Preparation method of bicyclic compound and application as antibacterial agent

Abstract

This relates to the compound represented by formula (Ⅰ) and its pharmaceutically acceptable salts, as well as the antifungal applications of the compound.

Description

[0001] This application claims the following priority:

[0002] CN202110354834.2, application date: March 30, 2021;

[0003] CN202110933030.8, application date: August 13, 2021;

[0004] CN202111057765.5, application date: September 9, 2021;

[0005] CN202111512144.1, application date: December 7, 2021;

[0006] CN202210294092.3, application date: March 23, 2022. Technical Field

[0007] This invention relates to methods for preparing bicyclic compounds and their application as antibacterial agents. The invention also relates to compounds of formula (I) and their pharmaceutically acceptable salts, as well as the antifungal applications of these compounds. Background Technology

[0008] In recent years, with the long-term and widespread use of broad-spectrum antibiotics, the increase in radiotherapy and chemotherapy, the popularization of bone marrow and organ transplantation, the increased use of immunosuppressants, and the development of interventional treatments such as heart valve implantation, the incidence and mortality rates of clinically invasive fungal infections caused by Candida, Aspergillus, and Cryptococcus neoformans have shown a significant upward trend. Globally, tens of millions of people are infected with fungi each year, and at least 1.5 million die from deep fungal invasion.

[0009] Currently used antifungal drugs include azoles, polyenes, and echinocandins. Azazoles are the largest class of antifungal drugs and the most common in clinical practice. They have a broad antifungal spectrum, low toxicity, and are better tolerated than amphotericin B, making them the most widely used.

[0010] Despite their widespread clinical use, these azole antifungal drugs each have their own drawbacks and limitations. For example, ketoconazole has significant side effects and is currently used primarily for topical application. Fluconazole, as a first-line drug for treating local and deep fungal infections, has limited activity and has developed serious resistance due to long-term use. Itraconazole has poor water solubility and low bioavailability; the cyclodextrin in its oral solution can also cause osmotic diarrhea, posing a significant risk to patients with renal insufficiency. Posaconazole is a strong CYP3A4 inhibitor; this strong drug-drug interaction (DDI) limits its clinical application, and its physicochemical and metabolic properties are also unsatisfactory, greatly reducing its therapeutic stability. Isaconazole is a moderate-strength CYP3A4 inhibitor, and the issue of drug DDI still exists.

[0011] Voriconazole is considered the most successful fluconazole derivative. It exhibits strong activity against deep-seated pathogenic fungi, including fluconazole-resistant strains such as Candida krusei and Candida parapsilosis, and is currently the leading drug for treating fungal infections, especially invasive fungal diseases caused by Aspergillus. Its disadvantage lies in its primary metabolism by CYP2C19 in the body, which can lead to excessively high blood drug concentrations due to individual differences in CYP2C19 metabolism, particularly causing adverse reactions in Chinese individuals. Side effects of voriconazole, such as visual disturbances and liver dysfunction, have also been reported.

[0012] Given the defects and limitations of existing cycloconazole antifungal drugs, it is of great clinical value to develop novel, highly effective, broad-spectrum, and low-toxicity CYP51 inhibitor antifungal drugs that are superior to existing drugs in terms of activity, metabolism, and drug interactions. This would overcome the limitations and defects of existing clinical drugs and overcome resistance to drugs such as fluconazole. Such drugs would be of great clinical value in the treatment and prevention of various fungal infections, especially deep infections caused by Candida and Aspergillus, and in reducing the mortality rate of invasive fungal infections. Summary of the Invention

[0013] In a first aspect, the present invention provides compounds of formula (I), their optical isomers, tautomers, and pharmaceutically acceptable salts thereof.

[0014]

[0015] in,

[0016] Ring A is selected from 5-6 member heteroaryl groups;

[0017] Ring B is selected from phenyl and 5-6-membered heteroaryl groups;

[0018] R3 is selected from OH, NH2, halogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, -OC(=O)C 1-6Alkyl group, -NHC(=O)C 1-6 alkyl, and -OC 1-6 Alkyl-OP(=O)2(OH)2;

[0019] R2, R4, and R5 are independently selected from H, CN, OH, F, Cl, Br, I, and C, respectively. 1-6 Alkyl and C 1-6 Heteroalkyl, the C 1-6 Alkyl or C 1-6 The heteroalkyl group is optionally surrounded by 1, 2, or 3 CN, OH, F, Cl, Br, I, or C atoms. 1-6 Alkyl substitution;

[0020] m, y, and z are each independently selected from 1, 2, 3, or 4;

[0021] n is selected from 0, 1, 2, or 3;

[0022] L1 is selected from single bonds, -NH-, and C. 1-6 Alkyl, C 2-6 Alkyne, phenyl and 5-6 heteroaryl, the C 1-6 Alkyl, C 2-6 Alkyne, phenyl, or 5-6 heteroaryl groups are optionally capped with 1, 2, or 3 CN, OH, F, Cl, Br, I, or C atoms. 1-6 Alkyl substitution;

[0023] L2 is selected from single bonds, O, S, NH, and C. 1-6 Alkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic, C 3-6 cycloalkyl and phenyl-OC 1-6 alkyl-, the C 1-6 Alkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic, C 3-6 cycloalkyl or phenyl-OC 1-6 Alkyl group - optionally surrounded by 1, 2, or 3 CN, OH, F, Cl, Br, I, or C 1-6 Alkyl substitution;

[0024] L3 is selected from single bonds, O, NH, -C(=O)-, -C(=O)NH-, C 1-6 Alkyl, 3-6 membered heterocyclic, C 3-6 Cycloalkyl, phenyl, and 5-6-membered heteroaryl groups, wherein the C 1-6 Alkyl, 3-6 membered heterocyclic, C 3-6 Cycloalkyl, phenyl, or 5-6 heteroaryl groups are optionally capped with 1, 2, or 3 CN, CF3, OH, F, Cl, Br, I, or C. 1-6 Alkyl substitution;

[0025] L4 is selected from H, F, Cl, Br, I, OH, CN, NH2, COOH, C(=O)C 1-6 Alkyl group, C(=O)NHC 1-6 Alkyl, C(=O)N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclic, C 1-6 Alkyl-5-6-membered heterocyclic groups, 5-6-membered heteroaryl groups, and benzo-4-6-membered heterocyclic groups, wherein the C(=O)C 1-6 Alkyl group, C(=O)NHC 1-6 Alkyl, C(=O)N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclic, C 1-6 Alkyl-5-6-membered heterocyclic group, 5-6-membered heteroaryl group, or benzo5-6-membered heterocyclic group may be optionally surrounded by 1, 2, 3, 4, or 5 R groups. L replace;

[0026] R L Selected from CN, OH, F, Cl, Br, I, NH2, C(=O)C 1-6 Alkyl group, C(=O)NHC 1-6 Alkyl, C(=O)N(C) 1-6 Alkyl)2, C 1-6 Alkyl and C 1-6 Heteroalkyl, the C(=O)C 1-6 Alkyl group, C(=O)NHC 1-6 Alkyl, C(=O)N(C) 1-6 Alkyl)2, C 1-6 Alkyl or C 1-6 The heteroalkyl group is optionally surrounded by 1, 2, or 3 CN, OH, NH2, F, Cl, Br, I, or C atoms. 1-6 Alkyl substitution;

[0027] The C 1-6 Heteroalkyl, 3-6 membered heterocyclic, 4-6 membered heterocyclic, 5-6 membered heterocyclic or 5-6 membered heteroaryl contain 1, 2, 3 or 4 heteroatoms or heterogroups independently selected from -O-, -NH-, -N=, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2- and N.

[0028] In a second aspect, the invention also provides compounds of formula (II), their optical isomers or tautomers,

[0029]

[0030] Among them, X - It is a pharmaceutically acceptable anion;

[0031] T is selected from CH or N;

[0032] R1 is selected from

[0033] Ra is independently selected from H and C, respectively. 1-6 alkyl;

[0034] Rb is independently selected from H and C, respectively. 1-6 Alkyl group, -C(=O)C 1-6 Alkyl group, -OC (=O)C 1-6 Alkyl group, -C(=O)OC 1-6 Alkyl and phenyl, the C 1-6 Alkyl group, -C(=O)C 1-6 Alkyl group, -OC (=O)C 1-6 Alkyl group, -C(=O)OC 1-6 Alkyl and phenyl groups are optionally surrounded by 1, 2, or 3 CN, OH, F, Cl, Br, I, or C atoms. 1-6 Alkyl substitution;

[0035] Rc is independently selected from H and C respectively. 1-6 Alkyl, phenyl, or 5-6 heteroaryl, wherein the phenyl or 5-6 heteroaryl is optionally substituted with 1, 2, or 3 Rs;

[0036] R is independently selected from CN, OH, F, Cl, Br, I, and C, respectively. 1-6 Alkyl, C 1-6 Heteroalkyl,

[0037] The C 1-6 Alkyl or C 1-6 The heteroalkyl group is optionally surrounded by 1, 2, or 3 CN, OH, F, Cl, Br, I, or C atoms. 1-6 Alkyl substitution;

[0038] Alternatively, Rb and Rc can be linked together to form a 5-6 member heterocyclic group, wherein the 5-6 member heterocyclic group is optionally composed of 1, 2, or 3... CN, OH, F, Cl, Br, I or C 1-6 Alkyl substitution;

[0039] Ring B is selected from phenyl and 5-6-membered heteroaryl groups;

[0040] R3 is selected from OH, NH2, halogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, -OC(=O)C1-6 Alkyl group, -NHC(=O)C 1-6 alkyl, and -OC 1-6 Alkyl-OP(=O)2(OH)2;

[0041] R2, R4, and R5 are independently selected from H, CN, OH, F, Cl, Br, I, and C, respectively. 1-6 Alkyl and C 1-6 Heteroalkyl, the C 1-6 Alkyl or C 1-6 The heteroalkyl group is optionally surrounded by 1, 2, or 3 CN, OH, F, Cl, Br, I, or C atoms. 1-6 Alkyl substitution;

[0042] m, y, and z are each independently selected from 1, 2, 3, or 4;

[0043] n is selected from 0, 1, 2, or 3;

[0044] L1 is selected from single bonds, -NH-, and C. 1-6 Alkyl, C 2-6 Alkyne, phenyl and 5-6 heteroaryl, the C 1-6 Alkyl, C 2-6 Alkyne, phenyl, or 5-6 heteroaryl groups are optionally capped with 1, 2, or 3 CN, OH, F, Cl, Br, I, or C atoms. 1-6 Alkyl substitution;

[0045] L2 is selected from single bonds, O, S, NH, and C. 1-6 Alkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic, C 3-6 cycloalkyl and phenyl-OC 1-6 alkyl-, the C 1-6 Alkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic, C 3-6 cycloalkyl or phenyl-OC 1-6 Alkyl group - optionally surrounded by 1, 2, or 3 CN, OH, F, Cl, Br, I, or C 1-6 Alkyl substitution;

[0046] L3 is selected from single bonds, O, NH, -C(=O)-, -C(=O)NH-, C 1-6 Alkyl, 3-6 membered heterocyclic, C 3-6 Cycloalkyl, phenyl, and 5-6-membered heteroaryl groups, wherein the C 1-6 Alkyl, 3-6 membered heterocyclic, C 3-6 Cycloalkyl, phenyl, or 5-6 heteroaryl groups are optionally capped with 1, 2, or 3 CN, CF3, OH, F, Cl, Br, I, or C. 1-6 Alkyl substitution;

[0047] L4 is selected from H, F, Cl, Br, I, OH, CN, NH2, COOH, C(=O)C 1-6 Alkyl group, C(=O)NHC 1-6 Alkyl, C(=O)N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclic, C 1-6 alkyl-5-6-membered heterocyclic groups, 5-6-membered heteroaryl groups, and benzo5-6-membered heterocyclic groups, wherein the C(=O)C 1-6 Alkyl group, C(=O)NHC 1-6 Alkyl, C(=O)N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclic, C 1-6 Alkyl-5-6-membered heterocyclic group, 5-6-membered heteroaryl group, or benzo5-6-membered heterocyclic group may be optionally surrounded by 1, 2, 3, 4, or 5 R groups. L replace;

[0048] R L Selected from CN, OH, F, Cl, Br, I, NH2, C(=O)C 1-6 Alkyl group, C(=O)NHC 1-6 Alkyl, C(=O)N(C) 1-6 Alkyl)2, C 1-6 Alkyl and C 1-6 Heteroalkyl, the C(=O)C 1-6 Alkyl group, C(=O)NHC 1-6 Alkyl, C(=O)N(C) 1-6 Alkyl)2, C 1-6 Alkyl or C 1-6 The heteroalkyl group is optionally surrounded by 1, 2, or 3 CN, OH, NH2, F, Cl, Br, I, or C atoms. 1-6 Alkyl substitution;

[0049] The C 1-6 Heteroalkyl, 3-6 membered heterocyclic, 4-6 membered heterocyclic, 5-6 membered heterocyclic or 5-6 membered heteroaryl contain 1, 2, 3 or 4 heteroatoms or heterogroups independently selected from -O-, -NH-, -N=, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2- and N.

[0050] In another aspect, the invention also provides formula (IA), its optical isomers, tautomers, and pharmaceutically acceptable salts thereof.

[0051]

[0052] in,

[0053] Rings A, R3, R4, R5, L1, L2, L3, L4, m, y, and z are defined as above, and each R... 2a R 2b R 2c R 2d R 2e Each of the following is independently selected from H, CN, OH, F, Cl, Br, I, and C. 1-6 Alkyl and C 1-6 Heteroalkyl, the C 1-6 Alkyl or C 1-6 The heteroalkyl group is optionally surrounded by 1, 2, or 3 CN, OH, F, Cl, Br, I, or C atoms. 1-6 Alkyl substitution.

[0054] In another aspect, the present invention also provides compounds of formula (II-A), their optical isomers or tautomers,

[0055]

[0056] in,

[0057] R1, R3, R4, R5, L1, L2, L3, L4, T, m, y, z, X - As defined above, each R 2a R 2b R 2c R 2d R 2e Each of the following is independently selected from H, CN, OH, F, Cl, Br, I, and C. 1-6 Alkyl and C 1-6 Heteroalkyl, the C 1-6 Alkyl or C 1-6 The heteroalkyl group is optionally surrounded by 1, 2, or 3 CN, OH, F, Cl, Br, I, or C atoms. 1-6 Alkyl substitution.

[0058] In some embodiments of the present invention, the above-mentioned X - Selected from Cl - I - ,Br - HSO4 - 1 / 2SO4 2- COO - CH3COO -CF3COO - and CF3CH3COO - .

[0059] In some embodiments of the present invention, the ring A is selected from... The remaining variables are as defined in this invention.

[0060] In some embodiments of the present invention, R3 is selected from OH, NH2, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 1-3 Alkylthio, -OC(=O)C 1-3 Alkyl groups and -NHC(=O)C 1-3 Alkyl groups, and other variables as defined in this invention.

[0061] In some embodiments of the present invention, R3 is selected from OH, F, Cl, Br, I, NH2, C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 1-3 Alkylthio, -OC 1-3 Alkyl-OP(=O)2(OH)2、-OC(=O)C 1-3 Alkyl groups and -NHC(=O)C 1-3 Alkyl groups, and other variables as defined in this invention.

[0062] In some embodiments of the present invention, R3 is selected from OH, F, Cl, Br, NH2, OCH3, The remaining variables are as defined in this invention.

[0063] In some embodiments of the present invention, Ra is independently selected from H, methyl, ethyl, n-propyl and isopropyl, and the remaining variables are as defined in the present invention.

[0064] In some embodiments of the present invention, the Rb is independently selected from H and C. 1-3 Alkyl group, -C(=O)C 1-3 Alkyl group, -OC (=O)C 1-3 Alkyl group, -C(=O)OC 1-3 Alkyl and phenyl, the C 1-3 Alkyl group, -C(=O)C 1-3 Alkyl group, -OC (=O)C 1-3 Alkyl group, -C(=O)OC 1-3 Alkyl and phenyl groups are optionally surrounded by 1, 2, or 3 CN, OH, F, Cl, Br, I, or C atoms. 1-3 Alkyl substitution, and other variables as defined in this invention.

[0065] In some embodiments of the present invention, the Rb is selected from H, CH3, The remaining variables are as defined in this invention.

[0066] In some embodiments of the present invention, the above-mentioned Rc is selected from H and -C. 1-6 Alkyl-OC(=O)C 1-6 Alkyl-NH-C 1-6 Alkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl, -C 1-6 Alkyl-OC(=O)-C 1-6 Alkyl, -phenyl-C 1-6 Alkyl-OC(=O)-C 1-6 Alkyl, -phenyl-C 1-6 Alkyl-OC(=O)-C 1-6 Alkyl-NH-C 1-6 Alkyl, -5-6-membered heteroaryl-C 1-6 Alkyl-NH-C 1-6 Alkyl, -5-6-membered heteroaryl-C 1-6 Alkyl-OC(=O)-C 1-6 Alkyl, -5-6-membered heteroaryl-C 1-6 Alkyl-OC(=O)-C 1-6 Alkyl-NH-C 1-6 Alkyl and -5-6-membered heteroaryl-C 1-6 Alkyl-NH-C 1-6 Alkyl, the -C 1-6 Alkyl-OC(=O)C 1-6 Alkyl-NH-C 1-6 Alkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl, -C 1-6 Alkyl-OC(=O)-C 1-6 Alkyl, -phenyl-C 1-6 Alkyl-OC(=O)-C 1-6 Alkyl, -phenyl-C 1-6 Alkyl-OC(=O)-C 1-6 Alkyl-NH-C 1-6 Alkyl, -5-6-membered heteroaryl-C 1-6 Alkyl-NH-C 1-6 Alkyl, -5-6-membered heteroaryl-C 1-6 Alkyl-OC(=O)-C 1-6 Alkyl, -5-6-membered heteroaryl-C 1-6 Alkyl-OC(=O)-C 1-6 Alkyl-NH-C 1-6 Alkyl or -5-6-membered heteroaryl-C1-6 Alkyl-NH-C 1-6 The alkyl group may be optionally substituted with 1, 2, 3 or 4 F, Cl, Br, I, methoxy or CN, and the other variables are as defined in this invention.

[0067] In some embodiments of the present invention, the above-mentioned Rc is selected from H and -C. 1-3 Alkyl-OC(=O)C 1-3 Alkyl-NH-C 1-3 Alkyl, -C 1-3 Alkyl-NH-C 1-3 Alkyl, -C 1-3 Alkyl-OC(=O)-C 1-3 Alkyl, -phenyl-C 1-3 Alkyl-OC(=O)-C 1-3 Alkyl, -phenyl-C 1-3 Alkyl-OC(=O)-C 1-3 Alkyl-NH-C 1-3 alkyl, pyridyl-C 1-3 Alkyl-NH-C 1-3 alkyl, pyridyl-C 1-3 Alkyl-OC(=O)-C 1-3 alkyl, pyridyl-C 1-6 Alkyl-OC(=O)-C 1-6 Alkyl-NH-C 1-6 Alkyl and pyridyl-C 1-6 Alkyl-NH-C 1-6 Alkyl, the -C 1-3 Alkyl-OC(=O)C 1-3 Alkyl-NH-C 1-3 Alkyl, -C 1-3 Alkyl-NH-C 1-3 Alkyl, -C 1-3 Alkyl-OC(=O)-C 1-3 Alkyl, -phenyl-C 1-3 Alkyl-OC(=O)-C 1-3 Alkyl, -phenyl-C 1-3 Alkyl-OC(=O)-C 1-3 Alkyl-NH-C 1-3 alkyl, pyridyl-C 1-3 Alkyl-NH-C 1-3 alkyl, pyridyl-C 1-3 Alkyl-OC(=O)-C 1-3 alkyl, pyridyl-C 1-3 Alkyl-OC(=O)-C 1-3 Alkyl-NH-C 1-3 alkyl or -pyridyl-C 1-3 Alkyl-NH-C1-3 The alkyl group may be optionally substituted with 1, 2, 3 or 4 F, Cl, Br, I, methoxy or CN, and the other variables are as defined in this invention.

[0068] In some embodiments of the present invention, the Rc mentioned above is independently selected from H and C. 1-6 Alkyl-OC(=O)C 1-6 Alkyl-NH-C 1-6 Alkyl, C 1-6 Alkyl-NH-C 1-6 Alkyl, C 1-6 Alkyl-C(=O)OC 1-6 alkyl, Each R X1 R X2 R X3 R X4 R X5 R y1 R y2 R y3 R y4 Selected independently from H, F, Cl, Br, I, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 1-6 Alkyl-C(=O)OC 1-6 Alkyl, C 1-6 Alkyl-OC(=O)C 1-6 Alkyl-NH-C 1-6 Alkyl, C 1-6 Alkyl-NH-C 1-6 Alkyl and C 1-6 Alkyl-OC(=O)C 1-6 Alkyl-NH2, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 1-6 Alkyl-C(=O)OC 1-6 Alkyl, C 1-6 Alkyl-OC(=O)C 1-6 Alkyl-NH-C 1-6 Alkyl, C 1-6 Alkyl-NH-C 1-6 Alkyl or C 1-6 Alkyl-OC(=O)C 1-6 Alkyl-NH2 is optionally surrounded by 1, 2, or 3 CN, OH, F, Cl, Br, I, or C. 1-6 Alkyl substitution, and other variables as defined in this invention.

[0069] In some embodiments of the present invention, the Rc mentioned above is independently selected from H and C. 1-3 Alkyl-OC(=O)C 1-3 Alkyl-NH-C 1-3 Alkyl, C 1-3 Alkyl-NH-C 1-3 Alkyl, C 1-3 Alkyl-C(=O)OC 1-3 alkyl, Each R X1 R X2 R X3 R X4 R X5 R y1 R y2 R y3 R y4 Selected independently from H, F, Cl, Br, I, CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, C 1-3 Alkyl-C(=O)OC 1-3 Alkyl, C 1-3 Alkyl-OC(=O)C 1-3 Alkyl-NH-C 1-3 Alkyl, C 1-3 Alkyl-NH-C 1-3 Alkyl and C 1-3 Alkyl-OC(=O)C 1-3 Alkyl-NH2, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, C 1-3 Alkyl-C(=O)OC 1-3 Alkyl, C 1-3 Alkyl-OC(=O)C 1-3 Alkyl-NH-C 1-3 Alkyl, C 1-3 Alkyl-NH-C 1-3 Alkyl or C 1-3 Alkyl-OC(=O)C 1-3 Alkyl-NH2 is optionally surrounded by 1, 2, or 3 CN, OH, F, Cl, Br, I, or C. 1-3 Alkyl substitution, and other variables as defined in this invention.

[0070] In some embodiments of the present invention, the above-mentioned Rc is selected from H, The remaining variables are as defined in this invention.

[0071] In some embodiments of the present invention, R1 is selected from... The remaining variables are as defined in this invention.

[0072] In some embodiments of the present invention, the above-described structural unit Selected from The remaining variables are as defined in this invention.

[0073] In some embodiments of the present invention, L1 is selected from single bonds, C 1-3 Alkyl, C 2-3 Alkyne, phenyl, pyridyl, thiophene, and oxazolyl, wherein C 1-3 Alkyl, C 2-3 The alkynyl, phenyl, pyridyl, thiophene, or oxazolyl groups are optionally surrounded by 1, 2, or 3 CN, OH, F, Cl, Br, I, or C groups. 1-6 Alkyl substitution, and other variables as defined in this invention.

[0074] In some embodiments of the present invention, L1 is selected from single bonds, -NH-, CH2, ... The remaining variables are as defined in this invention.

[0075] In some embodiments of the present invention, L2 is selected from single bonds, O, S, and C. 1-3 Alkyl, 5-6 membered heterocyclic group, C 5-6 cycloalkyl and phenyl-OC 1-3 alkyl-, the C 1-3 Alkyl, 5-6 membered heterocyclic group, C 5-6 cycloalkyl or phenyl-OC 1-3 Alkyl group - optionally surrounded by 1, 2, or 3 CN, OH, F, Cl, Br, I, or C 1-6 Alkyl substitution, and other variables as defined in this invention.

[0076] In some embodiments of the present invention, L2 is selected from single bonds, O, S, CH2, NH, NCH3, ... The remaining variables are as defined in this invention.

[0077] In some embodiments of the present invention, the L3 is selected from single bonds, 5-6 membered heterocyclic groups, and C. 5-6 Cycloalkyl, phenyl, and pyridyl groups, the 5-6 membered heterocyclic groups, C 5-6 Cycloalkyl, phenyl, or pyridyl groups are optionally surrounded by 1, 2, or 3 CN, OH, F, Cl, Br, I, or C groups. 1-3Alkyl substitution, and other variables as defined in this invention.

[0078] In some embodiments of the present invention, L3 is selected from single bonds, O, NH, CH2, CH2CH2, -C(=O)-, -C(=O)NH-, The remaining variables are as defined in this invention.

[0079] In some embodiments of the present invention, the L4 is selected from H, F, Cl, Br, I, OH, CN, NH2, COOH, C(=O)C 1-3 Alkyl group, C(=O)NHC 1-3 Alkyl, C(=O)N(C) 1-3 Alkyl)2, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2,4-dihydro-3H-1,2,4-triazol-3-one, piperazine, benzo-1,3-methylenedioxopentane, pyridinyl, thiazolyl, 1,2,4-oxadiazolyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, aziridine, morpholinyl, and 1,3-dioxolane-2-one, wherein C(=O)C 1-3 Alkyl group, C(=O)NHC 1-3 Alkyl, C(=O)N(C) 1-3 Alkyl)2, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2,4-dihydro-3H-1,2,4-triazol-3-one, piperazine, benzo-1,3-methylenedioxopentane, pyridinyl, thiazolyl, 1,2,4-oxadiazolyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, aziridine, morpholinyl, or 1,3-dioxolane-2-one is optionally surrounded by 1, 2, 3, 4, or 5 R... L Replacement, the remaining variables are as defined in this invention.

[0080] In some embodiments of the present invention, the above-mentioned R L Selected from CN, OH, F, Cl, Br, I, NH2, C(=O)C 1-3 Alkyl group, C(=O)NHC 1-3 Alkyl, C(=O)N(C) 1-3 Alkyl)2, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 alkylthio and C1-3 Alkylamino, the C(=O)C 1-3 Alkyl group, C(=O)NHC 1-3 Alkyl, C(=O)N(C) 1-3 Alkyl)2, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 alkylthio or C 1-3 The alkylamino group is optionally surrounded by 1, 2, or 3 CN, OH, NH2, F, Cl, Br, I, or C. 1-6 Alkyl substitution, and other variables as defined in this invention.

[0081] In some embodiments of the present invention, the L4 is selected from H, F, Cl, Br, I, OH, CN, CH3, CH2CF3, NH2, CHF2, CF3, OCH3, OCF3, OCHF2, OCH2CH3, COOH, CONHMe, CONMe2, NMe2, CH2OH, The remaining variables are as defined in this invention.

[0082] In some embodiments of the present invention, the above-described structural unit Selected from H, I, CN, OH, COOH, C 1-6 Alkyl, C 1-6 Heteroalkyl, -C(=O)-C 1-6 Alkyl group, -C(=O)NHC 1-6 Alkyl, -C(=O)N(C) 1-6 Alkyl)2, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, benzo3-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, -phenyl-OC 1-6 Alkyl, -phenyl-OC 1-6 Alkyl-C(=O)NHC 1-6 Alkyl, -phenyl-SC 1-6 Alkyl, -phenyl-NH-C 1-6 Alkyl, -5-6-membered heteroaryl-OC 1-6 Alkyl, -5-6-membered heteroaryl-SC 1-6 Alkyl, -5-6-membered heteroaryl-NH-C 1-6 Alkyl, -phenyl-OC 1-6 Alkyl-OC 1-6 Alkyl, -phenyl-C(=O)NHC 1-6 Alkyl, -phenyl-OC 1-6 Alkyl-C(=O)OH, -phenyl-OS(=O)2NH2, -C 1-6 Alkyl-O-phenyl, -C1-6 alkyl-O-phenyl-C 1-6 Alkyl, -C 1-6 Alkyl-phenyl, -phenyl-3-6-membered heterocyclic group, -phenyl-O-3-6-membered heterocyclic group, -phenyl-OC 3-6 cycloalkyl, -phenyl-OC 1-6 Alkyl-C 3-6 cycloalkyl, -phenyl-OC 1-6 Alkyl-3-6-membered heterocyclic group, -phenyl-OC 1-6 Alkyl-C(=O)-3-6-membered heterocyclic group, -phenyl-O-5-6-membered heteroaryl group, -phenyl-OC group 1-6 alkyl-5-6-membered heteroaryl, -phenyl-3-6-membered heterocyclic -phenyl-3-6-membered heterocyclic -C 1-6 Alkyl, phenyl-3-6-membered heterocyclic group--C 1-6 Alkyl, -C 2-6 alkenyl-phenyl-OC 1-6 Alkyl-phenyl, -C 2-6 alkenyl-phenyl-C 1-6 Alkyl, -C 1-6 Alkyl-3-6-membered heterocyclic-O-phenyl, -phenyl-5-6-membered heteroaryl, -5-6-membered heteroaryl-3-6-membered heterocyclic, -phenyl-O-3-6-membered heterocyclic-C(=O)-C 1-6 Alkyl, -phenyl-O-5-6-membered heteroaryl-C(=O)OC 1-6 Alkyl and -5-6 heteroaryl -5-6 heteroaryl, wherein C 1-6 Alkyl, C 1-6 Heteroalkyl, -C(=O)-C 1-6 Alkyl group, -C(=O)NHC 1-6 Alkyl, -C(=O)N(C) 1-6 Alkyl)2, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, benzo3-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, -phenyl-OC 1-6 Alkyl, -phenyl-OC 1-6 Alkyl-C(=O)NHC 1-6 Alkyl, -phenyl-SC 1-6 Alkyl, -phenyl-NH-C 1-6 Alkyl, -5-6-membered heteroaryl-OC 1-6 Alkyl, -5-6-membered heteroaryl-SC 1-6 Alkyl, -5-6-membered heteroaryl-NH-C 1-6 Alkyl, -phenyl-OC 1-6 Alkyl-OC 1-6 Alkyl, -phenyl-C(=O)NHC 1-6Alkyl, -phenyl-OC 1-6 Alkyl-C(=O)OH, -phenyl-OS(=O)2NH2, -C 1-6 Alkyl-O-phenyl, -C 1-6 alkyl-O-phenyl-C 1-6 Alkyl, -C 1-6 Alkyl-phenyl, -phenyl-3-6-membered heterocyclic group, -phenyl-O-3-6-membered heterocyclic group, -phenyl-OC 3-6 cycloalkyl, -phenyl-OC 1-6 Alkyl-C 3-6 cycloalkyl, -phenyl-OC 1-6 Alkyl-3-6-membered heterocyclic group, -phenyl-OC 1-6 Alkyl-C(=O)-3-6-membered heterocyclic group, -phenyl-O-5-6-membered heteroaryl group, -phenyl-OC group 1-6 alkyl-5-6-membered heteroaryl, -phenyl-3-6-membered heterocyclic -phenyl-3-6-membered heterocyclic -C 1-6 Alkyl, phenyl-3-6-membered heterocyclic group--C 1-6 Alkyl, -C 2-6 alkenyl-phenyl-OC 1-6 Alkyl-phenyl, -C 2-6 alkenyl-phenyl-C 1-6 Alkyl, -C 1-6 Alkyl-3-6-membered heterocyclic-O-phenyl, -phenyl-5-6-membered heteroaryl, -5-6-membered heteroaryl-3-6-membered heterocyclic, -phenyl-O-3-6-membered heterocyclic-C(=O)-C 1-6 Alkyl, -phenyl-O-5-6-membered heteroaryl-C(=O)OC 1-6 Alkyl or -5-6 heteroaryl -5-6 heteroaryl group optionally surrounded by 1, 2, 3, 4, 5 or 6 F, Cl, Br, I, CN, CF3, OH, COOH, C 1-6 Alkyl or C 1-6 Heteroalkyl substitution.

[0083] In some embodiments of the present invention, the above-described structural unit Selected from H, I, CN, OH, CH3, NHCH3, CF3, C(=O)OH, C(=O)NHMe, C(=O)NMe2, The remaining variables are as defined in this invention.

[0084] In another aspect, the invention also provides compounds of the following formula, their optical isomers, tautomers, and pharmaceutically acceptable salts thereof, selected from...

[0085]

[0086]

[0087]

[0088]

[0089]

[0090]

[0091]

[0092]

[0093]

[0094]

[0095] In another aspect, the invention also provides compounds of the following formula, their optical isomers, tautomers, and pharmaceutically acceptable salts thereof, selected from...

