990] Example 19: Preparation of Compound 19

[0991] Step 1: Preparation of compound 19-3

[0992]

[0993] At room temperature (20°C), compound 19-1 (9.5 g, 57.93 mmol), compound 19-2 (29.20 g, 173.79 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium 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). Under a nitrogen atmosphere, the mixture was heated to 100°C and stirred for 12 h. The mixture was cooled to room temperature and concentrated to remove most of the solvent. 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 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.

[0994] 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).MS(ESI)m / z(M+H)+ =175.9.

[0995] Step 2: Preparation of compound 19-4

[0996]

[0997] Compound 19-3 (10.37 g, 59.18 mmol) was dissolved in methanol (50 mL) and 10% palladium on carbon (1 g) was added under a nitrogen atmosphere. After the addition, the system was replaced with hydrogen. Under a hydrogen atmosphere (15 psi), the system was stirred at room temperature (25°C) for 12 h. The system was filtered and the filtrate was concentrated. The residue was dissolved in dichloromethane (100 mL) and washed with 2M aqueous hydrochloric acid (50 mL). The aqueous phase was adjusted to pH 9-10 with sodium hydroxide and extracted with dichloromethane (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 19-4, which was used directly in the next reaction without further purification.

[0998] 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).MS(ESI)m / z(M+H) + =180.0.

[0999] Step 3: Preparation of compound 19-5

[1000]

[1001] At room temperature (20°C), compound 3-8 (4.8 g, 11.37 mmol), compound 19-4 (2.65 g, 14.78 mmol), tris(dibenzylideneacetone)dipalladium (1.2 g, 1.31 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (750 mg, 1.30 mmol), and cesium carbonate (11.11 g, 34.11 mmol) were dissolved in toluene (40 mL). Under a nitrogen atmosphere, the mixture was heated to 100°C and stirred for 16 hours. The mixture 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.

[1002] 1H NMR(400MHz,Chloroform-d)δ8.97(s,1H),8.90(br d,J=3.7Hz,1H),7.67(brdd,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).

[1003] MS (ESI) m / z (M+H) + =474.4.

[1004] Step 4: Preparation of compound 19-6

[1005]

[1006] 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 portionwise at 0°C. The mixture was allowed to react at 0°C for 20 min, followed by the dropwise addition of acetyl chloride (3.73 g, 47.52 mmol, 3.39 mL). After the addition, the mixture was allowed to react at room temperature (25°C) for 16 h under a nitrogen atmosphere. The reaction was quenched by the addition of water (20 mL). Saturated aqueous potassium carbonate was added, and the mixture was stirred at room temperature (25°C) for 1 h. The mixture was then 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, which was then purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0-100%) to yield compound 19-6.

[1007] MS (ESI) m / z (M+H) + =516.3.

[1008] Step 5: Preparation of compound 19-7

[1009]

[1010] At room temperature (20°C), compound 19-6 (1 g, 1.94 mmol) was dissolved in toluene (10 mL), and potassium tert-butoxide (1 M, 6.28 mL) was added. After addition, the system was reacted at room temperature (25°C) for 0.5 h under a nitrogen atmosphere. The reaction was quenched by adding water (20 mL), and the pH was adjusted to neutral with 1N hydrochloric acid. 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 step without further purification.

[1011] 1 H 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).

[1012] MS (ESI) m / z (M+H) + =484.0.

[1013] Step 6: Preparation of compound 19-8

[1014]

[1015] 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 at room temperature (20°C). After the addition was complete, the mixture was heated to 80°C and stirred for 2 h. After cooling to room temperature, the mixture was concentrated to remove most of the glacial acetic acid. The residue was poured into ice water (50 mL) to separate the precipitate. The filter cake was washed with water and dried to obtain compound 19-8, which was used directly in the next step without further purification.

[1016] 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).

[1017] MS (ESI) m / z (M+H) + =529.0.

[1018] Step 7: Preparation of compound 19-9

[1019]

[1020] 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 addition, the mixture was heated to 80°C and stirred for 2 h. The mixture 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 obtain compound 19-9.

[1021] 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).

[1022] MS (ESI) m / z (M+H) + =547.0.

[1023] Step 8: Preparation of compound 19-10

[1024]

[1025] Compound 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). Under a nitrogen atmosphere, the mixture was heated to 80°C and stirred for 1 hour. The mixture 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 19-10.

[1026] MS (ESI) m / z (M+H) + =741.1.

[1027] Step 9: Preparation of compound 19-11

[1028]

[1029] Compound 19-10 (270 mg, 364.49 μmol) and Molecular sieves (1 g) were dissolved in N-methylpyrrolidone (8 mL). A 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1.09 mL) was added at room temperature. After addition, the system was heated to 130°C and stirred for 16 h under a nitrogen atmosphere. The system was cooled to room temperature, water (20 mL) was added, and the mixture was extracted 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 obtain compound 19-11.

[1030] MS (ESI) m / z (M+H) + =694.1.

[1031] Step 10: Preparation of compound 19-12

[1032]

[1033] 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 addition, the mixture was warmed to room temperature (25°C) and stirred for 2 h under a nitrogen atmosphere. Methanol (5 mL) was added and stirred for 10 min. The mixture was concentrated and lyophilized to obtain compound 19-12 (hydrobromide salt), which was used directly in the next step without further purification.

[1034] MS (ESI) m / z (M+H) + =580.1.

[1035] Step 11: Preparation of compounds 19A and 19B

[1036]

[1037] Compound 19-12 (70 mg, 120.77 μmol, hydrobromide salt) was dissolved in tetrahydrofuran (2 mL) and saturated aqueous sodium bicarbonate (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 minutes. Methanol (2 mL) and a saturated aqueous potassium carbonate solution (2 mL) were added to the system, and stirring was continued at room temperature (25°C) for 1 hour. The system was diluted with water (10 mL) and 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 sequentially by medium-pressure column chromatography (methanol / dichloromethane (v / v) = 0-10%) and high-performance preparative liquid chromatography (separation conditions: chromatographic 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.

[1038] Compound 19A:

[1039] 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).

[1040] MS (ESI) m / z (M+H) + =634.3.

[1041] HPLC 91% purity; retention time 3.84 min.

[1042] Separation conditions: Chromatographic column: Xbridge Shield RP-18, 5μm, 2.1*50mm; column temperature: 50°C; mobile phase: water (0.2mL / L ammonia solution)-acetonitrile; acetonitrile: 10%-80% for 6min, 80% for 2min; flow rate: 0.8mL / min.

[1043] Compound 19B:

[1044] 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).

[1045] MS (ESI) m / z (M+H) + =634.3.

[1046] HPLC 91% purity; retention time 3.88 min.

[1047] Separation conditions: Chromatographic column: Xbridge Shield RP-18, 5μm, 2.1*50mm; column temperature: 50°C; mobile phase: water (0.2mL / L ammonia solution)-acetonitrile; acetonitrile: 10%-80% for 6min, 80% for 2min; flow rate: 0.8mL / min.

[1048] Example 20: Preparation of Compound 20

[1049] Step 1: Preparation of compound 20-1

[1050]

[1051] Compound 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). Under a nitrogen atmosphere, the mixture was heated to 80°C and stirred for 12 h. The mixture was concentrated to obtain a crude product, which was then purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0-100%) to afford compound 20-1.

[1052] MS (ESI) m / z (M+H) + =769.1.

[1053] Step 2: Preparation of compound 20-2

[1054]

[1055] 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 mixture was heated to 80°C and stirred for 45 minutes. The mixture was concentrated, diluted with dichloromethane (20 mL), and filtered. 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 step without further purification.

[1056] MS (ESI) m / z (M+H) + =707.2.

[1057] Step 3: Preparation of compound 20-3

[1058]

[1059] Compound 20-2 (100 mg, 141.49 μmol) and potassium carbonate (52.99 mg, 383.44 μmol) were dissolved in acetone (2 mL). Methyl iodide (271.12 mg, 1.91 mmol, 118.91 μL) was added at room temperature (25°C). After addition, the mixture was heated to 40°C and stirred for 16 h under a nitrogen atmosphere. The mixture was concentrated, and dichloromethane (10 mL) and water (10 mL) were added for separation and 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.

[1060] MS (ESI) m / z (M+H) + =721.3.

[1061] Step 4: Preparation of compound 20-4

[1062]

[1063] 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 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 salt), which was used directly in the next reaction without further purification.

[1064] MS (ESI) m / z (M+H) + =607.1.

[1065] Step 5: Preparation of compound 20

[1066]

[1067] Compound 20-4 (100 mg, 164.84 μmol, hydrobromide salt) was dissolved in tetrahydrofuran (2 mL) and saturated aqueous sodium bicarbonate (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 minutes. Methanol (2 mL) and a saturated aqueous potassium carbonate solution (2 mL) were added to the system, and stirring was continued at room temperature (25°C) for 1 hour. The system was diluted with water (10 mL) and 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 preparative liquid chromatography (separation conditions: chromatographic 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.

[1068] Compound 20A:

[1069] 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).

[1070] MS (ESI) m / z (M+H) + =661.1.

[1071] HPLC 95% purity; retention time 10.49 min.

[1072] Separation conditions: Column: WELCH MLtimate LP-C18 150*4.6mm, 5μm; Column temperature: 40°C; 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:

[1073] 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).

[1074] MS (ESI) m / z (M+H) + =661.1.

[1075] HPLC 94% purity; retention time 10.82 min.

[1076] Separation conditions: Chromatographic column: WELCHMLtimate LP-C18 150*4.6mm, 5μm; column temperature: 40°C; mobile phase: water (0.0688% trifluoroacetic acid solution)-acetonitrile (0.0625% trifluoroacetic acid solution); acetonitrile: 10%-80% 10 min, 80% 5 min; flow rate: 1.5 mL / min.

[1077] Example 21: Preparation of Compound 21

[1078] Step 1: Preparation of compound 21-1

[1079]

[1080] Compound 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). Under a nitrogen atmosphere, the mixture was heated to 80°C and stirred for 12 h. The mixture was concentrated to obtain a crude product, which was then purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0-100%) to obtain compound 21-1.