[0096]

[0097]

[0098]

[0099]

[0100]

[0101]

[0102]

[0103]

[0104]

[0105]

[0106] In another aspect, the invention also provides compounds of the following formula, their optical isomers, tautomers, and pharmaceutically acceptable salts thereof, selected from...

[0107]

[0108]

[0109]

[0110]

[0111]

[0112]

[0113]

[0114]

[0115]

[0116]

[0117] In another aspect of the invention, the use of the aforementioned compounds, their optical isomers, tautomers, or pharmaceutically acceptable salts thereof in the preparation of antifungal drugs is also proposed.

[0118] Definitions and Explanations

[0119] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0120] As used in this invention, the phrase "at least one" when referring to a list of one or more elements should be understood to mean at least one element selected from any one or more elements in the list of elements, but does not necessarily include at least one of every element specifically listed in the list of elements, and does not exclude any combination of elements in the list of elements. This definition also allows for the optional presence of elements other than those specifically identified in the list of elements referred to by the phrase "at least one," whether related to or unrelated to those specifically identified elements.

[0121] The term “pharmaceutically acceptable” as used herein refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0122] The term "pharmaceutically acceptable anion" refers to pharmaceutically acceptable anions of inorganic acids (e.g., mineral acids), such as chloride anion, bromide anion, iodide anion, sulfate anion, or bisulfate anion; or anions derived from organic acids, such as aliphatic, aromatic, or aryliphatic carboxylic acids or sulfonic acids, such as acetoxy anion, trifluoroacetoxy anion, methanesulfonyloxy anion, etc.

[0123] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of this invention, prepared by reacting a compound having specific substituents discovered in this invention with a relatively non-toxic acid or base. When the compounds of this invention contain relatively acidic functional groups, base addition salts can be obtained by contacting a neutral form of such compound with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts or similar salts. When the compounds of this invention contain relatively basic functional groups, acid addition salts can be obtained by contacting a neutral form of such compound with a sufficient amount of acid in a solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, trifluoroacetic acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; as well as salts of amino acids (such as arginine) and salts of organic acids such as glucuronic acid. Certain compounds of the present invention contain both basic and acidic functional groups, and thus can be converted into either a base or an acid addition salt.

[0124] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture thereof.

[0125] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Therefore, for example, if a group is substituted by 0-2 Rs, the group can optionally be substituted by at most two Rs, and R has independent options in each case. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce stable compounds. For example, Can be selected wait.

[0126] A hyphen ("-") not between two letters or symbols indicates the connection site of a substituent. For example, C 1-6 Alkyl carbonyl group - refers to a carbonyl group connected to the rest of the molecule via a carbonyl group. 1-6 Alkyl groups. However, when the linking site of the substituent is obvious to those skilled in the art, such as halogen substituents, the "-" may be omitted.

[0127] When the group valence bond is marked with a dashed line At times, for example, in In the diagram, the dashed line represents the connection point between the group and other parts of the molecule. When the single bond has... At times, for example, in In the diagram, the dashed line represents a single bond or the absence of a bond, which also means... Represents a single key Or dual keys

[0128] The terms “substituted” or “replaced by” refer to the substitution of one or more hydrogen atoms on a particular atom by a substituent, which may include deuterium and hydrogen variants, provided that the valence state of the particular atom is normal and the substituted compound is stable. The terms “optionally substituted” or “optionally replaced by” mean that it may or may not be substituted, unless otherwise specified, and the type and number of substituents may be arbitrary on a chemically feasible basis.

[0129] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Therefore, for example, if a group is substituted by 1, 2, or 3 R's, the group can optionally be substituted by 1, 2, or 3 R's, and R' has independent options in each case. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound.

[0130] When one of the variables is selected as a single bond, it means that the two groups it connects to are directly connected, for example... When L1 represents a single bond, it means that the structure is actually

[0131] When the listed substituents do not specify which atom they are attached to the substituted group, such substituents can be bonded to any of their atoms. For example, a pyridinium substituent can be attached to the substituted group by any carbon atom on the pyridine ring.

[0132] When the listed linking groups do not specify their linking direction, the linking direction is arbitrary, for example, The linking group L is -CH2O-. In this case, -CH2O- can be connected to a phenyl group and a cyclopentyl group in the same direction as the reading order from left to right to form a structure. Alternatively, the phenyl and cyclopentyl groups can be connected in the reverse order of reading from left to right to form the phenyl group. The combination of linking groups, substituents, and / or their variants is permitted only if such a combination produces a stable compound.

[0133] Unless otherwise specified, the number of atoms in a ring is usually defined as the elemental number of the ring. For example, a “3-6 elemental ring” refers to a “ring” with 3-6 atoms arranged around it.

[0134] Unless otherwise specified, the term "C" 1-6 "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C 1-6 Alkyl groups include C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-4 C6 and C5 alkyl groups, etc.; they can be monovalent (e.g., CH3), divalent (-CH2-), or polyvalent (e.g., hypo-alkyl groups). C 1-6 Examples of alkyl groups include, but are not limited to, CH3, wait.

[0135] Unless otherwise specified, the term "C" 1-4 "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 4 carbon atoms. The C 1-4 Alkyl groups include C 1-2 C 1-3 C 3-4 and C 2-3 Alkyl groups, etc.; they can be monovalent (e.g., CH3), divalent (-CH2-), or polyvalent (e.g., alkyl groups). C 1-4 Examples of alkyl groups include, but are not limited to, CH3, wait.

[0136] Unless otherwise specified, "C 2-6 "Alkenyl" is used to denote a hydrocarbon group consisting of 2 to 6 carbon atoms, either straight-chain or branched, containing at least one carbon-carbon double bond. The carbon-carbon double bond can be located at any position within the group. The C... 2-6 Alkenes include C 2-4 C 2-3 C4, C3, and C2 alkenyl groups, etc.; they can be monovalent, divalent, or polyvalent. 2-6Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, and hexadienyl.

[0137] Unless otherwise specified, "C 2-3 "Alkenyl" is used to denote a hydrocarbon group consisting of 2 to 3 carbon atoms, either straight-chain or branched, containing at least one carbon-carbon double bond. The carbon-carbon double bond can be located at any position within the group. The C... 2-3 Alkenyl groups include C3 and C2 alkenyl groups; the C 2-3 Alkenes can be monovalent, divalent, or polyvalent. C 2-3 Examples of alkenes include, but are not limited to, those that are alkenyl groups. wait.

[0138] Unless otherwise specified, "C 2-6 "Alkyne" is used to denote a hydrocarbon group consisting of 2 to 6 carbon atoms, either straight-chain or branched, containing at least one carbon-carbon triple bond. The carbon-carbon triple bond can be located at any position within the group. It can be monovalent, divalent, or polyvalent. The C... 2-6 Alkyne groups include C 2-3 C 2-4 C 2-5 C 3-4 C 3-5 C 3-6 C 4-5 C 4-6 C 5-6 C6, C5, C4, C3, and C2 alkynyl groups. 2-6 Examples of alkynyl groups include, but are not limited to, those that are not part of the list. wait.

[0139] Unless otherwise specified, "C 2-3 "Alkyne" is used to denote a hydrocarbon group consisting of 2 to 3 carbon atoms, either straight-chain or branched, containing at least one carbon-carbon triple bond. The carbon-carbon triple bond can be located at any position within the group. It can be monovalent, divalent, or polyvalent. The C... 2-3 Alkynyl groups include C3 and C2 alkynyl groups. 2-3 Examples of alkynyl groups include, but are not limited to, those that are not part of the list. wait.

[0140] The term "heteroalkyl" on its own or in combination with another term refers to a stable straight-chain or branched alkyl group or a combination thereof consisting of a certain number of carbon atoms and at least one heteroatom or heterogroup. In some embodiments, the heteroatom is selected from B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. In other embodiments, the heterogroup is selected from -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O)2-, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)-, and -S(=O)N(H)-. In some embodiments, the heteroalkyl group is C 1-6 Heteroalkyl; in other embodiments, the heteroalkyl group is C10. 1-3 Heteroalkyl. Heteroatoms or heteroatomic groups can be located in any internal position of a heteroalkyl group, including the position where the alkyl group is attached to the rest of the molecule, but the term "alkoxy" is a conventional expression and refers to those alkyl groups that are attached to the rest of the molecule by an oxygen atom. Examples of heteroalkyl groups include, but are not limited to, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH2(CH3)2, -CH2-CH2-O-CH3, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)(CH2CH3), -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, -CH2-S-CH2-CH3, -CH2-CH2, -S(=O)-CH3, -CH2-CH2-S(=O)2-CH3, and at most two heteroatoms can be consecutive, such as -CH2-NH-OCH3.

[0141] Unless otherwise specified, the term "C" 1-6 "Alkoxy" refers to alkyl groups containing 1 to 6 carbon atoms that are attached to the rest of the molecule by an oxygen atom. The C 1-6 Alkoxy groups include C 1-4 C 1-3 C 1-2 C 2-6 C 2-4 C6, C5, C4, and C3 alkoxy groups, etc. 1-6 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), hexoxy, etc.

[0142] Unless otherwise specified, the term "C"1-3 "Alkoxy" refers to alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule by an oxygen atom. The C 1-3 Alkoxy groups include C 1-3 C 1-2 C 2-3 C1, C2, and C3 alkoxy groups, etc. C 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), etc.

[0143] Unless otherwise specified, the term "C" 1-6 "Alkylamino" refers to alkyl groups containing 1 to 6 carbon atoms that are attached to the rest of the molecule via an amino group. The C 1-6 Alkylamino groups include C 1-4 C 1-3 C 1-2 C 2-6 C 2-4 C6, C5, C4, C3, and C2 alkylamino groups, etc. 1-6 Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -N(CH2CH3)(CH2CH3), -NHCH2CH2CH3, -NHCH2(CH3)2, -NHCH2CH2CH2CH3, etc.

[0144] Unless otherwise specified, the term "C" 1-3 "Alkylamino" refers to alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule via an amino group. The C 1-3 Alkylamino groups include C 1-3 C 1-2 C 2-3 C1, C2, and C3 alkylamino groups, etc. C 1-3 Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -NHCH2CH2CH3, -NHCH2(CH3)2, etc.

[0145] Unless otherwise specified, the term "C" 1-6 "Alkylthio" refers to alkyl groups containing 1 to 6 carbon atoms that are attached to the rest of the molecule via a sulfur atom. The C 1-6 Alkyl thio groups include C 1-4 C 1-3 C 1-2 C 2-6 C 2-4 C6, C5, C4, C3, and C2 alkylthio groups, etc. C 1-6Examples of alkylthio groups include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, etc.

[0146] Unless otherwise specified, the term "C" 1-3 "Alkylthio" refers to alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule via a sulfur atom. The C 1-3 Alkyl thio groups include C 1-3 C 1-2 C 2-3 C1, C2, and C3 alkylthio groups, etc. C 1-3 Examples of alkylthio groups include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, etc.

[0147] Unless otherwise specified, "C 3-6 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which can be monocyclic or bicyclic. 3-6 Cycloalkyl groups include C 3-5 C 4-5 and C 5-6 Cycloalkyl groups, etc.; they can be monovalent, divalent, or polyvalent. C 3-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0148] Unless otherwise specified, the term "3-6 membered heterocyclic group" on its own or in combination with other terms refers to a saturated or partially unsaturated cyclic group consisting of 3 to 6 ring atoms, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)). p (where p is 1 or 2). It includes monocyclic and bicyclic systems, with bicyclic systems including spirocyclic, fused, and bridged rings. Furthermore, regarding this "3-6 membered heterocyclic group," the heteroatom can occupy the connection position between the heterocyclic group and the rest of the molecule. The 3-6 membered heterocyclic group includes 4-6, 5-6, 4, 5, and 6 membered heterocyclic groups, etc. Examples of 3-6 membered heterocyclic groups include, but are not limited to, azirrobutyl, oxobutyl, thiobutyl, 1,3-dioxopentane, etc. Pyrroloalkyl, pyrazolalkyl, imidazoalkyl, tetrahydrothiophene (including tetrahydrothiophene-2-yl and tetrahydrothiophene-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperidinyl and 2-piperidinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxalkyl, dithiaalkyl, isoxazolalkyl, isothiazolalkyl, 1,2-oxazinyl, 1,2-thiaazinyl, hexahydropyridazinyl, homopiperidinyl or homopiperidinyl, etc.

[0149] Unless otherwise specified, the term "5-6 membered heterocyclic group" on its own or in combination with other terms refers to a saturated or partially unsaturated cyclic group consisting of 5 to 6 ring atoms, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)). p (where p is 1 or 2). It includes monocyclic and bicyclic systems, with bicyclic systems including spirocyclic, fused, and bridged rings. Furthermore, regarding this "5-6 membered heterocyclic group," the heteroatom can occupy the connection position between the heterocyclic group and the rest of the molecule. The 5-6 membered heterocyclic group includes 5-membered and 6-membered heterocyclic groups, etc. Examples of 5-6 membered heterocyclic groups include, but are not limited to, 1,3-dioxolane, Pyrroloalkyl, pyrazolalkyl, imidazoalkyl, tetrahydrothiophene (including tetrahydrothiophene-2-yl and tetrahydrothiophene-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperidinyl and 2-piperidinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxalkyl, dithiaalkyl, isoxazolalkyl, isothiazolalkyl, 1,2-oxazinyl, 1,2-thiaazinyl, hexahydropyridazinyl, homopiperidinyl or homopiperidinyl, etc.

[0150] Unless otherwise specified, the terms "5-6 membered heteroaryl" and "5-6 membered heteroaryl" are used interchangeably in this invention. The term "5-6 membered heteroaryl" refers to a monocyclic group with a conjugated π-electron system consisting of 5 to 6 ring atoms, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)). p(where p is 1 or 2). The 5-6 membered heteroaryl group can be attached to the rest of the molecule via a heteroatom or a carbon atom. The 5-6 membered heteroaryl group includes both 5-membered and 6-membered heteroaryl groups. Examples of the 5-6 membered heteroaryl group include, but are not limited to, pyrrole (including N-pyrrole, 2-pyrrole, and 3-pyrrole), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl), imidazole (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl), oxazolyl (including 2-oxazolyl, 4-oxazolyl, and 5-oxazolyl), and triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl). (and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isooxazolyl, 4-isooxazolyl and 5-isooxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl, etc.), furanyl (including 2-furanyl and 3-furanyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).

[0151] Unless otherwise specified, C n-n+m Or C n -C n+m This includes any specific case with n to n+m carbons, such as C 1-12 Including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 C 11 and C 12 It also includes any range from n to n+m, such as C 1-12 Including C 1-3 C 1-6 C 1-9 C 3-6 C 3-9 C 3-12 C 6-9 C 6-12 and C 9-12 Similarly, n-membered to n+m-membered rings represent the number of atoms in the ring from n to n+m. For example, 3-12-membered rings include 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, and 12-membered rings, and also include any range from n to n+m. For example, 3-12-membered rings include 3-6-membered, 3-9-membered, 5-6-membered, 5-7-membered, 5-10-membered, 6-7-membered, 6-8-membered, 6-9-membered, and 6-10-membered rings, etc.

[0152] The term "leaving group" refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (such as affinity substitution). For example, representative leaving groups include trifluoromethanesulfonates; chlorine, bromine, and iodine; sulfonate groups, such as methanesulfonates, toluenesulfonates, p-bromobenzenesulfonates, p-toluenesulfonates, etc.; acyloxy groups, such as acetoxy groups, trifluoroacetoxy groups, etc.

[0153] The term "protecting group" includes, but is not limited to, "amino protecting group," "hydroxyl protecting group," or "thiol protecting group." The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the nitrogen position of an amino group. Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), triphenylmethyl (Tr), 1,1-di-(4'-methoxyphenyl)methyl; silyl, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), etc. The term "hydroxyl protecting group" refers to a protecting group suitable for preventing hydroxyl side reactions. Representative hydroxyl protecting groups include, but are not limited to: alkyl groups, such as methyl, ethyl, and tert-butyl; acyl groups, such as alkanolyl groups (e.g., acetyl); arylmethyl groups, such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), and diphenylmethyl (diphenylmethyl, DPM); silyl groups, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), etc.

[0154] Those skilled in the art will understand that some compounds of formula (I) may contain one or more chiral centers, and thus have two or more stereoisomers. Therefore, the compounds of the present invention may exist as a single stereoisomer (e.g., enantiomer, diastereomer) and mixtures thereof in any proportion, such as racemates, and, where appropriate, as tautomers and geometric isomers.

[0155] The compounds of this invention can exist in specific geometric or stereoisomeric forms. This invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of protection claimed by this invention.

[0156] As used in this article, "stereoisomer" refers to compounds that have the same chemical composition but differ in the spatial arrangement of atoms or groups. Stereoisomers include enantiomers, diastereomers, and conformational isomers.

[0157] The term "enantiomer" as used in this article refers to two stereoisomers of a compound that are non-overlapping mirror images of each other.

[0158] As used herein, the term "diastereomer" refers to a stereoisomer that has two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers possess different physical properties, such as melting point, boiling point, spectral properties, or biological activity. Mixtures of diastereomers can be separated using high-resolution analytical methods such as electrophoresis and chromatography such as HPLC.

[0159] Stereochemical definitions and conventions can be found in SP Parker, ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994. Many organic compounds exist in an optically active form, meaning they possess the ability to rotate the plane of polarized light. In describing optically active compounds, the prefixes D and L, or R and S, are used to indicate the absolute configuration of the molecule with respect to its chiral center. The prefixes d and l, or (+) and (-), are used to indicate that the compound rotates the plane of polarized light, where (-) or l indicates that the compound is levorotatory. Compounds with the prefix (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers can also be called enantiomers, and mixtures of such isomers are often called enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur in chemical reactions or methods where there is no stereoselectivity or stereospecificity. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two optically inactive enantiomers.

[0160] Racemic mixtures can be used in their original form or resolved into individual isomers. Resolution yields stereochemically pure compounds or mixtures enriched with one or more isomers. Methods for isomer separation are well-known (see Allinger NL and Eliel EL, "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971), including physical methods such as chromatography using chiral adsorbents. Individual chiral isomers can be prepared from chiral precursors. Alternatively, a single isomer can be chemically separated from a mixture by forming a diastereomeric salt with a chiral acid (e.g., a single enantiomer of 10-camphorsulfonic acid, camphoric acid, α-bromocamphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, etc.), the salt is fractionally crystallized, and one or both of the separated bases are then released. This process can optionally be repeated to obtain one or two isomers that substantially do not contain the other isomer, i.e., the desired stereoisomers with an optical purity of, for example, at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% by weight. Alternatively, as is well known to those skilled in the art, a racemic compound can be covalently attached to a chiral compound (auxiliary compound) to obtain a diastereomeric isomer.

[0161] The compounds of this invention can exist in specific forms. Unless otherwise stated, the terms "tautomer" or "tautomer form" refer to isomers of different functional groups in dynamic equilibrium at room temperature, capable of rapidly interconverting into each other. If tautomerization is possible (e.g., in solution), chemical equilibrium of the tautomer can be achieved. For example, proton tautomers (also called prototropic tautomers) include interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions involving the rearrangement of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between the two tautomers, pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0162] The compounds of this invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium. 3 H), Iodine-125 125 I) or C-14 14C). For example, deuterium can be used to replace hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than that between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds of this invention, regardless of radioactivity, are included within the scope of this invention.

[0163] "Optional" or "optionally" means that the event or condition described below may occur but is not required to occur, and the description includes both the scenario in which said event or condition occurs and the scenario in which said event or condition does not occur.

[0164] The compounds of the present invention can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention.

[0165] The solvent used in this invention is commercially available.

[0166] Compounds are named according to conventional naming principles in the field or using Software naming conventions are used; commercially available compounds use supplier catalog names.

[0167] The compounds disclosed in this invention may have one or more chiral centers, each independently possessing an R configuration or an S configuration. Some compounds disclosed in this invention have chiral centers labeled *R, *S, R*, or S*, indicating that the absolute configuration of the chiral center is unidentified, but the compound has undergone chiral resolution and the chiral center is a monomorphic chiral center. This indicates that the compound is a monomorphic enantiomer monomer, a monomorphic diastereomer monomer, or a mixture of diastereomers with a monomorphic chiral center configuration (e.g., other chiral center configurations have not been resolved). When the absolute configuration (R configuration or S configuration) of the chiral center of a compound disclosed in this invention is unidentified, such compounds can be identified based on their retention time (R) under appropriate chromatographic column conditions (e.g., column type, column packing material, column size, mobile phase, etc.). T This is hereby confirmed.

[0168] The invention is explained in more detail in the following embodiments. However, it should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention in any way. Unless otherwise specified, experimental methods in the following embodiments are generally performed under conventional conditions for such reactions or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and parts by weight. Unless otherwise stated, liquid ratios are volume ratios.

[0169] Undefined technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains. Attached Figure Description

[0170] Figure 1 This is the X-ray single-crystal diffraction pattern of compound 3A. Detailed Implementation

[0171] The present application is described in detail below with reference to embodiments, but this does not imply any adverse limitations on the present application. The present application has been described in detail herein, and specific embodiments thereof have also 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.

[0172] Unless otherwise specified, all experimental materials and reagents used in the following examples are available from commercially available sources.

[0173] In all embodiments, 1 H-NMR, 13 C-NMR and 19 F-NMR spectra were recorded using a Bruker Ascend 400 mHz NMR spectrometer and processed using Topspin software. A deuterated solvent was used as an internal deuterium lock. 13 C-NMR and 19 F-NMR 1 H-decoupling. Assignment based on a defined chemical shift / coupling mode, or according to 2D Cosy, HMBC, HSQC, or NOESY experiments. Peak multiplicity is defined as: s singlet, d doublet, t triplet, q quartet, m multiplet, br broad peak, br.s broad singlet; coupling constant (J) accurate to 0.1 Hz. Mass spectrometry was recorded using an Agilent 1260 (ESI) or Shimadzu LC-MS-2020 (ESI) or Agilent 6215 (ESI) mass spectrometer; reversed-phase preparative HPLC separation was performed using an Agilent 1290 UV-guided fully automated purification system. C18 OBD™ 21.2*250mm 10μm column) or a fully automated purification system guided by Gilson GX281 UV (or C18 OBD™ 21.2*250mm 10μm column) C18 OBD™ 19*250mm 10μm column) or Waters QDa-guided fully automated purification system ( The separation was performed using a C18 OBD 29*250mm 10μm column. Unless otherwise specified, separation was performed using a SepaFlash pre-packed normal-phase silica column (Sinopharm Chemical Reagent Co., Ltd.), TLC analytical plates (Yantai Jiangyou Silica Gel Development Co., Ltd., model: HSGF254, size: 2.5×5cm), and all eluent ratios were volume ratios.

[0174] The Chinese names of the reagents represented by chemical formulas or English letter abbreviations are as follows:

[0175] CD3OD represents deuterated methanol; DMSO-d6 represents deuterated dimethyl sulfoxide; Chloroform-d or CDCl3 represents deuterated chloroform; AcOH represents acetic acid; AlCl3 represents aluminum trichloride; Aq represents aqueous solution; N2 represents nitrogen; Ar represents argon; B2Pin2 represents pinacol diborate; BBr3 represents boron tribromide; BH3 represents borane; (Boc)2O represents ditert-butyl dicarbonate; Et3SiH represents triethylsilane; HATU represents 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphorus. Salts; HOBt represents 1-hydroxybenzotriazole; K2CO3 represents potassium carbonate; KOAc represents potassium acetate; MeONa represents sodium methoxide; LDA represents lithium diisopropylamino; LiHMDS represents lithium bis(trimethylsilyl)amino; LiOH represents lithium hydroxide; m-CPBA represents m-chloroperoxybenzoic acid; Na2CO3 represents sodium carbonate; NaBH4 represents sodium borohydride; NaCl represents sodium chloride; NaHCO3 represents sodium bicarbonate; NaOH represents sodium hydroxide; Na2SO4 represents sodium sulfate; NBS represents N-bromosuccinimide; n-BuLi represents n-butyllithium; NH4Cl represents... Ammonium chloride; NMP represents N-methyl-2-pyrrolidone; PBr3 represents phosphorus tribromide; Pd(dppf)Cl2 or PdCl2(dppf) represents 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride; Pd(OAc)2 represents palladium acetate; conc. represents concentrated; (COCl)2 represents oxalyl chloride; Cs2CO3 represents cesium carbonate; CuCl represents cuprous chloride; CuI represents cuprous iodide; DCM represents dichloromethane; Dioxane or 1,4-dioxane represents 1,4-dioxane; MeCN, ACN, or CH3CN represents acetonitrile; MeOH or met hanol represents methanol; EtOH or ethanol represents ethanol; DEA represents diethylamine; DIPEA or DIEA represents N,N-diisopropylethylamine; DMAP represents 4-dimethylaminopyridine; DMF represents N,N-dimethylformamide; DMSO represents dimethyl sulfoxide; EA or EtOAc represents ethyl acetate; PE represents petroleum ether; THF represents tetrahydrofuran; Toluene or tol. represents toluene; SOCl2 represents dichlorosulfoxide; TFA represents trifluoroacetic acid; FA represents formic acid; TMSCN represents trimethylsilylcyanide; H2O represents water; HCl represents hydrogen chloride gas; HCl aq.The following symbols represent various parameters: hydrochloric acid aqueous solution; °C represents degrees Celsius; rt or RT represents room temperature; h represents hours; min represents minutes; g represents grams; mg represents milligrams; mL represents milliliters; mmol represents millimoles; M represents moles; cm represents centimeters; mm represents millimeters; μm represents micrometers; nm represents nanometers; mL / min represents milliliters per minute; Hz represents hertz; MHz represents megahertz; bar represents pressure unit bar; psi represents pressure unit pound per square inch; N2 represents nitrogen; HPLC represents high performance liquid chromatography; ID represents inner diameter; LCMS or LC-MS represents liquid chromatography-mass spectrometry; m / z represents mass-to-charge ratio; ESI represents electrospray ionization; CO2 represents carbon dioxide; TLC represents thin-layer chromatography; UV represents ultraviolet light; MC represents methylcellulose; SBECD represents sodium sulfobutyrate beta-cyclodextrin.

[0176] Example 1: Preparation of compounds 1A and 1B

[0177]

[0178] Preparation of compounds 1-4

[0179] Compound 1-1 (28.2 g, 96 mmol) was added to a three-necked flask and purged three times with nitrogen. Anhydrous diethyl ether (100 mL) was added to the flask, and methyllithium (1.6 M, 120 mL, 192 mmol) was added dropwise at -78 °C. The reaction system was stirred at -78 °C for 5 minutes, then gradually heated to 0 °C and stirred for 3 hours. Compound 1-3 (15 g, 60 mmol) was then added to the reaction system, and stirring continued at room temperature for 16 hours. After the reaction was complete, the reaction system was extracted with EtOAc (100 mL × 3). The organic phases were combined, dried, and concentrated to obtain a crude product. This crude product was purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-5%) to obtain the title compound 1-4 (10 g) as a pale yellow liquid, with a yield of 33%. 1 H NMR (400MHz, CDCl3) δ4.33 (q, J=7.2Hz, 2H), 2.44 (s, 6H), 1.36 (t, J=7.2Hz, 3H). 19 F NMR (376MHz, CDCl3) δ-109.15 (s, 2F).

[0180] Preparation of compounds 1-6

[0181] Iron triacetylacetone (2.2 g, 6.3 mmol) was added to a three-necked flask, and the mixture was purged with nitrogen three times. Anhydrous THF (80 mL), compounds 1-4 (10 g, 31.6 mmol), and TMEDA (1.5 g, 12.6 mmol) were added sequentially to the flask. The reaction mixture was stirred for 5 minutes. A Grignard reagent solution of magnesium 4-methoxyphenyl bromide in THF (0.5 M, 102 mL, 50.6 mmol) was slowly added dropwise to the flask, and the reaction was continued at room temperature with stirring for 16 hours. After the reaction was complete, the mixture was extracted with EtOAc (30 mL × 3). The organic phases were combined, dried, and concentrated to obtain a crude product. This crude product was purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-5%) to obtain the title compound 1-6 (2.1 g) as a pale yellow liquid, with a yield of 23%. 1 H NMR (400MHz, CDCl3) δ 7.19-7.04 (m, 2H), 6.92-6.77 (m, 2H), 4.36 (q, J = 7.1Hz, 2H), 3.79 (s, 3H), 2.16 (s, 6H), 1.37 (t, J = 7.1Hz, 3H). 19 F NMR (376MHz, CDCl3) δ-111.34 (s, 2F).

[0182] Preparation of compounds 1-8

[0183] Compounds 1-7 (1.1 g, 5.6 mmol) were added to a three-necked flask and purged three times with nitrogen. Anhydrous diethyl ether (15 mL) was added to the flask, and n-butyllithium (1.6 M, 3.5 mL, 5.6 mmol) was added dropwise at -78 °C. After stirring at -78 °C for 45 minutes, anhydrous diethyl ether solution (10 mL) containing compound 1-6 (1.5 g, 5.1 mmol) was added dropwise, and stirring continued for 1 hour. After the reaction was complete, saturated ammonium chloride solution (5 mL) was added to quench the reaction, and the mixture was extracted with EtOAc (20 mL × 3). The organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-5%) to obtain the title compound 1-8 (1.6 g) as a yellow solid, with a yield of 86%. 1 H NMR (400MHz, CDCl3) δ7.92-7.77(m,1H),7.18-7.06(m,2H),7.03-6.88(m,2H),6.88-6.80(m,2H),3.79(s,3H),2.21(s,6H). 19F NMR (376MHz, CDCl3) δ-99.65 (d, J = 13.4Hz, 1F), -103.94 (q, J = 13.8Hz, 1F), -107.21 (d, J = 14.8Hz, 2F).

[0184] Preparation of compounds 1-10

[0185] Compounds 1-8 (300 mg, 0.8 mmol) were dissolved in a mixed solution of dichloromethane (5.0 mL) and water (2.0 mL). Trimethyl sulfoxide 1-9 (272 mg, 1.2 mmol) and solid sodium hydroxide (66 mg, 1.7 mmol) were added, and the reaction mixture was stirred at 65 °C for 48 hours. After the reaction was completed, the reaction mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-5%) to obtain the title compound 1-10 (275 mg), with a yield of 89%. 1 H NMR(400MHz, CDCl3)δ7.59(q,J=7.9Hz,1H),7.12-7.04(m,2H),6.97-6.89(m,1H),6.88–6.7 8(m,3H),3.78(s,3H),3.40(d,J=5.2Hz,1H),2.95(qd,J=4.0,1.4Hz,1H),2.11–2.00(m,6H).

[0186] Preparation of Compound 1

[0187] Compound 1-10 (275 mg, 0.73 mmol) was dissolved in DMF solution (1.5 mL), and compound 1-H tetrazolium 1-11 (102 mg, 1.5 mmol) and potassium carbonate (151 mg, 1.1 mmol) were added. The reaction system was sealed and stirred at 80 °C for 16 hours. After the reaction system cooled, the reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10 Prep-C18 250×21.2 mm; column temperature: 25 °C; gradient: 55%-75% acetonitrile in 12 min; flow rate: 30 mL / min) to obtain title compound 1 (100 mg, yield 31%) and the corresponding regioisomer compound 1-12 (50 mg, yield 16%).

[0188] Compound 1: LC-MS (ESI): m / z 447.0 [MH] - . 1H NMR (400MHz, CDCl3) δ8.52(s,1H),7.71–7.58(m,1H),7.01(d,J=8.7Hz,2H),6.83(m,2H),6.80(d,J=8.7Hz,2H),5.44(d,J= 14.6Hz, 1H), 5.04 (d, J = 14.6Hz, 1H), 3.77 (s, 3H), 3.75 (brs, 1H), 2.04 (dd, J = 9.4, 1.8Hz, 3H), 1.85 (dd, J = 9.5, 1.9Hz, 3H).

[0189] Compounds 1-12: LC-MS (ESI): m / z 447.0 [MH] - . 1 H NMR (400MHz, CDCl3) δ8.39(s,1H),7.64(d,J=6.5Hz,1H),7.02(d,J=8.6Hz,2H),6.87–6.76(m,4H),5.74(d,J=14.3 Hz, 1H), 5.28 (d, J = 14.3Hz, 1H), 4.24 (s, 1H), 3.77 (s, 3H), 2.04 (dd, J = 9.5, 1.8Hz, 3H), 1.85 (dd, J = 9.5, 1.8Hz, 3H).

[0190] Preparation of compounds 1A and 1B

[0191] Compound 1 (70 mg) was separated by chiral preparative separation using SFC (preparative separation method, instrument model: MGⅡ preparative SFC (SFC-14); column model: ChiralCel OX, 250×30mm ID, 5μm; mobile phase: A: CO2, B: ethanol (0.1% NH4+) 3· H2O); Elution gradient: B 30%; Flow rate: 60 mL / min; Column pressure: 100 bar; Column temperature: 38 °C; Detection wavelength: 220 nm; Period: ~5 min) to obtain title compounds 1A (28 mg) and 1B (28 mg).

[0192] Compound 1A: LC-MS (ESI): m / z 447.2 [MH] -Chiral analysis method (Column type: Chiralcel OX-3 100×4.6mm ID, 3μm; Mobile phase: A: CO2, B: ethanol (0.05% DEA); Elution gradient: elution from 5% B to 40% B over 4 minutes and maintaining 40% B for 2.5 minutes, followed by equilibration with 5% B for 1.5 minutes; Flow rate: 2.8 mL / min; Column temperature: 35℃; Column pressure: 1500 psi; Detection wavelength: 220 nm; R T =3.413min). 1 H NMR (400MHz, CDCl3) δ8.55(s,1H),7.64(td,J=9.1,6.4Hz,1H),7.08–6.91(m,2H),6.91–6.69(m,4H),5.45(d,J=14. 5Hz, 1H), 5.04 (d, J = 14.6Hz, 1H), 4.03 (s, 1H), 3.76 (s, 3H), 2.03 (dd, J = 9.5, 1.9Hz, 3H), 1.84 (dd, J = 9.5, 1.9Hz, 3H).

[0193] Compound 1B: LC-MS (ESI): m / z 447.2 [MH] - Chiral analysis method (Column type: Chiralcel OX-3 100×4.6mm ID, 3μm; Mobile phase: A: CO2, B: ethanol (0.05% DEA); Elution gradient: elution from 5% B to 40% B over 4 minutes and maintain 40% B for 2.5 minutes, then equilibrate with 5% B for 1.5 minutes; Flow rate: 2.8 mL / min; Column temperature: 35℃; Column pressure: 1500 psi; Detection wavelength: 220 nm; Rt = 2.743 min). 1 H NMR (400MHz, CDCl3) δ8.53(s,1H),7.64(td,J=9.1,6.6Hz,1H),7.05–6.94(m,2H),6.94–6.73(m,4H),5.45(d,J=14. 5Hz, 1H), 5.04 (d, J = 14.6Hz, 1H), 3.87 (s, 1H), 3.77 (s, 3H), 2.04 (dd, J = 9.5, 1.9Hz, 3H), 1.85 (dd, J = 9.4, 1.8Hz, 3H).

[0194] Example 2: Preparation of compounds 2A and 2B

[0195]

[0196] Preparation of compound 2-1

[0197] Compounds 1-8 (1.8 g, 4.95 mmol) were added to a microwave-safe tube, followed by acetic acid (5 mL) and an aqueous solution of hydrogen bromide (48 wt.% in H2O, 5 mL). The tube was sealed at 95 °C and reacted for 16 hours. After cooling, the mixture was evaporated to dryness and extracted with EtOAc (30 mL × 3). The organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-30%) to give the title compound 2-1 (1.3 g) as a brownish-yellow liquid, with a yield of 72%. LC-MS (ESI): m / z 348.8 [MH] - .

[0198] Preparation of compound 2-2

[0199] Compound 2-1 (500 mg, 1.4 mmol) was dissolved in DMF (3 mL), and potassium carbonate (296 mg, 2.1 mmol) and 2,2,2-trifluoroethyltrifluoromethanesulfonate (500 mg, 2.1 mmol) were added. The mixture was then sealed in a tube at 65 °C for 16 hours. After cooling, the mixture was extracted with EtOAc. The organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was then purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-5%) to give the title compound 2-2 (340 mg), a pale yellow oil, in 55% yield. 1 H NMR (400MHz, CDCl3) δ7.93–7.77(m,1H),7.21–7.10(m,2H),7.00(dd,J=2.3,1.2Hz,1H), 6.93(ddd,J=9.5,7.9,1.6Hz,1H),6.91–6.86(m,2H),4.33(q,J=8.1Hz,2H),2.23(s,6H). 19 F NMR (376MHz, CDCl3) δ-73.96 (s, 3F), -99.55 (d, J = 13.6Hz, 1F), -103.71–-104.08 (m, 1F), -107.08–-107.36 (d, 2F).

[0200] Preparation of compounds 2-3

[0201] Compound 2-2 (340 mg, 0.79 mmol) was dissolved in a mixed solvent of dichloromethane (3 mL) and water (3 mL), and trimethyl sulfoxide (433 mg, 1.97 mmol) and sodium hydroxide (79 mg, 1.97 mmol) were added. The reaction mixture was refluxed for 16 hours. After cooling to room temperature, the reaction mixture was extracted with DCM, and the organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-5%) to give title compound 2-3 (260 mg), a pale yellow oil, in 73% yield. 1HNMR(400MHz, CDCl3)δ7.59(td,J=8.3,6.4Hz,1H),7.13–7.07(m,2H),6.93(tdd,J=7.9,2.6,1.1Hz, 1H), 6.89–6.80 (m, 3H), 4.32 (q, J = 8.1Hz, 2H), 3.40 (d, J = 5.2Hz, 1H), 2.95 (m, 1H), 2.12–2.01 (m, 6H). 19 F NMR (376MHz, CDCl3) δ -73.96 (s, 3F), -107.46 (d, J = 8.6Hz, 1F), -108.26 (dt, J = 11.9, 8.1Hz, 1F), -110.91 (dd, J = 48.7, 9.6Hz, 2F).

[0202] Preparation of compound 2

[0203] 1,2,4-triazole (171 mg, 2.48 mmol) was dissolved in DMF (3 mL), and NaH (99 mg, 2.48 mmol) was added at 0 °C. After reacting for 30 minutes, compound 2-3 (221 mg, 0.49 mmol) was added, and the reaction mixture was sealed at 70 °C for 16 hours. After cooling, the reaction mixture was filtered, and the crude filtrate was purified by preparative separation (chromatographic column: Agilent 10 Prep-C18 250 x 21.2 mm; column temperature: 25 °C; mobile phase: water (0.1% FA)-acetonitrile; acetonitrile ratio in the mobile phase increased from 55% to 75% within 12 minutes; flow rate: 30 mL / min) to give title compound 2 (106 mg, yield 42%). LC-MS (ESI): m / z 516.2 [M+H] + . 1 H NMR(400MHz, CDCl3)δ8.21(s,1H),7.86(s,1H),7.81–7.67(m,1H),7.10–7.01(m,2H),6.90–6.80(m,3H),6.77(ddd,J=11.4,8.4,2.5Hz,1H),5 .32(brs,1H),5.22(d,J=14.1Hz,1H),4.85(d,J=14.1Hz,1H),4.31(q,J=8.2Hz,2H),2.07(dd,J=9.5,1.9Hz,3H),1.91(dd,J=9.5,1.8Hz,3H).

[0204] Preparation of compounds 2A and 2B

[0205] Compound 2 was separated by chiral SFC (preparative separation method, instrument model: MGⅡpreparativeSFC (SFC-14); column model: ChiralPak AD, 250×30mm ID, 10μm; mobile phase: A:CO2, B:methanol (0.1% NH3.H2O); elution gradient: B 10%; flow rate: 60mL / min; column pressure: 100bar; column temperature: 38℃; detection wavelength: 220nm; cycle: ~4.40min) to obtain title compounds 2A (44mg) and 2B (42.6mg).

[0206] Compound 2A: LC-MS (ESI): m / z 516.2 [M+H] + Chiral analysis method (Column type: Chiralpak AD-3 150×4.6mm ID, 3μm; Mobile phase: A:CO2, B:methanol (0.05% DEA); Elution gradient: 5% B to 40% B within 5 minutes, maintain 40% B for 2.5 minutes, then equilibrate with 5% B for 2.5 minutes; Flow rate: 2.5 mL / min; Column temperature: 35℃; Column pressure: 1500 psi; Detection wavelength: 220 nm; R T =2.557min). 1 H NMR (400MHz, CDCl3) δ7.91(s,1H),7.59(s,1H),7.54–7.41(m,1H),6.89–6.74(m,2H),6.62–6.55(m,3H),6.50(ddd,J=11.3,8.4,2.5Hz,1H),5 .05(brs,1H),4.95(d,J=14.2Hz,1H),4.58(d,J=14.1Hz,1H),4.05(q,J=8.1Hz,2H),1.81(dd,J=9.5,1.9Hz,3H),1.65(dd,J=9.5,1.9Hz,3H).

[0207] Compound 2B: LC-MS (ESI): m / z 516.2 [M+H] + Chiral analysis method (Column type: Chiralpak AD-3 150×4.6mm ID, 3μm; Mobile phase: A:CO2, B:methanol (0.05% DEA); Elution gradient: 5% B to 40% B within 5 minutes, maintain 40% B for 2.5 minutes, then equilibrate with 5% B for 2.5 minutes; Flow rate: 2.5 mL / min; Column temperature: 35℃; Column pressure: 1500 psi; Detection wavelength: 220 nm; R T =2.298min). 1H NMR(400MHz, CDCl3)δ8.09(s,1H),7.83(s,1H),7.74(td,J=9.0,6.4Hz,1H),7.13–7.02(m,2H),6.90–6.80(m,3H),6.76(ddd,J=12.1,8.4,2.6Hz,1 H), 5.31 (brs, 1H), 5.20 (d, J = 14.2Hz, 1H), 4.83 (d, J = 14.2Hz, 1H), 4.31 (q, J = 8.2Hz, 2H), 2.07 (dd, J = 9.5, 1.9Hz, 3H), 1.91 (dd, J = 9.5, 1.9Hz, 3H).

[0208] Preparation of compound 2-P1

[0209]

[0210] Preparation of compound 2-P1-2

[0211] Compound 2 (100 mg, 0.19 mmol), compound 2-P1-1 (N-methyl-N-(3-[((N-tert-butoxycarbonyl-N-methylamino)acetoxy)methyl]pyridin-2-yl)carbamate (1-chloroethyl) ester, CAS: 338990-31-1, 103 mg, 0.25 mmol), sodium iodide (38 mg, 0.25 mmol), and EtOAc (1.5 mL) were reacted at 50 °C for 16 hours. The reaction solution was filtered, and the crude filtrate was purified by preparative separation (chromatographic column: Agilent 10 Prep-C18 250 x 21.2 mm; column temperature: 25 °C; mobile phase: water (0.1% FA)-acetonitrile; acetonitrile ratio 40%-60% in 12 min; flow rate 30 mL / min) to give the title compound 2-P1-2 (80 mg, yield 47%). LC-MS (ESI): m / z 895.50 [M-Cl] + .

[0212] Preparation of compound 2-P1

[0213] Compound 2-P1-2 (80 mg, 0.09 mmol) and EtOAc (1.0 mL) were added to a reaction flask, and a 1,4-dioxane hydrochloric acid solution (4.0 M, 1 mL) was added dropwise at 0 °C. The reaction was carried out at room temperature for 16 hours. After the reaction was completed, the reaction system was extracted with EtOAc (100 mL × 3), the aqueous phases were combined, and lyophilized to give the title compound 2-P1 (36 mg, 50% yield) as a pale yellow solid. Compound 2-P1: LC-MS (ESI): m / z 795.40 [M-Cl] + .

[0214] Example 3: Preparation of compounds 3A and 3B

[0215]

[0216] Preparation of compound 3

[0217] Compounds 2-3 (260 mg, 0.58 mmol) were dissolved in DMF (1.5 mL), and 1-H tetrazolium (82 mg, 1.2 mmol) and potassium carbonate (121 mg, 0.87 mmol) were added. The reaction mixture was sealed at 80 °C for 16 hours. After the reaction system cooled, the reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparation method: column: Agilent 10 Prep-C18 250 x 21.2 mm; mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; column temperature: 25 °C; gradient: 60%-80% acetonitrile in 12 min; flow rate: 30 mL / min) to obtain title compound 3 (120 mg, yield 40%) and the corresponding regioisomer compound 3-1 (61 mg, yield 20%).

[0218] Compound 3: LC-MS (ESI): m / z 514.8 [MH] - . 1 H NMR (400MHz, CDCl3) δ8.52(s,1H),7.65(td,J=8.9,6.3Hz,1H),7.11–6.98(m,2H),6.93–6.76(m,4H),5.44(d,J=14.6Hz,1 H), 5.05 (d, J = 14.6Hz, 1H), 4.30 (q, J = 8.1Hz, 2H), 3.77 (brs, 1H), 2.05 (dd, J = 9.5, 1.9Hz, 3H), 1.86 (dd, J = 9.5, 1.9Hz, 3H).

[0219] Compound 3-1: LC-MS (ESI): m / z 515.0 [MH] - . 1 H NMR(400MHz, CDCl3)δ8.40(s,1H),7.64(td,J=9.0,6.5Hz,1H),7.09–7.00(m,2H),6.88–6.76(m,4H),5.74(d,J=14.2Hz,1 H), 5.28 (d, J = 14.2Hz, 1H), 4.30 (q, J = 8.1Hz, 2H), 4.23 (brs, 1H), 2.05 (dd, J = 9.5, 1.9Hz, 3H), 1.86 (dd, J = 9.5, 1.9Hz, 3H).

[0220] Preparation of compounds 3A and 3B

[0221] Compound 3 (55 mg) was chirally separated by SFC (preparative separation method, instrument model: MGⅡpreparative SFC (SFC-14); column model: ChiralPak IC, 250×30mm ID, 10μm; mobile phase: A is CO2, B is ethanol (containing 0.1% ammonia); elution gradient: B 15%; flow rate: 60 mL / min; column pressure: 100 bar; column temperature: 38℃; detection wavelength: 220 nm; cycle: ~4 min) to obtain title compounds 3A (22 mg) and 3B (27 mg).

[0222] Compound 3A: LC-MS (ESI): m / z 517.2 [M+H] + Chiral analysis method (Column type: Chiralpak IC-3 150×4.6mm ID, 3μm; Mobile phase: A: CO2, B: ethanol (0.05% DEA); Elution gradient: 5% B to 40% B within 5 minutes, maintain 40% B for 2.5 minutes, then equilibrate with 5% B for 2.5 minutes; Flow rate: 2.5 mL / min; Column temperature: 35℃; Column pressure: 1500 psi; Detection wavelength: 220 nm; R T =2.547min). 1 H NMR(400MHz, CDCl3)δ8.52(s,1H),7.65(td,J=8.9,6.3Hz,1H),7.09–7.01(m,2H),6.93–6.77(m,4H),5.44(d,J=14.5Hz, 1H), 5.05 (d, J = 14.6Hz, 1H), 4.30 (q, J = 8.1Hz, 2H), 3.83 (s, 1H), 2.05 (dd, J = 9.4, 1.9Hz, 3H), 1.86 (dd, J = 9.4, 1.9Hz, 3H).

[0223] Compound 3B: LC-MS (ESI): m / z 515.0 [MH] - Chiral analysis method (Column type: Chiralpak IC-3 150×4.6mm ID, 3μm; Mobile phase: A: CO2, B: ethanol (0.05% DEA); Elution gradient: 5% B to 40% B within 5 minutes, maintain 40% B for 2.5 minutes, then equilibrate with 5% B for 2.5 minutes; Flow rate: 2.5 mL / min; Column temperature: 35℃; Column pressure: 1500 psi; Detection wavelength: 220 nm; R T =2.166min). 1H NMR (400MHz, CDCl3) δ8.52 (s, 1H), 7.65 (td, J = 8.9, 6.3Hz, 1H), 7.08–7.00 (m, 2H), 6.92–6.77(m,4H),5.44(d,J=14.6Hz,1H),5.05(d,J=14.6Hz,1H),4.30(q,J=8. 1Hz, 2H), 3.83 (s, 1H), 2.05 (dd, J=9.5, 1.9Hz, 3H), 1.86 (dd, J=9.5, 1.9Hz, 3H).

[0224] Compound 3A was cultured in single crystals, and X-ray single-crystal diffraction confirmed that the absolute configuration of the chiral center was R-configuration. Figure 1 ).

[0225] Preparation of compound 3A-P1

[0226]

[0227] Preparation of compound 3A-P1

[0228] Compound 3A (100 mg, 0.19 mmol) was added to a sealed reaction tube, along with NaH (38 mg, 0.95 mmol) and THF (1 mL). The reaction was carried out at 0 °C for 30 minutes, followed by the addition of phosphorus oxychloride (0.5 mL) and the reaction was continued at room temperature for 16 hours. Saturated sodium bicarbonate aqueous solution was then added to the reaction mixture, and the reaction was continued at 50 °C for 16 hours. After cooling, the reaction mixture was filtered, and the crude filtrate was purified by preparative separation (chromatographic column: Welch). C18 21.2x250mm; column temperature: 25℃; mobile phase: water (10mM / L NH4HCO3)-acetonitrile; acetonitrile ratio in mobile phase 35%-75% in 12min; flow rate 30mL / min), yielding the title compound 3A-P1 (40mg, yield 35%).

[0229] Compound 3A-P1: LC-MS (ESI): m / z 597.00 [M+H] + . 1H NMR(400MHz, DMSO-d6)δ10.15(s,1H),8.06(td,J=9.0,6.7Hz,1H),7.14(ddd,J=12.1,9.1,2.7Hz,1H),7.07–6.98(m,3H),6.95–6.90(m,2H), 6.17(d,J=14.4Hz,1H),5.53(d,J=14.4Hz,1H),4.68(q,J=8.9Hz,2H),3.65(t,J=6.6Hz,2H),1.93(dd,J=9.5,1.7Hz,3H),1.81–1.75(m,3H). 19 F NMR(376MHz, DMSO-d6)δ-72.59(m,3F),-101.67(m,1F),-108.07(m,2F),-110.19(m,1F).

[0230] Preparation of compound 3A-P2

[0231]

[0232] Preparation of compound 3A-2

[0233] Compound 3A (100 mg, 0.19 mmol) was dissolved in DMF (5.0 mL), and cesium carbonate (190 mg, 0.58 mmol) was added with stirring. After reacting for 15 minutes, compound 3A-1 (127 mg, 0.39 mmol) was added, and the reaction was carried out at 50 °C with stirring for 12 hours. The reaction solution was filtered, and the crude product of the filtrate was purified by preparative separation (preparation method: chromatographic column: Welch). C18 21.2 x 250 mm; column temperature: 25 °C; mobile phase: water (10 mM / L NH4HCO3) - acetonitrile; acetonitrile ratio in the mobile phase 25%-45% in 12 min; flow rate 30 mL / min) yielded the title compound 3A-2 (80 mg, yield: 51%). LC-MS (ESI): m / z 807.3 [M+H] + .

[0234] Preparation of compound 3A-P2

[0235] Compound 3A-2 (70 mg, 0.09 mmol) was dissolved in methanol (5.0 mL), and wet palladium on carbon (10%, 10 mg) was added. The mixture was purged three times with nitrogen and then twice with hydrogen, and hydrogenated at room temperature for 3 hours. The reaction solution was filtered, and the crude product of the filtrate was purified by preparative separation (preparation method: chromatographic column: Welch). C18 21.2x250mm; column temperature: 25℃; mobile phase: water (10mM / LNH4HCO3)-acetonitrile; acetonitrile ratio in mobile phase 25%-45% in 12min; flow rate 30mL / min) to give title compound 3A-P2 (50mg, yield: 92%).

[0236] Compound 3A-P2: LC-MS (ESI): m / z 625.0 [MH] - . 1 H NMR(400MHz, DMSO-d6)δ9.80(s,1H),7.80(td,J=9.0,6.6Hz,1H),7.18(ddd,J=12.1,9.0,2.7Hz,1H),7.12–7.05(m,2H),7.00(td,J=8.5,8.0,2.7 Hz,1H),6.96–6.89(m,2H),5.65–5.47(m,3H),5.37–5.27(m,1H),4.67(q ,J=8.9Hz,2H),1.97(dd,J=9.4,1.6Hz,3H),1.84(dd,J=9.5,1.6Hz,3H).

[0237] Example 4: Preparation of compounds 4A and 4B

[0238]

[0239] Preparation of compound 4-1

[0240] Compound 2-2 (362 mg, 0.84 mmol) was dissolved in THF (2 mL), and 2-methylpropyl-2-thiamine (304 mg, 2.5 mmol) and tetraethyl titanate (573 mg, 2.5 mmol) were added. The mixture was sealed in a tube at 80 °C for 16 hours. After cooling to room temperature, the reaction was quenched with distilled water (0.2 mL). The solvent was evaporated, and the residue was dissolved in DCM (10 mL). The mixture was filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-15%) to obtain the title compound 4-1 (336 mg) as a pale yellow oil, with a yield of 75%. LC-MS (ESI): m / z 536.2 [M+H] + .

[0241] Preparation of compound 4-2

[0242] Compound 4-1 (316 mg, 0.59 mmol) was dissolved in THF (2 mL), and cesium fluoride (134 mg, 0.88 mmol) and TMSCN (88 mg, 0.88 mmol) were added. The reaction was carried out at room temperature for 16 hours. Extraction was performed with EtOAc, and the organic phases were combined, dried, and concentrated to obtain the crude product. Purification was achieved by normal-phase silica gel column chromatography (EtOAc / PE = 0-100%) to give the title compound 4-2 (330 mg), in 99% yield. LC-MS (ESI): m / z 563.0 [M+H] + .

[0243] Preparation of compound 4-3

[0244] Compound 4-2 (310 mg, 0.55 mmol) was dissolved in MeOH (5 mL). The reaction system was cooled to 0 °C and NiCl₂ was added to the reaction solution. 2( 141 mg (1.1 mmol) was added in portions, followed by sodium borohydride (314 mg, 8.3 mmol), and the reaction was stirred at 0 °C for 3 hours. Distilled water (100 mL) was added to the reaction mixture, and the mixture was extracted with EtOAc (100 mL × 3). The organic phase was filtered through diatomaceous earth and concentrated to obtain a crude product. This crude product was purified by normal-phase silica gel column chromatography (MeOH / DCM = 0-5%) to give the title compound 4-3 (159 mg) as a solid, in 51% yield. LC-MS (ESI): m / z 567.0 [M+H] + .

[0245] Preparation of compound 4-4

[0246] Compound 4-3 (159 mg, 0.28 mmol) was dissolved in AcOH (5 mL) solution in a microwave tube, and trimethyl orthoformate (149 mg, 1.4 mmol), sodium acetate (23 mg, 0.28 mmol) and TMSN were added to the solution. 3( 323 mg (2.81 mmol) was microwaved and sealed in a tube, then reacted at 75 °C for 16 hours. After cooling, the mixture was extracted with EtOAc (100 mL × 3), the organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was then purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-100%) to obtain the title compound 4-4 (180 mg), in 99% yield. LC-MS (ESI): m / z 618.2 [MH] - .

[0247] Preparation of compound 4

[0248] Compound 4-4 (180 mg, 0.29 mmol) was dissolved in methanol (3 mL) and stirred at 0 °C. Then, dioxane hydrochloride solution (4 M, 2 mL) was added dropwise, and the reaction was stirred at 0 °C for 4 hours. The reaction was quenched by adding saturated NaHCO3 aqueous solution (5 mL) dropwise to the reaction system. Extraction was performed with EtOAc, and the organic solvent was concentrated. The mixture was then filtered with methanol. The crude filtrate was purified by preparative separation (preparation method: column: Agilent 10 Prep-C18 250 x 21.2 mm; column temperature: 25 °C; mobile phase: water (0.1% FA) - acetonitrile; acetonitrile ratio 55%-75% in 12 min; flow rate 30 mL / min) to obtain title product 4 (50 mg, yield: 33%). LC-MS (ESI): m / z 516.2 [M+H] + .

[0249] Preparation of compounds 4A and 4B

[0250] Compound 4 (75 mg) was chirally separated by SFC (preparative separation method, instrument model: MGⅡpreparative SFC (SFC-1); column model: Cellulose-2, 250×30mm ID, 10μm; mobile phase: A:CO2, B:ethanol; elution gradient: B 40%; flow rate: 70mL / min; column pressure: 100bar; column temperature: 38℃; detection wavelength: 220nm; cycle: ~8min) to obtain title compounds 4A (23.3 mg) and 4B (17.2 mg).

[0251] Compound 4A: LC-MS (ESI): m / z 516.2 [M+H] + Chiral analysis method (Column type: Cellulose-2 150×4.6mm ID, 3μm; Mobile phase: A: CO2, B: ethanol (0.05% DEA); Elution gradient: 5% B to 40% B within 5 minutes, maintain 40% B for 2.5 minutes, then equilibrate with 5% B for 2.5 minutes; Flow rate: 2.5 mL / min; Column temperature: 35℃; Column pressure: 1500 psi; Detection wavelength: 220 nm; R T =6.026min). 1H NMR(400MHz, CDCl3)δ8.51(s,1H),7.69(td,J=9.3,6.3Hz,1H),7.14–6.96(m,2H),6.96–6.76(m,4H),5.47(d,J=14 .4Hz, 1H), 4.93 (d, J = 14.4Hz, 1H), 4.30 ( q, J = 8.1Hz, 2H), 2.03 ( dd, J = 9.4, 1.8Hz, 3H), 1.83 ( dd, J = 9.5, 1.8Hz, 3H).

[0252] Compound 4B: LC-MS (ESI): m / z 516.2 [M+H] + Chiral analysis method (Column type: Cellulose-2 150×4.6mm ID, 3μm; Mobile phase: A: CO2, B: ethanol (0.05% DEA); Elution gradient: 5% B to 40% B within 5 minutes, maintain 40% B for 2.5 minutes, then equilibrate with 5% B for 2.5 minutes; Flow rate: 2.5 mL / min; Column temperature: 35℃; Column pressure: 1500 psi; Detection wavelength: 220 nm; R T =4.285min). 1 H NMR(400MHz, CDCl3)δ8.50(s,1H),7.69(td,J=9.3,8.9,6.3Hz,1H),7.09–6.97(m,2H),6.93–6.78(m,4H),5.47(d,J= 14.4Hz, 1H), 4.92 (d, J = 14.4Hz, 1H), 4.30 (q, J = 8.1Hz, 2H), 2.03 (dd, J = 9.5, 1.8Hz, 3H), 1.82 (dd, J = 9.5, 1.8Hz, 3H).

[0253] Example 5: Preparation of Compound 5

[0254]

[0255] Preparation of compound 5-2

[0256] Compound 5-1 (3.1 g, 14.8 mmol) was added to a three-necked flask and purged three times with nitrogen. Anhydrous diethyl ether (20 mL) was added to the flask, and n-butyllithium (1.6 M, 9.3 mL, 14.8 mmol) was added dropwise at -78 °C. After stirring at -78 °C for 45 min, anhydrous diethyl ether solution (20 mL) containing compound 1-6 (4.0 g, 13.5 mmol) was added dropwise, and stirring continued for 1 h. After the reaction was complete, saturated ammonium chloride solution (5 mL) was added to quench the reaction, and the mixture was extracted with EtOAc (20 mL × 3). The organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-5%) to obtain the title compound 5-2 (2.9 g) as a yellow solid, with a yield of 56%. 1 H NMR (400MHz, CDCl3) δ7.77–7.73(m,1H),7.28–7.25(m,1H),7.24–7.21(m,1H),7.14–7.11(m,2H),6.86–6.83(m,2H),3.79(s,3H),2.21(s,6H).

[0257] Preparation of compound 5-3

[0258] Compound 5-2 (2.9 g, 7.62 mmol) was added to a sealed tube, followed by acetic acid (15 mL) and an aqueous solution of hydrogen bromide (48 wt.% in H2O, 15 mL). The mixture was reacted at 95 °C for 16 hours. After cooling, the mixture was evaporated to dryness and extracted with EtOAc (30 mL × 3). The organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was then purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-30%) to give the title compound 5-3 (1.4 g) as a brownish-yellow solid, with a yield of 50%. 1 H NMR (400MHz, DMSO-d6) δ9.36 (s, 1H), 7.82 (t, J = 8.1 Hz, 1H), 7.75 (dd, J = 10.8, 2. 0Hz,1H),7.57–7.50(m,1H),7.09–6.99(m,2H),6.74–6.62(m,2H),2.11(s,6H).

[0259] Preparation of compound 5-4

[0260] Compound 5-3 (1.0 g, 2.7 mmol) was dissolved in DMF (5 mL), and potassium carbonate (376 mg, 4.1 mmol) and 2,2,2-trifluoroethyltrifluoromethanesulfonate (949 mg, 4.1 mmol) were added. The mixture was then sealed in a tube at 65 °C for 16 hours. After cooling, the mixture was extracted with EtOAc. The organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was then purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-5%) to give the title compound 5-4 (350 mg), a pale yellow oil, in 28% yield. 1 H NMR(400MHz, CDCl3)δ7.78(t,J=8.0Hz,1H),7.30–7.28(m,1H),7.27–7.24(m, 1H), 7.19–7.13 (m, 2H), 6.94–6.88 (m, 2H), 4.36 (q, J = 8.0Hz, 2H), 2.25 (s, 6H).

[0261] Preparation of compound 5-5

[0262] Compound 5-4 (450 mg, 1.0 mmol) was dissolved in a mixed solvent of dichloromethane (3 mL) and water (3 mL), and trimethyl sulfoxide (441 mg, 2.0 mmol) and sodium hydroxide (80 mg, 2.0 mmol) were added. The reaction mixture was refluxed for 16 hours. After cooling to room temperature, the reaction mixture was extracted with DCM. The organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was purified by normal-phase silica gel column chromatography (EtOAc / PE = 0.5%) to obtain the title compound 5-5 (450 mg), a pale yellow oil, in 97% yield. TLC analysis (EtOAc:PE = 1:20): Rf = 0.2.

[0263] Preparation of compound 5

[0264] 1,2,4-triazole (149 mg, 2.1 mmol) was dissolved in DMF (2 mL), and NaH (86 mg, 60%, 2.1 mmol) was added at 0 °C. After reacting for 30 minutes, compound 5-5 (200 mg, 0.43 mmol) was added, and the reaction mixture was sealed at 80 °C for 16 hours. After cooling, the reaction mixture was filtered, and the crude filtrate was purified by preparative separation (chromatographic column: Agilent 10 Prep-C18 250 x 21.2 mm; column temperature: 25 °C; mobile phase: water (0.1% FA)-acetonitrile; acetonitrile ratio 50%-70% in 12 min; flow rate 30 mL / min), yielding title compound 5 (130 mg, yield 56%). LC-MS (ESI): m / z 532.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.37(s,1H),7.70(s,1H),7.54(t,J=8.8Hz,1H),7.40(dd,J=11.6,2.0Hz,1H),7.19(dd,J=8 .8,2.4Hz,1H),7.12–7.05(m,2H),6.95(m,3H),5.14(d,J=14.4Hz,1H),4.87–4.47(m,3H),1.98(m,3H),1.77(m,3H). 19 F NMR(376MHz, DMSO-d6)δ-72.56(t,3F),-104.23(d,1F),-109.32(dd,2F).

[0265] Example 6: Preparation of compounds 6A and 6B

[0266]

[0267] Preparation of compound 6-1

[0268] Compounds 1-7 (0.732 g, 3.8 mmol) were added to a three-necked flask and purged three times with nitrogen. Anhydrous diethyl ether (10 mL) was added to the flask, and n-butyllithium (2.5 M, 1.52 mL, 3.8 mmol) was added dropwise at -78 °C. After stirring the reaction system at -78 °C for 45 minutes, anhydrous diethyl ether solution (10 mL) containing compound 1-4 (1.0 g, 3.16 mmol) was added dropwise, and stirring continued for 1 hour. After the reaction was complete, saturated ammonium chloride solution (5 mL) was added to quench the reaction, and the mixture was extracted with EtOAc (20 mL × 3). The organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-5%) to obtain the title compound 6-1 (0.8 g) as a colorless oil, with a yield of 66%. 1 H NMR (400MHz, CDCl3) δ7.83–7.79(m,1H),7.02–6.97(m,1H),6.95–6.90(m,1H),2.51(s,6H).

[0269] Preparation of compound 6-2

[0270] Compound 6-1 (0.8 g, 2.08 mmol) was added to a three-necked flask and purged three times with nitrogen. Anhydrous methanol (10 mL) was added to the flask, and tri-tert-butylsilane (0.543 g, 2.71 mmol) was added dropwise while cooling at 25 °C. After stirring the reaction mixture at 25 °C for 45 minutes, the reaction was confirmed by LC-MS. 2 g of silica gel was added to the reaction mixture, which was then concentrated. The solution was purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-5%) to obtain the title compound 6-2 (0.4 g) as a colorless oil, with a yield of 74%. 1 H NMR (400MHz, CDCl3) δ7.84–7.80(m,1H),7.00–6.97(m,1H),6.94–6.89(m,1H),2.57(s,1H),2.00(s,6H).