[1081] MS (ESI) m / z (M+H) + =740.2.

[1082] Step 2: Preparation of compound 21-2

[1083]

[1084] 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 mixture was heated to 80°C and stirred for 45 minutes. The mixture was concentrated, diluted with dichloromethane (20 mL), and filtered. 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 step without further purification.

[1085] MS (ESI) m / z (M+H) + =678.1.

[1086] Step 3: Preparation of compound 21-3

[1087]

[1088] Compound 21-2 (120 mg, 177.07 μmol) and potassium carbonate (66.31 mg, 479.77 μmol) were dissolved in acetone (2 mL). Methyl iodide (339.29 mg, 2.39 mmol, 148.81 μL) was added at room temperature (25°C). After addition, the mixture was heated to 40°C and stirred for 16 h under a nitrogen atmosphere. The mixture was concentrated, and dichloromethane (10 mL) and water (10 mL) were added for separation and 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.

[1089] MS (ESI) m / z (M+H) + =692.2.

[1090] Step 4: Preparation of compound 21-4

[1091]

[1092] 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 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 salt), which was used directly in the next reaction without further purification.

[1093] MS (ESI) m / z (M+H) + =578.1.

[1094] Step 5: Preparation of compounds 21A and 21B

[1095]

[1096] Compound 21-4 (100 mg, 151.86 μmol, hydrobromide salt) was dissolved in tetrahydrofuran (2 mL) and saturated aqueous sodium bicarbonate 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 minutes. Methanol (2 mL) and aqueous potassium carbonate solution (2 mL) were added to the system, and stirring was continued at room temperature (25°C) for 1 hour. The system was diluted with water (10 mL) and 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 preparative liquid chromatography (HPLC) (separation conditions: column: Phenomenex Gemini-NX 80*30mm*3μm; mobile phase: [water (10mM ammonium bicarbonate solution)-acetonitrile]; acetonitrile percentage: 38%-68% over 9min) to give compounds 21A and 21B.

[1097] Compound 21A:

[1098] 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).

[1099] MS (ESI) m / z (M+H) + =632.2.

[1100] Compound 21B:

[1101] 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).

[1102] MS (ESI) m / z (M+H) + =632.3.

[1103] Step 6: Separation of isomers of compound 21A

[1104]

[1105] The diastereoisomers of compound 21A were purified by SFC (separation conditions: column: Phenomenex-Cell μLose-2 (250 mm*30 mm, 10 μm); mobile phase: [0.1% ammonia in methanol]; methanol percentage: 40%-40%). After concentration, compound 21A-1 and compound 21A-2 were obtained.

[1106] Compound 21A-1:

[1107] 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).

[1108] MS (ESI) m / z (M+H) + =632.2.

[1109] HPLC 92% purity; retention time 8.18 min.

[1110] Separation conditions: Chromatographic column: WELCH Ultimate LP-C18 150*4.6mm 5μm; column temperature: 40°C; mobile phase: water (0.0688% trifluoroacetic acid solution)-acetonitrile (0.0625% trifluoroacetic acid solution); acetonitrile: 10%-80% 10 min, 80% 5 min; flow rate: 1.5 mL / min; SFC 90% ee retention time: 4.707 min.

[1111] Separation conditions: Chromatographic column: Cellulose 2 100*4.6mm ID, 3μm; column temperature: 35°C; 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.

[1112] Compound 21A-2:

[1113] 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).

[1114] MS (ESI) m / z (M+H) + =632.2.

[1115] HPLC 98% purity; retention time 8.17 min.

[1116] Separation conditions: Chromatographic column: WELCH Ultimate LP-C18 150*4.6mm 5μm; column temperature: 40°C; mobile phase: water (0.0688% trifluoroacetic acid solution)-acetonitrile (0.0625% trifluoroacetic acid solution); acetonitrile: 10%-80% 10 min, 80% 5 min; flow rate: 1.5 mL / min SFC 100% ee. Retention time: 5.145 min.

[1117] Separation conditions: Chromatographic column: Cellulose 2 100*4.6mm ID, 3μm; column temperature: 35°C; 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.

[1118] Step 7: Separation of isomers of compound 21B

[1119]

[1120] The diastereoisomers of compound 21B were purified by SFC (separation conditions: column: DAICEL CHIRALPAK AD-H (250 mm*30 mm, 5 μm); mobile phase: [0.1% ammonia in ethanol]; ethanol: 35%-35%). After concentration, compound 21B-1 and compound 21B-2 were obtained.

[1121] Compound 21B-1:

[1122] 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).

[1123] MS (ESI) m / z (M+H) + =632.1.

[1124] HPLC 99% purity; retention time 8.38 min.

[1125] Separation conditions: Chromatographic column: WELCH Ultimate LP-C18 150*4.6mm 5μm; column temperature: 40°C; mobile phase: water (0.0688% trifluoroacetic acid solution)-acetonitrile (0.0625% trifluoroacetic acid solution); acetonitrile: 10%-80% 10 min, 80% 5 min; flow rate: 1.5 mL / min SFC 100% ee. Retention time: 4.041 min.

[1126] Separation conditions: Chromatographic column: Chiralpak AD-3 150×4.6mm ID, 3μm; column temperature: 35°C; 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.

[1127] Compound 21B-2:

[1128] 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).

[1129] MS (ESI) m / z (M+H) + =632.1.

[1130] HPLC 99% purity; retention time 8.30 min.

[1131] Separation conditions: Column: WELCH Ultimate LP-C18 150*4.6mm 5μm; Column temperature: 40°C; 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.

[1132] Separation conditions: Chromatographic column: Chiralpak AD-3 150×4.6mm ID, 3μm; column temperature: 35°C; 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.

[1133] Example 22: Preparation of Compound 22

[1134] Step 1: Preparation of compound 22-1

[1135]

[1136] 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 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 salt), which was used directly in the next reaction without further purification.

[1137] MS (ESI) m / z (M+H) + =564.1.

[1138] Step 2: Preparation of compounds 22A and 22B

[1139]

[1140] Compound 22-1 (80 mg, 124.13 μmol, hydrobromide salt) was dissolved in tetrahydrofuran (2 mL) and saturated aqueous sodium bicarbonate 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 minutes. Methanol (2 mL) and aqueous potassium carbonate solution (2 mL) were added to the system, and stirring was continued at room temperature (25°C) for 1 hour. The system was diluted with water (10 mL) and 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 preparative liquid chromatography (HPLC) (separation conditions: column: Phenomenex Gemini-NX 80*30mm*3μm; mobile phase: [water (10mM ammonium bicarbonate solution)-acetonitrile]; acetonitrile percentage: 37%-67% over 9min) to give compounds 22A and 22B.

[1141] Compound 22A:

[1142] 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).

[1143] MS (ESI) m / z (M+H) + =618.2.

[1144] Compound 22B:

[1145] 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).

[1146] MS (ESI) m / z (M+H) + =618.2&618.1.

[1147] Step 3: Separation of isomers of compound 22A

[1148]

[1149] The diastereoisomers of compound 21A were purified by SFC (separation conditions: column: DAICEL CHIRALCEL OD-H (250 mm*30 mm, 5 μm); mobile phase: [Neu-ethanol]; ethanol%: 50%-50%). After concentration, compound 22A-1 and compound 22A-2 were obtained.

[1150] Compound 22A-1:

[1151] 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).

[1152] MS (ESI) m / z (M+H) + =618.1.

[1153] HPLC 100% purity; retention time 7.85 min.

[1154] Separation conditions: Column: WELCH Ultimate LP-C18 150 x 4.6 mm 5 μm; Column temperature: 40°C; Mobile phase: Water (0.0688% trifluoroacetic acid solution)-Acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10% to 80% over 10 minutes, then 80% over 5 minutes; Flow rate: 1.5 mL / min. SFC 100% ee. Retention time: 4.917 minutes.

[1155] Separation conditions: Chromatographic column: Chiralcel OD-3 100*4.6mm ID, 3μm; column temperature: 35°C; 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.

[1156] Compound 22A-2:

[1157] 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).

[1158] MS (ESI) m / z (M+H) + =618.1.

[1159] HPLC 99.3% purity; retention time 7.91 min.

[1160] Separation conditions: Chromatographic column: WELCHMLtimate LP-C18 150*4.6mm 5μm; column temperature: 40°C; mobile phase: water (0.0688% trifluoroacetic acid solution)-acetonitrile (0.0625% trifluoroacetic acid solution); acetonitrile: 10%-80% 10 min, 80% 5 min; flow rate: 1.5 mL / min SFC 98.5% ee. Retention time 5.310 min.

[1161] Separation conditions: Chromatographic column: Chiralcel OD-3 100*4.6mm ID, 3μm; column temperature: 35°C; 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.

[1162] Step 4: Separation of isomers of compound 22B

[1163]

[1164] The diastereoisomers of compound 21A were purified by SFC (separation conditions: column: DAICEL CHIRALCEL OD-H (250 mm*30 mm, 5 μm); mobile phase: [Neu-methanol]; methanol percentage: 40%-40%). After concentration, compound 22B-1 and compound 22B-2 were obtained.

[1165] Compound 22B-1:

[1166] 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).

[1167] MS (ESI) m / z (M+H) + =618.1.

[1168] HPLC 93.6% purity; retention time 8.14 min.

[1169] Separation conditions: Column: WELCH Ultimate LP-C18 150 x 4.6 mm 5 μm; Column temperature: 40°C; Mobile phase: Water (0.0688% trifluoroacetic acid solution)-Acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10% to 80% over 10 minutes, then 80% over 5 minutes; Flow rate: 1.5 mL / min. SFC 100% ee. Retention time: 3.589 minutes.

[1170] Separation conditions: Chromatographic column: Chiralcel OD-3 100*4.6mm ID, 3μm; column temperature: 35°C; mobile phase: CO2-methanol (0.05% DEA); methanol: 40%-40%; flow rate: 2.8mL / min.

[1171] Compound 22B-2:

[1172] 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(brd,J=6.8Hz,3H),1.08(d,J=6.8Hz,3H).