[0271] Preparation of compound 6-3

[0272] Compound 6-2 (400 mg, 1.55 mmol) was dissolved in a mixed solution of dichloromethane (5.0 mL) and water (2.0 mL). Trimethyl sulfoxide (1.36 g, 6.20 mmol) and solid sodium hydroxide (372 mg, 9.29 mmol) were added, and the reaction mixture was stirred at 65 °C for 48 hours. After the reaction was completed, the reaction mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-5%) to obtain the title compound 6-3 (400 mg) as a colorless oil, with a yield of 95%. 1 H NMR (400MHz, CDCl3) δ7.56–7.52(m,1H),6.93–6.90(m,1H),6.85–6.79(m,1H ),3.35(d,J=5.6Hz,1H),2.92–2.90(m,1H),2.45(s,1H),1.88–1.82(m,6H).

[0273] Preparation of compound 6

[0274] Compound 6-3 (400 mg, 1.47 mmol) was dissolved in DMF solution (1.5 mL), and compound 1-H tetrazolium (514 mg, 7.35 mmol) and potassium carbonate (1.02 g, 7.35 mmol) were added. The reaction system was sealed and stirred at 80 °C for 2 hours. After the reaction system cooled, the reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10 Prep-C18 250×21.2 mm; column temperature: 25 °C; gradient: 50%-70% acetonitrile in 12 min; flow rate: 30 mL / min) to obtain title compound 6 (170 mg, yield 34%) and the corresponding regioisomer compound 6-4 (75 mg).

[0275] Compound 6: LC-MS (ESI): m / z 343.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.11(s,1H),7.53–7.46(m,1H),7.30–7.24(m,1H),7.07(s,1H)7.02–7.00(m,1 H),5.38(d,J=14.4Hz,1H),4.96(d,J=14.4Hz,1H),2.34(s,1H),1.78–1.75(m,3H),1.57–1.54(m,3H). 19 F NMR(376MHz, DMSO-d6)δ-103.14(m,1F),-109.63(d,1F),-109.72(m,2F).

[0276] Regioisomer compound 6-4: LC-MS (ESI): m / z 343.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.75(s,1H),7.55–7.49(m,1H),7.28–7.22(m,1H),7.11(s,1H),7.02–6.97(m, 1H),5.56(d,J=14.0Hz,1H),5.19(d,J=14.0Hz,1H),2.33(s,1H),1.77–1.74(m,3H),1.56–1.53(m,3H). 19 F NMR(376MHz, DMSO-d6)δ-102.72(m,1F),-109.43(m,2F),-110.09(d,1F).

[0277] Preparation of compounds 6A and 6B

[0278] Compound 6 (170 mg) was chirally separated by SFC (preparative separation method, instrument model: MGⅡpreparative SFC (SFC-1); column model: Cellulose-2, 250×30mm ID, 10μm; mobile phase: A:CO2, B:ethanol; elution gradient: B 40%; flow rate: 70mL / min; column pressure: 100bar; column temperature: 38℃; detection wavelength: 220nm; cycle: ~8min) to obtain title compounds 6A (69.6 mg, single enantiomer) and 6B (76 mg, single enantiomer).

[0279] Compound 6A: LC-MS (ESI): m / z 343.2 [M+H] + Chiral analysis method (Column type: Cellulose-2 150×4.6mm ID, 3μm; Mobile phase: A: CO2, B: ethanol (0.05% DEA); Elution gradient: 5% B to 40% B within 5 minutes, maintain 40% B for 2.5 minutes, then equilibrate with 5% B for 2.5 minutes; Flow rate: 2.5 mL / min; Column temperature: 35℃; Column pressure: 1500 psi; Detection wavelength: 220 nm; R T =6.026min). 1 H NMR(400MHz,DMSO-d6)δ9.12(s,1H),7.53-7.47(m,1H),7.30-7.24(m,1H),7.08(s,1H),7.03-6.98(m, 1H),5.38(d,J=14.5Hz,1H),4.96(d,J=14.6Hz,1H),2.35(s,1H),1.79-1.76(m,3H),1.57-1.55(m,3H). 19 F NMR(376MHz,Chloroform-d)δ-103.03–-103.25(m,1F),-109.61–-109.63(m,1F),-109.72–-109.75(m,2F).

[0280] Compound 6B: LC-MS (ESI): m / z 343.2 [M+H] +Chiral analysis method (Column type: Cellulose-2 150×4.6mm ID, 3μm; Mobile phase: A: CO2, B: ethanol (0.05% DEA); Elution gradient: 5% B to 40% B within 5 minutes, maintain 40% B for 2.5 minutes, then equilibrate with 5% B for 2.5 minutes; Flow rate: 2.5 mL / min; Column temperature: 35℃; Column pressure: 1500 psi; Detection wavelength: 220 nm; R T =6.026min). 1 H NMR(400MHz,DMSO-d6)δ9.12(s,1H),7.53-7.47(m,1H),7.31-7.24(m,1H),7.08(s,1H),7.03-6.98(m, 1H),5.38(d,J=14.5Hz,1H),4.96(d,J=14.6Hz,1H),2.35(s,1H),1.79-1.76(m,3H),1.57-1.55(m,3H). 19 F NMR(376MHz,Chloroform-d)δ-103.04–-103.25(m,1F),-109.61–-109.63(m,1F),-109.72–-109.75(m,2F).

[0281] Example 7: Preparation of compounds 7A and 7B

[0282]

[0283] Preparation of compound 7

[0284] Compound 5-5 (250 mg, 0.54 mmol) was dissolved in DMF (2.5 mL), and 1-H tetrazolium (189 mg, 2.7 mmol) and potassium carbonate (373 mg, 2.7 mmol) were added. The reaction mixture was sealed at 80 °C for 16 hours. After the reaction system cooled, the reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparation method: column: Agilent 10 Prep-C18 250 x 21.2 mm; mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; column temperature: 25 °C; gradient: 60%-80% acetonitrile in 12 min; flow rate: 30 mL / min) to obtain title compound 7 (120 mg, yield 34%) and the corresponding regioisomer compound 7-1 (56 mg, yield 20%).

[0285] Compound 7: LC-MS (ESI): m / z 532.8 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ9.15(s,1H),7.75–7.33(m,2H),7.30–7.18(m,2H),7.16–7.01(m,2H),7.01–6.81(m,2H),5.44(d ,J=14.6Hz,1H),5.02(d,J=14.6Hz,1H),4.70(q,J=8.9Hz,2H),2.00(dd,J=9.4,1.7Hz,3H),1.79(dd,J=9.4,1.7Hz,3H). 19 F NMR(376MHz, DMSO-d6)δ-72.56(m,3F),-104.65(m,1F),-109.14(d,2F).

[0286] Regioisomer compound 7-1: LC-MS (ESI): m / z 533.20 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.71(s,1H),7.48(t,J=8.6Hz,1H),7.40(dd,J=11.9,2.2Hz,1H),7.20(s,1H),7.15(dd,J=8.6,2.2Hz,1H),7.08–6.96(m,2H ),6.94–6.78(m,2H),5.54(d,J=14.2Hz,1H),5.18(d,J=14.2Hz,1H),4.63 (q, J=8.8Hz, 2H), 1.92 (dd, J=9.4, 1.7Hz, 3H), 1.71 (dd, J=9.4, 1.7Hz, 3H). 19 F NMR(376MHz, DMSO-d6)δ-72.57(s,3F),-104.28(dd,1F),-108.88(m,2F).

[0287] Preparation of compounds 7A and 7B

[0288] Compound 7 (110 mg) was chirally separated by SFC (preparative separation method, instrument model: MGⅡpreparative SFC (SFC-14); column model: ChiralCel OX, 250×30mm ID, 5μm; mobile phase: A:CO2, B:ethanol; elution gradient: B 15%; flow rate: 60mL / min; column pressure: 100bar; column temperature: 38℃; detection wavelength: 220nm; cycle: ~16min) to obtain title compounds 7A (54 mg, single enantiomer) and 7B (51 mg, single enantiomer).

[0289] Compound 7A: LC-MS (ESI): m / z 533.0 [M+H] + Chiral analysis method (Column type: Chiralcel OX-3 100×4.6mm ID, 3μm; Mobile phase: A: CO2, B: ethanol (0.05% DEA); Elution gradient: elution from 5% B to 40% B over 4 minutes and maintaining 40% B for 2.5 minutes, followed by equilibration with 5% B for 1.5 minutes; Flow rate: 2.8 mL / min; Column temperature: 35℃; Column pressure: 1500 psi; Detection wavelength: 220 nm; Rt = 2.072 min). 1 H NMR(400MHz,DMSO-d6)δ9.15(s,1H),7.58-7.39(m,2H),7.27-7.18(m,2H),7.14-7.07(m,2H),7.02-6.89(m,2H ),5.43(d,J=14.4Hz,1H),5.02(d,J=14.4Hz,1H),4.70(q,J=8.9Hz,2H),2.06-1.90(m,3H),1.84-1.70(m,3H). 19 F NMR(376MHz, DMSO-d6)δ-72.57(s,3F),-103.06–-105.12(m,1F),-107.63–-112.35(m,2F).

[0290] Compound 7B: LC-MS (ESI): m / z 533.0 [M+H] + Chiral analysis method (Column type: Chiralcel OX-3 100×4.6mm ID, 3μm; Mobile phase: A: CO2, B: ethanol (0.05% DEA); Elution gradient: elution from 5% B to 40% B over 4 minutes and maintain 40% B for 2.5 minutes, then equilibrate with 5% B for 1.5 minutes; Flow rate: 2.8 mL / min; Column temperature: 35℃; Column pressure: 1500 psi; Detection wavelength: 220 nm; Rt = 2.445 min). 1 H NMR(400MHz,DMSO-d6)δ9.15(s,1H),7.58–7.39(m,2H),7.27–7.18(m,2H),7.14–7.07(m,2H),7.02–6.89(m,2H ),5.43(d,J=14.4Hz,1H),5.02(d,J=14.4Hz,1H),4.70(q,J=8.9Hz,2H),2.06–1.90(m,3H),1.84–1.70(m,3H). 19F NMR(376MHz, DMSO-d6)δ-72.57(s,3F),-103.06–-105.12(m,1F),-107.63–-112.35(m,2F).

[0291] Example 8: Preparation of compounds 8A and 8B

[0292]

[0293] Preparation of compound 8-1

[0294] Compound 2-1 (1.0 g, 2.85 mmol) was added to a 100 mL three-necked flask, followed by the addition of DMF (10 mL), N-phenylbis(trifluoromethanesulfonyl)imide (1.33 g, 3.43 mmol), and TEA (866 mg, 8.56 mmol). The reaction mixture was stirred at room temperature for 4 hours under nitrogen protection. Water (20 mL) was added, and the mixture was extracted with EtOAc (10 mL × 3). The organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was purified by normal-phase silica gel column chromatography (EtOAc / PE = 0.5%) to obtain the title compound 8-1 (900 mg) as a brown solid, with a yield of 65%. TLC analysis (EtOAc:PE = 1:20): Rf = 0.2.

[0295] Preparation of compound 8-2

[0296] Compound 8-1 (300 mg, 0.62 mmol) was added to a microwave tube, along with DMF (3 mL), zinc cyanide (87 mg, 0.75 mmol), and tetrakis(triphenylphosphine)palladium (36 mg, 0.03 mmol). The reaction system was microwave-treated at 80 °C for 40 hours under nitrogen protection. After cooling, water (10 mL) was added, and the mixture was extracted with EtOAc (10 mL × 3). The organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-5%) to obtain the title compound 8-2 (110 mg) as a yellow solid, with a yield of 49%. 1 H NMR (400MHz, Chloroform-d) δ7.92–7.82(m,1H),7.68–7.54(m,2H),7.35–7.27(m,2H),7.05–6.96(m,1H),6.99–6.88(m,1H),2.30(s,6H).

[0297] Preparation of compound 8-3

[0298] Compound 8-2 (110 mg, 0.30 mmol) was dissolved in a mixed solvent of dichloromethane (3 mL) and water (3 mL), and trimethyl sulfoxide (202 mg, 0.91 mmol) and sodium hydroxide (37 mg, 0.91 mmol) were added. The reaction mixture was refluxed for 16 hours. After cooling to room temperature, the reaction mixture was extracted with DCM (10 mL × 3). The organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-5%) to obtain the title compound 8-3 (110 mg, 96% yield), a pale yellow oil. LC-MS (ESI): m / z 374.2 [M+H] + .

[0299] Preparation of compound 8

[0300] Compound 8-3 (110 mg, 0.29 mmol) was dissolved in DMF (2.5 mL), and 1-H tetrazolium (103 mg, 1.47 mmol) and potassium carbonate (203 mg, 1.47 mmol) were added. The reaction mixture was sealed at 80 °C for 16 hours. After the reaction system cooled, the reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparation method: chromatographic column: Agilent 10 Prep-C18 250 x 21.2 mm; mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; column temperature: 25 °C; gradient: 60%-80% acetonitrile in 12 min; flow rate: 30 mL / min) to obtain title compound 8 (40 mg, yield 30%) and the corresponding regioisomer compound 8-4 (10 mg, yield 7%).

[0301] Compound 8: LC-MS (ESI): m / z 444.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.16 (s, 1H), 7.75 (d, J = 7.8Hz, 2H), 7.43–7.14 (m, 6H), 5.45 (d ,J=14.4Hz,1H),5.03(d,J=14.4Hz,1H),2.10(d,J=9.4Hz,3H),1.90(d,J=9.4Hz,3H). 19 F NMR(376MHz, DMSO-d6)δ-108.33–-109.44(m,2F),-112.88–-113.99(m,1F),-118.19(d,1F).

[0302] Compound 8-4: LC-MS (ESI): m / z 444.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.78(s,1H),7.75(d,J=7.9Hz,2H),7.45–7.18(m,6H),5.63(d ,J=14.2Hz,1H),5.26(d,J=14.2Hz,1H),2.08(d,J=9.4Hz,3H),1.88(d,J=9.4Hz,3H). 19 F NMR(376MHz, DMSO-d6)δ-108.78(m,2F),-112.97(m,1F),-118.53(d,1F).

[0303] Preparation of compounds 8A and 8B

[0304] Compound 8 (110 mg) was chirally separated by SFC (preparative separation method, instrument model: MGⅡpreparative SFC (SFC-14); column model: ChiralPak AD, 250×30mm ID, 10μm; mobile phase: A:CO2, B:ethanol (0.1% NH3H2O); elution gradient: B 20%; flow rate: 60mL / min; column pressure: 100bar; column temperature: 38℃; detection wavelength: 220nm; cycle: ~4min) to obtain title compounds 8A (48 mg, single enantiomer) and 8B (48 mg, single enantiomer).

[0305] Compound 8A: LC-MS (ESI): m / z 444.2 [M+H] + Chiral analysis method (Column type: AD-3 150×4.6mm ID, 3μm; Mobile phase: A:CO2, B:ethanol (0.05%DEA); Elution gradient: elution of 5%B to 40%B within 5 minutes and maintaining 40%B for 2.5 minutes, followed by equilibration with 5%B for 2.5 minutes; Flow rate: 2.5mL / min; Column temperature: 35℃; Column pressure: 1500psi; Detection wavelength: 220nm; Rt = 3.242min). 1 H NMR(400MHz,DMSO-d6)δ9.14(s,1H),7.79–7.69(m,2H),7.62–7.47(m,1H),7.40–7.24(m,3H),7.21(s,1H) ,7.08–6.94(m,1H),5.44(d,J=14.6Hz,1H),5.02(d,J=14.6Hz,1H),2.19–2.02(m,3H),1.92–1.76(m,3H). 19FNMR(376MHz, DMSO-d6)δ-102.76–-103.20(m,1F),-109.37–-109.47(m,1F),-109.48–-109.61(m,2F).

[0306] Compound 8B: LC-MS (ESI): m / z 444.2 [M+H] + Chiral analysis method (Column type: AD-3 150×4.6mm ID, 3μm; Mobile phase: A:CO2, B:ethanol (0.05%DEA); Elution gradient: elution of 5%B to 40%B within 5 minutes and maintaining 40%B for 2.5 minutes, followed by equilibration with 5%B for 2.5 minutes; Flow rate: 2.5mL / min; Column temperature: 35℃; Column pressure: 1500psi; Detection wavelength: 220nm; Rt = 2.878min). 1 H NMR(400MHz,DMSO-d6)δ9.14(s,1H),7.79–7.69(m,2H),7.62–7.47(m,1H),7.40–7.24(m,3H),7.21(s,1H) ,7.08–6.94(m,1H),5.44(d,J=14.5Hz,1H),5.02(d,J=14.6Hz,1H),2.19–2.02(m,3H),1.92–1.76(m,3H). 19 FNMR(376MHz, DMSO-d6)δ-102.76–-103.20(m,1F),-109.37–-109.47(m,1F),-109.48–-109.61(m,2F).

[0307] Example 9: Preparation of compounds 9A and 9B

[0308]

[0309] Preparation of compound 9-2

[0310] Compound 9-1 (2.5 g, 13.0 mmol) was added to a three-necked flask and purged three times with nitrogen. Anhydrous diethyl ether (20 mL) was added to the flask, and n-butyllithium (2.5 M, 5.7 mL, 14.3 mmol) was added dropwise at -78 °C. The reaction mixture was stirred at -78 °C for 45 minutes, and then anhydrous diethyl ether solution (20 mL) containing compound 1-6 (4.2 g, 14.3 mmol) was added dropwise, with stirring continued for 1 hour. After the reaction was complete, saturated ammonium chloride aqueous solution (5 mL) was added to quench the reaction, and the mixture was extracted with EtOAc (20 mL × 3). The organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-5%) to obtain the title compound 9-2 (1.9 g) as a yellow solid, with a yield of 63%. 1 H NMR (400MHz, CDCl3) δ7.91–7.81(m,1H),7.15–7.10(d,J=8.0Hz,2H),7.01–6.90(m,2H),6.87–6.83(d,J=8.0Hz,2H),3.79(s,3H),2.21(s,6H).

[0311] Preparation of compound 9-3

[0312] Compound 9-2 (1.9 g, 5.2 mmol) was added to a sealed tube, followed by acetic acid (15 mL) and an aqueous solution of hydrogen bromide (48 wt.% in H2O, 15 mL). The mixture was sealed at 95 °C and reacted for 16 hours. After cooling, the mixture was evaporated to dryness and extracted with EtOAc (30 mL × 3). The organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-30%) to obtain the title compound 9-3 (1.4 g) as a brownish-yellow solid, with a yield of 77%. 1 H NMR(400MHz,DMSO-d6)δ9.37(s,1H),7.93–7.87(m,1H),7.58–7.52(m,1H),7 .35–7.30(m,1H),7.04(d,J=8.0Hz,2H),7.70(d,J=8.0Hz,2H),2.11(s,6H).

[0313] Preparation of compound 9-4

[0314] Compound 9-3 (300 mg, 0.86 mmol) was dissolved in DMF (5 mL), and potassium carbonate (178 mg, 1.29 mmol) and 2,2,2-trifluoroethyltrifluoromethanesulfonate (299 mg, 1.29 mmol) were added. The mixture was then sealed in a tube at 65 °C for 16 hours. After cooling, the mixture was extracted with EtOAc (30 mL × 3). The organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-5%) to give the title compound 9-4 (130 mg), a pale yellow oil, in 35% yield. 1 H NMR (400MHz, DMSO-d6) δ7.94–7.88(m,1H),7.59–7.53(m,1H),7.36–7.31(m,1H),7. 22(d,J=8.0Hz,2H),7.02(d,J=8.0Hz,2H),4.77–4.70(q,J=8.0Hz,2H),2.17(s,6H).

[0315] Preparation of compound 9-5

[0316] Compound 9-4 (130 mg, 0.3 mmol) was dissolved in a mixed solvent of dichloromethane (3 mL) and water (3 mL), and trimethyl sulfoxide (198 mg, 0.9 mmol) and sodium hydroxide (36 mg, 0.9 mmol) were added. The reaction mixture was refluxed for 16 hours. After cooling to room temperature, the reaction mixture was extracted with DCM (30 mL × 3). The organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was purified by normal-phase silica gel column chromatography (EtOAc / PE = 0.5%) to obtain the title compound 9-5 (110 mg), a pale yellow oil, in 82% yield. TLC analysis (EtOAc:PE = 1:20): Rf = 0.2. 1 H NMR (400MHz, DMSO-d6) δ7.70–7.65(m,1H),7.38–7.33(m,1H),7.19–7.17(m,1H),7.17–7.14(d,J=8.0Hz,2 H), 7.00 (d, J = 8.0Hz, 2H), 4.72 (q, J = 8.8Hz, 2H), 3.39 (d, J = 4.0Hz, 1H), 3.10 (d, J = 4.0Hz, 1H), 2.04 (s, 6H).

[0317] Preparation of compound 9

[0318] Compound 9-5 (130 mg, 0.29 mmol) was dissolved in DMF solution (1.5 mL), and compound 1-H tetrazolium (102 mg, 1.45 mmol) and potassium carbonate (200 mg, 1.45 mmol) were added. The reaction system was sealed and stirred at 80 °C for 2 hours. After the reaction system cooled, the reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10 Prep-C18 250×21.2 mm; column temperature: 25 °C; gradient: 60%-80% acetonitrile in 12 min; flow rate: 30 mL / min) to obtain title compound 9 (36 mg, yield 24%) and the corresponding regioisomer compound 9-6 (10 mg, yield 6%).

[0319] Compound 9: LC-MS (ESI): m / z 517.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.13(s,1H),7.57–7.51(m,1H),7.32–7.26(m,1H),7.16(s,1H),7.09(d,J=8.0,2H),7.03–6.98(m,1H),6.9 6(d,J=8.0,2H),5.45(d,J=16.0Hz,1H),5.03(d,J=16.0Hz,1H),4.70(q,J=8.8Hz,2H),2.00(d,J=8.0Hz,3H),1.79(d,J=8.0Hz,3H). 19 F NMR(376MHz, DMSO-d6)δ-72.32(s,3F),-103.09(m,1F),-109.23(d,2F),-109.60(d,1F).

[0320] Compound 9-6: LC-MS (ESI): m / z 517.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.76(s,1H),7.59–7.53(m,1H),7.30–7.24(m,1H),7.20(s,1H),7.09(d,J=8.0,2H),7.03–6.97(m,1H),6.9 5(d,J=8.0,2H), 5.63(d,J=16.0Hz,1H), 5.26(d,J=16.0Hz,1H), 4.69(q,J=8.8Hz,2H), 1.99(d,J=8.0Hz,3H), 1.77(d,J=8.0Hz,3H). 19F NMR(376MHz, DMSO-d6)δ-72.32(s,3F),-102.56–-102.78(m,1F),-108.90–-109.11(m,2F),-109.96(d,1F).

[0321] Preparation of compounds 9A and 9B

[0322] Compound 9 (96 mg) was chirally separated by SFC (preparative separation method, instrument model: MGⅡpreparative SFC (SFC-14); column model: ChiralPak AD, 250×30mm ID, 10μm; mobile phase: A:CO2, B:ethanol; elution gradient: B 10%; flow rate: 60mL / min; column pressure: 100bar; column temperature: 38℃; detection wavelength: 220nm; cycle: ~5.2min) to obtain title compounds 9A (23 mg, single enantiomer) and 9B (23 mg, single enantiomer).

[0323] Compound 9A: LC-MS (ESI): m / z 517.0 [M+H] + Chiral analysis method (Column type: AD-3 150×4.6mm ID, 3μm; Mobile phase: A:CO2, B:ethanol (0.05%DEA); Elution gradient: elution of 5%B to 40%B within 5 minutes and maintaining 40%B for 2.5 minutes, followed by equilibration with 5%B for 2.5 minutes; Flow rate: 2.5mL / min; Column temperature: 35℃; Column pressure: 1500psi; Detection wavelength: 220nm; Rt = 2.838min). 1 H NMR(400MHz, DMSO-d6)δ9.16(s,1H),7.34–7.20(m,4H),7.12–7.07(m,2H),6.97–6.92(m,2H),5.44(d,J= 14.4Hz,1H),5.02(d,J=14.4Hz,1H),4.78–4.61(q,J=8.8Hz,2H),2.01(d,J=9.6,3H),1.81(d,J=9.6,3H). 19 FNMR(376MHz, DMSO-d6)δ-72.57(s,3F),-108.73–-108.96(m,2F),-113.15–-113.47(m,1F),-118.27–-118.42(m,1F).

[0324] Compound 9B: LC-MS (ESI): m / z 517.0 [M+H] +Chiral analysis method (Column type: AD-3 150×4.6mm ID, 3μm; Mobile phase: A:CO2, B:ethanol (0.05%DEA); Elution gradient: elution of 5%B to 40%B within 5 minutes and maintaining 40%B for 2.5 minutes, followed by equilibration with 5%B for 2.5 minutes; Flow rate: 2.5mL / min; Column temperature: 35℃; Column pressure: 1500psi; Detection wavelength: 220nm; Rt = 2.108min). 1 H NMR(400MHz, DMSO-d6)δ9.15(s,1H),7.35–7.20(m,4H),7.12–7.07(m,2H),6.98–6.93(m,2H),5.44(d,J= 14.4Hz,1H),5.02(d,J=14.4Hz,1H),4.74–4.67(q,J=8.8Hz,2H),2.01(d,J=9.2,3H),1.81(d,J=9.6,3H). 19 FNMR(376MHz, DMSO-d6)δ-72.57(s,3F),-108.71–-108.96(m,2F),-113.13–-113.47(m,1F),-118.27–-118.42(m,1F).

[0325] Example 10: Preparation of compounds 10A and 10B

[0326]

[0327] Preparation of compound 10

[0328] Compound 1,2,4-triazole (380 mg, 5.51 mmol) was dissolved in 1.5 mL of DMF solution and cooled to 0 °C. Sodium hydride (133 mg, 5.51 mmol) was added, and the reaction was allowed to proceed for 30 minutes. Compound 6-3 (300 mg, 1.1 mmol) was then added. The reaction mixture was stirred at 80 °C for 2 hours. After cooling, the reaction mixture was filtered, and the crude filtrate was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10 Prep-C18 250 × 21.2 mm; column temperature: 25 °C; gradient: 40%-60% acetonitrile in 12 min; flow rate: 30 mL / min) to obtain title compound 10 (130 mg, yield 34%).

[0329] Compound 10: LC-MS (ESI): m / z 342.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.34(s,1H),7.68(s,1H),7.55–7.49(m,1H),7.22–7.16(m,1H),6.99–6.94(m,1H),6.81(s,1H) ,5.09(d,J=14.4Hz,1H),4.71(d,J=14.4Hz,1H),2.33(s,1H),1.76(dd,J=9.6,2.0Hz,3H),1.54(dd,J=9.6,2.0Hz,3H). 19 F NMR(376MHz, DMSO-d6)δ-102.60–-102.82(m,1F),-109.85(d,1F),-109.95(s,1F),-110.57(d,1F).

[0330] Preparation of compounds 10A and 10B

[0331] Compound 10 (130 mg) was chirally separated by SFC (preparative separation method, instrument model: MGⅡpreparative SFC (SFC-1); column model: Cellulose-2, 250×30mm ID, 10μm; mobile phase: A:CO2, B:ethanol; elution gradient: B 40%; flow rate: 70mL / min; column pressure: 100bar; column temperature: 38℃; detection wavelength: 220nm; cycle: ~8min) to obtain title compound 10A (59 mg, single enantiomer) and 10B (65 mg, single enantiomer).

[0332] Compound 10A: LC-MS (ESI): m / z 342.2 [M+H] + Chiral analysis method (Column type: Cellulose-2 150×4.6mm ID, 3μm; Mobile phase: A: CO2, B: ethanol (0.05% DEA); Elution gradient: 5% B to 40% B within 5 minutes, maintain 40% B for 2.5 minutes, then equilibrate with 5% B for 2.5 minutes; Flow rate: 2.5 mL / min; Column temperature: 35℃; Column pressure: 1500 psi; Detection wavelength: 220 nm; R T =6.026min). 1H NMR (400MHz, DMSO-d6) δ8.41(s,1H),7.74(s,1H),7.61-7.55(m,1H),7.28-7.22(m,1H),7.06-7.01(m,1H),6. 88(s,1H),5.15(d,J=14.4Hz,1H),4.77(d,J=14.4Hz,1H),2.39(s,1H),1.83-1.81(m,3H),1.62-1.59(m,3H). 19 F NMR(376MHz,Chloroform-d)δ-102.60–-102.81(m,1F),-109.84–-109.95(m,2F),-110.56–-110.58(m,1F).

[0333] Compound 10B: LC-MS (ESI): m / z 342.2 [M+H] + Chiral analysis method (Column type: Cellulose-2 150×4.6mm ID, 3μm; Mobile phase: A: CO2, B: ethanol (0.05% DEA); Elution gradient: 5% B to 40% B within 5 minutes, maintain 40% B for 2.5 minutes, then equilibrate with 5% B for 2.5 minutes; Flow rate: 2.5 mL / min; Column temperature: 35℃; Column pressure: 1500 psi; Detection wavelength: 220 nm; R T =6.026min). 1 H NMR (400MHz, DMSO-d6) δ8.41(s,1H),7.74(s,1H),7.61-7.55(m,1H),7.28-7.22(m,1H),7.06-7.01(m,1H),6. 88(s,1H),5.15(d,J=14.4Hz,1H),4.77(d,J=14.4Hz,1H),2.39(s,1H),1.83-1.81(m,3H),1.62-1.59(m,3H). 19 F NMR(376MHz,Chloroform-d)δ-102.60–-102.82(m,1F),-109.84–-109.95(m,2F),-110.56–-110.58(m,1F).

[0334] Example 11: Preparation of Compound 11

[0335]

[0336] Preparation of compound 11-1

[0337] The compound trimethyl sulfoxide iodide (790 mg, 3.59 mmol) was dissolved in a mixed solvent of THF (10 mL) and DMSO (6 mL), followed by the addition of potassium tert-butoxide (402.8 mg, 3.59 mmol). After stirring at room temperature for 1 hour, the mixture was cooled to 0 °C, and compound 6-1 (1.25 g, 3.26 mmol) was added and stirred for 2 hours. The reaction was quenched by adding hydrochloric acid aqueous solution (1 M, 1 mL). The reaction system was extracted with EtOAc (30 mL × 3), the organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was then passed through a normal-phase silica gel column (PE / EtOAc = 0%-100%) to give a pale yellow liquid (480 mg, yield 35%). 1 H NMR (400MHz, CDCl3) δ7.54–7.48(m,1H),6.95–6.82(m,2H),3.34(d,J=8Hz,1H),2.90–2.89(m,1H),2.36–2.31(m,6H).

[0338] Preparation of compound 11

[0339] Compound 11-1 (230 mg, 0.58 mmol) was dissolved in DMF solution (3.0 mL), and compound 1-H tetrazolium (48.1 mg, 0.69 mmol) and potassium carbonate (91.8 mg, 0.66 mmol) were added. The reaction system was sealed and stirred at 80 °C for 2 hours. After the reaction system cooled, the reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparation method: instrument: Gilson-GX-281, flow rate: 25 mL / min, mobile phase: acetonitrile, 0.1% FA aqueous solution, method: 5%-73% acetonitrile, Agilent Pursuit XRs 10 C18 250*21.2 mm column, peak time: 9.0-9.6 min) to obtain title compound 11 (34.7 mg) and the corresponding regioisomer compound 11-2 (17.7 mg).

[0340] Compound 11: LC-MS (ESI): m / z 469.1 [M+H] + . 1 H NMR(400MHz,CD3OD)δ8.87(s,1H),7.58–7.57(m,1H),7.00(m,1H),6.92(m,1H),5.55(d,J =13.6Hz, 1H), 4.97 (d, J = 13.6Hz, 1H), 2.30 (dd, J = 9.2, 2Hz, 3H), 2.09 (dd, J = 9.2, 2Hz, 3H).

[0341] Compound 11-2: LC-MS (ESI): m / z 469.1 [M+H] + .1 H NMR(400MHz,CD3OD)δ8.46(s,1H),7.58–7.55(m,1H),7.00–6.95(m,1H),6.91–6.87(m,1H),5.6 8(d,J=13.6Hz,1H), 5.27(d,J=13.6Hz,1H) 2.30(dd,J=9.2,2Hz,3H), 2.09(dd,J=9.2,2Hz,3H).