[1173] MS (ESI) m / z (M+H) + =618.1.

[1174] HPLC 99.3% purity; retention time 8.12 min.

[1175] Separation conditions: Chromatographic column: WELCH Ultimate LP-C18 150*4.6mm 5μm; column temperature: 40°C; mobile phase: water (0.0688% trifluoroacetic acid solution)-acetonitrile (0.0625% trifluoroacetic acid solution); acetonitrile: 10%-80% 10 min, 80% 5 min; flow rate: 1.5 mL / min SFC 97.8% ee. Retention time: 4.079 min.

[1176] Separation conditions: Chromatographic column: Chiralcel OD-3 100*4.6mm ID, 3μm; column temperature: 35°C; mobile phase: CO2-methanol (0.05% DEA); methanol: 40%-40%; flow rate: 2.8mL / min.

[1177] Example 23: Preparation of Compound 23

[1178] Step 1: Preparation of compound 23-1

[1179]

[1180] Under nitrogen, compound 18-6 (450 mg, 842.16 μmol) was dissolved in acetonitrile (8 mL). Diisopropylethylamine (545.29 mg, 4.22 mmol, 734.90 μL) and compound JMKX-1805-Inter 5A (326.31 mg, 1.26 mmol) were added sequentially. 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 obtain compound 23-1.

[1181] MS (ESI) m / z (M+H) + =756.2.

[1182] Step 2: Preparation of compound 23-2

[1183]

[1184] 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 mixture was heated to 80°C and stirred for 45 minutes. The mixture was concentrated, diluted with dichloromethane (20 mL), and filtered. 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 step without further purification.

[1185] MS (ESI) m / z (M+H) + =694.1.

[1186] Step 3: Preparation of compound 23-3

[1187]

[1188] Compound 23-2 (150 mg, 216.09 μmol) and potassium carbonate (80.94 mg, 585.60 μmol) were dissolved in acetone (2 mL). Methyl iodide (414.06 mg, 2.92 mmol, 181.61 μL) was added at room temperature (25°C). After addition, the mixture was heated to 40°C and stirred for 16 h under a nitrogen atmosphere. The mixture was concentrated, and dichloromethane (10 mL) and water (10 mL) were added for separation and 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.

[1189] MS (ESI) m / z (M+H) + =708.1.

[1190] Step 4: Preparation of compound 23-4

[1191]

[1192] 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 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 salt), which was used directly in the next reaction without further purification.

[1193] MS (ESI) m / z (M+H) + =594.1.

[1194] Step 5: Preparation of compounds 23A and 23B

[1195]

[1196] Compound 23-4 (130 mg, 153.92 μmol, hydrobromide salt) was dissolved in tetrahydrofuran (5 mL) and saturated aqueous sodium bicarbonate (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 minutes. Methanol (2 mL) and a saturated aqueous potassium carbonate solution (2 mL) were added to the system, and stirring was continued at room temperature (25°C) for 1 hour. The system was diluted with water (10 mL) and 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 preparative liquid chromatography (HPLC) (separation conditions: column: Phenomenex Gemini-NX 80*30mm*3μm; mobile phase: [water (10mM ammonium bicarbonate aqueous solution)-acetonitrile]; acetonitrile percentage: 44%-74% over 9min) to give compounds 23A and 23B.

[1197] Compound 23A:

[1198] 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.

[1199] Compound 23B:

[1200] 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(brd, 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.

[1201] Step 6: Separation of isomers of compound 23A

[1202]

[1203] The diastereoisomers of compound 23A were purified by SFC (separation conditions: column: DAICEL CHIRALCEL OJH (250 mm*30 mm, 5 μm); mobile phase: [0.1% aqueous ammonia in isopropanol]; isopropanol percentage: 35%-35%). After concentration, compounds 23A-1 (2.46 mg, yield 12.30%) and 23A-2 (4.07 mg, yield 20.35%) were obtained.

[1204] Compound 23A-1:

[1205] 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).

[1206] MS (ESI) m / z (M+H) + =648.2.

[1207] SFC retention time: 2.544 min

[1208] Separation conditions: Chromatographic column: Chiralcel OJ-3 100mm x 4.6mm ID, 3μm; column temperature: 35°C; 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: 2.8mL / min.

[1209] Compound 23A-2:

[1210] 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),2.04(s,3H), 1.76-1.63(m,3H),1.25(d,J=6.8Hz,3H),1.15(d,J=6.8Hz,3H).MS(ESI)m / z(M+H) + =648.2.

[1211] SFC retention time: 2.670 min.

[1212] Separation conditions: Chromatographic column: Chiralcel OJ-3 100mm x 4.6mm ID, 3μm; column temperature: 35°C; 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: 2.8mL / min.

[1213] Step 7: Separation of isomers of compound 23B

[1214]

[1215] The diastereoisomers of compound 23B were purified by SFC (separation conditions: column: REGIS (s,s) WHELK-O1 (250 mm*30 mm, 5 μm); mobile phase: [0.1% ammonia in ethanol]; ethanol percentage: 40%-40%). After concentration, compound 23B-1 and compound 23B-2 were obtained.

[1216] Compound 23B-1:

[1217] 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).MS(ESI)m / z(M+H) + =648.2.

[1218] SFC retention time: 5.051 min

[1219] Separation conditions: Chromatographic column: (S,S)-Whelk-O1 100 mm x 4.6 mm ID, 3 μm; column temperature: 35°C; 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.

[1220] Compound 23B-2:

[1221] 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).

[1222] MS (ESI) m / z (M+H) + =648.2.

[1223] SFC retention time: 5.618 min

[1224] Separation conditions: Chromatographic column: (S,S)-Whelk-O1 100 mm x 4.6 mm ID, 3 μm; column temperature: 35°C; 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.

[1225] Example 24: Preparation of Compound 24

[1226] Step 1: Preparation of compound 24-1

[1227]

[1228] Compound 21-2 (100 mg, 147.56 μmol) and potassium carbonate (123 mg, 889.98 μmol) were dissolved in N,N-dimethylformamide (3 mL). 2-Bromo-N,N-dimethylethylamine (100 mg, 429.29 μmol, HBr) and potassium iodide (25 mg, 150.60 μmol) were added at room temperature (25°C). After addition, the mixture was heated to 100°C and stirred for 16 h. The mixture was diluted with ethyl acetate (30 mL) and washed sequentially with water (20 mL) and saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product, which was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 1 / 15) to obtain compound 24-1.

[1229] MS (ESI) m / z (M+H) + =749.4.

[1230] Step 2: Preparation of compound 24-2

[1231]

[1232] 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 stirred at room temperature (20°C) for 8 h under a nitrogen atmosphere. The reaction solution was quenched with methanol (5 mL), stirred for 10 min, and concentrated under reduced pressure to obtain compound 24-2 (hydrobromide salt), which was used directly in the next reaction without further purification.

[1233] MS (ESI) m / z (M+H) + =635.2.

[1234] Step 3: Preparation of compounds 24A, 24B, 24C and 24D

[1235]

[1236] Compound 24-2 (45 mg, 62.88 μmol, hydrobromide salt) was dissolved in tetrahydrofuran (2 mL) and saturated aqueous sodium bicarbonate (2.16 g, 25.71 mmol, 1 mL). A solution of acrylic anhydride (15 mg, 118.94 μmol) in tetrahydrofuran (0.5 mL) was added at room temperature (25°C). The mixture was stirred at room temperature (25°C) for 2 h. Methanol (1 mL) and saturated aqueous potassium carbonate (2 M, 1 mL) were added, and stirring was continued at room temperature (25°C) for 1.5 h. The mixture was diluted with water (10 mL), adjusted to pH ~7 with 1N HCl, and extracted with ethyl acetate (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to obtain the crude product. The crude product was purified by high-performance preparative liquid chromatography (HPLC) (Separation conditions: Phenomenex Gemini-NX 80*30mm*3μm column; mobile phase: water (10mM ammonium bicarbonate aqueous solution)-acetonitrile; acetonitrile percentage: 40%-70% over 9 minutes) and then by SFC (Separation conditions: DAICEL CHIRALCEL OD (250mm*30mm, 10μm column); mobile phase: 0.1% ammonia in isopropanol; isopropanol percentage: 25%-25% and DAICEL CHIRALPAK AD-H (250mm*30mm, 5μm column); mobile phase: 0.1% ammonia in ethanol; ethanol percentage: 25%-25%). After concentration, compounds 24A, 24B, 24C, and 24D were obtained.

[1237] Compound 24A:

[1238] 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).

[1239] MS (ESI) m / z (M+H) + =689.2.

[1240] SFC retention time: 3.949 min.

[1241] Separation conditions: Chromatographic column: Chiralpak AD-3 150 mm x 4.6 mm ID, 3 μm; column temperature: 35°C; 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.

[1242] Compound 24B:

[1243] 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).

[1244] MS (ESI) m / z (M+H) + =689.4.

[1245] SFC retention time: 3.389 min.

[1246] Separation conditions: Chromatographic column: Chiralpak AD-3 150 mm x 4.6 mm ID, 3 μm; column temperature: 35°C; 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.

[1247] Compound 24C:

[1248] 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).

[1249] MS (ESI) m / z (M+H) + =689.4.

[1250] SFC retention time: 3.917 min.

[1251] Separation conditions: Chromatographic column: Chiralpak AD-3 150 mm x 4.6 mm ID, 3 μm; column temperature: 35°C; 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.

[1252] Compound 24D:

[1253] 1 H 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

[1254] -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).

[1255] MS (ESI) m / z (M+H) + =689.4.

[1256] SFC retention time: 4.278 min.

[1257] Separation conditions: Chromatographic column: Chiralpak AD-3 150 mm x 4.6 mm ID, 3 μm; column temperature: 35°C; 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.

[1258] Example 25: Preparation of Compounds 25A and 25B

[1259] Step 1: Preparation of compound 25-1

[1260]

[1261] Compound 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). The mixture was heated to 100°C and stirred for 4 h. The mixture was concentrated to obtain a crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0-35%) to obtain compound 25-1.

[1262] MS (ESI) m / z (M+H) + =649.0.

[1263] Step 2: Preparation of compound 25-2

[1264]

[1265] Compound 25-1 (326 mg, 0.502 mmol) and iron powder (200 mg, 3.6 mmol) were dissolved in acetic acid (15 mL). Under a nitrogen atmosphere, the mixture was heated to 85°C and stirred for 1 hour. The mixture was filtered through celite, and the filtrate was concentrated. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 25-2. This was used directly in the next reaction without further purification.

[1266] MS (ESI) m / z (M+H) + =587.0.

[1267] Step 3: Preparation of compound 25-3

[1268]

[1269] 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 mixture of dioxane (18 mL) and water (1.8 mL). Under a nitrogen atmosphere, the mixture was heated to 100°C and stirred for 2 h. The reaction mixture was concentrated to obtain a crude product, which was then purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0-50%) to yield compound 25-3.

[1270] MS (ESI) m / z (M+H) + =707.2.

[1271] Step 4: Preparation of compound 25-4

[1272]

[1273] Compound 25-3 (40 mg, 0.057 mmol) and potassium carbonate (21 mg, 0.15 mmol) were dissolved in acetone (3 mL). Methyl iodide (21 mg, 0.15 mmol) was added at room temperature (20°C). After addition, the mixture was heated to 60°C and stirred for 3 h under a nitrogen atmosphere. The mixture 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) = 0-50%) to obtain compound 25-4.

[1274] MS (ESI) m / z (M+H) + =721.2.

[1275] Step 5: Preparation of compound 25-5

[1276]

[1277] Compound 25-4 (50 mg, 0.069 mmol) and hydrochloric acid (6N, 2 mL) were added to a mixture of methanol (2 mL) and tetrahydrofuran (0.2 mL). The mixture was heated to 55°C and reacted for 10 minutes. The reaction mixture was concentrated to obtain crude compound 25-5, which was used directly in the next reaction without further purification.

[1278] MS (ESI) m / z (M+H) + =577.2.

[1279] Step 6: Preparation of compound 25

[1280]

[1281] Compound 25-5 (40 mg, 0.069 mmol) was dissolved in dichloromethane (5 mL), the system was cooled to 0°C, triethylamine (39 mg, 0.39 mmol) and acryloyl chloride (23 mg, 0.26 mmol) were added dropwise, and the system was reacted at 0°C for 0.5 h. The system was quenched with methanol and concentrated to obtain a crude product. The crude product was dissolved in methanol (5 mL), potassium carbonate (140 mg) was added thereto, and after the addition was complete, the system was stirred at room temperature (20°C) for 30 min. The system was adjusted to pH ~ 6 with hydrochloric acid, and extracted 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 a crude product. The crude product was purified by high-performance preparative liquid phase (separation conditions: chromatographic column 5μm F5 LC Column 150 x 21.2 mm, mobile phase: water (0.1% FA)-acetonitrile; acetonitrile 22%-42% in 9 min; flow rate 30 mL / min) to obtain compound 25.

[1282] MS (ESI) m / z (M+H) + =631.2.

[1283] Step 7: Preparation of compounds 25A and 25B

[1284]

[1285] The diastereoisomers of compound 25 were purified by SFC (ChiralPak AD, 250×30 mm ID, 10 μm; mobile phase: [CO2-ethanol (0.1% ammonia)]; ethanol percentage: 35%; flow rate: 80 mL / min; column temperature: 38°C). After concentration, compound 25A and compound 25B were obtained.

[1286] Compound 25A

[1287] 1H 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).

[1288] MS (ESI) m / z (M+H) + =631.2.

[1289] SFC 100% ee. Retention time 4.102 min.

[1290] Separation conditions: Column: ChiralPak AD-3, 150×4.6mm ID, 3μm; Mobile phase: [CO2-ethanol (0.05% DEA)]; Ethanol percentage: 5%-40% for 5 min, 40% for 2.5 min, 5% for 2.5 min; Flow rate: 2.5 mL / min; Column temperature: 35°C

[1291] Compound 25B

[1292] 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).

[1293] MS (ESI) m / z (M+H) + =631.2.

[1294] SFC 100% ee. Retention time 5.424 min.

[1295] Separation conditions: Column: ChiralPak AD-3, 150×4.6mm ID, 3μm; Mobile phase: [CO2-ethanol (0.05% DEA)]; Ethanol percentage: 5%-40% for 5 min, 40% for 2.5 min, 5% for 2.5 min; Flow rate: 2.5 mL / min; Column temperature: 35°C

[1296] Example 26: Preparation of Compound 26

[1297] Step 1: Preparation of compound 26-2

[1298]

[1299] 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 to the mixture at room temperature (25°C). After addition, the mixture was heated to 120°C and stirred for 3 h under a nitrogen atmosphere. The mixture was concentrated, diluted with ethyl acetate (20 mL), and filtered. The filtrate was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to obtain the crude product, which was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 1 / 10) to obtain compound 26-2.

[1300] MS (ESI) m / z (M+H) + =765.5.

[1301] Step 2: Preparation of compound 26-3

[1302]

[1303] 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 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 solution, 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.

[1304] MS (ESI) m / z (M+H) + =651.3.

[1305] Step 3: Preparation of compounds 26A and 26B

[1306]

[1307] Compound 26-3 (280 mg, 430.01 μmol) was dissolved in tetrahydrofuran (3 mL) and saturated aqueous sodium bicarbonate (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 mixture was stirred at room temperature (25°C) for 30 min. The mixture was diluted with water (10 mL) and 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 preparative liquid chromatography (HPLC) (Separation conditions: Phenomenex Gemini-NX 80*30mm*3μm column; mobile phase: water (10mM ammonium bicarbonate aqueous solution)-acetonitrile; acetonitrile percentage: 55%-85% over 9 min), followed by SFC (Separation conditions: DAICEL CHIRALPAK AD-H 250mm*30mm, 5μm column; mobile phase: CO2-(0.1% aqueous ammonia)-isopropanol; isopropanol percentage: 35%-35%). After concentration, compounds 26A, 26B, 26C, and 26D were obtained.

[1308] Compound 26A:

[1309] 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).

[1310] MS (ESI) m / z (M+H) + =705.3.

[1311] HPLC retention time: 6.9 min.

[1312] Separation conditions: Column: WELCH Ultimate LP-C18 150 x 4.6 mm 5 μm; Column temperature: 40°C; Mobile phase: Water (0.0688% trifluoroacetic acid solution)-Acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10% to 80% for 10 minutes, then 80% for 5 minutes; Flow rate: 1.5 mL / min. SFC retention time: 4.077 minutes.

[1313] Separation conditions: Chromatographic column: Chiralpak AD-3 150x 4.6mm ID, 3μm; column temperature: 35°C; mobile phase: CO2-isopropanol (0.05% DEA); isopropanol: 5%-40% 5min, 40% 2.5min, 5% 2.5min; flow rate: 2.5mL / min.

[1314] Compound 26B:

[1315] 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).

[1316] MS (ESI) m / z (M+H) + =705.3.

[1317] HPLC retention time: 6.67 min.

[1318] Separation conditions: Chromatographic column: WELCH Ultimate LP-C18 150*4.6mm 5μm; column temperature: 40°C; 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

[1319] Separation conditions: Chromatographic column: Chiralpak AD-3 150x 4.6mm ID, 3μm; column temperature: 35°C; mobile phase: CO2-isopropanol (0.05% DEA); isopropanol: 5%-40% 5min, 40% 2.5min, 5% 2.5min; flow rate: 2.5mL / min.

[1320] Compound 26C:

[1321] 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).

[1322] MS (ESI) m / z (M+H) + =705.3.

[1323] HPLC retention time: 6.67 min.

[1324] Separation conditions: Chromatographic column: WELCH Ultimate LP-C18 150*4.6mm 5μm; column temperature: 40°C; 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

[1325] Separation conditions: Chromatographic column: Chiralpak AD-3 150x 4.6mm ID, 3μm; column temperature: 35°C; mobile phase: CO2-isopropanol (0.05% DEA); isopropanol: 5%-40% 5min, 40% 2.5min, 5% 2.5min; flow rate: 2.5mL / min.

[1326] Compound 26D:

[1327] 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).

[1328] MS (ESI) m / z (M+H) + =705.3.

[1329] HPLC retention time: 6.88 min.

[1330] Separation conditions: Chromatographic column: WELCH Ultimate LP-C18 150*4.6mm 5μm; column temperature: 40°C; mobile phase: water (0.0688% trifluoroacetic acid solution)-acetonitrile (0.0625% trifluoroacetic acid solution); acetonitrile: 10%-80% for 10 minutes, 80% for 5 minutes; flow rate: 1.5 mL / min; SFC retention time: 5.114 minutes

[1331] Separation conditions: Chromatographic column: Chiralpak AD-3 150x 4.6mm ID, 3μm; column temperature: 35°C; mobile phase: CO2-isopropanol (0.05% DEA); isopropanol: 5%-40% 5min, 40% 2.5min, 5% 2.5min; flow rate: 2.5mL / min.

[1332] Example 27: Preparation of Compound 27

[1333] Step 1: Preparation of compound 27-1

[1334]

[1335] 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 mixture was stirred at 25°C for 16 h. The reaction solution was concentrated to obtain compound 27-1, which was used directly in the next reaction without further purification.

[1336] MS (ESI) m / z (M+H) + =665.3.

[1337] Step 2: Preparation of compound 27

[1338]

[1339] Compound 27-1 (200 mg, 300.67 μmol) was dissolved in tetrahydrofuran (2 mL) and saturated aqueous sodium bicarbonate (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 mixture was stirred at room temperature (25°C) for 30 min. The mixture was diluted with water (10 mL) and 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 preparative liquid chromatography (HPLC) (Separation conditions: Phenomenex Gemini-NX 80*30mm*3μm column; mobile phase: water (10mM ammonium bicarbonate aqueous solution)-acetonitrile; acetonitrile percentage: 49%-79% over 9 min), followed by SFC (Separation conditions: DAICEL CHIRALPAK AD-H 250mm*30mm, 5μm column; mobile phase: CO2-(0.1% ammonia)ethanol; ethanol percentage: 25%-25%). After concentration, compounds 27A, 27B, 27C, and 27D were obtained.