[0342] Example 12: Preparation of Compound 12

[0343]

[0344] Preparation of compound 12-2

[0345] Compound 12-1 (4 g, 25.62 mmol) was dissolved in a dichloromethane solution (50 mL). The reaction system was cooled to -10 °C, and triethylamine (3.88 g, 38.39 mmol) was added. The mixture was stirred for 0.5 h. Subsequently, TMSOTf (6.38 g, 30.71 mmol) was slowly added dropwise to the reaction system. The reaction system was stirred at -10 °C for 2 h. Water (50 mL) was added to the reaction solution, the dichloromethane phase was separated, dried over anhydrous sodium sulfate, and petroleum ether (100 mL) was added. The mixture was filtered through silica gel to give the title compound 12-2 (4.4 g, 75% yield). 1 H NMR (400MHz, Chloroform-d) δ7.57–7.51(m,1H),6.88–6.77(m,2H),4.96(t,J=1.2Hz,1H),4.66(t,J=1.6Hz,1H),0.25(s,9H).

[0346] Preparation of compound 12-4

[0347] Compound 12-3 (4 g, 23.51 mmol) was dissolved in a dichloromethane solution (50 mL) and cooled to 0 °C. DMAP (0.574 g, 4.7 mmol) and N-hydroxyphthalimide (4.22 g, 25.9 mmol) were added, and the mixture was stirred for 0.5 h. EDCI (6.78 g, 35.3 mmol) was added. The reaction mixture was stirred at 0 °C for 2 h. The reaction was quenched with water (50 mL), the dichloromethane organic phase was separated, dried, and filtered through silica gel to give the title compound 12-4 (6 g, 81% yield). 1H NMR (400MHz, Chloroform-d) δ7.90 (dd, J=5.6, 2.8Hz, 2H), 7.80 (dd, J=5.6, 2.8Hz, 2H), 3.73 (s, 3H), 2.56 (s, 6H).

[0348] Preparation of compound 12-5

[0349] Compound 12-4 (3.3 g, 10.5 mmol), compound 12-2 (4.78 g, 20.9 mmol), and tris(2-phenylpyridinium)iridium(III) (CAS No.: 94928-86-6, 69 mg, 0.1 mmol) were dissolved in DMF solution (50 mL), and argon gas was introduced for 3 minutes to displace the air. The reaction solution was irradiated with 12 W blue light for 24 hours (LED track lighting fixture, Zhongshan Huifan Lighting Co., Ltd., product model G1006-12W). The reaction system was concentrated to obtain a crude product, which was purified by normal phase silica gel column chromatography (EtOAc / PE = 0-5%) to obtain the title compound 12-5 (900 mg, yield 30%) as a colorless liquid. 1 H NMR (400MHz, Chloroform-d) δ7.93–7.86(m,1H),6.98-6.93(m,1H),6.88-6.82(m,1H),3.64(s,3H),3.15(d,J=2.8Hz,2H),2.06(s,6H).

[0350] Preparation of compound 12-6

[0351] Compound 12-5 (0.55 g, 2.0 mmol), N-fluorobis(benzenesulfonamide) (NFSI, 2.5 g, 7.9 mmol), and 1,3-dimethyl-2-imidazolinone (1.0 g, 8.7 mmol) were added to a three-necked flask, and the mixture was purged with nitrogen three times. Anhydrous THF (15 mL) was added to the flask, and LiHMDS (1.3 M, 7.5 mL, 9.9 mmol) was added dropwise at -78 °C. The reaction mixture was stirred at -78 °C for 10 minutes. The reaction was then quenched by adding 25% sodium thiosulfate aqueous solution (20 mL) dropwise. After stirring for 0.5 hours, the mixture was gradually heated to room temperature. The mixture was extracted with EtOAc (20 mL × 3), and the organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-5%) to obtain the title compound 12-6 (300 mg, yield 48%) as a yellow oil. 1H NMR (400MHz, Chloroform-d) δ7.86-7.80(m,1H),7.02-6.97(m,1H),6.95-6.90(m,1H),3.70(s,3H),2.27(s,6H). 19 F NMR(376MHz,Chloroform-d)δ-99.15(s,1F),-103.57–-103.80(m,1F),-107.43(s,1F),-107.48(s,1F).

[0352] Preparation of compound 12-7

[0353] Compound 12-6 (300 mg, 0.95 mmol) was dissolved in a mixed solvent of dichloromethane (3 mL) and water (3 mL), and trimethyl sulfoxide (835 mg, 3.8 mmol) and sodium hydroxide (227 mg, 5.7 mmol) were added. The reaction mixture was refluxed for 16 hours. After cooling to room temperature, the reaction mixture was extracted with DCM (20 mL × 3). The organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-5%) to obtain a pale yellow oily substance containing the title compound 12-7 (313 mg, crude product, 100% yield, containing a pair of enantiomers). 1 H NMR(400MHz,Chloroform-d)δ7.63–7.48(m,1H),6.95–6.89(m,1H),6.87–6.81( m,1H),3.67(s,3H),3.36(d,J=5.2Hz,1H),2.94–2.89(m,1H),2.15–2.06(m,6H).

[0354] Preparation of compound 12-8

[0355] Compound 12-7 (300 mg, 0.9 mmol) was added to a three-necked flask and purged three times with nitrogen. Anhydrous THF (20 mL) was added to the flask, and methyl magnesium bromide (3.0 M, 1.2 mL, 3.6 mmol) was added dropwise at -78 °C. The reaction system was stirred at -78 °C for 45 minutes, and the reaction was detected by LC-MS to indicate the end of the reaction. The reaction was quenched by adding saturated ammonium chloride solution (5 mL), and extracted with EtOAc (20 mL × 3). The organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-5%) to obtain the title compound 12-8 (300 mg, crude product, 100% yield) as a yellow solid. 1H NMR(400MHz,Chloroform-d)δ7.58–7.52(m,1H),6.93–6.88(m,1H),6.85–6.80( m,1H),3.35(d,J=5.2Hz,1H),2.97–2.88(m,1H),1.74–1.68(m,6H),1.13(s,6H).

[0356] Preparation of compound 12

[0357] Compound 12-8 (300 mg, 0.9 mmol) was dissolved in DMF solution (1.5 mL), and compound 1-H tetrazolium 1-11 (191 mg, 2.72 mmol) and potassium carbonate (376 mg, 2.7 mmol) were added. The reaction system was sealed and stirred at 80 °C for 16 hours. After the reaction system cooled, the reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10 Prep-C18 250×21.2 mm; column temperature: 25 °C; gradient: 35%-55% acetonitrile in 12 min; flow rate: 30 mL / min) to obtain title compound 12 (60 mg, yield 16%, containing a pair of enantiomers) and the corresponding regioisomer compound 12-9 (12 mg, yield 4%, containing a pair of enantiomers). Compound 12: LC-MS (ESI): m / z 401.0 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ9.12(s,1H),7.51–7.45(m,1H),7.31–7.25(m,1H),7.06(s,1H),7.03–6.98(m,1H),5.39(d,J=14.4H z, 1H), 4.97 (d, J = 14.4Hz, 1H), 4.12 (s, 1H), 1.56 (dd, J = 9.6, 1.6Hz, 3H), 1.36 (dd, J = 9.6, 1.6Hz, 3H), 0.92 (d, J = 2.4Hz, 6H). 19 F NMR (376MHz, DMSO-d6) δ-102.90–-103.14(m,1F),-103.18(d,J=9.6Hz,1F),-109.26(d,J=11.3Hz,1F),-109.80(d,J=9.5H,1F).

[0358] Compound 12-9: LC-MS (ESI): m / z 401.0 [M+H] + . 1H NMR(400MHz, DMSO-d6)δ8.76(s,1H),7.54–7.48(m,1H),7.28–7.22(m,1H),7.10(s,1H),7.03–6.98(m,1H),5.57(d,J=14.4H z,1H),5.20(d,J=14.4Hz,1H),4.11(s,1H),1.55(dd,J=9.4,1.6Hz,3H),1.35(dd,J=9.6,1.6Hz,3H),0.91(d,J=2.4Hz,6H). 19 F NMR (376MHz, DMSO-d6) δ-102.58–-102.21(m,1F),-102.76(dd,J=21.9,9.4Hz,1F),-109.00–-109.20(m,1F),-110.16(d,J=9.5Hz,1F).

[0359] Example 13: Preparation of Compound 13

[0360]

[0361] Preparation of compound 13-1

[0362] Compound 11-1 (3 g, 7.5 mmol) and pinacol diboronate (4.21 g, 22.6 mmol) were added to a three-necked flask and purged three times with nitrogen. Anhydrous diethyl ether (150 mL) was added to the flask, and tert-butyllithium (1.3 M, 17.4 mL, 22.6 mmol) was added dropwise at -78 °C. The reaction mixture was stirred at -78 °C for 120 min. The reaction mixture was quenched with saturated ammonium chloride solution (50 mL), extracted with EtOAc (20 mL × 3), and the organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-5%) to obtain the title compound (1.2 g, 40% yield) as a colorless oil. 1 HNMR(400MHz,Chloroform-d)δ7.59–7.52(m,1H),6.92–6.87(m,1H),6.84–6.79( m,1H),3.34(d,J=5.2Hz,1H),2.92–2.89(m,1H),1.96–1.87(m,6H),1.22(s,12H).

[0363] Preparation of compound 13-2

[0364] Compound 13-1 (500 mg, 1.26 mmol) was dissolved in 1.5 mL of DMF solution, and compound 1-H-tetrazole 1-11 (439 mg, 6.3 mmol) and potassium carbonate (0.867 g, 6.3 mmol) were added. The reaction system was sealed and stirred at 80 °C for 2 hours. After the reaction system cooled, the reaction solution was filtered, and the filtrate was evaporated to dryness to obtain crude mixed compound 13-2, which was directly used in the next reaction. LC-MS (ESI): m / z 469.2 [M+H] + .

[0365] Preparation of compound 13

[0366] The mixed compound 13-2 (580 mg, 1.47 mmol, crude) was dissolved in a mixed solvent of tetrahydrofuran (15 mL) and water (5 mL). The reaction system was cooled to -5 °C. Sodium perborate trihydrate (441 mg, 4.4 mmol) was added in portions. The mixture was stirred for 5 minutes, and the reaction was detected as complete by LC-MS. Extracted with ethyl acetate (30 mL × 3), washed with water, dried, and concentrated in the organic phase to obtain crude product. The crude product was then prepared and purified (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10 Prep-C18 250 × 21.2 mm; column temperature: 25℃; gradient: 30%-50% acetonitrile in 12 min; flow rate: 30 mL / min) to obtain title compound 13 (200 mg, yield 47%, containing one enantiomer) and its corresponding regioisomer compound 13-3 (100 mg, yield 23%, containing one enantiomer).

[0367] Compound 13: LC-MS (ESI): m / z 359.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.11(s,1H),7.51–7.45(m,1H),7.29–7.23(m,1H),7.07(br.s,1H),7.03–6.98(m, 1H),6.34(br.s,1H),5.39(d,J=14.5Hz,1H),4.96(d,J=14.6Hz,1H),1.78–1.76(m,3H),1.55–1.53(m,3H). 19 FNMR(376MHz, DMSO-d6)δ-103.07–-103.29(m,1F),-106.29(s,1F),-106.39(s,1F),-109.73–-109.75(d,J=9.6Hz,1F).

[0368] Compound 13-3: LC-MS (ESI): m / z 359.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.75(s,1H),7.54–7.47(m,1H),7.28–7.21(m,1H),7.11(s,1H),7.02–6.97(m, 1H),6.31(s,1H),5.57(d,J=14.2Hz,1H),5.19(d,J=14.2Hz,1H),1.77–1.74(m,3H),1.54–1.52(m,3H). 19 FNMR(376MHz, DMSO-d6)δ-102.69–-102.91(m,1F),-105.98–-106.15(m,2F),-109.11(d,J=9.6Hz,1F).

[0369] Example 14: Preparation of compounds 14A and 14B

[0370]

[0371] Preparation of compound 14-1

[0372] Compound 12-3 (4 g, 23.5 mmol) was added to a three-necked flask and purged three times with argon. Tetrahydrofuran (40 mL) was then added, and the reaction mixture was cooled to 0 °C. Borane dimethyl sulfide (2 mL THF, 13 mL, 26 mmol) was slowly added dropwise. After completion, the reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched with 10 mL of methanol, and the solution was evaporated to dryness to give the title compound 14-1 (3.6 g, 98.0% yield). 1 H NMR (400MHz, Chloroform-d) δ3.67(s,3H),3.62(s,2H),1.98(s,6H).

[0373] Preparation of compound 14-2

[0374] Compound 14-1 (3.3 g, 21.1 mmol) and p-toluenesulfonyl chloride (4.83 g, 25.4 mmol) were added to a three-necked flask and purged three times with argon. Dichloromethane (40 mL) was then added, and the reaction mixture was cooled to 0 °C. Triethylamine (2.57 g, 25.4 mmol) was slowly added dropwise. The reaction system was stirred at room temperature for 16 hours, then the organic phase was evaporated to dryness, and purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-50%) to give the title compound 14-2 (5.5 g, 84% yield) as a white solid. 1H NMR (400MHz, DMSO-d6) δ7.85–7.72(dd,J=8.0,4.0Hz,2H),7.56–7.41(dd,J=8.0,4.0Hz,2H),4.07(s,2H),3.58(s,3H),2.43(s,3H),1.86(s,6H).

[0375] Preparation of compound 14-3

[0376] Lithium aluminum hydride (0.7 g, 19.33 mmol) was added to a three-necked flask and purged three times with argon. Anhydrous tetrahydrofuran (40 mL) was then added, and the reaction mixture was cooled to 0 °C. Compound 14-2 (3 g, 9.67 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL) and slowly added dropwise to the reaction system. After completion, the reaction system was stirred at room temperature for 16 hours. At 0 °C, water (0.7 mL), sodium hydroxide aqueous solution (15%, 0.7 mL), and water (2.1 mL) were slowly added dropwise to quench the reaction. Anhydrous magnesium sulfate was added, the mixture was stirred vigorously, filtered, and the filtrate was evaporated to dryness to give the title compound 14-3 (0.950 g, 87% yield) as a colorless oil. 1 HNMR(400MHz,Chloroform-d)δ3.54(s,2H),1.55(s,6H),1.16(s,3H).

[0377] Preparation of compound 14-4

[0378] Compound 14-3 (0.950 g, 8.47 mmol) was added to a three-necked flask. Carbon tetrachloride (15 mL), hexanilide (15 mL), and water (15 mL) were then added, and the reaction mixture was cooled to 0 °C. Sodium periodate (7.25 g, 33.88 mmol) and RuCl3 trihydrate (0.332 g, 1.3 mmol) were added, and the reaction mixture was stirred at room temperature for 16 hours. The organic phase was evaporated to dryness, and the residue was extracted with dichloromethane. The organic phase was dried, filtered, and evaporated to dryness. The residue was purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-50%) to give the title compound 14-5 (0.750 g, 70% yield) as a white solid. 1 H NMR(400MHz,Chloroform-d)δ8.97(br.s,1H),1.95(s,6H),1.19(s,3H).

[0379] Preparation of compound 14-5

[0380] Compound 14-4 (0.750 g, 5.95 mmol) was dissolved in 15 mL of dichloromethane solution. The reaction system was cooled to 0 °C, and DMAP (0.145 g, 1.19 mmol) and N-hydroxyphthalimide (1.16 g, 7.13 mmol) were added. The reaction system was stirred for half an hour. EDCI (1.71 g, 8.92 mmol) was then added. The reaction system was stirred at 0 °C for 2 hours. The reaction was quenched by adding 50 mL of water, and the dichloromethane phase was separated, dried, and filtered through silica gel to obtain the title compound 14-5 (1.3 g, 80% yield). 1 H NMR (400MHz, Chloroform-d) δ7.89–7.77(m,2H),7.80–7.77(m,2H),2.17(s,6H),1.25(s,3H).

[0381] Preparation of Compound 14-6

[0382] Compound 14-5 (2.9 g, 10.69 mmol), compound 12-2 (4.88 g, 21.38 mmol), and tris(2-phenylpyridine)iridium(III) (703 mg, 1.07 mmol) were dissolved in DMF solution (25 mL), and argon gas was introduced for 3 minutes to purge the solution. The reaction mixture was then irradiated with 12 W blue light (LED track lighting fixture, Zhongshan Huifan Lighting Co., Ltd., product model G1006-12W) for 24 hours. The crude product was concentrated and purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-5%) to obtain the title compound 14-6 (230 mg, yield 9%) as a colorless liquid. 1 H NMR (400MHz, Chloroform-d) δ7.90–7.84(m,1H),6.97–6.92(m,1H),6.88–6.82(m,1H),3.10(d,J=2.8Hz,2H),1.60(s,6H),1.11(s,3H).

[0383] Preparation of Compounds 14-7

[0384] Compound 14-6 (0.230 g, 0.973 mmol), N-fluorobis(benzenesulfonamide) (NFSI, 1.23 g, 3.89 mmol), and 1,3-dimethyl-2-imidazolinone (0.333 g, 2.92 mmol) were added to a three-necked flask, which was then purged three times with nitrogen. Anhydrous THF (15 mL) was added to the flask, and LiHMDS (1.3 M, 3.89 mL, 5.1 mmol) was added dropwise at -78 °C. The reaction system was stirred at -78 °C for 10 minutes, and then quenched by adding 20 mL of 25% sodium thiosulfate aqueous solution dropwise. The mixture was then gradually heated to room temperature with stirring. Extracted with EtOAc (20 mL × 3), the organic phases were combined, dried and concentrated to obtain a crude product, which was then purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-5%) to obtain the title compound 14-6 (150 mg, yield 57%) as a yellow oil. 1 H NMR (400MHz, Chloroform-d) δ7.85–7.77(m,1H),7.00–6.95(m,1H),6.93–6.88(m,1H),1.83(s,6H),1.20(s,3H). 19 F NMR(376MHz,Chloroform-d)δ-100.02(m,1F),-104.21(m,1F),-107.36(d,J=13.4Hz,2F).

[0385] Preparation of Compounds 14-8

[0386] Compound 14-7 (150 mg, 0.555 mmol) was dissolved in a mixed solvent of dichloromethane (3 mL) and water (3 mL), and trimethyl sulfoxide (363 mg, 1.65 mmol) and sodium hydroxide (99 mg, 2.48 mmol) were added. The reaction mixture was refluxed for 16 hours. After cooling to room temperature, the reaction mixture was extracted with DCM (30 mL × 3). The organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-5%) to obtain a pale yellow oil containing the title compound 14-8 (150 mg, 100% yield, crude product, containing a pair of enantiomers). 1 H NMR(400MHz,Chloroform-d)δ7.56–7.43(m,1H),6.86–6.81(m,1H),6.78–6.72(m,1 H),3.27(dd,J=5.6,0.8Hz,1H),2.86–2.83(m,1H),1.66–1.56(m,6H),1.07(s,3H).

[0387] Preparation of compound 14

[0388] Compound 14-8 (150 mg, 0.523 mmol) was dissolved in DMF solution (1.5 mL), and compound 1-H tetrazolium 1-11 (183 mg, 2.72 mmol) and potassium carbonate (362 mg, 2.62 mmol) were added. The reaction system was sealed and stirred at 80 °C for 16 hours. After the reaction system cooled, the reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10 Prep-C18 250×21.2 mm; column temperature: 25 °C; gradient: 55%-75% acetonitrile in 12 min; flow rate: 30 mL / min) to obtain title compound 14 (90 mg, yield 48.0%, containing one enantiomer) and its regioisomer compound 14-9 (45 mg, yield 24.0%, containing one enantiomer). Compound 14: LC-MS (ESI): m / z 357.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.10(s,1H),7.51–7.45(m,1H),7.29–7.22(m,1H),7.03(s,1H),7.02–6.97(m,1H),5.38 (d,J=14.6Hz,1H),4.95(d,J=14.6Hz,1H),1.61(dd,J=9.6,1.8Hz,3H),1.40(dd,J=9.6,1.8Hz,3H),1.03(s,3H). 19 FNMR(376MHz, DMSO-d6)δ-103.04–-103.26(m,1F),-109.17–-109.28(m,2F),-109.82(d,J=9.6Hz,1F).

[0389] Compound 14-9: LC-MS (ESI): m / z 357.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.74(s,1H),7.54–7.48(m,1H),7.27–7.21(m,1H),7.07(s,1H),7.01–6.96(m, 1H),5.56(d,J=14.2Hz,1H),5.18(d,J=14.2Hz,1H),1.61–1.58(m,3H),1.41–1.38(m,3H),1.03(s,3H). 19FNMR(376MHz, DMSO-d6)δ-102.64–-102.86(m,1F),-108.82–-109.04(m,2F),-110.19(d,J=9.6Hz,1F).

[0390] Preparation of compounds 14A and 14B

[0391] Compound 14 (90 mg) was chirally separated by SFC (preparative separation method, instrument model: MGⅡpreparative SFC (SFC-1); column model: Cellulose-2, 250×30mm ID, 10μm; mobile phase: A:CO2, B:ethanol; elution gradient: B 40%; flow rate: 70mL / min; column pressure: 100bar; column temperature: 38℃; detection wavelength: 220nm; cycle: ~8min) to obtain title compounds 14A (43 mg, single enantiomer) and 14B (41 mg, single enantiomer).

[0392] Compound 14A: LC-MS (ESI): m / z 357.0 [M+H] + Chiral analysis method (Column type: Cellulose-2 150×4.6mm ID, 3μm; Mobile phase: A: CO2, B: ethanol (0.05% DEA); Elution gradient: 5% B to 40% B within 5 minutes, maintain 40% B for 2.5 minutes, then equilibrate with 5% B for 2.5 minutes; Flow rate: 2.5 mL / min; Column temperature: 35℃; Column pressure: 1500 psi; Detection wavelength: 220 nm; R T =6.026min). 1 H NMR(400MHz,DMSO-d6)δ9.10(s,1H),7.51–7.45(m,1H),7.28–7.22(m,1H),7.03(s,1H),7.02–6.97(m, 1H),5.38(d,J=14.5Hz,1H),4.95(d,J=14.6Hz,1H),1.63–1.60(m,3H),1.41–1.39(m,3H),1.03(s,3H). 19 F NMR(376MHz,Chloroform-d)δ-103.04–-103.26(m,1F),-109.18–-109.28(m,2F),-109.82(d,J=9.6Hz,1F).

[0393] Compound 14B: LC-MS (ESI): m / z 357.0 [M+H] +Chiral analysis method (Column type: Cellulose-2 150×4.6mm ID, 3μm; Mobile phase: A: CO2, B: ethanol (0.05% DEA); Elution gradient: 5% B to 40% B within 5 minutes, maintain 40% B for 2.5 minutes, then equilibrate with 5% B for 2.5 minutes; Flow rate: 2.5 mL / min; Column temperature: 35℃; Column pressure: 1500 psi; Detection wavelength: 220 nm; R T =6.026min). 1 H NMR(400MHz,DMSO-d6)δ9.10(s,1H),7.51–7.45(m,1H),7.28–7.22(m,1H),7.03(s,1H),7.02–6.96(m, 1H),5.38(d,J=14.5Hz,1H),4.95(d,J=14.6Hz,1H),1.63–1.60(m,3H),1.41–1.39(m,3H),1.03(s,3H). 19 F NMR(376MHz,Chloroform-d)δ-103.04–-103.26(m,1F),-109.18–-109.28(m,2F),-109.84(d,J=9.6Hz,1F).

[0394] Example 15: Preparation of Compound 15

[0395]

[0396] Preparation of compound 15-1

[0397] Compound 12-6 (600 mg, 1.9 mmol) was dissolved in ammonia in methanol (7.0 M, 6 mL). The tube was sealed and stirred at 80 °C for 16 hours. After the reaction was complete, the product was dried and concentrated to obtain a crude product, which was then purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-30%) to give the title compound 15-1 (420 mg, 73% yield). LC-MS (ESI): m / z 302.2 [M+H] + .

[0398] Preparation of compound 15-2

[0399] Compound 15-1 (420 mg, 1.39 mmol) was dissolved in DMF (4 mL) and purged three times with nitrogen. Cyanurium chloride (386 mg, 2.09 mmol) was added at 0 °C. The reaction mixture was slowly heated to room temperature and stirred for 2 hours. After the reaction was complete, the mixture was extracted with EtOAc (30 mL × 3), the organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was then purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-5%) to obtain the title compound 15-2 (180 mg, 45% yield). LC-MS (ESI): m / z 284.1 [M+H] + .

[0400] Preparation of compound 15-3

[0401] Compound 15-2 (180 mg, 0.63 mmol) was dissolved in a mixed solution of dichloromethane (5.0 mL) and water (2.0 mL). Trimethyl sulfoxide 1-9 (209 mg, 0.95 mmol) and solid sodium hydroxide (38 mg, 0.95 mmol) were added, and the reaction mixture was stirred at 65 °C for 16 hours. After the reaction was complete, the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-5%) to obtain the title compound 15-3 (180 mg, 95% yield). LC-MS (ESI): m / z 298.1 [M+H] + .

[0402] Preparation of compound 15

[0403] Compound 15-3 (180 mg, 0.73 mmol) was dissolved in DMF solution (1.5 mL), and compound 1-H tetrazolium 1-11 (222 mg, 3.18 mmol) and potassium carbonate (439 mg, 3.18 mmol) were added. The reaction system was sealed and stirred at 80 °C for 16 hours. After the reaction system cooled, the reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10 Prep-C18 250×21.2 mm; column temperature: 25 °C; gradient: 55%-85% acetonitrile in 12 min; flow rate: 30 mL / min) to obtain title compound 15 (75 mg, yield 33%, containing a pair of enantiomers) and the corresponding regioisomer compound 15-4 (35 mg, yield 16%, containing a pair of enantiomers). Compound 15: LC-MS (ESI): m / z 368.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ9.05(s,1H),7.55–7.34(m,1H),7.34–7.15(m,2H),7.09–6.84(m, 1H),5.30(d,J=14.6Hz,1H),4.90(d,J=14.6Hz,1H),2.33–2.11(m,3H),2.12–1.78(m,3H). 19 F NMR(376MHz, DMSO-d6)δ-102.74–-103.17(m,1F),-109.14(m,1F),-109.95(m,1F),-110.05(s,1F).

[0404] Compound 15-4: LC-MS (ESI): m / z 368.2 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ8.76(s,1H),7.64–7.47(m,1H),7.35(s,1H),7.33–7.22(m,1H),7.05–6. 93(m,1H),5.56(d,J=14.3Hz,1H),5.19(d,J=14.3Hz,1H),2.31–2.16(m,3H),2.11–1.97(m,3H). 19 F NMR(376MHz, DMSO-d6)δ-102.29–-102.88(m,1F),-109.34–-109.55(m,1F),-109.60–-109.97(m,2F).

[0405] Example 16: Preparation of Compound 16

[0406]

[0407] Preparation of compound 16-1

[0408] Compound 15 (50 mg, 0.14 mmol) was dissolved in methanol (2.0 mL), and DIPEA (26 mg, 0.2 mmol) and hydroxylamine hydrochloride (14 mg, 0.2 mmol) were added separately. The tube was sealed and stirred at 80 °C for 16 hours. After the reaction was completed, the mixture was dried and concentrated to give the title compound 16-1 (54 mg, crude product). LC-MS (ESI): m / z 401.2 [M+H] + .

[0409] Preparation of compound 16

[0410] Compound 16-1 (54 mg, 0.14 mmol) was dissolved in trimethyl orthoformate (1.0 mL), and one drop of TFA was added. The reaction system was sealed and stirred at 60 °C for 2 hours. After the reaction system cooled, the crude product was evaporated to dryness and then purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10 Prep-C18 250×21.2 mm; column temperature: 25 °C; gradient: 55%–75% acetonitrile in 12 min; flow rate: 30 mL / min) to give title compound 16 (20 mg, yield 36%, containing a pair of enantiomers).

[0411] Compound 16: LC-MS (ESI): m / z 411.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.53(s,1H),9.14(s,1H),7.61–7.49(m,1H),7.35–7.25(m,1H),7.28(s,1H),7.09–6.98 (m,1H),5.42(d,J=14.6Hz,1H),5.02(d,J=14.6Hz,1H),2.17(dd,J=9.4,1.9Hz,3H),1.96(dd,J=9.4,1.9Hz,3H). 19 F NMR(376MHz, DMSO-d6)δ-102.94(m,1F),-109.36(m,1F),-109.73(m,2F).

[0412] Example 17: Preparation of Compound 17

[0413]

[0414] Preparation of compound 17-2

[0415] Compound 1-1 (100 g, 336.9 mmol) was added to a three-necked flask and purged three times with nitrogen. Anhydrous diethyl ether (500 mL) was added to the flask, and methyllithium (1.6 M, 421 mL, 673.8 mmol) was added dropwise at -78 °C. The reaction system was stirred at -78 °C for 5 minutes, then gradually heated to 0 °C and stirred for 3 hours. Subsequently, compound triethylboron (1.0 M, 16.8 mmol, 16.8 mL) and compound 17-1 (38.4 g, 168 mmol) were added to the reaction system, and stirring was continued at room temperature for 16 hours. After the reaction was completed, the reaction system was extracted with EtOAc (500 mL × 3), the organic phases were combined, dried and concentrated to obtain the crude product, which was purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-5%) to obtain the title compound 17-2 (32 g, yield 64%) as a pale yellow liquid. 1 H NMR (400MHz, Chloroform-d) δ 4.14 (q, J = 8.0 Hz, 2H), 2.64 ( q, J = 8.0 Hz, 1H), 2.24 ( s, 6H), 1.26 ( t, J = 8.0 Hz, 3H), 1.09 ( d, J = 8.0 Hz, 3H).

[0416] Preparation of compound 17-3

[0417] Iron triacetylacetone (7.9 g, 21.7 mmol) was added to a three-necked flask, and the mixture was purged with nitrogen three times. Anhydrous THF (80 mL), compound 17-2 (32 g, 108.8 mmol), and TMEDA (5.0 g, 43.52 mmol) were added sequentially to the flask. The reaction mixture was stirred for 5 minutes. A Grignard reagent solution of magnesium 4-methoxyphenyl bromide in THF (0.5 M, 435 mL, 217.6 mmol) was slowly added dropwise to the flask, and the reaction was continued at room temperature with stirring for 16 hours. After the reaction was complete, the mixture was extracted with EtOAc (300 mL × 3). The organic phases were combined, dried, and concentrated to obtain a crude product. This crude product was purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-5%) to obtain the title compound 17-3 (8.0 g, yield 26.8%) as a pale yellow liquid. 1 H NMR(400MHz,Chloroform-d)δ7.14–7.12(m,2H),6.84–6.82(m,2H),4.16(q,J=8.0Hz,2H),3 .79(s,3H),2.65(q,J=8.0Hz,1H),1.92(s,6H),1.28(t,J=8.0Hz,3H),1.14(d,J=8.0Hz,3H).

[0418] Preparation of compound 17-4

[0419] Compound 17-3 (5.5 g, 20 mmol) was added to a three-necked flask and purged three times with nitrogen. Anhydrous THF (50 mL) was added to the flask, and LDA (2.0 M, 20 mL, 40 mmol) was added dropwise at -78 °C. The reaction mixture was stirred at -78 °C for 45 minutes, and then anhydrous THF solution (50 mL) containing N-fluorobis(benzenesulfonyl)imide (NFSI, 10.3 g, 40 mmol) was added dropwise, with stirring continued for 12 hours. After the reaction was complete, saturated ammonium chloride solution (50 mL) was added to quench the reaction, and the mixture was extracted with EtOAc (200 mL × 3). The organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-20%) to obtain the title compound 17-4 (3.2 g, yield 54.7%) as a pale yellow liquid. 1 HNMR(400MHz,Chloroform-d)δ7.14–7.12(m,2H),6.86–6.83(m,2H),4.27(q,J=8. 0Hz, 2H), 3.79 (s, 3H), 2.08–2.00 (m, 6H), 1.58–1.52 (m, 3H), 1.30 (t, J = 8.0Hz, 3H).