[1340] Compound 27A:

[1341] 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).

[1342] MS (ESI) m / z (M+H) + =719.3.

[1343] HPLC retention time: 4.761 min.

[1344] Separation conditions: Chromatographic column: Xbridge Shield RP-18, 5μm, 2.1*50mm; column temperature: 50°C; mobile phase: water (0.2mL / L ammonia solution)-acetonitrile; acetonitrile: 10%-80% for 6min, 80% for 2min; flow rate: 0.8mL / min.

[1345] SFC retention time 4.329 min.

[1346] Separation conditions: Chromatographic column: Chiralpak IG-3 100×4.6mm ID, 3μm; column temperature: 35°C; 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.

[1347] Compound 27B:

[1348] 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).

[1349] MS (ESI) m / z (M+H) + =719.3.

[1350] HPLC retention time 4.775 min.

[1351] Separation conditions: Chromatographic column: Xbridge Shield RP-18, 5μm, 2.1*50mm; column temperature: 50°C; mobile phase: water (0.2mL / L ammonia solution)-acetonitrile; acetonitrile: 10%-80% for 6min, 80% for 2min; flow rate: 0.8mL / min.

[1352] SFC retention time: 4.523 min.

[1353] Separation conditions: Chromatographic column: Chiralpak IG-3 100×4.6mm ID, 3μm; column temperature: 35°C; 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.

[1354] Compound 27C:

[1355] 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),2.45-2.33(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).MS(ESI)m / z(M+H) + =719.3.

[1356] HPLC retention time 4.732 min.

[1357] Separation conditions: Chromatographic column: Xbridge Shield RP-18, 5μm, 2.1*50mm; column temperature: 50°C; mobile phase: water (0.2mL / L ammonia solution)-acetonitrile; acetonitrile: 10%-80% for 6min, 80% for 2min; flow rate: 0.8mL / min.

[1358] SFC retention time 8.150 min.

[1359] Separation conditions: Chromatographic column: ChiralPak IC-3 150×4.6mm ID, 3μm; column temperature: 40°C; mobile phase: CO2-ethanol (0.05% DEA); isopropanol: 5%-40% 5.5min, 40% 3min, 5% 1.5min; flow rate: 2.5mL / min.

[1360] Compound 27D:

[1361] 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).MS(ESI)m / z(M+H) + =719.3.

[1362] HPLC retention time 4.716 min.

[1363] Separation conditions: Chromatographic column: Xbridge Shield RP-18, 5μm, 2.1*50mm; column temperature: 50°C; mobile phase: water (0.2mL / L ammonia solution)-acetonitrile; acetonitrile: 10%-80% for 6min, 80% for 2min; flow rate: 0.8mL / min.

[1364] SFC retention time: 6.545 min.

[1365] Separation conditions: Chromatographic column: ChiralPak IC-3 150×4.6mm ID, 3μm; column temperature: 40°C; mobile phase: CO2-ethanol (0.05% DEA); isopropanol: 5%-40% 5.5min, 40% 3min, 5% 1.5min; flow rate: 2.5mL / min.

[1366] Example 28: Preparation of Compound 28

[1367] Step 1: Preparation of compound 28-2

[1368]

[1369] Compound 28-1 (1 g, 4.61 mmol), ammonium acetate (2.13 g, 27.65 mmol), diacetyl iodobenzene (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 temperature was raised to 70°C and the reaction was allowed to proceed for 30 min. After cooling the reaction to room temperature (25°C), saturated sodium thiosulfate (5 mL) was added. The reaction mixture 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.

[1370] 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).

[1371] Step 2: Preparation of compound 28-3

[1372]

[1373] At room temperature (20°C), compound 28-2 (760 mg, 3.55 mmol), pinacol diboron (1.35 g, 5.33 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (289.97 mg, 355.08 μmol), and potassium acetate (1.05 g, 10.65 mmol) were dissolved in 1,4-dioxane (5 mL). Under a nitrogen atmosphere, the mixture was heated to 100°C and stirred for 16 hours. The mixture 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) = 0-5%) to obtain compound 28-3.

[1374] Step 3: Preparation of compound 28-5

[1375]

[1376] 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 mixture of dioxane (3 mL) and water (0.3 mL). Under a nitrogen atmosphere, the mixture was heated to 100°C and stirred for 5 h. The mixture 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 obtain compound 28-5.

[1377] MS (ESI) m / z (M+H) + =701.1.

[1378] Step 4: Preparation of compound 28-6

[1379]

[1380] 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 uL) was added. The system was heated to 80°C and reacted for 4 h. The system was cooled to room temperature (25°C) and concentrated. The residue was dissolved in ethyl acetate (10 mL) and extracted with 1N hydrochloric acid (20 mL x 3). The aqueous phases were combined, the pH was adjusted to ~8 with 1M sodium hydroxide, and 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.

[1381] MS (ESI) m / z (M+H) + =713.4.

[1382] Step 5: Preparation of compound 28-7

[1383]

[1384] 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 mixture was stirred at 25°C for 1 h. The reaction solution was concentrated to obtain compound 28-7, which was used directly in the next reaction without further purification. MS (ESI) m / z (M+H) + =613.3.

[1385] Step 6: Preparation of compound 28

[1386]

[1387] Compound 28-7 (50 mg, 81.61 μmol) was dissolved in tetrahydrofuran (3 mL) and saturated aqueous NaHCO₃ (3 mL). Acrylic anhydride (11.32 mg, 89.77 μmol) was added at room temperature (25°C). After addition, the mixture was stirred at room temperature (25°C) for 2 h. The mixture was diluted with water (10 mL) and 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 preparative liquid chromatography (HPLC) (Separation conditions: Phenomenex Gemini-NX 80*30mm*3μm column; mobile phase: water (10mM ammonium bicarbonate aqueous solution)-acetonitrile; acetonitrile percentage: 36%-66% over 9 min), followed by SFC (Separation conditions: DAICEL CHIRALPAK IG (250mm*30mm, 10μm column; mobile phase: CO2-(0.1% ammonia) methanol; methanol percentage: 55%-55%). After concentration, compounds 28A, 28B, and 28C were obtained.

[1388] Compound 28A:

[1389] 1H 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).

[1390] MS (ESI) m / z (M+H) + =667.3.

[1391] HPLC retention time: 6.49 min.

[1392] Separation conditions: Column: WELCH Ultimate C18 150 x 4.6 mm, 5 μm; Column temperature: 40°C; Mobile phase: Water (0.0688% trifluoroacetic acid solution)-Acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10% to 80% over 10 min, then 80% over 5 min; Flow rate: 1.5 mL / min. SFC retention time: 1.661 min.

[1393] Separation conditions: Chromatographic column: Chiralpak IG-3 50*4.6mm ID, 3μm; column temperature: 35°C; mobile phase: CO2-methanol (0.05% DEA); methanol: 40%-40%; flow rate: 4mL / min.

[1394] Compound 28B:

[1395] 1H 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).MS(ESI)m / z(M+H) + =667.3.

[1396] HPLC retention time: 6.66 min.

[1397] Separation conditions: Column: WELCH Ultimate C18 150 x 4.6 mm, 5 μm; Column temperature: 40°C; Mobile phase: Water (0.0688% trifluoroacetic acid solution)-Acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10% to 80% over 10 min, then 80% over 5 min; Flow rate: 1.5 mL / min. SFC retention time: 4.234 min.

[1398] Separation conditions: Chromatographic column: Chiralpak IG-3 50*4.6mm ID, 3μm; column temperature: 35°C; mobile phase: CO2-methanol (0.05% DEA); methanol: 40%-40%; flow rate: 4mL / min.

[1399] Compound 28C:

[1400] 1H 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).

[1401] MS (ESI) m / z (M+H) + =667.3.

[1402] HPLC retention time: 6.77 min.

[1403] Separation conditions: Chromatographic column: WELCH Ultimate C18 150*4.6mm, 5μm; column temperature: 40°C; mobile phase: water (0.0688% trifluoroacetic acid solution)-acetonitrile (0.0625% trifluoroacetic acid solution); acetonitrile: 10%-80% 10 min, 80% 5 min; flow rate: 1.5 mL / min; SFC retention time: 2.725 min.

[1404] Separation conditions: Chromatographic column: Chiralpak IG-3 50*4.6mm ID, 3μm; column temperature: 35°C; mobile phase: CO2-methanol (0.05% DEA); methanol: 40%-40%; flow rate: 4mL / min.

[1405] Example 29: Preparation of Compound 29

[1406] Step 1: Preparation of compound 29-1

[1407]

[1408] 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 addition, the mixture was heated to 120°C and stirred for 2 h under a nitrogen atmosphere. The mixture 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.

[1409] MS (ESI) m / z (M+H) + =778.2.

[1410] Step 2: Preparation of compound 29-2

[1411]

[1412] Compound 29-1 (150 mg, 0.2 mmol) and hydrochloric acid (6N, 7 mL) were added to a mixture of methanol (0.6 mL) and tetrahydrofuran (6 mL). The mixture was heated to 55°C and reacted for 10 minutes. The mixture was concentrated to obtain crude compound 29-2, which was used directly in the next reaction without further purification.

[1413] MS (ESI) m / z (M+H) + =634.2.

[1414] Step 3: Preparation of compound 29

[1415]

[1416] Compound 29-2 (140 mg, 0.2 mmol) was dissolved in dichloromethane (10 mL), the system was cooled to 0°C, triethylamine (0.3 mL, 2.1 mmol) and acryloyl chloride (27 mg, 0.3 mmol) were added dropwise, and the system was reacted at 0°C for 0.5 h. The system was quenched with methanol and concentrated to obtain a crude product. The crude product was dissolved in methanol (5 mL), potassium carbonate (140 mg) was added, and after the addition, the system was stirred at room temperature (20°C) for 30 min. The system was adjusted to pH ~ 6 with hydrochloric acid, and extracted 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 a crude product. The crude product was purified by high-performance preparative liquid chromatography (separation conditions: Welch column C18 21.2×250 mm, 10 μm; column temperature: 25°C; mobile phase: water (10 mM / L NH4HCO3)-acetonitrile; acetonitrile 40%-60% 9 min; flow rate 30 mL / min) to obtain compound 29.