[0420] Preparation of compound 17-5

[0421] Compound 2,4-difluorobromobenzene (2.5 g, 13.1 mmol) was added to a three-necked flask and purged three times with nitrogen. Anhydrous diethyl ether (15 mL) was added to the flask, and n-butyllithium (1.6 M, 8.2 mL, 13.1 mmol) was added dropwise at -78 °C. After stirring the reaction system at -78 °C for 45 minutes, anhydrous diethyl ether solution (10 mL) containing compound 17-4 (3.2 g, 10.9 mmol) was added dropwise, and the reaction was continued with stirring for 1 hour. After the reaction was complete, the reaction system was quenched with saturated ammonium chloride solution (5 mL), extracted with EtOAc (20 mL × 3), the organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-5%) to obtain the title compound 17-5 (2.8 g, 71% yield) as a yellow solid. 1 H NMR(400MHz,Chloroform-d)δ7.60–7.54(m,1H),7.13–7.11(m,2H),7.94–6.9 1(m,2H),6.88–6.83(m,2H),3.79(s,3H),2.11–2.01(s,6H),1.67–1.61(m,3H)

[0422] Preparation of compound 17-6

[0423] The compound trimethyl sulfoxide (1.8 g, 8.3 mmol) was dissolved in DMSO (15.0 mL) and THF (5.0 mL), and then NaH (60% purity, 319 mg, 8.3 mmol) was added. After stirring at room temperature for 1 hour, a DMSO solution (5 mL) containing compound 17-5 (1.0 g, 2.77 mmol) was added, and the reaction system was stirred at room temperature for 16 hours. After the reaction was completed, the reaction system was quenched with saturated ammonium chloride solution (50 mL), extracted with EtOAc (20 mL × 3), the organic phases were combined, dried and concentrated to obtain the crude product, which was purified by normal phase silica gel column chromatography (EtOAc / PE = 0-30%) to obtain the title compound 17-6 (580 mg, yield 55%, containing two pairs of enantiomers) as a yellow oil. 1 H NMR(400MHz,Chloroform-d)δ7.62–7.53(m,1H),7.26–7.10(m,2H),6.90–6.89(m,2H),6.83–6.77 (m,2H),3.78(s,3H),3.32–3.32(m,1H),2.91–2.89(m,1H),2.05–1.96(m,6H),1.50–1.44(m,3H).

[0424] Preparation of compound 17

[0425] Compound 17-6 (240 mg, 0.64 mmol) was dissolved in 1.5 mL of DMF solution, and compound 1-H tetrazolium (90 mg, 1.28 mmol) and potassium carbonate (132 mg, 0.96 mmol) were added. The reaction system was stirred at 80 °C for 16 hours. After the reaction system cooled, the reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10 Prep-C18 250×21.2 mm; column temperature: 25 °C; gradient: 50%-70% acetonitrile in 12 min; flow rate: 30 mL / min) to give title compound 17 (56.5 mg, yield 19.8%, containing two pairs of enantiomers).

[0426] Compound 17: LC-MS (ESI): 445.2 [M+H] + . 1H NMR(400MHz,Chloroform-d)δ9.11(s,1H),8.11(br s,1H),7.85(s,1H),7.84–7.81(m,1H),7.55–7.49(m,1H),7.18–7.13(m,3H),7.12 –7.09(m,4H),6.97–6.93(m,1H),6.82–6.80(m,4H),6.40(s,1H),6.23(s,1H),5.4 4(d,J=16Hz,1H),4.95(d,J=16Hz,1H),4.05–3.99(m,1H),3.72(s,3H),3.69(s,3H ),1.87–1.83(m,6H),1.68–1.65(m,6H),1.43(d,J=12Hz,3H),1.37(d,J=8Hz,3H).

[0427] Example 18: Preparation of compounds 18A and 18B

[0428]

[0429] Preparation of compound 18-1

[0430] Compound 17-3 (29 g, 105.8 mmol) was added to a three-necked flask and purged three times with nitrogen. Acetic acid (300 mL) and hydrobromic acid aqueous solution (300 mL) were added to the flask, respectively. The reaction mixture was stirred at 110 °C for 16 hours. The reaction solution was concentrated to obtain a crude product, which was then slurried with dichloromethane (100 mL) and filtered to obtain the title compound 18-1 (22 g, 89% yield) as a brown solid. LC-MS (ESI): 233.2 [M+H] + .

[0431] Preparation of compound 18-2

[0432] Compound 18-1 (22 g, 94.8 mmol) was added to a three-necked flask and purged three times with nitrogen. Anhydrous DCM (200 mL) and DMF (2 mL) were added sequentially to the flask. The reaction mixture was stirred for 5 minutes, and oxaloyl chloride (12.1 mL, 142.2 mmol) was slowly added dropwise to the flask. The mixture was stirred at room temperature for 2 hours. The reaction solution was evaporated to dryness, dissolved in DCM (80 mL), and then added dropwise to a three-necked flask containing ethanol (150 mL) and stirred for 2 hours. After the reaction was complete, the mixture was poured into water (100 mL), extracted with EtOAc (200 mL × 3), and the organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-20%) to give the title compound 18-2 (18 g, 73% yield) as a pale yellow liquid. LC-MS (ESI): 261.2 [M + H] + .

[0433] Preparation of compound 18-3

[0434] Compound 18-2 (18 g, 69.2 mmol) was added to a three-necked flask, followed by trifluoroethyl trifluoromethanesulfonate (CAS: 6226-25-1, 24.08 g, 103.8 mmol) and potassium carbonate (19.1 g, 138.4 mmol). The mixture was purged with nitrogen three times, and then DMF (120 mL) was added. The reaction mixture was stirred at 70 °C for 16 hours. Water (500 mL) was then added to the reaction mixture, and the mixture was extracted with EtOAc (200 mL × 3). The organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-20%) to obtain the title compound 18-3 (15 g, yield 63.3%) as a pale yellow liquid. LC-MS (ESI): 343.0 [M+H] + .

[0435] Preparation of compound 18-4

[0436] Compound 18-3 (15 g, 43.8 mmol) was added to a three-necked flask and purged three times with nitrogen. Anhydrous THF (150 mL) was added to the flask, and LDA (2.0 M, 44 mL, 88 mmol) was added dropwise at -78 °C. After stirring at -78 °C for 45 minutes, anhydrous THF solution (100 mL) containing N-fluorobis(benzenesulfonamide) (NFSI, 22.6 g, 87.6 mmol) was added dropwise, and the mixture was slowly heated to room temperature for 16 hours. After the reaction was complete, saturated ammonium chloride solution (300 mL) was added to quench the reaction, and the mixture was extracted with EtOAc (100 mL × 3). The organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-20%) to obtain the title compound 18-4 (5 g, 31% yield) as a pale yellow liquid. 1 HNMR(400MHz,Chloroform-d)δ7.18–7.15(m,2H),6.96–6.86(m,2H),4.36–4.27 (m,2H),4.30–4.24(m,2H),2.16–1.93(m,6H),1.57(d,J=8.0Hz,3H),1.26(t,J=8.0Hz,3H).

[0437] Preparation of compound 18-5

[0438] Compound 2,4-difluorobromobenzene (3.0 g, 15.9 mmol) was added to a three-necked flask and purged three times with nitrogen. Anhydrous diethyl ether (30 mL) was added to the flask, and n-butyllithium (1.6 M, 10 mL, 16.0 mmol) was added dropwise at -78 °C. After stirring the reaction system at -78 °C for 45 minutes, anhydrous diethyl ether solution (20 mL) containing compound 18-4 (4.8 g, 13.3 mmol) was added dropwise, and stirring continued for 1 hour. After the reaction was complete, saturated ammonium chloride aqueous solution (100 mL) was added to quench the reaction, and the mixture was extracted with EtOAc (20 mL × 3). The organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-5%) to obtain the title compound 18-5 (4.6 g, 80% yield) as a yellow solid. 1 H NMR(400MHz,Chloroform-d)δ7.59–7.53(m,1H),7.17–7.13(m,2H),7.07–6.96(m,1 H),6.95–6.91(m,3H),4.32(q,J=8.0Hz,2H),2.13–2.10(m,6H),1.64(d,J=30Hz,3H)

[0439] Preparation of compound 18-6

[0440] The compound trimethyl sulfoxide (8.1 g, 37.3 mmol) was dissolved in a mixed solvent of DMSO (15.0 mL) and THF (10.0 mL), followed by the addition of NaH (60% purity, 1.4 g, 37.3 mmol). After stirring at room temperature for 1 hour, a DMSO solution containing compound 18-5 (4.5 g, 10.5 mmol) (20.0 mL) was added, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction mixture was quenched with a saturated ammonium chloride aqueous solution (100 mL), extracted with EtOAc (50 mL × 3), and the organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-30%) to obtain the title compound 18-6 (1.5 g, yield 32%, containing a pair of enantiomers) as a yellow oil. 1 H NMR(400MHz,Chloroform-d)δ7.62–7.53(m,1H),7.26–7.10(m,2H),6.90–6.89(m,2H),6.83–6.77(m,2 H),4.35–4.29(q,J=8Hz,2H),3.32(m,1H),2.91–2.89(m,1H),2.05–1.96(m,6H),1.47(d,J=30Hz,3H).

[0441] Preparation of compound 18-7

[0442] Compound 18-6 (1.5 g, 3.39 mmol) was dissolved in NH3 / MeOH (7.0 M, 70 mL, 490 mmol), and the tube was sealed and reacted at 80 °C for 16 hours. After the reaction was completed, the reaction mixture was concentrated to obtain a crude product, which was then passed through a reverse-phase C18 column (ACN / H2O = 0-50%) to the title compound 18-7 (450 mg, yield 32%, containing a pair of enantiomers) as a yellow oil. LC-MS (ESI): 460.2 [M+H] + .

[0443] Preparation of compound 18

[0444] Compound 18-7 (450 mg, 0.98 mmol) was dissolved in HOAc solution (3 mL), and sodium acetate (80 mg, 0.98 mmol), trimethyl orthoformate (311 mg, 2.94 mmol), and TMSN3 (87.4 mg, 4.9 mmol) were added separately. The reaction system was sealed and stirred at 70 °C for 16 hours. After the reaction system cooled, the reaction solution was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10 Prep-C18 250×21.2 mm; column temperature: 25 °C; gradient: 55%-75% acetonitrile in 12 min; flow rate: 30 mL / min) to give title compound 18 (380 mg, yield 75%, containing a pair of enantiomers).

[0445] Compound 18: LC-MS (ESI): 513.2 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ9.11(s,1H),7.53–7.49(m,1H),7.18–7.14(m,1H),7.30–7.08(m,2H),7.07–6.92(m,3H),6.24(s,1 H),5.45(d,J=12Hz,1H),4.95(d,J=20Hz,1H),4.70(q,J=8.0Hz,2H),1.92–1.89(m,3H),1.87–1.85(m,3H),1.66(d,J=8.0Hz,3H). 19 F NMR(376MHz, DMSO-d6)δ-100.27(m,1F),-111.20(m,2F),-112.38(m,1F),-154.99(m,3F).

[0446] Preparation of compounds 18A and 18B

[0447] Compound 18 (360 mg, containing a pair of enantiomers) was chirally separated by SFC (preparative separation method, instrument model: MGⅡpreparative SFC (SFC-14); column: ChiralCel OD, 250×30 mm ID, 10 μm; mobile phase: A: CO2 B: isopropanol (0.1% NH3H2O); elution gradient: B 40%; flow rate: 100 mL / min; column pressure: 100 bar; column temperature: 35℃; detection wavelength: 220 nM; cycle time: ~9.5 min) to obtain title compound 18A (164 mg, a single enantiomer) and title compound 18B (167 mg, a single enantiomer).

[0448] Compound 18A: LC-MS (ESI): 513.2 [M+H] + Chiral separation (Column: Chiralpak OD-3 150×4.6mm ID, 3μm; Mobile phase: A: CO2, B: isopropanol (0.05% DEA); Elution gradient: 5% B to 40% B in the mobile phase over 5 minutes, then maintain 40% B for 2.5 minutes, followed by equilibration with 5% B for 2.5 minutes; Column temperature: 35℃; Column pressure: 1500psi; Detection wavelength: 220nM; R T =2.464 min). 1 HNMR(400MHz,Chloroform-d)δ9.10(s,1H),7.55–7.49(m,1H),7.18–7.12(m,1H),7.06–7.04(m,2H),6.97–6.92(m,3H),6.38(s ,1H),5.45(d,J=16Hz,1H),4.95(q,J=16Hz,1H),4.70(q,J=8Hz,2H),1.92–1.89(m,3H),1.70–1.68(m,3H),1.54(d,J=20Hz,3H). 19 F NMR(376MHz, DMSO-d6)δ-100.45(m,1F),-111.24(m,3F),-155.15(m,3F).

[0449] Compound 18B: LC-MS (ESI): 513.2 [M+H] + Chiral separation (Column: Chiralpak OD-3 150×4.6mm ID, 3μm; Mobile phase: A: CO2, B: isopropanol (0.05% DEA); Elution gradient: 5% B to 40% B within 5 minutes, maintain 40% B for 2.5 minutes, then equilibrate with 5% B for 2.5 minutes; Flow rate: 2.5 mL / min; Column temperature: 35℃; Column pressure: 1500 psi; Detection wavelength: 220 nm; R T =3.509min). 1H NMR(400MHz,Chloroform-d)δ9.11(s,1H),7.55–7.49(m,1H),7.18–7.16(m,1H),7.15–7.07(m,2H),6.97–6.92(m,3H),6.38(s, 1H), 5.45 (d, J = 16Hz, 1H), 4.95 (d, J = 16Hz, 1H), 4.69 (q, J = 8Hz, 2H), 1.92–1.89 (m, 3H), 1.70–1.68 (m, 3H), 1.54 (d, J = 20Hz, 3H). 19 F NMR(376MHz, DMSO-d6)δ-100.43(m,1F),-111.25(m,3F),-155.05(m,3F).

[0450] Example 19: Preparation of Compound 19

[0451]

[0452] Preparation of compound 19-3

[0453] Compound 19-1 (2.9 g, 14.45 mmol), DMF (20 mL), K2CO3 (4.0 g, 28.9 mmol), and compound 19-2 (3.4 g, 17.34 mmol) were added sequentially to a reaction flask at room temperature. The reaction system was reacted at 80 °C for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and ice water (5 mL) was added. Extraction was performed using EtOAc (20 mL × 3). The organic phase was dried, filtered, concentrated, and purified by normal-phase column chromatography (petroleum ether / ethyl acetate = 0%–100%) to obtain the title compound 19-3 (2.9 g, 71% yield) as a colorless liquid. 1 H NMR (400MHz, CDC13): δ7.69 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 9.2 Hz, 2H), 6.88 (d, J = 9.2 Hz, 2H), 5.12 (s, 2H).

[0454] Preparation of compound 19-4

[0455] At room temperature, compound 19-3 (2.9 g, 10.1 mmol), trimethylsilylacetylene (3.95 g, 40.3 mmol), TEA (5 mL), DMF (15 mL), Pd(PPh3)2Cl2 (0.7 g, 1.0 mmol), and CuI (95.3 mg, 0.5 mmol) were added sequentially to a reaction flask. The mixture was purged with nitrogen three times and reacted at 80 °C for 15 hours. The reaction solution was cooled to room temperature, and ice water (5 mL) was added. Extraction was performed using EtOAc (20 mL × 3). The organic phase was dried, filtered, concentrated, and purified by normal-phase column chromatography (petroleum ether / ethyl acetate = 0%–100%) to obtain the title compound 19-4 (1.66 g, 54% yield) as a colorless liquid. 1 H NMR (400MHz, CDC13): δ7.68(d,J=8.4Hz,2H), 7.52(d,J=8.4Hz,2H), 7.39(d,J=9.2Hz,2H), 6.83(d,J=9.2Hz,2H), 5.09(s,2H), 0.24(s,9H).

[0456] Preparation of compound 19-5

[0457] Compound 19-4 (4.0 g, 13.1 mmol) was dissolved in a mixed solution of THF (40 mL) and MeOH (40 mL) at room temperature, and K2CO3 (18.1 g, 131 mmol) was added. The reaction system was stirred at room temperature for 6 hours, then ice water (5 mL) was added, and the mixture was extracted with EtOAc (20 mL × 3). After drying and concentration, the mixture was purified by normal-phase column chromatography (petroleum ether / ethyl acetate = 0%–100%) to obtain the title compound 19-5 (1.8 g, 59% yield) as a colorless solid. 1 H NMR (400MHz, CDC13): δ7.69 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 9.2 Hz, 2H), 6.90 (d, J = 9.2 Hz, 2H), 5.13 (s, 2H), 3.00 (s, 1H).

[0458] Preparation of compound 19-6

[0459] Compound 12-6 (316 mg, 1.0 mmol) was dissolved in a mixed solvent of THF (6 mL) and H₂O (2 mL) at room temperature, and LiOH (48 mg, 2 mmol) was added. The reaction system was allowed to react at room temperature for 16 hours. After the reaction was completed, the pH of the reaction system was adjusted to approximately 3 with hydrochloric acid aqueous solution (1.0 M), and extracted with DCM (20 mL × 3). The organic phases were combined, dried, concentrated, and purified by normal phase column chromatography (petroleum ether / ethyl acetate = 0%–100%) to obtain the title compound 19-6 (0.23 g, yield 76%). LC-MS (ESI): 303.0 [M + H₂] + .

[0460] Preparation of compound 19-7

[0461] Compound 19-6 (0.23 g, 0.76 mmol) was dissolved in DCM (20 mL) at room temperature, and N-hydroxyphthalimide (124 mg, 0.76 mmol), DMAP (9.3 mg, 0.076 mmol), and N,N'-diisopropylcarbodiimide (106 mg, 0.84 mmol) were added to the solution. The reaction system was subjected to nitrogen protection for 16 hours. After the reaction was completed, ice water (5 mL) was added to quench the reaction, and the mixture was extracted with EtOAc (20 mL × 3). After drying and concentration, the mixture was purified by normal phase column chromatography (petroleum ether / ethyl acetate = 0%-100%) to obtain the title compound 19-7 (0.17 g, 50% yield) as a colorless solid. 1 H NMR (400MHz, CDC13): δ7.91–7.79(m,5H),7.04–6.91(m,2H),2.53(s,6H).

[0462] Preparation of compound 19-8

[0463] At room temperature, compounds CuCl (0.85 mg, 0.0086 mmol), Cu(acac)2 (2.25 mg, 0.0086 mmol), and compound 19-7 (50 mg, 0.11 mmol) were added to reaction flasks, followed by the addition of THF (5 mL) solvent. The mixture was then purged three times with nitrogen. Compound 19-5 (20 mg, 0.086 mmol) and TEA (21.8 mg, 0.215 mmol) were then added sequentially, and the mixture was purged three times with nitrogen again. The reaction mixture was then irradiated with a Blue LED lamp for 20 hours. After the reaction was completed, the reaction system was stirred with silica gel and purified by normal phase column chromatography (petroleum ether / ethyl acetate = 0%-100%) to obtain the title compound 19-8 (5 mg, yield 11.9%). 1H NMR (400MHz, CDC13): δ7.85–7.82(m,1H),7.59–7.57(m,2H),7.54–7.52(m,2H),7.36–7.34(m,2H),7.01–6.85(m,4H),5.12(s,2H),2.31(s,6H).

[0464] Preparation of compound 19-9

[0465] At room temperature, trimethyl sulfoxide iodide (24.2 mg, 0.11 mmol) and potassium tert-butoxide (12.1 mg, 0.11 mmol) were added to a mixed solvent of THF (5 mL) and DMSO (3 mL), respectively. After stirring at room temperature for 1 hour, the reaction system was cooled to 0 °C. Compound 19-8 (50 mg, 0.10 mmol) was added, and the reaction was stirred at 60 °C for 12 hours. The reaction was quenched with ice water (5 mL), extracted with EtOAc (20 mL × 3), washed with water and saturated brine, dried, filtered, concentrated, and purified by normal-phase column chromatography (petroleum ether / ethyl acetate = 0%–100%) to obtain the title compound 19-9 (45 mg, yield 87.1%) as a pale yellow liquid. 1 H NMR (400MHz, CDC13): δ7.68–7.36(m,2H),7.55–7.51(m,3H),7.34–7.32(m,2H),6.92– 6.84(m,4H),5.10(s,2H),3.36(d,J=4Hz,1H),2.91(d,J=4Hz,1H),2.18–2.12(m,6H).

[0466] Preparation of compound 19

[0467] Compound 19-9 (40 mg, 0.08 mmol) was added to DMF (3 mL) at room temperature, followed by the addition of 1-H tetrazolium (7.23 mg, 0.10 mmol) and potassium carbonate (13.1 mg, 0.095 mmol). The reaction was stirred at 80 °C for 16 hours. The reaction was quenched with ice water (5 mL), extracted with EtOAc (20 mL × 3), dried and concentrated, and then prepared by reversed-phase chromatography to obtain the title compound 19 (3.25 mg) and its regiomeric compound 19-10 (1.98 mg).

[0468] Compound 19: LC-MS: m / z 574.3 [M+H] + . 1H NMR(400MHz,CD3OD)δ8.89(s,1H),7.74–7.72(m,2H),7.61–7.59(m,3H),7.26–7. 24(m,2H),6.93–6.90(m,4H),5.55(d,J=12Hz,1H),5.17(s,2H),4.95(d,J=12Hz, 1H), 2.10 (dd, J=9.2, 1.6Hz, 3H), 1.89 (dd, J=9.2, 1.6Hz, 3H).

[0469] Compounds 19-10: LC-MS: m / z 574.3 [M+H] + . 1 H NMR(400MHz,CD3OD)δ8.46(s,1H),7.14–7.12(m,2H),7.63–7.58(m,3H),7.26–7.24(m,2H),6.97–6.89(m,4H),5.7 0(d,J=14.4Hz,1H),5.28(d,J=14.4Hz,1H),5.18(s,2H),2.08(dd,J=9.2,1.6Hz,3H),1.87(dd,J=9.2,1.6Hz,3H).

[0470] Example 20: Preparation of compounds 20A and 20B

[0471]

[0472] Preparation of compound 20-1

[0473] Compound 2-1 (1.2 g, 3.43 mmol) was dissolved in a mixed solvent of dichloromethane (15 mL) and water (15 mL), and trimethyl sulfoxide (3.02 g, 13.7 mmol) and sodium hydroxide (549 mg, 13.7 mmol) were added. The reaction mixture was refluxed for 16 hours. After cooling to room temperature, the pH of the reaction mixture was adjusted to 6–7 with dilute hydrochloric acid, and the mixture was extracted with DCM (20 mL × 3). The organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was purified by normal-phase silica gel column chromatography (EtOAc / PE = 0–10%) to obtain the title compound 20-1 (1.17 g, 94% yield) as a pale yellow oil. LC-MS (ESI): m / z 363.0 [MH] - . 1H NMR (400MHz, DMSO-d6) δ9.34(s,1H),7.67(td,J=8.5,6.5Hz,1H),7.35(ddd,J=10.5,9.3,2.6Hz,1H),7.16(tdd,J=8 .5,2.6,0.9Hz,1H),7.02–6.93(m,2H),6.74–6.63(m,2H),3.40–3.36(m,1H),3.11–3.05(m,1H),2.03–1.94(m,6H). 19 F NMR(376MHz, DMSO-d6)δ-107.77–-107.88(m,1F),-108.07–-108.22(m,1F),-108.71–-108.81(m,1F),-108.93–-109.06(m,1F).

[0474] Preparation of compound 20

[0475] Compound 20-1 (1.17 g, 3.21 mmol) was dissolved in DMF solution (10 mL), and compound 1-H tetrazolium (225 mg, 12.9 mmol) and potassium carbonate (444 mg, 12.9 mmol) were added separately. The reaction system was sealed and stirred at 80 °C for 16 hours. After the reaction system cooled, the reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10 Prep-C18 250×21.2 mm; column temperature: 25 °C; gradient: 40%-60% acetonitrile in 12 min; flow rate: 30 mL / min) to obtain title compound 20 (500 mg, yield 36%, containing a pair of enantiomers) and its corresponding regioisomer compound 20-2 (200 mg, yield 14%, containing a pair of enantiomers).

[0476] Compound 20: LC-MS (ESI): m / z 435.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.31(br.s,1H),9.14(s,1H),7.53(m,1H),7.28(m,1H),7.16(s,1H),7.00(m,1H),6.96–6.84(m,2 H),6.67–6.58(m,2H),5.42(d,J=12Hz,1H),5.01(d,J=12Hz,1H),1.94(dd,J=9.5,1.7Hz,3H),1.72(dd,J=9.5,1.7Hz,3H). 19F NMR (376MHz, DMSO-d6) δ-102.85–-103.32(m,1F),-109.01–-109.42(m,2F),-109.67(d,J=9.2Hz,1F).

[0477] Compound 20-2: LC-MS (ESI): m / z 435.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.30(s,1H),8.76(s,1H),7.56(m,1H),7.26(m,1H),7.18(s,1H),7.00(m,1H),6.95–6.85(m,2H),6 .69–6.55(m,2H),5.42(d,J=14.2Hz,1H),5.23(d,J=14.2Hz,1H),1.93(dd,J=9.5,1.7Hz,3H),1.71(dd,J=9.5,1.7Hz,3H). 19 F NMR(376MHz, DMSO-d6)δ-102.38–-102.95(m,1F),-108.69–-109.22(m,2F),-110.02(d,J=9.6Hz,1F).

[0478] Preparation of compounds 20A and 20B

[0479] Compound 20 (100 mg) was chirally separated by SFC (preparative separation method, instrument model: MGⅡpreparative SFC (SFC-14); column model: ChiralPak AD, 250×30mm ID, 10μm; mobile phase: A:CO2, B:ethanol; elution gradient: B 20%; flow rate: 60mL / min; column pressure: 100bar; column temperature: 38℃; detection wavelength: 220nm; cycle: ~5min) to obtain title compounds 20A (48 mg, single enantiomer) and 20B (46 mg, single enantiomer).

[0480] Compound 20A: LC-MS (ESI): 435.0 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ9.30(br.s,1H),9.13(s,1H),7.53(m,1H),7.28(m,1H),7.25–7.15(br.s,1H),7.00(m, 1H),6.96–6.84(m,2H),6.71–6.55(m,2H),5.42(d,J=12Hz,1H),5.01(d,J=12Hz,1H),1.94(m,3H),1.72(m,3H). 19 F NMR (376MHz, DMSO-d6) δ-102.97–-103.19(m,1F),-109.17–-109.27(m,2F),-109.67(d,J=8.9 Hz,1F).

[0481] Compound 20B: LC-MS (ESI): 435.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.30(br.s,1H),9.14(s,1H),7.53(m,1H),7.28(m,1H),7.25–7.14(br.s,1H),7.00(m,1H),6.95–6.84(m ,2H),6.70–6.57(m,2H),5.41(d,J=14.6Hz,1H),5.01(d,J=14.6Hz,1H),1.94(dd,J=9.5,1.7Hz,3H),1.72(dd,J=9.5,1.7Hz,3H). 19 F NMR (376MHz, DMSO-d6) δ-102.97–-103.19(m,1F),-109.18–-109.28(m,2F),-109.68(d,J=9.5Hz,1F).

[0482] Example 21: Preparation of compounds 21A and 21B

[0483]

[0484] Preparation of compound 21

[0485] 1,2,4-triazole (415 mg, 6 mmol) was dissolved in DMF (6 mL), and NaH (240 mg, 6 mmol) was added at 0 °C. After reacting for 10 minutes, 20-1 (364 mg, 1 mmol) was added, and the reaction mixture was sealed at 70 °C for 16 hours. After cooling, the reaction solution was filtered, and the crude product of the filtrate was purified by preparative separation (chromatographic column: Welch). C18 column, 21.2 x 250 mm; column temperature: 25 °C; mobile phase: water (10 mM / L NH4HCO3) - acetonitrile; acetonitrile content in the mobile phase: 55%-75% in 12 min; flow rate: 30 mL / min), yielded title compound 21 (194 mg, 45% yield, containing a pair of enantiomers). LC-MS (ESI): 434.0 [M+H]+. 1 H NMR(400MHz,Chloroform-d)δ8.14(br.s,1H),7.84(s,1H),7.74(td,J=9.0,6.5Hz,1H),7.04–6.93(m,2H),6.88–6.62(m,4H ),5.28(br.s,1H),5.21(d,J=14.2Hz,1H),4.84(d,J=14.2Hz,1H),2.05(dd,J=9.5,1.8Hz,3H),1.89(dd,J=9.5,1.8Hz,3H).

[0486] Preparation of compounds 21A and 21B

[0487] Compound 21 (115 mg) was chirally separated by SFC (preparative separation method, instrument model: MGⅡpreparative SFC (SFC-14); column: ChiralPak AD, 250×30mm ID, 10μm; mobile phase: A:CO2, B:methanol; elution gradient: B 35%; flow rate: 80mL / min; column pressure: 100bar; column temperature: 38℃; detection wavelength: 220nm; cycle: ~3min) to obtain title compounds 21A (36 mg, single enantiomer) and 21B (40 mg, single enantiomer).

[0488] Compound 21A: LC-MS (ESI): 434.2 [M+H] + Chiral analysis method (Column: Chiralpak AD-3150×4.6mm ID, 3μm; Mobile phase: A:CO2, B:methanol (0.05% DEA); Elution gradient: B 40%; Flow rate: 2.5mL / min; Column temperature: 35℃; Column pressure: 1500psi; Detection wavelength: 220nM; RT = 1.262min). 1H NMR(400MHz,Chloroform-d)δ8.05(s,1H),7.83(s,1H),7.74(td,J=9.0,6.5Hz,1H),7.06–6.91(m,2H),6.91–6.80( m,1H),6.80–6.68(m,2H),5.29–5.15(m,2H),4.82(d,J=14.2Hz,1H),2.05(dd,J=9.4,1.7Hz,3H),1.97–1.83(m,3H). 19 F NMR (376MHz, Chloroform-d) δ -105.26 (d, J = 42.5Hz, 1F), -108.38 (d, J = 13.8Hz, 1F), -110.73 (d, J = 45.7Hz, 1F), -111.11 (d, J = 13.4Hz, 1F).

[0489] Compound 21B: LC-MS (ESI): 434.2 [M+H] + Chiral analysis method (Column: Chiralpak AD-3150×4.6mm ID, 3μm; Mobile phase: A:CO2, B:methanol (0.05% DEA); Elution gradient: B 40%; Flow rate: 2.5mL / min; Column temperature: 35℃; Column pressure: 1500psi; Detection wavelength: 220nM; RT = 0.969min). 1 H NMR(400MHz,Chloroform-d)δ8.03(s,1H),7.77(s,1H),7.67(td,J=9.0,6.5Hz,1H),6.96–6.86(m,2H),6.82–6.69(m,1H), 6.69–6.62(m,2H),5.13(d,J=14.4Hz,2H),4.76(d,J=14.2Hz,1H),1.98(dd,J=9.4,1.8Hz,3H),1.83(dd,J=9.5,1.8Hz,3H). 19 F NMR (376MHz, Chloroform-d) δ -105.20 (d, J = 49.2Hz, 1F), -108.36 (d, J = 13.8Hz, 1F), -110.73 (d, J = 46.3Hz, 1F), -111.08 (d, J = 12.9Hz, 1F).

[0490] Example 22: Preparation of compounds 22A and 22B

[0491]

[0492] Preparation of compound 22

[0493] Compound 20 (100 mg, 0.23 mmol) was dissolved in 1.5 mL of DMF solution, and compound 2,2-difluoroethyl trifluoromethanesulfonate (247 mg, 1.15 mmol) and potassium carbonate (159 mg, 1.15 mmol) were added. The reaction system was sealed and stirred at 80 °C for 16 hours. After the reaction system cooled, the reaction solution was filtered, and the crude product of the filtrate was purified by preparative separation (chromatographic column: Welch). C18 21.2x250mm; column temperature: 25℃; mobile phase: water (10mM / L NH4HCO3)-acetonitrile; acetonitrile ratio in the mobile phase 50%-70% in 12 min; flow rate 30 mL / min) to give title compound 22 (35 mg, yield 30%, containing a pair of enantiomers).

[0494] Compound 22: LC-MS (ESI): m / z 499.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.14(s,1H),7.69–7.47(m,1H),7.36–7.24(m,1H),7.16(s,1H),7.10–6.97(m,3H),6.97–6.84(m,2H),6.35 (tt,J=56,4Hz,1H),5.43(d,J=14.5Hz,1H),5.01(d,J=14.6Hz,1H),4.25(dt,J=16,4Hz,2H),2.00–1.96(m,3H),1.83–1.70(m,3H). 19 F NMR(376MHz, DMSO-d6)δ-102.51–-103.44(m,1F),-108.76–-109.48(m,1F),-109.38–-110.30(m,2F),-125.74(s,2F).

[0495] Preparation of compounds 22A and 22B

[0496] Compound 22 (100 mg) was separated by chiral preparative separation using SFC (preparative separation method, instrument model: MGⅡpreparative SFC (SFC-1); column model: Cellulose-2, 250×30 mm ID, 5 μm; mobile phase: A: CO2, B: ethanol; elution gradient: B 30%; flow rate: 70 mL / min; column pressure: 100 bar; column temperature: 38 ℃; detection wavelength: 220 nm; cycle time: ~4.33 min) to obtain title compounds 22A (45 mg) and 22B (43 mg).