[1417] MS (ESI) m / z (M+H) + =688.2.

[1418] Step 4: Preparation of compounds 29A and 29B

[1419]

[1420] The diastereoisomers of compound 29 were purified by SFC (ChiralPak AD, 250×30 mm ID, 10 μm; mobile phase: [CO2-ethanol (0.1% ammonia)]; ethanol percentage: 25%; flow rate: 60 mL / min; column temperature: 38°C). After concentration, compound 29A and compound 29B were obtained.

[1421] Compound 29A:

[1422] 1 H 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).

[1423] MS (ESI) m / z (M+H) + =688.3.

[1424] SFC 100% ee. Retention time 3.559 min.

[1425] Separation conditions: Column: ChiralPak AD-3, 150×4.6mm ID, 3μm; Mobile phase: [CO2-ethanol (0.05% DEA)]; Ethanol percentage: 5%-40% for 5 min, 40% for 2.5 min, 5% for 2.5 min; Flow rate: 2.5 mL / min; Column temperature: 35°C

[1426] Compound 29B:

[1427] 1 H 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=16.4Hz,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=14.1Hz,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).

[1428] MS (ESI) m / z (M+H) + =688.3.

[1429] HPLC retention time: 5.269 min.

[1430] Separation conditions: Column: Waters XBridge 4.6*100 mm, 3.5 μm; Column temperature: 40°C; Mobile phase: Water (10 mM ammonium bicarbonate)-acetonitrile; Acetonitrile: 5% to 95% over 7 min; Flow rate: 1.2 mL / min. SFC: 100% ee. Retention time: 4.349 min.

[1431] Separation conditions: Chromatographic 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℃.

[1432] Example 30: Preparation of Compound 30

[1433] Step 1: Preparation of compound 30-1

[1434]

[1435] 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 mixture of dioxane (18 mL) and water (1.8 mL). Under a nitrogen atmosphere, the mixture was heated to 100°C and stirred for 2 h. The reaction mixture was concentrated to obtain a crude product, which was then purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0-50%) to yield compound 30-1.

[1436] MS (ESI) m / z (M+H) + =677.2.

[1437] Step 2: Preparation of compound 30-2

[1438]

[1439] 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 addition, the mixture was heated to 120°C and stirred for 2 h under a nitrogen atmosphere. The mixture 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.

[1440] MS (ESI) m / z (M+H) + =748.2.

[1441] Step 3: Preparation of compound 30-3

[1442]

[1443] Compound 30-2 (80 mg, 0.107 μmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (1 mL) was added, and the 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.

[1444] MS (ESI) m / z (M+H) + =648.4.

[1445] Step 4: Preparation of compound 30

[1446]

[1447] Compound 30-3 (70 mg, 0.107 mmol) was dissolved in dichloromethane (10 mL), and the system was cooled to 0°C. Triethylamine (0.1 mL, 0.7 mmol) and acryloyl chloride (14 mg, 0.2 mmol) were added dropwise, and the system was reacted at 0°C for 0.5 h. The system was quenched with water and concentrated to obtain a crude product, which was then extracted 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 a crude product. The crude product was purified by high-performance preparative liquid chromatography (separation conditions: Welch column). C18 21.2×250 mm, 10 μm; column temperature: 25°C; mobile phase: water (10 mM / L NH4HCO3)-acetonitrile; acetonitrile 45%-75% 9 min; flow rate 30 mL / min) to obtain compound 30.

[1448] MS (ESI) m / z (M+H) + =702.2.

[1449] Step 5: Preparation of compounds 30A and 30B

[1450]

[1451] The diastereoisomers of compound 30 were purified by SFC (ChiralPak AD, 250×30 mm ID, 10 μm; mobile phase: [CO2-ethanol (0.1% ammonia)]; ethanol percentage: 35%; flow rate: 80 mL / min; column temperature: 38°C). After concentration, compound 30A and compound 30B were obtained.

[1452] Compound 30A:

[1453] 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).

[1454] MS (ESI) m / z (M+H) + =702.3.

[1455] SFC 100% ee. Retention time 3.619 min.

[1456] Separation conditions: Chromatographic 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℃.

[1457] Compound 30B:

[1458] 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).

[1459] MS (ESI) m / z (M+H) + =702.3.

[1460] SFC 100% ee. Retention time 4.635 min.

[1461] Separation conditions: Column: ChiralPak AD-3, 150×4.6mm ID, 3μm; Mobile phase: [CO2-ethanol (0.05% DEA)]; Ethanol percentage: 5%-40% for 5 min, 40% for 2.5 min, 5% for 2.5 min; Flow rate: 2.5 mL / min; Column temperature: 35°C

[1462] Example 31: Preparation of Compound 31

[1463] Step 1: Preparation of compound 31-2

[1464]

[1465] Potassium nitrate (10.49 g, 103.72 mmol) was dissolved in concentrated sulfuric acid (80 mL). The mixture was stirred at room temperature (20°C) for 1 h. Compound 31-1 (10 g, 57.62 mmol) was then added portionwise. After addition, the mixture was heated to 80°C and stirred for 2 h. The mixture 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.

[1466] Step 2: Preparation of compound 31-3

[1467]

[1468] Compound 31-2 (12.6 g, 57.65 mmol) was dissolved in 20% aqueous sulfuric acid (200 mL). The temperature was raised to 85°C and stirred for 16 h. The mixture was cooled to room temperature (20°C), diluted with water (1 L), and extracted with ethyl acetate (2 x 500 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to obtain compound 31-3.

[1469] 1 H NMR (400MHz, DMSO-d6) δ = 7.77 (d, J = 7.8Hz, 1H).

[1470] Step 3: Preparation of compound 31-4

[1471]

[1472] 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 addition, the mixture was heated to 70°C and stirred for 16 hours. The mixture was 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.

[1473] Step 4: Preparation of compound 31-5

[1474]

[1475] Compound 31-4 (6 g, 23.85 mmol) was dissolved in a mixture of ethyl acetate (50 mL) and dichloromethane (50 mL). Stannous chloride dihydrate (26.91 g, 119.25 mmol) was added. After addition, the mixture was stirred at room temperature (20°C) for 16 h. The mixture was filtered, and the filtrate was concentrated to obtain compound 31-5.

[1476] 1 H NMR (400 MHz, CHLOROFORM-d) δ = 7.50 (dd, J = 2.3, 9.8 Hz, 1H), 5.74 (br s, 2H), 3.92 (s, 3H). Step 5: Preparation of compound 31-6

[1477]

[1478] 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). Tert-butyl nitrite (11.17 g, 108.31 mmol, 12.88 mL) was added at 0°C. Under a nitrogen atmosphere, the mixture was heated to 80°C and stirred for 2 h. After cooling to room temperature (20°C), the mixture was quenched with aqueous sodium thiosulfate (100 mL). The mixture was 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, which was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0-7%) to obtain compound 31-6.

[1479] 1 H NMR (400MHz, DMSO-d6) δ = 7.82-7.74 (m, 1H), 3.89 (s, 3H).

[1480] Step 6: Preparation of compound 31-7

[1481]

[1482] At room temperature (20°C), compound 31-6 (7 g, 21.05 mmol), compound 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). Under a nitrogen atmosphere, the mixture was heated to 100°C and stirred for 16 h. The mixture was cooled to room temperature and concentrated. The residue was extracted with water (50 mL) and ethyl acetate (30 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 31-7.

[1483] 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).

[1484] Step 7: Preparation of compound 31-8

[1485]

[1486] 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 portionwise. After addition, the mixture was stirred at 0°C for 30 min. Acetyl chloride (3.98 g, 50.74 mmol, 3.62 mL) was added dropwise at 0°C. After addition, the mixture was warmed to room temperature (20°C) under a nitrogen atmosphere and allowed to react for 16 h. The reaction was quenched by addition of water (300 mL) and 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, which was then purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0-100%) to obtain compound 31-8.

[1487] MS (ESI) m / z (M+H) + =397.0.

[1488] Step 8: Preparation of compound 31-9

[1489]

[1490] At room temperature (20°C), compound 31-8 (1.5 g, 3.78 mmol) was dissolved in toluene (40 mL), and potassium tert-butoxide (1 M, 11.34 mL) was added. After addition, 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), and the pH was adjusted to neutral with 1N hydrochloric acid. The product 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 step without further purification.

[1491] MS (ESI) m / z (M+H) + =364.9.

[1492] Step 9: Preparation of compound 31-10

[1493]

[1494] 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 at room temperature (20°C). After the addition was complete, the mixture was heated to 80°C and stirred for 2 h. After cooling to room temperature, the mixture was concentrated to remove most of the glacial acetic acid. The residue was poured into ice water (10 mL) to separate the precipitate. The filter cake was washed with water and dried to obtain compound 31-10, which was used directly in the next step without further purification.

[1495] MS (ESI) m / z (M+H) + =409.9.

[1496] Step 10: Preparation of compound 31-11

[1497]

[1498] 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 uL) was added at room temperature (20°C). The mixture was heated to 80°C and stirred for 2 h. After cooling to room temperature (20°C), the mixture was poured into water (20 mL) and extracted with ethyl acetate (3 x 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 31-11, which was used directly in the next step without further purification.

[1499] 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).

[1500] Step 11: Preparation of compound 31-12

[1501]

[1502] 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 uL) were dissolved in tetrahydrofuran (10 mL). The mixture was heated to 70°C and stirred for 20 h. The mixture 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.

[1503] MS (ESI) m / z (M+H) + =650.1.

[1504] 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)

[1505] Step 12: Preparation of compound 31-13

[1506]

[1507] 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). Under a nitrogen atmosphere, the mixture was heated to 85°C and stirred for 1 hour. The mixture was filtered through celite, and the filtrate was concentrated. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 31-13. This was used directly in the next reaction without further purification.

[1508] MS (ESI) m / z (M+H) + =588.1.

[1509] Step 13: Preparation of compound 28-4

[1510]

[1511] 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 uL) was added at room temperature (20°C). After addition, the mixture was heated to 40°C and stirred under a nitrogen atmosphere for 16 hours. The mixture 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 28-4.

[1512] 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).

[1513] Step 14: Preparation of compound 31-14

[1514]

[1515] Compound 28-4 (100 mg, 166.09 μmol), o-fluorophenylboronic acid (46.48 mg, 332.19 μmol), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (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 mixture of dioxane (1 mL) and water (0.1 mL). Under a nitrogen atmosphere, the mixture was heated to 100°C and stirred for 5 h. The system was concentrated to obtain a crude product, which was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0-40%) to obtain compound 31-14.

[1516] MS (ESI) m / z (M+H) + =662.6.

[1517] Step 15: Preparation of compound 31-15

[1518]

[1519] 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 addition, the mixture was stirred at room temperature (25°C) for 2 h. The solution was concentrated to obtain compound 31-15, which was used directly in the next reaction without further purification.

[1520] MS (ESI) m / z (M+H) + =562.1.

[1521] Step 16: Preparation of compound 31

[1522]

[1523] Compound 31-15 (90 mg, 150.49 μmol, hydrochloride) was dissolved in tetrahydrofuran (5 mL) and sodium bicarbonate (63.21 mg,

[1524] To a solution of 1% acetic anhydride (752.44 μmol) in tetrahydrofuran (5 mL) was added dropwise a 0.5 M solution of acrylic anhydride (361.17 μL). After the addition was complete, the reaction was allowed to proceed at room temperature (20°C) for 1 h. The reaction was quenched with methanol (0.1 mL) and extracted with ethyl acetate (5 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product, which was then purified by high-performance preparative liquid chromatography (HPLC) using a Phenomenex Gemini-NX 80*30 mm*3 μm column and mobile phase: water (10 mM ammonium bicarbonate)-acetonitrile; 46% to 76% acetonitrile over 9 min) to yield compound 31.

[1525] MS (ESI) m / z (M+H) + =616.4.

[1526] Step 17: Preparation of compounds 31A and 31B

[1527]

[1528] The diastereoisomers of compound 31 were purified by SFC (Phenomenex-Cellulose-2 (250 mm*30 mm, 10 μm); mobile phase: [CO 2 -methanol (0.1% aqueous ammonia)]; methanol: 50%). After concentration, compound 31A and compound 31B were obtained.

[1529] Compound 31A:

[1530] 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).

[1531] MS (ESI) m / z (M+H) + =616.2

[1532] HPLC retention time: 4.12 min.

[1533] Separation conditions: Chromatographic column: WELCH Ultimate LP-C18 150*4.6mm, 5μm; column temperature: 40°C; mobile phase: water (0.0688% trifluoroacetic acid solution)-acetonitrile (0.0625% trifluoroacetic acid solution); acetonitrile: 10%-80% 10 min, 80% 5 min; flow rate: 1.5 mL / min; SFC retention time: 5.115 min.

[1534] Separation conditions: Chromatographic column: Cellulose 2 150*4.6mm ID, 5μm; column temperature: 35°C; mobile phase: CO2-methanol (0.05% DEA); methanol: 40%-40%; flow rate: 2.5mL / min.

[1535] Compound 31B:

[1536] 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).

[1537] MS (ESI) m / z (M+H) +=616.2.

[1538] HPLC retention time: 4.11 min.

[1539] Separation conditions: Chromatographic column: WELCH Ultimate LP-C18 150*4.6mm, 5μm; column temperature: 40°C; 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: 7.223 min

[1540] Separation conditions: Chromatographic column: Cellulose 2 150*4.6mm ID, 5μm; column temperature: 35°C; mobile phase: CO2-methanol (0.05% DEA); methanol: 40%-40%; flow rate: 2.5mL / min.

[1541] Example 32: Preparation of Compound 32

[1542] Step 1: Preparation of compound 32-2

[1543]

[1544] Compound 28-4 (120 mg, 199.31 μmol), compound 32-1 (70.15 mg, 398.62 μmol), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (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 mixture of dioxane (1 mL) and water (0.1 mL). Under a nitrogen atmosphere, the mixture was heated to 100°C and stirred for 5 h. The system was concentrated to obtain a crude product, which was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0-60%) to obtain compound 32-2.

[1545] MS (ESI) m / z (M+H) + =698.3.

[1546] Step 2: Preparation of compound 32-3

[1547]

[1548] 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 addition, the mixture was stirred at room temperature (25°C) for 2 h. The solution was concentrated to obtain compound 32-3, which was used directly in the next reaction without further purification.

[1549] MS (ESI) m / z (M+H) + =598.1.

[1550] Step 3: Preparation of compound 32

[1551]

[1552] Compound 32-3 (92 mg, 145.08 μmol, hydrochloride) was dissolved in tetrahydrofuran (5 mL) and an aqueous solution of sodium bicarbonate (121.88 mg, 1.45 mmol) (5 mL). A 0.5 M solution of acrylic anhydride in tetrahydrofuran (377.21 μL) was added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature (20°C) for 2 h. The reaction was quenched with methanol (0.1 mL) and extracted with ethyl acetate (5 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 then purified by high-performance preparative liquid chromatography (HPLC) using a Phenomenex Gemini-NX 80*30 mm*3 μm column and a mobile phase consisting of water (10 mM ammonium bicarbonate)-acetonitrile; the reaction mixture was stirred for 39% to 69% acetonitrile over 9 min) to yield compounds 32A, 32B, 32C, and 32D.

[1553] Compound 32A:

[1554] 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).

[1555] MS (ESI) m / z (M+H) + =652.2.

[1556] HPLC retention time: 3.49 min.

[1557] Separation conditions: Column: WELCH Ultimate LP-C18 150*4.6mm, 5μm; Column temperature: 40°C; 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 32B:

[1558] 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).

[1559] MS (ESI) m / z (M+H) + =652.2.

[1560] HPLC retention time: 3.53 min.

[1561] Separation conditions: Column: WELCH Ultimate LP-C18 150 x 4.6 mm, 5 μm; Column temperature: 40°C; Mobile phase: Water (0.0688% trifluoroacetic acid solution)-Acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10% to 80% for 10 min, then 80% for 5 min; Flow rate: 1.5 mL / min.

[1562] Compound 32C:

[1563] 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).

[1564] MS (ESI) m / z (M+H) + =652.2.

[1565] HPLC retention time: 3.66 min.

[1566] Separation conditions: Column: WELCH Ultimate LP-C18 150 x 4.6 mm, 5 μm; Column temperature: 40°C; Mobile phase: Water (0.0688% trifluoroacetic acid solution)-Acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10% to 80% for 10 min, then 80% for 5 min; Flow rate: 1.5 mL / min.

[1567] Compound 32D:

[1568] 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).

[1569] MS (ESI) m / z (M+H) + =652.2.

[1570] HPLC retention time 3.70 min

[1571] Separation conditions: Column: WELCH Ultimate LP-C18 150 x 4.6 mm, 5 μm; Column temperature: 40°C; Mobile phase: Water (0.0688% trifluoroacetic acid solution)-Acetonitrile (0.0625% trifluoroacetic acid solution); Acetonitrile: 10% to 80% for 10 min, then 80% for 5 min; Flow rate: 1.5 mL / min.

[1572] Example 33: Preparation of Compound 33

[1573] Step 1: Preparation of compound 33-2

[1574]

[1575] Compound 28-4 (100 mg, 166.09 μmol), compound 33-1 (68.15 mg, 249.14 μmol), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (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 mixture of dioxane (2 mL) and water (0.2 mL). Under a nitrogen atmosphere, the mixture was heated to 100°C and stirred for 5 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 obtain compound 33-2.

[1576] MS (ESI) m / z (M+H) ...