[0497] Compound 22A: Chiral analysis method (Column type: Cellulose-2, 150×4.6mm ID, 3μm; Mobile phase: A: CO2, B: Ethanol (0.05% DEA); Elution gradient: B 40%; Flow rate: 2.5mL / min; Column temperature: 35℃; Column pressure: 100bar; Detection wavelength: 220nm; Rt=1.465min). LC-MS (ESI): m / z 499.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.14(s,1H),7.69-7.47(m,1H),7.36–7.24(m,1H),7.16(s,1H),7.10–6.97(m,3H),6.97–6.84(m,2H) ,6.54–6.12(m,1H),5.43(d,J=14.5Hz,1H),5.01(d,J=14.6Hz,1H),4.38–4.13(m,2H),2.00–1.96(m,3H),1.83–1.70(m,3H). 19 F NMR(376MHz, DMSO-d6)δ-102.51–-103.44(m,1F),-109.19–-109.64(m,3F),-125.74(s,2F).

[0498] Compound 22B: Chiral analysis method (Column type: Cellulose-2, 150×4.6mm ID, 3μm; Mobile phase: A:CO2, B:ethanol (0.05% DEA); Elution gradient: B 40%; Flow rate: 2.5mL / min; Column temperature: 35℃; Column pressure: 100bar; Detection wavelength: 220nm; Rt=1.134min). LC-MS (ESI): m / z 499.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.14(s,1H),7.69-7.47(m,1H),7.36–7.24(m,1H),7.16(s,1H),7.10–6.97(m,3H),6.97–6.84(m,2H) ,6.54–6.12(m,1H),5.43(d,J=14.5Hz,1H),5.01(d,J=14.6Hz,1H),4.38–4.13(m,2H),2.00–1.96(m,3H),1.83–1.70(m,3H). 19F NMR(376MHz, DMSO-d6)δ-102.95–-103.16(m,1F),-109.20–-109.64(m,3F),-125.73(s,2F).

[0499] Example 23: Preparation of compound 23

[0500]

[0501] Preparation of compound 23

[0502] Compound 21 (100 mg, 0.23 mmol) was dissolved in DMF solution (1.5 mL), and compound 2,2-difluoroethyl trifluoromethanesulfonate (247 mg, 1.15 mmol) and potassium carbonate (159 mg, 1.15 mmol) were added. The reaction system was sealed and stirred at 80 °C for 16 hours. After the reaction system cooled, the reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10 Prep-C18 250×21.2 mm; column temperature: 25 °C; gradient: 50%-70% acetonitrile in 12 min; flow rate: 30 mL / min) to give title compound 23 (20 mg, yield 17%, containing a pair of enantiomers).

[0503] Compound 23: LC-MS (ESI): m / z 498.2 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ8.36(s,1H),7.69(s,1H),7.60–7.48(m,1H),7.24–7.14(m,1H),7.11–7.01(m,2H),7.00–6.95(m,1H),6.90(d,J=8.2H z,3H),6.35(tt,J=56,4Hz,1H),5.14(d,J=14.4Hz,1H),4.76(d,J=14.4Hz,1H),4.24(dt,J=16,4Hz,2H),2.00–1.93(m,3H),1.78–1.72(m,3H). 19 F NMR(376MHz, DMSO-d6)δ-102.34–-102.94(m,1F),-109.33–-109.70(m,2F),-110.34–-110.60(m,1F),-125.73(s,2F).

[0504] Example 24: Preparation of compound 24

[0505]

[0506] Preparation of compound 24

[0507] Compound 20 (60 mg, 0.14 mmol), silver trifluoromethanesulfonate (177 mg, 0.69 mmol), SelectFluor (98 mg, 0.276 mmol), N-fluorobisbenzenesulfonamide (NFSI, 87 mg, 0.28 mmol), and cesium fluoride (126 mg, 0.83 mmol) were added to three-necked flasks, and the mixture was purged three times with argon gas. Then, trifluorotoluene (5 mL), toluene (2.5 mL), 2-fluoropyridine (67 mg, 0.69 mmol), and (trifluoromethyl)trimethylsilane (98 mg, 0.69 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. The reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10 Prep-C18 250×21.2mm; column temperature: 25℃; gradient: 55%-75% acetonitrile in 12 min; flow rate: 30 mL / min) to give title compound 24 (10 mg, yield 16.0%, containing a pair of enantiomers). Compound 24: LC-MS (ESI): m / z 503.0 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ9.16(s,1H),7.60–7.53(m,1H),7.34–7.30(m,1H),7.29–7.27(m,4H),7.20(s,1H),7.05–7. 00(m,1H),5.45(d,J=14.6Hz,1H),5.04(d,J=14.6Hz,1H),2.06(dd,J=9.6,1.8Hz,3H),1.85(dd,J=9.6,1.8Hz,3H).

[0508] Example 25: Preparation of Compound 25

[0509]

[0510] Preparation of compound 25

[0511] Compound 21 (50 mg, 0.137 mmol), silver trifluoromethanesulfonate (70 mg, 0.274 mmol), SelectFluor (121 mg, 0.343 mmol), N-fluorobis(benzenesulfonamide) (NFSI, 108 mg, 0.343 mmol), and cesium fluoride (104 mg, 0.686 mmol) were added to three-necked flasks, and the mixture was purged three times with argon. Then, trifluorotoluene (5 mL), toluene (2.5 mL), 2-fluoropyridine (66 mg, 0.686 mmol), and (trifluoromethyl)trimethylsilane (97 mg, 0.686 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. The reaction solution was filtered, and the crude product from the filtrate was purified by preparative separation (chromatographic column: Welch). C18 21.2 x 250 mm; column temperature: 25 °C; mobile phase: water (10 mM / L NH4HCO3) - acetonitrile; acetonitrile ratio in mobile phase 55%-75% in 12 min; flow rate 30 mL / min) yielded title compound 25 (3.5 mg, containing a pair of enantiomers).

[0512] Compound 25: 1 H NMR(400MHz,DMSO-d6)δ8.37(s,1H),7.69(s,1H),7.60–7.53(m,1H),7.27–7.17(m,5H),7.00–6.97(m, 1H),6.92(s,1H),5.14(d,J=14.4Hz,1H),4.77(d,J=14.5Hz,1H),2.04–2.01(m,3H),1.82–1.80(m,3H). 19 F NMR(376MHz, DMSO-d6)δ-56.80(s,3F),-102.51–-102.62(m,1F),-109.55–-109.66(m,2F),-110.40(d,J=9.6Hz,1F).

[0513] Example 26: Preparation of Compound 26

[0514]

[0515] Preparation of compound 26

[0516] Compound 20 (100 mg, 0.23 mmol) was dissolved in THF (3.0 mL), and NaH (19 mg, 0.46 mmol) was added at 0 °C. After 5 minutes, ethyl 2-bromo-2,2-difluoroacetate (140 mg, 0.69 mmol) was added, and the reaction was carried out at room temperature for 16 hours. The reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparation method: chromatographic column: Welch). C18 21.2 x 250 mm; column temperature: 25 °C; mobile phase: water (10 mM / L NH4HCO3) - acetonitrile; acetonitrile content in the mobile phase: 45%-75% in 12 min; flow rate: 30 mL / min) to give title compound 26 (4 mg, yield 3.6%).

[0517] Compound 26: LC-MS: 485.2 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ8.53(s,1H),7.65(td,J=8.9,6.3Hz,1H),7.11–7.05(m,2H),7.02(d,J=8.6Hz,2H),6.94–6.76(m,2H),6.45 (t,J=73.9Hz,1H),5.44(d,J=14.6Hz,1H),5.05(d,J=14.6Hz,1H),3.96(s,1H),2.06(dd,J=9.4,1.9Hz,3H),1.87(dd,J=9.4,1.9Hz,3H). 19 F NMR(376MHz,Chloroform-d)δ-80.80(s,2F),-106.83(d,J=9.5Hz,1F),-110.19–-110.31(m,2F),-110.44–-110.48(m,1F).

[0518] Example 27: Preparation of compounds 27, 27A, 27B, 27A-P1 and 27A-P2

[0519]

[0520] Preparation of compound 27

[0521] Compound 1,2,4-triazole (101 mg, 1.47 mmol) was dissolved in DMF solution (2.0 mL) and cooled to 0 °C. Sodium hydride (60%, 59 mg, 1.47 mmol) was added, and the reaction was allowed to proceed for half an hour. Compound 8-3 (110 mg, 0.29 mmol) was then added. The reaction mixture was stirred at 80 °C for 2 hours. After the reaction mixture cooled, the reaction solution was filtered. The crude filtrate was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10 Prep-C18 250 × 21.2 mm; column temperature: 25 °C; gradient: 70%-90% acetonitrile in 12 min; flow rate: 30 mL / min) to give title compound 27 (77 mg, yield 59%, containing a pair of enantiomers).

[0522] Compound 27: LC-MS (ESI): m / z 443.2 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ8.43(s,1H),7.87–7.77(m,2H),7.75(s,1H),7.68–7.55(m,1H),7.47–7.34(m,2H),7.31–7. 20(m,1H),7.11–6.94(m,2H),5.20(d,J=14.4Hz,1H),4.83(d,J=14.4Hz,1H),2.23–2.04(m,3H),2.04–1.79(m,3H). 19 F NMR(376MHz, DMSO-d6)δ-102.19–-102.99(m,1F),-109.38–-109.93(m,2F),-110.23–-110.53(m,1F).

[0523] Preparation of compounds 27A and 27B

[0524] Compound 27 (70 mg) was chirally separated by SFC (preparative separation method, instrument model: MGⅡpreparative SFC (SFC-14); column model: ChiralPak AD, 250×30mm ID, 10μm; mobile phase: A:CO2, B:ethanol (0.1% NH3H2O); elution gradient: B 20%; flow rate: 60 mL / min; column pressure: 100 bar; column temperature: 38℃; detection wavelength: 220 nm; cycle: ~2.8 min) to obtain title compounds 27A (30 mg, single enantiomer) and 27B (35 mg, single enantiomer).

[0525] Compound 27A: LC-MS (ESI): m / z 443.2 [M+H] + Chiral analysis method (Column type: AD-3 150×4.6mm ID, 3μm; Mobile phase: A:CO2, B:ethanol (0.05%DEA); Elution gradient: elution of 5%B to 40%B within 5 minutes and maintaining 40%B for 2.5 minutes, followed by equilibration with 5%B for 2.5 minutes; Flow rate: 2.5mL / min; Column temperature: 35℃; Column pressure: 1500psi; Detection wavelength: 220nm; Rt = 3.226min). 1H NMR(400MHz, DMSO-d6)δ8.43(s,1H),7.87–7.77(m,2H),7.75(s,1H),7.68–7.55(m,1H),7.47–7.34(m,2H),7.31–7. 20(m,1H),7.11–6.94(m,2H),5.20(d,J=14.4Hz,1H),4.83(d,J=14.4Hz,1H),2.23–2.04(m,3H),2.04–1.79(m,3H). 19 F NMR(376MHz, DMSO-d6)δ-102.19–-102.99(m,1F),-109.38–-109.93(m,2F),-110.23–-110.53(m,1F).

[0526] Compound 27B: LC-MS (ESI): m / z 443.2 [M+H] + Chiral analysis method (Column type: AD-3 150×4.6mm ID, 3μm; Mobile phase: A:CO2, B:ethanol (0.05% DEA); Elution gradient: elution from 5% B to 40% B over 5 minutes and maintain 40% B for 2.5 minutes, then equilibrate with 5% B for 2.5 minutes; Flow rate: 2.5 mL / min; Column temperature: 35℃; Column pressure: 1500 psi; Detection wavelength: 220 nm; Rt = 3.000 min). 1 H NMR(400MHz, DMSO-d6)δ8.43(s,1H),7.87–7.77(m,2H),7.75(s,1H),7.68–7.55(m,1H),7.47–7.34(m,2H),7.31–7. 20(m,1H),7.11–6.94(m,2H),5.20(d,J=14.4Hz,1H),4.83(d,J=14.4Hz,1H),2.23–2.04(m,3H),2.04–1.79(m,3H). 19 F NMR(376MHz, DMSO-d6)δ-102.19–-102.99(m,1F),-109.38–-109.93(m,2F),-110.23–-110.53(m,1F).

[0527] Preparation of compound 27A-P1

[0528]

[0529] Compound 27A (100 mg, 0.23 mmol) was dissolved in THF (1 mL), and NaH (45 mg, 1.13 mmol) was added at 0 °C. The reaction was continued for 30 minutes, and phosphorus oxychloride (0.5 mL) was added dropwise. The mixture was then transferred to room temperature and reacted for 16 hours. Saturated sodium bicarbonate solution was added to the reaction mixture, and the reaction was carried out at 50 °C for 16 hours. After the reaction mixture cooled, it was filtered, and the crude filtrate was purified by preparative separation (chromatographic column: Welch). C18 column (21.2 x 250 mm); column temperature: 25 °C; mobile phase: water (10 mM / L NH4HCO3) - acetonitrile; acetonitrile content in the mobile phase: 20%-40% in 12 min; flow rate: 30 mL / min), yielding the title compound 27A-P1 (40 mg, yield: 35%). LC-MS (ESI): m / z 523.0 [M+H] + . 1 H NMR(400MHz, Methanol-d4)δ8.87(s,1H),7.98(q,J=8.4Hz,1H),7.72(s,1H),7.65–7.57(m,2H),7.31–7.23(m,2H),6.9 9–6.81(m,2H),6.08(d,J=15.0Hz,1H),5.36(d,J=15.0Hz,1H),2.11(dd,J=9.4,1.9Hz,3H),1.93(dd,J=9.5,1.8Hz,3H). 19 F NMR(376MHz, Methanol-d4)δ-101.27–-101.95(m,2F),-108.52–-108.97(m,1F),-111.67(d,1F).

[0530] Preparation of compound 27A-P2

[0531]

[0532] Preparation of compound 27A-1

[0533] Compound 27A (200 mg, 0.45 mmol) was dissolved in DMF (2 mL), and diphenylchloromethyl phosphate (294 mg, 0.9 mmol) and Cs₂CO₃ (440 mg, 1.35 mmol) were added. The reaction system was reacted at 80 °C for 16 hours. After the reaction system cooled, the reaction solution was extracted and evaporated to dryness to obtain the title compound 27A-1, which was directly added to the next reaction.

[0534] Preparation of compound 27A-P2

[0535] Compound 27A-1 (200 mg, 0.45 mmol) was dissolved in MeOH (2 mL), and palladium on carbon (20 mg) was added. The reaction system was purged with hydrogen three times, and the reaction was carried out at room temperature for 16 hours. The reaction solution was filtered, and the crude product of the filtrate was purified by preparative separation (chromatographic column: Welch). C18 21.2x250mm; column temperature: 25℃; mobile phase: water (10mM / L NH4HCO3)-acetonitrile; acetonitrile content in the mobile phase 15%-35% in 12 min; flow rate 30 mL / min), yielded the title compound 27A-P2: LC-MS (ESI): m / z 553.2 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ8.70(s,1H),7.88-7.77(m,1H),7.75-7.67(m,3H),7.33(d,J=8.0Hz,2H),7.25(m,2H),7.18-7.10(m,1H),7.01–6.94(m ,1H),5.59(dd,J=10.6,5.3Hz,1H),5.38(t,J=7.2Hz,1H),5.31(d,J=15 .3Hz,1H),5.16(d,J=15.3Hz,1H),2.11–2.03(m,3H),1.97–1.87(m,3H).

[0536] Example 28: Preparation of compounds 28A and 28B

[0537]

[0538] Preparation of compound 28-1

[0539] Compound 9-3 (1.21 g, 3.4 mmol), triethylamine (1.04 g, 10.4 mmol), and DMF (10 mL) were added to a three-necked flask, and the mixture was purged with nitrogen three times. The reaction mixture was stirred at 0 °C for 5 minutes, and then N-phenylbis(trifluoromethanesulfonyl)imide (CAS: 37595-74-7, 1.6 g, 4.5 mmol) was slowly added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, saturated sodium chloride solution (20 mL) was added to the reaction mixture, and the mixture was extracted with EtOAc (20 mL × 3). The organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-5%) to obtain the title compound 28-1 (1.2 g, 72% yield) as a yellow oil. 1H NMR (400MHz, DMSO-d6) δ7.96–7.85(m,1H),7.61–7.53(m,1H),7.49–7.41(m,4H),7.37–7.30(m,1H),2.24(s,6H).

[0540] Preparation of compound 28-2

[0541] Compound 28-1 (1.46 g, 3.02 mmol) was added to a microwave tube, along with DMF (5 mL), zinc cyanide (0.43 g, 3.63 mmol), and tetrakis(triphenylphosphine)palladium (0.17 g, 0.15 mmol). The mixture was reacted in a microwave-safe atmosphere at 80 °C for 40 hours. After cooling, water (10 mL) was added, and the mixture was extracted with EtOAc (10 mL × 3). The organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was then purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-5%) to obtain the title compound 28-2 (0.66 g, 61% yield) as a yellow solid. 1 H NMR (400MHz, Chloroform-d) δ7.90–7.84(m,1H),7.62(d,J=8.0Hz,2H),7.32(d,J=8.0Hz,2H),7.04–6.91(m,2H),2.30(s,6H).

[0542] Preparation of compound 28-3

[0543] Compound 28-2 (0.66 g, 1.84 mmol) was dissolved in a mixed solvent of dichloromethane (3 mL) and water (3 mL), and trimethyl sulfoxide (1.21 g, 5.52 mmol) and sodium hydroxide (0.22 g, 5.52 mmol) were added. The reaction mixture was refluxed for 16 hours. After cooling to room temperature, the reaction mixture was extracted with DCM, and the organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-5%) to obtain the title compound 28-3 (560 mg, 82% yield, containing a pair of enantiomers) as a pale yellow oil. 1 H NMR (400MHz, DMSO-d6) δ7.80 (d, J = 8.0 Hz, 2H), 7.49–7.33 (m, 5H), 3.42 (d, J = 4.0 Hz, 1H), 3.20–3.07 (m, 1H), 2.15 (s, 6H).

[0544] Preparation of compound 28

[0545] Compound 28-3 (110 mg, 0.29 mmol) was dissolved in DMF (2.5 mL), and 1-H tetrazolium (103 mg, 1.47 mmol) and potassium carbonate (203 mg, 1.47 mmol) were added. The reaction mixture was sealed at 80 °C for 16 hours. After the reaction system cooled, the reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparation method: chromatographic column: Agilent 10 Prep-C18 250 x 21.2 mm; mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; column temperature: 25 °C; gradient: 60%-80% acetonitrile in 12 min; flow rate: 30 mL / min) to obtain the title compound 28 (30 mg, yield 22%, containing a pair of enantiomers) and the corresponding regioisomer compound 28-4 (10 mg, yield 7%, containing a pair of enantiomers).

[0546] Compound 28: LC-MS (ESI): m / z 444.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.16 (s, 1H), 7.75 (d, J = 8.4Hz, 2H), 7.43–7.17 (m, 6H ),5.45(d,J=14.4Hz,1H),5.03(d,J=14.4Hz,1H),2.10(d,J=9.2Hz,3H),1.89 (d,J=9.2Hz,3H). 19 F NMR (376MHz, DMSO-d6) δ-108.80–-109.14(m,2F),-113.09–-113.50(m,1F),-118.23(d,1F).

[0547] Compound 28-4: LC-MS (ESI): m / z 444.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.78(s,1H),7.75(d,J=8.4Hz,2H),7.38–7.31(m,3H),7.31–7.22(m,3H ), 5.63 (d, J = 14.4Hz, 1H), 5.26 (d, J = 14.4Hz, 1H), 2.08 (d, J = 9.2Hz, 3H), 1.88 (d, J = 9.2Hz, 3H). 19 F NMR (376MHz, DMSO-d6) δ-108.31–-109.09(m,2F),-112.79–-113.19(m,1F),-118.54(d,1F).

[0548] Preparation of compounds 28A and 28B

[0549] Compound 28 (147 mg) was chirally separated by SFC (preparative separation method, instrument model: MGⅡpreparative SFC (SFC-14); column model: ChiralPak AD, 250×30mm ID, 10μm; mobile phase: A:CO2, B:ethanol; elution gradient: B 25%; flow rate: 70mL / min; column pressure: 100bar; column temperature: 38℃; detection wavelength: 220nm; cycle: ~3min) to obtain title compounds 28A (78 mg, single enantiomer) and 28B (76 mg, single enantiomer).

[0550] Compound 28A: LC-MS (ESI): m / z 444.0 [M+H] + Chiral analysis method (Column type: AD-3 150×4.6mm ID, 3μm; Mobile phase: A:CO2, B:ethanol (0.05%DEA); Elution gradient: elution of 5%B to 40%B within 5 minutes and maintaining 40%B for 2.5 minutes, followed by equilibration with 5%B for 2.5 minutes; Flow rate: 2.5mL / min; Column temperature: 35℃; Column pressure: 1500psi; Detection wavelength: 220nm; Rt = 1.464min). 1 H NMR (400MHz, DMSO-d6) 1 H NMR(400MHz,DMSO-d6)δ9.15(s,1H),7.78–7.71(m,2H),7.38–7.33(m,2H),7.33–7.21(m, 4H), 5.45 (d, J=14.4Hz, 1H), 5.03 (d, J=14.4Hz, 1H), 2.13–2.07 (m, 3H), 1.93–1.86 (m, 3H). 19 F NMR(376MHz, DMSO-d6)δ-108.94–-109.04(m,2F),-113.06–-113.59(m,1F),-118.21(d,1F).

[0551] Compound 28B: LC-MS (ESI): m / z 444.0 [M+H] +Chiral analysis method (Column type: AD-3 150×4.6mm ID, 3μm; Mobile phase: A:CO2, B:ethanol (0.05%DEA); Elution gradient: 5%B to 40%B within 5 minutes, maintain 40%B for 2.5 minutes, then equilibrate with 5%B for 2.5 minutes; Flow rate: 2.5mL / min; Column temperature: 35℃; Column pressure: 1500psi; Detection wavelength: 220nm; Rt = 1.025min). 1 H NMR(400MHz,DMSO-d6)δ9.15(s,1H),7.78–7.71(m,2H),7.38–7.33(m,2H),7.33–7.21(m, 4H), 5.45 (d, J=14.4Hz, 1H), 5.03 (d, J=14.4Hz, 1H), 2.13–2.07 (m, 3H), 1.93–1.86 (m, 3H). 19 F NMR(376MHz, DMSO-d6)δ-108.94–-109.04(m,2F),-113.06–-113.59(m,1F),-118.21(m,1F).

[0552] Example 29: Preparation of compounds 29A and 29B

[0553]

[0554] Preparation of compound 29

[0555] Compound 28-3 (110 mg, 0.29 mmol) was dissolved in DMF (2.5 mL), and 1,2,4-triazole (103 mg, 1.47 mmol) and potassium carbonate (203 mg, 1.47 mmol) were added. The reaction mixture was sealed at 80 °C for 16 hours. After the reaction system cooled, the reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparation method: chromatographic column: Agilent 10 Prep-C18 250 x 21.2 mm; mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; column temperature: 25 °C; gradient: 60%-80% acetonitrile in 12 min; flow rate: 30 mL / min) to give title compound 29 (50 mg, yield 36%, containing a pair of enantiomers).

[0556] Compound 29: LC-MS (ESI): m / z 443.0 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.31(s,1H),7.68(d,J=8.4Hz,2H),7.63(s,1H),7.32–7.25(m,2H),7.24–7.09(m,3H ), 6.97 (s, 1H), 5.09 (d, J = 14.4Hz, 1H), 4.71 (d, J = 14.4Hz, 1H), 2.01 (d, J = 9.2Hz, 3H), 1.80 (d, J = 9.2Hz, 3H). 19 F NMR(376MHz, DMSO-d6)δ-108.99–-109.54(m,2F),-112.51–-113.38(m,1F),-118.79(d,1F).

[0557] Preparation of compounds 29A and 29B

[0558] Compound 29 (45 mg) was chirally separated by SFC (preparative separation method, instrument model: MGⅡpreparative SFC (SFC-14); column model: ChiralPak AD, 250×30mm ID, 10μm; mobile phase: A:CO2, B:ethanol (0.1% NH3H2O); elution gradient: B 20%; flow rate: 60mL / min; column pressure: 100bar; column temperature: 38℃; detection wavelength: 220nm; cycle: ~4min) to obtain title compounds 29A (12 mg, single enantiomer) and 29B (18 mg, single enantiomer).

[0559] Compound 29A: LC-MS (ESI): m / z 443.0 [M+H] + Chiral analysis method (Column type: AD-3 150×4.6mm ID, 3μm; Mobile phase: A:CO2, B:ethanol (0.05%DEA); Elution gradient: elution of 5%B to 40%B within 5 minutes and maintaining 40%B for 2.5 minutes, followed by equilibration with 5%B for 2.5 minutes; Flow rate: 2.5mL / min; Column temperature: 35℃; Column pressure: 1500psi; Detection wavelength: 220nm; Rt = 3.135min). 1H NMR (400MHz, DMSO-d6) δ8.38(s,1H),7.75(d,J=8.4Hz,2H),7.70(s,1H),7.35(d,J=8.4Hz,2H),7.29–7.18(m, 3H), 7.02 (s, 1H), 5.15 (d, J = 14.4Hz, 1H), 4.78 (d, J = 14.4Hz, 1H), 2.08 (d, J = 9.2Hz, 3H), 1.87 (d, J = 9.2Hz, 3H). 19 F NMR (376MHz, DMSO-d6) δ-109.18--109.28(m,2F),-112.68--113.21(m,1F),-118.79(d,J=22.6Hz,1F).

[0560] Compound 29B: LC-MS (ESI): m / z 443.0 [M+H] + Chiral analysis method (Column type: Chiralpak AD-3 150×4.6mm ID, 3μm; Mobile phase: A: CO2, B: ethanol (0.05% DEA); Elution gradient: 5% B to 40% B in the mobile phase over 5 minutes, maintain 40% B for 2.5 minutes, then equilibrate with 5% B for 2.5 minutes; Flow rate: 2.5 mL / min; Column temperature: 35℃; Column pressure: 1500 psi; Detection wavelength: 220 nm; Rt = 2.753 min). 1 H NMR (400MHz, DMSO-d6) δ8.38(s,1H),7.75(d,J=8.4Hz,2H),7.70(s,1H),7.35(d,J=8.4Hz,2H),7.29–7.18(m, 3H), 7.02 (s, 1H), 5.15 (d, J = 14.4Hz, 1H), 4.78 (d, J = 14.4Hz, 1H), 2.08 (d, J = 9.6Hz, 3H), 1.87 (d, J = 9.6Hz, 3H). 19 F NMR (376MHz, DMSO-d6) δ-109.18–-109.27(m,2F),-112.73–-113.17(m,1F),-118.79(d,J=18.8Hz,1F).

[0561] Example 30: Preparation of compound 30

[0562]

[0563] Preparation of compound 30-1

[0564] Iron triacetylacetone (2.2 g, 6.3 mmol) was added to a three-necked flask, and the mixture was purged with nitrogen three times. Anhydrous THF (80 mL), compound 1-4 (10 g, 31.6 mmol), and TMEDA (1.5 g, 12.6 mmol) were added sequentially to the flask. The reaction mixture was stirred for 5 minutes. A Grignard reagent solution of magnesium 3-methoxyphenyl bromide in THF (1.0 M, 51 mL, 51 mmol) was slowly added dropwise to the flask, and the reaction was continued at room temperature for 16 hours with stirring. After the reaction was complete, the mixture was extracted with EtOAc (30 mL × 3). The organic phases were combined, dried, and concentrated to obtain a crude product. This crude product was purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-5%) to obtain the title compound 30-1 (2.1 g, 23% yield) as a pale yellow liquid. 1 H NMR (400MHz, DMSO-d6) δ7.28–7.20(m,1H),6.87–6.77(m,3H),4.35(q,J=7.1Hz,2H),3.74(s,3H),2.14(s,6H),1.29(t,J=7.1Hz,3H).

[0565] Preparation of compound 30-2

[0566] Compound 2,4-difluorobromobenzene (1.1 g, 5.6 mmol) was added to a three-necked flask and purged three times with nitrogen. Anhydrous diethyl ether (15 mL) was added to the flask, and n-butyllithium (1.6 M, 3.5 mL, 5.6 mmol) was added dropwise at -78 °C. After stirring the reaction system at -78 °C for 45 minutes, anhydrous diethyl ether solution (10 mL) containing compound 30-1 (1.5 g, 5.1 mmol) was added dropwise, and stirring continued for 1 hour. After the reaction was complete, saturated ammonium chloride solution (5 mL) was added to quench the reaction, and the mixture was extracted with EtOAc (20 mL × 3). The organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-5%) to obtain the title compound 30-2 (1.6 g, 86% yield) as a yellow solid. 1 H NMR(400MHz,Chloroform-d)δ7.92–7.82(m,1H),7.25–7.20(m,1H),7.05–6.97(m,1H ),6.96–6.89(m,1H),6.83–6.77(m,2H),6.75–6.71(m,1H),3.80(s,3H),2.24(s,6H).

[0567] Preparation of compound 30-3

[0568] Compound 30-2 (1.8 g, 4.95 mmol) was added to a microwave-safe tube, followed by acetic acid (5 mL) and an aqueous solution of hydrogen bromide (48 wt% aqueous solution, 5 mL). The tube was sealed at 95 °C and reacted for 16 hours. After cooling, the mixture was evaporated to dryness and extracted with EtOAc (30 mL × 3). The organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-30%) to obtain the title compound 30-3 (1.3 g, 72% yield) as a brownish-yellow liquid. LC-MS (ESI): m / z 349.0 [MH] - .

[0569] Preparation of compound 30-4

[0570] Compound 30-3 (1.0 g, 2.85 mmol) was added to a 100 mL three-necked flask, followed by the addition of DMF (10 mL), N-phenylbis(trifluoromethanesulfonyl)imide (1.33 g, 3.43 mmol), and TEA (866 mg, 8.56 mmol). The reaction mixture was stirred at room temperature for 4 hours under nitrogen protection. The reaction was quenched with water (20 mL), and the mixture was extracted with EtOAc (10 mL × 3). The organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-5%) to obtain the title compound 30-4 (450 mg, 33% yield) as a brown solid. LC-MS (ESI): m / z 483.0 [M+H] + .

[0571] Preparation of compound 30-5

[0572] Compound 30-4 (300 mg, 0.62 mmol) was added to a microwave tube, followed by DMF (3 mL), zinc cyanide (87 mg, 0.75 mmol), and tetrakis(triphenylphosphine)palladium (36 mg, 0.03 mmol). The reaction system was microwave-treated at 80 °C for 40 hours under nitrogen protection. After cooling, water (10 mL) was added, and the mixture was extracted with EtOAc (10 mL × 3). The organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-5%) to obtain the title compound 30-5 (110 mg, 49% yield) as a yellow solid. LC-MS (ESI): m / z 376.0 [M + H₂O - H] - .

[0573] Preparation of compound 30-6

[0574] Compound 30-5 (110 mg, 0.30 mmol) was dissolved in a mixed solvent of dichloromethane (3 mL) and water (3 mL), and trimethyl sulfoxide (202 mg, 0.91 mmol) and sodium hydroxide (37 mg, 0.91 mmol) were added. The reaction mixture was refluxed for 16 hours. After cooling to room temperature, the reaction mixture was extracted with DCM (10 mL × 3). The organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-5%) to obtain the title compound 30-6 (110 mg, 96% yield, containing a pair of enantiomers) as a pale yellow oil. LC-MS (ESI): m / z 374.2 [M+H] + .

[0575] Preparation of compound 30

[0576] Compound 30-6 (300 mg, 0.80 mmol) was dissolved in DMF (3 mL), and 1-H tetrazolium (281 mg, 4.0 mmol) and potassium carbonate (555 mg, 4.0 mmol) were added. The reaction mixture was sealed at 80 °C for 16 hours. After the reaction system cooled, the reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparation method: chromatographic column: Agilent 10 Prep-C18 250x21.2 mm; mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; column temperature: 25 °C; gradient: 60%-80% acetonitrile in 12 min; flow rate: 30 mL / min) to obtain title compound 30 (110 mg, yield 30%, containing one enantiomer) and the corresponding regioisomer compound 30-7 (55 mg, yield 15%, containing one enantiomer).

[0577] Compound 30: LC-MS (ESI): m / z 444.2 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ9.20(s,1H),7.80–7.72(m,1H),7.72–7.66(m,1H),7.65–7.56(m,1H),7.57–7.50(m,2H),7.40–7.31( m,1H),7.26(s,1H),7.12–7.01(m,1H),5.50(d,J=14.6Hz,1H),5.08(d,J=14.6Hz,1H),2.21–2.02(m,3H),2.02–1.67(m,3H). 19 F NMR(376MHz, DMSO-d6)δ-102.81–-103.30(m,1F),-109.26–-109.42(m,1F),-109.42–-109.65(m,2F).