Claims

1. A compound represented by formula (I-B), its optical isomers and pharmaceutically acceptable salts thereof, in, R1 and R2 are independently selected from H, halogen and C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with 1, 2 or 3 R; R3 is selected from H, halogen, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl-O- and C 3-6 Cycloalkyl-O-, the C 1-6 Alkyl, C 1-6 Heteroalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl-O- or C 3-6 Cycloalkyl-O- is optionally substituted with 1, 2 or 3 R; R4 is independently selected from H, halogen, OH, NH2, CN, 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 and 5-6 membered heteroaryl-5-6 membered heterocycloalkyl, wherein the 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 is optionally substituted by 1, 2 or 3 R; R5 is selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl-C 1-3 alkyl-, 3-8 membered heterocycloalkyl, phenyl, naphthyl, 5-10 membered heteroaryl, phenyl-5-6 membered heterocycloalkyl and 5-6 membered heteroaryl-5-6 membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl-C 1-3 Alkyl-, 3- to 8-membered heterocycloalkyl, phenyl, naphthyl, 5- to 10-membered heteroaryl, phenyl-5- to 6-membered heterocycloalkyl, or 5- to 6-membered heteroaryl-5- to 6-membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R; L1 is selected from -C(=O)-, -S(=O)- and -S(=O)2-; R6 is 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)-, 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; R7 are 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 heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Alkyl-OC(=O)- or -C 1-6 Alkyl-3- to 6-membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R; T1 and T2 are independently selected from N and -C(R8)-; R8 is selected from H, halogen, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R; R9 is selected from H, halogen, OH, NH2, CN, C 1-6 Alkyl and C 1-6 Heteroalkyl, the C 1-6 Alkyl or C 1-6 Heteroalkyl is optionally substituted with 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, the C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 The alkylamino group is optionally substituted with 1, 2 or 3 R groups; R is independently selected from H, halogen, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Heterocycloalkane, C 3-6 Cycloalkyl, 5- to 6-membered heterocycloalkyl, C 3-6 Cycloalkyl-O- and 5- to 6-membered heterocycloalkyl-O-, the C 1-6 Alkyl, C 1-6 Heterocycloalkane, 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'; R' is selected from F, Cl, Br, I, OH, NH2 and CH3; Ring A is independently selected from C 6-10 Aryl, 5-10 membered heteroaryl, phenyl and 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl and 5-6 membered heterocycloalkyl; n is selected from 0, 1, 2, 3 or 4; m is selected from 0, 1, 2, 3 or 4; D1 is selected from O; Y is selected from N, CH or C; for And when for When R2, R 10 does not exist; for when middle for When X1 and X2 are independently selected from -N=, -C(R7)= and -C(R7)2-C(R7)=; when middle for When X1 and X2 are independently selected from a single bond, -O-, -S-, S(=O), S(=O)2, -N(R6)-, -C(=O)-, -C(R7)2- and -C(R7)2-C(R7)2-; And, Y cannot connect two When the bond between Y and R9 is When , R9 does not exist; The above 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 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, in, R1 and R2 are independently selected from H, halogen and C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with 1, 2 or 3 R; R3 is selected from H, halogen, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl-O- and C 3-6 Cycloalkyl-O-, the C 1-6 Alkyl, C 1-6 Heteroalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl-O- or C 3-6 Cycloalkyl-O- is optionally substituted with 1, 2 or 3 R; R4 is independently selected from H, halogen, OH, NH2, CN, 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 and 5-6 membered heteroaryl-5-6 membered heterocycloalkyl, wherein the 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 is optionally substituted by 1, 2 or 3 R; R5 is selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl-C 1-3 alkyl-, 3-8 membered heterocycloalkyl, phenyl, naphthyl, 5-10 membered heteroaryl, phenyl-5-6 membered heterocycloalkyl and 5-6 membered heteroaryl-5-6 membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl-C 1-3 Alkyl-, 3- to 8-membered heterocycloalkyl, phenyl, naphthyl, 5- to 10-membered heteroaryl, phenyl-5- to 6-membered heterocycloalkyl, or 5- to 6-membered heteroaryl-5- to 6-membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R; L1 is selected from -C(=O)-, -S(=O)- and -S(=O)2-; R6 is 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)-, 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; R7 are 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 heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Alkyl-OC(=O)- or -C 1-6 Alkyl-3- to 6-membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R; T1 and T2 are independently selected from N and -C(R8)-; R8 is selected from H, halogen, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R; R is independently selected from H, halogen, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Heterocycloalkane, C 3-6 Cycloalkyl, 5- to 6-membered heterocycloalkyl, C 3-6 Cycloalkyl-O- and 5- to 6-membered heterocycloalkyl-O-, the C 1-6 Alkyl, C 1-6 Heterocycloalkane, 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'; R' is selected from F, Cl, Br, I, OH, NH2 and CH3; Ring A is independently selected from C 6-10 Aryl, 5- to 10-membered heteroaryl, phenyl and 5- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl and 5- to 6-membered heterocycloalkyl; n is selected from 0, 1, 2, 3 or 4; for And when for When , R2 does not exist; for when middle for When X1 and X2 are independently selected from -N=, -C(R7)= and -C(R7)2-C(R7)=; when middle for When X1 and X2 are independently selected from a single bond, -O-, -S-, S(=O), S(=O)2, -N(R6)-, -C(=O)-, -C(R7)2- and -C(R7)2-C(R7)2-; The above 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 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.

3. The compound according to claim 1 or 2, its optical isomers and pharmaceutically acceptable salts thereof, which are selected from in, X1 and X2 are independently selected from a single bond, -O-, -S-, S(=O), S(=O)2, -N(R6)-, -C(=O)-, -C(R7)2- and -C(R7)2-C(R7)2-, and R1, R2, R3, R4, R5, L1, R6, R7, T1, T2, ring A and n are as defined in claim 1 or 2.

4. The compound according to claim 3, its optical isomers and pharmaceutically acceptable salts thereof, wherein: R 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- to 6-membered heterocycloalkyl, C 3-6 Cycloalkyl-O- and -5- to 6-membered heterocycloalkyl-O-, 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's.

5. The compound according to claim 4, its optical isomers and pharmaceutically acceptable salts thereof, wherein: R is independently selected from H, F, Cl, Br, I, OH, NH2, CN, Me, CH2CH3, 6. The compound according to claim 1 or 2, its optical isomers and pharmaceutically acceptable salts thereof, wherein: R1 and R2 are independently selected from H, F, Me, CF3, 7. The compound according to claim 6, its optical isomers and pharmaceutically acceptable salts thereof, wherein: Structural unit Selected from 8. The compound according to claim 1 or 2, its optical isomers and pharmaceutically acceptable salts thereof, wherein: R3 is selected from H, halogen, OH, NH2, CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 1-3 Alkylthio, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl-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 heterocycloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl-O- or C 3-6 Cycloalkyl-O- is optionally substituted with 1, 2 or 3 R groups.

9. The compound according to claim 8, its optical isomers and pharmaceutically acceptable salts thereof, wherein: R3 is selected from H, F, Cl, Br, I, OH, NH2, CN, Me, CF3, 10. The compound according to claim 1 or 2, its optical isomers and pharmaceutically acceptable salts thereof, wherein: R4 is independently selected from H, halogen, OH, NH2, CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 1-3 Alkylthio, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, pyridyl, pyrimidyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, benzofuranyl, benzothienyl and indolyl, wherein 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 by 1, 2 or 3 R.

11. The compound according to claim 10, its optical isomers and pharmaceutically acceptable salts thereof, wherein: R4 is selected from H, F, Cl, Br, I, OH, NH2, CN, Me, CF3, 12. The compound according to claim 1 or 2, its optical isomers and pharmaceutically acceptable salts thereof, 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, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, 1H-benzo[d]imidazolyl, benzopyrazolyl, purinyl, quinolyl, isoquinolyl, quinolinyl, isoquinolin-1(2H)-onyl, isoindolyl-1-onyl, benzo[d]oxazol-2(H)-onyl, benzo[d]oxazol-2(3H)-onyl, H-benzo[d][1,2,3]triazolyl, 1H-pyrazolo[3,4-b]pyridinyl, benzo[d]thiazolyl and 1,3-dihydro-2H-benzo[d]imidazol-2-onyl, the phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, benzofuranyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, 1H-benzo[d]imidazolyl, benzopyrazolyl, purinyl, quinolyl, isoquinolyl, isoquinolinyl, 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]pyridinyl, benzo[d]thiazolyl or 1,3-dihydro-2H-benzo[d]imidazol-2-one is optionally substituted with 1, 2 or 3 R.

13. The compound according to claim 12, its optical isomers and pharmaceutically acceptable salts thereof, wherein: Structural unit select 14. The compound according to claim 1 or 2, its optical isomers and pharmaceutically acceptable salts thereof, wherein: R5 is selected from H, C 1-3 Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydro-2H-pyranyl, piperidinyl, piperazinyl, 5-6 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, quinolyl, isoquinolyl, isoquinolin-1(2H)-onyl, isoindolin-1-onyl, benzo[d]oxazol-2(H)-onyl and 1,3-dihydro-2H-benzo[d]imidazolyl-2-onyl, the C 1-3 Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydro-2H-pyranyl, piperidinyl, piperazinyl, 5-6 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, quinolyl, isoquinolyl, isoquinolin-1(2H)-onyl, isoindolin-1-onyl, benzo[d]oxazol-2(H)-onyl or 1,3-dihydro-2H-benzo[d]imidazol-2-onyl is optionally substituted with 1, 2 or 3 R.

15. The compound according to claim 14, its optical isomers and pharmaceutically acceptable salts thereof, wherein: R5 is selected from H, Me, 16. The compound according to claim 1 or 2, its optical isomers and pharmaceutically acceptable salts thereof, wherein: R7 are independently selected from H, halogen, OH, NH2, CN, 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 heterocycloalkyl, 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 heterocycloalkyl group may be substituted by 1, 2 or 3 R groups.

17. The compound according to claim 16, its optical isomers and pharmaceutically acceptable salts thereof, wherein: R7 is independently selected from H, F, Cl, Br, I, OH, NH2, CN, Me, CF3, 18. The compound according to claim 1 or 2, its optical isomers and pharmaceutically acceptable salts thereof, wherein: R6 are 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)-, the C 1-3 Alkyl, C 1-3 Alkyl-S(=O)2-, 3- to 6-membered heterocycloalkyl, -C 1-3 Alkyl 3-6 membered heterocycloalkyl or C 3-6 Cycloalkyl-C(═O)- is optionally substituted with 1, 2 or 3 R groups.

19. The compound according to claim 18, its optical isomers and pharmaceutically acceptable salts thereof, wherein: R6 are independently selected from H, CN, Me, CF3, 20. The compound according to claim 18, its optical isomers and pharmaceutically acceptable salts thereof, wherein: X1 and X2 are independently selected from a single bond, CH2, CH2CH2, C(=O), O, S, NH, N(CH3), S(=O), S(=O)2, 21. The compound according to claim 1 or 2, its optical isomers and pharmaceutically acceptable salts thereof, wherein: R8 is selected from H, halogen, OH, NH2, CN, 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 is optionally substituted with 1, 2 or 3 R groups.

22. The compound according to claim 21, its optical isomers and pharmaceutically acceptable salts thereof, wherein: R8 is selected from H, F, Cl, Br, I, OH, NH2, CN, Me, CF3, 23. The compound according to claim 1, its optical isomers and pharmaceutically acceptable salts thereof, wherein: Structural unit Selected from 24. The compound of the following formula, its optical isomers and pharmaceutically acceptable salts thereof:

25. A pharmaceutical composition comprising the compound according to 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 the compound according to any one of claims 1 to 24, its optical isomers and pharmaceutically acceptable salts thereof, or the pharmaceutical composition according to claim 25 in the preparation of a medicament for preventing and / or treating a KRAS-G12C-related disease.

27. The use according to claim 26, wherein the KRAS-G12C related disease is selected from non-small cell lung cancer, colon cancer and pancreatic cancer.

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