[0578] Compound 30-7: LC-MS (ESI): m / z 444.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.77(s,1H),7.73–7.66(m,1H),7.66–7.60(m,1H),7.60–7.52(m,1H),7.52–7.43(m,2H),7.32 –7.21(m,2H),7.06–6.95(m,1H),5.61(d,J=14.2Hz,1H),5.25(d,J=14.2Hz,1H),2.19–1.98(m,3H),1.90–1.75(m,3H). 19 F NMR(376MHz, DMSO-d6)δ-102.31–-102.85(m,1F),-108.91–-109.33(m,2F),-109.81–-110.08(m,1F).

[0579] Example 31: Preparation of compound 31

[0580]

[0581] Preparation of compound 31-1

[0582] Compound 30-3 (700 mg, 2 mmol) was dissolved in DMF (8 mL), and potassium carbonate (552 mg, 4 mmol) and 2,2,2-trifluoroethyltrifluoromethanesulfonate (928 mg, 4 mmol) were added. The reaction mixture was sealed in a tube at 65 °C for 16 hours. After cooling, the mixture was extracted with EtOAc (10 mL × 3). The organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-10%) to obtain the title compound 31-1 (750 mg, 87% yield) as a colorless oil. LC-MS (ESI): m / z 431.0 [MH] - .

[0583] Preparation of compound 31-2

[0584] Compound 31-1 (750 mg, 1.74 mmol) was dissolved in a mixed solution of dichloromethane (15.0 mL) and water (5.0 mL), followed by the sequential addition of trimethyl sulfoxide (1.53 g, 6.94 mmol) and solid sodium hydroxide (278 mg, 6.94 mmol). The reaction mixture was stirred at 65 °C for 12 hours. After the reaction was complete, the mixture was extracted with dichloromethane (20 mL × 3), and the organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was then purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-10%) to obtain the title compound 31-2 (540 mg, 70% yield). 1 H NMR (400MHz, DMSO-d6) δ7.68(td,J=8.4,6.4Hz,1H),7.35(ddd,J=10.5,9.3,2.6Hz,1H),7.27(t,J=7.8Hz,1H),7.23–7 .11(m,1H),6.98–6.82(m,3H),4.74(q,J=8.9Hz,2H),3.39(d,J=4.7Hz,1H),3.09(dt,J=4.3,1.8Hz,1H),2.07(s,6H).

[0585] Preparation of compound 31

[0586] Compound 31-2 (540 mg, 1.2 mmol) was dissolved in DMF solution (10 mL), and compound 1-H tetrazolium (339 mg, 4.84 mmol) and potassium carbonate (668 mg, 4.84 mmol) were added. The reaction system was sealed and stirred at 80 °C for 12 hours. After the reaction system cooled, the reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10 Prep-C18 250×21.2 mm; column temperature: 25 °C; gradient: 60%-80% acetonitrile in 12 min; flow rate: 30 mL / min) to obtain title compound 31 (310 mg, yield 50%, containing one enantiomer) and the corresponding regioisomer compound 31-3 (120 mg, yield 19%, containing one enantiomer). Compound 31: LC-MS (ESI): m / z 517.0 [M+H] + . 1H NMR(400MHz, DMSO-d6)δ9.14(s,1H),7.54(td,J=9.0,6.7Hz,1H),7.36–7.15(m,3H),7.01(td,J=8.4,2.6Hz,1H),6.95–6.85(m,1H),6.86–6 .74(m,2H),5.43(d,J=14.6Hz,1H),5.02(d,J=14.6Hz,1H),4.72(q,J=8.9Hz,2H),2.01(dd,J=9.3,1.7Hz,3H),1.80(dd,J=9.4,1.7Hz,3H). 19 F NMR(376MHz, DMSO-d6)δ-72.59(s,3F),-102.95–-103.16(m,1F),-109.27–-109.38(m,2F),-109.59(d,J=9.6Hz,1F).

[0587] Compound 31-3: LC-MS (ESI): m / z 517.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.77(s,1H),7.57(td,J=9.0,6.7Hz,1H),7.34–7.15(m,3H),7.00(td,J=8.5,2.6Hz,1H),6.89(ddd,J=8.2,2.6,0.9Hz,1H) ,6.84–6.74(m,2H),5.61(d,J=14.2Hz,1H),5.25(d,J=14.2Hz,1H),4.72( q, J=8.9Hz, 2H), 2.00 (dd, J=9.4, 1.7Hz, 3H), 1.79 (dd, J=9.5, 1.7Hz, 3H). 19 F NMR(376MHz, DMSO-d6)δ-72.59(s,3F),-102.54–-102.76(m,1F),-108.93–-109.13(m,2F),-109.94(d,J=9.6Hz,1F).

[0588] Example 32: Preparation of compounds 32A and 32B

[0589]

[0590] Preparation of compound 32-1

[0591] Compound 8-1 (500 mg, 1.04 mmol), tris(dibenzylacetone)dipalladium (CAS: 51364-51-3, 95 mg, 0.1 mmol), 2-(di-tert-butylphosphine)-3,6-dimethoxy-2'-4'-6'tri-1-propyl-1,1'-bisphenyl (t-BuBrettPhos, 101 mg, 0.21 mmol), potassium chloride (156 mg, 2.07 mmol), and potassium fluoride (30 mg, 0.52 mmol) were added to a microwave tube, purged three times with nitrogen, and 1,4-dioxane (15 mL) was added as a solvent. The reaction system was then incubated in a microwave oven at 120 °C for 2 hours. After cooling, the sample was extracted with EtOAc (20 mL × 3). The organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was then purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-10%) to obtain the title compound 32-1 (260 mg, yield 68%) as a colorless liquid. LC-MS (ESI): m / z 385.0 [M + H₂O - H] - . 1 H NMR (400MHz, DMSO-d6) δ7.98–7.86(m,1H),7.62–7.51(m,1H),7.44–7.21(m,5H),2.20(s,6H). 19 F NMR(376MHz, DMSO-d6)δ-99.53–-100.21(m,1F),-105.17–-105.88(m,1F),-106.37–-107.02(m,2F).

[0592] Preparation of compound 32-2

[0593] Compound 32-1 (250 mg, 0.68 mmol) was dissolved in a mixed solvent of dichloromethane (8 mL) and water (8 mL), and trimethyl sulfoxide (598 mg, 2.72 mmol) and sodium hydroxide (109 mg, 2.72 mmol) were added. The reaction mixture was refluxed for 16 hours. After cooling to room temperature, the reaction mixture was extracted with DCM (20 mL × 3). The organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-10%) to obtain the title compound 32-2 (210 mg, 81% yield) as a pale yellow oil. 1 H NMR (400MHz, DMSO-d6) δ7.76–7.60(m,1H),7.44–7.29(m,3H),7.28–7.12(m,3H),3.43–3.37(m,1H),3.13–3.04(m,1H),2.08(s,6H). 19F NMR (376MHz, DMSO-d6) δ-107.77 (d, J=8.8Hz, 1F), -108.18 (q, J=11.1Hz, 1F), -108.83 (dd, J=61.0, 12.2Hz, 2F).

[0594] Preparation of compound 32

[0595] Compound 32-2 (200 mg, 0.52 mmol) was dissolved in DMF solution (5 mL), and compound 1-H tetrazolium (73 mg, 1.05 mmol) and potassium carbonate (145 mg, 1.05 mmol) were added. The reaction system was sealed and stirred at 80 °C for 16 hours. After the reaction system cooled, the reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10 Prep-C18 250×21.2 mm; column temperature: 25 °C; gradient: 60%-80% acetonitrile in 12 min; flow rate: 30 mL / min) to obtain title compound 32 (110 mg, yield 46%, containing a pair of enantiomers) and the corresponding regioisomer compound 32-3 (47 mg, yield 20%, containing a pair of enantiomers). Compound 32: LC-MS (ESI): m / z 453.2 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ9.13(s,1H),7.54(td,J=9.0,6.7Hz,1H),7.37–7.22(m,3H),7.21–7.11(m,3H),7.00(td,J=8. 5,2.7Hz,1H),5.42(d,J=14.5Hz,1H),5.01(d,J=14.5Hz,1H),2.02(dd,J=9.4,1.7Hz,3H),1.80(dd,J=9.5,1.7Hz,3H). 19 F NMR (376MHz, DMSO-d6) δ-102.82–-103.26(m,1F),-109.26–-109.50(m,2F),-109.58(d,J=9.5Hz,1F).

[0596] Compound 32-3: LC-MS (ESI): m / z 453.2 [M+H] + . 1H NMR(400MHz, DMSO-d6)δ8.76(s,1H),7.56(td,J=9.0,6.7Hz,1H),7.36–7.29(m, 2H),7.24(d,J=17.3Hz,2H),7.18–7.11(m,2H),6.99(td,J=8.5,2.6Hz,1H),5.61 (d,J=14.2Hz,1H),5.24(d,J=14.3Hz,1H),2.00(dd,J=9.5,1.8Hz,3H),1.79(dd,J=9.4,1.7Hz,3H). 19 F NMR (376MHz, DMSO-d6) δ-102.42–-102.83(m,1F),-108.87–-109.32(m,2F),-109.93(d,J=9.4Hz,1F).

[0597] Preparation of compounds 32A and 32B

[0598] Compound 32 (90 mg) was chirally separated by SFC (preparative separation method, instrument model: MGⅡpreparative SFC (SFC-14); column model: ChiralPak AD, 250×30mm ID, 10μm; mobile phase: A:CO2, B:ethanol (0.1% NH3·H2O); elution gradient: B 15%; flow rate: 60 mL / min; column pressure: 100 bar; column temperature: 38℃; detection wavelength: 220 nm; cycle: ~3.5 min) to obtain title compounds 32A (54 mg, single enantiomer) and 32B (44 mg, single enantiomer).

[0599] Compound 32A: LC-MS (ESI): m / z 453.2 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ9.13(s,1H),7.54(td,J=9.0,6.7Hz,1H),7.37–7.24(m,3H),7.20–7.11(m,3H),7.01(td,J=8. 5,2.6Hz,1H),5.43(d,J=14.5Hz,1H),5.01(d,J=14.6Hz,1H),2.02(dd,J=9.4,1.7Hz,3H),1.80(dd,J=9.4,1.7Hz,3H). 19F NMR (376MHz, DMSO-d6) δ-102.81–-103.31(m,1F),-109.22–-109.51(m,2F),-109.57(d,J=9.6Hz,1F).

[0600] Compound 32B: LC-MS (ESI): m / z 453.2 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ9.14(s,1H),7.54(td,J=9.0,6.7Hz,1H),7.37–7.23(m,3H),7.22–7.09(m,3H),7.01(td,J=8. 5,2.7Hz,1H),5.43(d,J=14.5Hz,1H),5.01(d,J=14.6Hz,1H),2.02(dd,J=9.5,1.7Hz,3H),1.80(dd,J=9.4,1.7Hz,3H). 19 F NMR (376MHz, DMSO-d6) δ-102.81–-103.35(m,1F),-109.25–-109.50(m,2F),-109.58(d,J=9.3Hz,1F).

[0601] Example 33: Preparation of compound 33

[0602]

[0603] Preparation of Grignard reagent 33-2

[0604] Magnesium shavings (2.9 g, 120 mmol) and elemental iodine (one stalk) were added to a three-necked flask, and the mixture was purged with nitrogen three times. Anhydrous THF (100 mL) was added to the flask, and a THF solution containing compound 33-1 (12.46 g, 62 mmol) was added dropwise at 78 °C (50 mL). The reaction mixture was stirred at 78 °C for 30 minutes, then gradually cooled to room temperature to obtain a THF solution of the title compound 33-2 (0.62 M, 100 mL), which was a light brown liquid.

[0605] Preparation of compound 33-3

[0606] Iron triacetylacetone (871 mg, 2.4 mmol) was added to a three-necked flask, and the mixture was purged with nitrogen three times. Anhydrous THF (20 mL), compound 1-4 (3.9 g, 12.34 mmol), and TMEDA (572 mg, 4.9 mmol) were added sequentially to the flask. The reaction mixture was stirred for 5 minutes. The Grignard reagent compound 33-2, prepared as described above, was then slowly added dropwise to the flask, and the reaction was continued with stirring at room temperature for 16 hours. After the reaction was complete, the mixture was extracted with EtOAc (30 mL × 3). The organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was then purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-15%) to obtain the title compound 33-3 (0.65 g, 17% yield) as a pale yellow liquid. 1 H NMR (400MHz, Chloroform-d) δ 6.76–6.74 (m, 1H), 6.69–6.64 (m, 2H), 5.93 (s, 2H), 4.36 (q, J = 8.0Hz, 2H), 2.14 (s, 6H), 1.37 (t, J = 8.0Hz, 3H).

[0607] Preparation of compound 33-4

[0608] Compound 1-bromo-2,4-difluorobenzene 1-7 (405 mg, 2.1 mmol) was added to a three-necked flask and purged three times with nitrogen. Anhydrous diethyl ether (15 mL) was added to the flask, and n-butyllithium (1.6 M, 1.3 mL, 2.1 mmol) was added dropwise at -78 °C. After stirring the reaction system at -78 °C for 45 minutes, anhydrous diethyl ether solution (10 mL) containing compound 33-3 (550 mg, 1.77 mmol) was added dropwise, and stirring continued for 1 hour. After the reaction was complete, saturated ammonium chloride solution (5 mL) was added to quench the reaction, and the mixture was extracted with EtOAc (20 mL × 3). The organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-5%) to obtain the title compound 33-4 (400 mg, yield 59.7%) as a yellow oil. 1 H NMR (400MHz, Chloroform-d) δ7.86–7.85(m,1H),7.00–7.92(m,2H),6.90(s,1H),6.76–6.64(m,2H),5.94(s,2H),2.14(s,6H).

[0609] Preparation of compound 33-5

[0610] Compound 33-4 (400 mg, 1.0 mmol) was dissolved in a mixture of dichloromethane (5.0 mL) and water (2.0 mL), and trimethyl sulfoxide 1-9 (544 mg, 2.4 mmol) and solid sodium hydroxide (132 mg, 3.4 mmol) were added. The reaction mixture was stirred at 65 °C for 48 hours. After the reaction was completed, the mixture was extracted with dichloromethane (20 mL × 3), the organic phases were combined, dried and concentrated to obtain the crude product, which was purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-5%) to obtain the title compound 33-5 (360 mg, 91% yield, containing a pair of enantiomers). 1 H NMR(400MHz,Chloroform-d)δ7.60–7.55(m,1H),6.95–6.93(m,1H),6.92–6.90(m,1H),6.86–6.84( m,1H),6.82–6.59(m,2H),5.92(s,2H),3.40(d,J=4.0Hz,1H),2.96–2.94(m,1H),2.07–2.00(m,6H).

[0611] Preparation of compound 33

[0612] Compound 33-5 (360 mg, 0.91 mmol) was dissolved in 1.5 mL of DMF solution, and compound 1-H-tetrazole 1-11 (102 mg, 1.5 mmol) and potassium carbonate (151 mg, 1.1 mmol) were added. The reaction system was sealed and stirred at 80 °C for 16 hours. After the reaction system cooled, the reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10 Prep-C18 250×21.2 mm; column temperature: 25 °C; gradient: 50%-70% acetonitrile in 12 min; flow rate: 30 mL / min) to obtain title compound 33 (106 mg, yield 25%, containing one enantiomer) and compound 33-6 (28 mg, yield 6.5%, containing one enantiomer).

[0613] Compound 33: LC-MS (ESI): 463.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ9.13(s,1H),7.56–7.50(m,1H),7.38–7.21(m,1H),7.15–7.02(m,1H),7.03–7.01(m,1H),7.00–6.98(m,1H),6.80– 6.78(m,1H),6.56–6.54(m,1H),5.94(s,2H),5.44–5.41(d,J=12Hz,1H),5.02–4.99(d,J=12Hz,1H),1.98–1.95(m,3H),1.76–1.73(m,3H).

[0614] Compound 33-6: LC-MS (ESI): 463.2 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ8.76(s,1H),7.59–7.52(m,1H),7.29–7.27(m,1H)7.26–7.24(m,1H)7.19–6.99(m,1H)6.79–6.77(m,1 H),6.72(s,1H),6.56–6.54(m,1H),5.94(s,2H),5.62–5.59(m,1H),5.25–5.22(m,1H),1.96–1.93(m,3H),1.75–1.72(m,3H).

[0615] Example 34: Preparation of compounds 34A and 34B

[0616]

[0617] Preparation of compound 34

[0618] Compound 20 (120 mg, 0.28 mmol) was dissolved in acetonitrile (5.0 mL), and potassium carbonate (76 mg, 0.55 mmol) was added with stirring. After reacting for 5 minutes, 2-bromo-N-methylacetamide (84 mg, 0.55 mmol) was added, and the reaction was stirred at 70 °C for 3 hours. The reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparation method: column: Agilent 10 Prep-C18 250 x 21.2 mm; column temperature: 25 °C; mobile phase: water (0.1% FA)-acetonitrile; acetonitrile ratio 40%-60% in 12 min; flow rate 30 mL / min) to give title compound 34 (105 mg, yield: 75%, containing a pair of enantiomers). LC-MS (ESI): m / z 506.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ9.13 (s, 1H), 7.99 (d, J = 5.1Hz, 1H),7.54(td,J=9.0,6.7Hz,1H),7.28(ddd,J=12.0,9.1,2.6Hz,1H),7.15(s,1H),7.09–6.96(m,3H),6.89–6.79(m,2H),5.42(d,J =14.5Hz,1H),5.02(d,J=14.5Hz,1H),4.40(s,2H),2.62(d,J=4.6Hz,3H),1.98(dd,J=9.4,1.7Hz,3H),1.76(dd,J=9.4,1.7Hz,3H). 19 F NMR (376MHz, DMSO-d6) δ-102.96–-103.18(m,1F),-109.21–-109.31(m,2F),-109.63(d,J=9.2Hz,1F).

[0619] Preparation of compounds 34A and 34B

[0620] Compound 34 (100 mg) was chirally separated by SFC (preparative separation method, instrument model: Thar 80 preparative SFC (SFC-17); column model: ChiralCel OD, 250×30 mm ID, 10 μm; mobile phase: A: CO2, B: ethanol (0.1% NH3H2O); elution gradient: B 40%; flow rate: 80 mL / min; column pressure: 100 bar; column temperature: 38 ℃; detection wavelength: 220 nm; cycle: ~5.1 min) to obtain title compounds 34A (50 mg, single enantiomer) and 34B (49 mg, single enantiomer).

[0621] Compound 34A: LC-MS (ESI): 506.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ9.13 (s, 1H), 7.98 (d, J = 5.4Hz, 1H), 7.54 (td, J = 9.0, 6. 7Hz,1H),7.28(ddd,J=12.0,9.0,2.6Hz,1H),7.14(s,1H),7.09–6.95(m,3H),6 .90–6.80(m,2H),5.42(d,J=14.5Hz,1H),5.02(d,J=14.5Hz,1H),4.40(s,2H), 2.62(d,J=4.7Hz,3H), 1.98(dd,J=9.5,1.7Hz,3H), 1.76(dd,J=9.5,1.7Hz,3H). 19 F NMR (376MHz, DMSO-d6) δ-102.96–-103.17(m,1F),-109.19–-109.30(m,2F),-109.63(d,J=9.2Hz,1F).

[0622] Compound 34B: LC-MS (ESI): 506.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.13 (s, 1H), 7.98 (d, J = 4.4Hz, 1H), 7.54 (td, J = 9.0, 6. 7Hz,1H),7.28(ddd,J=12.0,9.1,2.7Hz,1H),7.14(s,1H),7.10–6.95(m,3H),6 .92–6.78(m,2H),5.42(d,J=14.5Hz,1H),5.02(d,J=14.5Hz,1H),4.40(s,2H), 2.62(d,J=4.7Hz,3H), 1.98(dd,J=9.4,1.7Hz,3H), 1.76(dd,J=9.5,1.7Hz,3H). 19 F NMR (376MHz, DMSO-d6) δ-102.96–-103.17(m,1F),-109.19–-109.29(m,2F),-109.63(d,J=9.2Hz,1F).

[0623] Example 35: Preparation of compounds 35A and 35B

[0624]

[0625] Preparation of compound 35

[0626] Compound 21 (100 mg, 0.23 mmol) was dissolved in acetonitrile (5 mL), and potassium carbonate (32 mg, 0.46 mmol) was added with stirring. After reacting for 5 minutes, 2-bromo-N-methylacetamide (35 mg, 0.46 mmol) was added, and the reaction was stirred at 70 °C for 3 hours. The reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparation method: column: Agilent 10 Prep-C18 250 x 21.2 mm; column temperature: 25 °C; mobile phase: water (0.1% FA)-acetonitrile; acetonitrile ratio 35%-55% in 12 min; flow rate 30 mL / min) to give title compound 35 (90 mg, yield 77%, containing a pair of enantiomers). LC-MS (ESI): m / z 505.2 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ8.36(s,1H),7.99(d,J=4.9Hz,1H),7.69(s,1H),7.56(td,J=9.0, 6.8Hz,1H),7.20(ddd,J=12.0,9.1,2.6Hz,1H),7.08–7.01(m,2H),6.97(td,J=8.4,2.6Hz ,1H),6.89(s,1H),6.88–6.79(m,2H),5.13(d,J=14.4Hz,1H),4.76(d,J=14.4Hz,1H),4.3 9(s,2H),2.62(d,J=4.6Hz,3H),1.96(dd,J=9.5,1.7Hz,3H),1.74(dd,J=9.5,1.7Hz,3H). 19 F NMR (376MHz, DMSO-d6) δ-102.41–-102.89(m,1F),-109.28–-109.73(m,2F),-110.46(d,J=9.5Hz,1F).

[0627] Preparation of compounds 35A and 35B

[0628] Compound 35 (87 mg) was separated by chiral preparative separation using SFC (preparative separation method, instrument model: MGⅡ preparative SFC (SFC-14); column model: ChiralCel OX, 250×30mm ID, 5μm; mobile phase: A: CO2, B: ethanol (0.1% NH4+) 3·H2O); Elution gradient: B 30%; Flow rate: 60 mL / min; Column pressure: 100 bar; Column temperature: 38 ℃; Detection wavelength: 220 nm; Period: ~11.5 min) yielded title compounds 35A (39 mg, monoenantiomer) and 35B (39 mg, monoenantiomer).

[0629] Compound 35A: LC-MS (ESI): m / z 505.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.36(s,1H),8.05–7.91(m,1H),7.69(s,1H),7.56(td,J=8.9,6. 7Hz,1H),7.20(ddd,J=12.0,9.1,2.6Hz,1H),7.07–7.01(m,2H),6.97(td,J=8.5,2.7Hz, 1H),6.89(s,1H),6.87–6.81(m,2H),5.14(d,J=14.5Hz,1H),4.76(d,J=14.5Hz,1H),4.4 0(s,2H),2.62(d,J=4.7Hz,3H),1.96(dd,J=9.5,1.7Hz,3H),1.74(dd,J=9.5,1.7Hz,3H). 19 F NMR (376MHz, DMSO-d6) δ-102.37–-102.91(m,1F),-109.30–-109.68(m,2F),-110.46(d,J=8.5Hz,1F).

[0630] Compound 35B: LC-MS (ESI): 505.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.36 (s, 1H), 8.04–7.94 (m, 1H), 7.69 (s, 1H), 7.56 (td, J = 9.0, 6. 8Hz,1H),7.20(ddd,J=12.0,9.1,2.7Hz,1H),7.08–7.01(m,2H),6.97(td,J=8.5,2.7Hz, 1H),6.89(s,1H),6.88–6.80(m,2H),5.14(d,J=14.5Hz,1H),4.76(d,J=14.4Hz,1H),4.4 0(s,2H),2.62(d,J=4.6Hz,3H),1.96(dd,J=9.4,1.7Hz,3H),1.74(dd,J=9.4,1.7Hz,3H). 19F NMR (376MHz, DMSO-d6) δ-102.41–-102.88(m,1F),-109.27–-109.75(m,2F),-110.46(d,J=9.1Hz,1F).

[0631] Example 36: Preparation of compounds 36A and 36B

[0632]

[0633] Preparation of compound 36

[0634] Compound 20 (100 mg, 0.23 mmol) was added to a sealing tube, followed by potassium carbonate (127 mg, 0.92 mmol), methyl propylene oxide (CAS: 558-30-5, 132 mg, 1.84 mmol), and acetonitrile (1 mL). The mixture was reacted at 70 °C for 16 hours. After cooling, the reaction mixture was filtered, and the crude product from the filtrate was purified by preparative separation (chromatographic column: Welch). C18 21.2x250mm; column temperature: 25℃; mobile phase: water (10mM / L NH4HCO3)-acetonitrile; acetonitrile content in the mobile phase 45%-65% in 12min; flow rate 30mL / min), yielded title compound 36 (55mg, yield 47%).

[0635] Compound 36: LC-MS (ESI): 507.20 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ8.56(br.s,1H),7.70–7.59(m,1H),7.04–6.97(m,2H),6.91–6.77(m,4H),5.48(d,J=14 .3Hz,1H),5.05(d,J=14.4Hz,1H),3.74(s,2H),2.04(dd,J=9.4,1.8Hz,3H),1.85(dd,J=9.4,1.8Hz,3H),1.32(s,6H). 19 F NMR(376MHz,Chloroform-d)δ-106.95(m,1F),-110.15(m,2F),-110.33(m,1F).

[0636] Preparation of compounds 36A and 36B

[0637] Compound 36 (150 mg) was chirally separated by SFC (preparative separation method, instrument model: WatersUPC2analytical SFC (SFC-H)); column model: ChiralPak AD, 150×4.6mm ID, 3μm; mobile phase: A:CO2, B:methanol (0.05%DEA); elution gradient: B 40%; flow rate: 2.5 mL / min; column pressure: 100 bar; column temperature: 35℃; detection wavelength: 220 nm; cycle time: ~2.8 min) to obtain title compounds 36A (70 mg, single enantiomer) and 36B (67 mg, single enantiomer).

[0638] Compound 36A: LC-MS (ESI): 507.00 [M+H] + Chiral analysis method (Column type: ChiralPakAD, 250×30mm ID, 10μm; Mobile phase: A:CO2, B:methanol (0.05% DEA); Elution gradient: elution of 5% B to 40% B within 5 minutes and maintaining 40% B for 2.5 minutes, followed by equilibration with 5% B for 2.5 minutes; Flow rate: 70 mL / min; Column temperature: 35℃; Column pressure: 1500 psi; Detection wavelength: 220 nm; Rt = 2.490 min). 1 H NMR(400MHz,DMSO-d6)δ9.13(s,1H),7.64–7.47(m,1H),7.34–7.21(m,1H),7.14(s,1H),7.07–6.96(m,3H),6.86–6.77(m,2H) ,5.42(d,J=14.5Hz,1H),5.00(d,J=14.6Hz,1H),4.59(s,1H),3.63(s,2H),2.06–1.89(m,3H),1.85–1.68(m,3H),1.16(s,6H). 19 F NMR(376MHz, DMSO-d6)δ-102.67–-103.41(m,1F),-108.99–-109.37(m,2F),-109.64(m,1F).

[0639] Compound 36B: LC-MS (ESI): 507.00 [M+H] +Chiral analysis method (Column type: ChiralPakAD, 250×30mm ID, 10μm; Mobile phase: A:CO2, B:methanol (0.05% DEA); Elution gradient: 5% B to 40% B in the mobile phase over 5 minutes, maintain 40% B for 2.5 minutes, then equilibrate with 5% B for 2.5 minutes; Flow rate: 70 mL / min; Column temperature: 35℃; Column pressure: 1500 psi; Detection wavelength: 220 nm; Rt = 1.989 min). 1 H NMR(400MHz,DMSO-d6)δ9.13(s,1H),7.60–7.49(m,1H),7.34–7.24(m,1H),7.14(s,1H),7.06–6.96(m,3H),6.85–6.78(m,2H) ,5.42(d,J=14.5Hz,1H),5.01(d,J=14.6Hz,1H),4.59(s,1H),3.64(s,2H),2.02–1.93(m,3H),1.81–1.69(m,3H),1.16(s,6H). 19 F NMR(376MHz, DMSO-d6)δ-102.42–-103.89(m,1F),-109.08–-109.43(m,2F),-109.64(m,1F).

[0640] Example 37: Preparation of compounds 37A and 37B

[0641]

[0642] Preparation of compound 37

[0643] Compound 21 (100 mg, 0.23 mmol) was added to a sealed test tube, followed by potassium carbonate (127 mg, 0.92 mmol), methyl propylene oxide (CAS: 558-30-5, 132 mg, 1.84 mmol), and DMF (1 mL). The reaction system was maintained at 100 °C for 2 days. After the reaction system cooled, the reaction solution was filtered, and the crude product of the filtrate was purified by preparative separation (chromatographic column: Welch). C18 21.2x250mm; column temperature: 25℃; mobile phase: water (10mM / L NH4HCO3)-acetonitrile; acetonitrile content in the mobile phase 55%-75% in 12 min; flow rate 30 mL / min) to give title compound 37 (61 mg, yield 53%).

[0644] Compound 37: LC-MS (ESI): m / z 506.2 [M+H] + . 1H NMR(400MHz,Chloroform-d)δ8.13(br.s,1H),7.84(s,1H),7.79–7.67(m,1H),7.07–6.98(m,2H),6.88–6.70(m,4H),5.34(br.s,1H),5.21 (d,J=14.4Hz,1H),4.84(d,J=14.4Hz,1H),3.75(s,2H),2.25(m,1H),2.06(dd,J=9.4,1.8Hz,3H),1.90(dd,J=9.4,1.8Hz,3H),1.32(s,6H). 19 F NMR(376MHz,Chloroform-d)δ-104.77–105.49(m,1F),-108.21–108.62(m,1F),-110.53–111.25(m,2F).

[0645] Preparation of compounds 37A and 37B

[0646] Compound 37 (50 mg) was chirally separated by SFC (preparative separation method, instrument model: MGⅡpreparative SFC (SFC-14); column model: ChiralPak IG, 250×30mm ID, 10μm; mobile phase: A:CO2, B:ethanol (0.1% NH3H2O); elution gradient: B 30%; flow rate: 70mL / min; column pressure: 100bar; column temperature: 38℃; detection wavelength: 220nm; cycle: ~5min) to obtain title compounds 37A (23 mg, single enantiomer) and 37B (25 mg, single enantiomer).

[0647] Compound 37A: LC-MS (ESI): m / z 506.00 [M+H] + Chiral analysis method (Column type: Waters UPC2 analytical SFC (SFC-H); Mobile phase: A: CO2, B: ethanol (0.05% DEA); Elution gradient: B 30%; Flow rate: 2.5 mL / min; Column temperature: 35℃; Column pressure: 100 psi; Detection wavelength: 220 nm; Rt = 2.528 min); 1H NMR(400MHz, DMSO-d6)δ8.36(s,1H),7.68(s,1H),7.59–7.53(m,1H),7.22–7.16(m,1H),7.03–6.96(m,3H),6.88(s,1H),6.83–6.79(m,2H),5. 13(d,J=14.4Hz,1H), 4.76(d,J=14.4Hz,1H), 4.59(s,1H), 3.63(s,2H), 1.96(dd,J=9.4,1.8Hz,3H), 1.73(dd,J=9.4,1.8Hz,3H), 1.16(s,6H). 19 F NMR(376MHz, DMSO-d6)δ-102.51–-102.73(m,1F),-109.42–-109.52(m,2F),-110.47–-110.49(m,1F).

[0648] Compound 37B: LC-MS (ESI): m / z 506.20 [M+H] + Chiral analysis method (Column type: Waters UPC2 analytical SFC (SFC-H); Mobile phase: A: CO2, B: ethanol (0.05% DEA); Elution gradient: B 30%; Flow rate: 2.5 mL / min; Column temperature: 35℃; Column pressure: 100 psi; Detection wavelength: 220 nm; Rt = 2.516 min). 1 H NMR(400MHz, DMSO-d6)δ8.36(s,1H),7.68(s,1H),7.59–7.53(m,1H),7.22–7.16(m,1H),7.03–6.96(m,3H),6.88(s,1H),6.83–6.79(m,2H),5. 13(d,J=14.4Hz,1H), 4.76(d,J=14.4Hz,1H), 4.59(s,1H), 3.63(s,2H), 1.96(dd,J=9.4,1.8Hz,3H), 1.73(dd,J=9.4,1.8Hz,3H), 1.16(s,6H). 19 F NMR(376MHz, DMSO-d6)δ-102.51–-102.73(m,1F),-109.42–-109.52(m,2F),-110.46–-110.49(m,1F).

[0649] Example 38: Preparation of compound 38

[0650]

[0651] Preparation of compound 38-2

[0652] The compound methyltriphenylphosphine bromide (CAS: 1779-49-3, 4.86 g, 12 mmol) was added to a three-necked flask and purged three times with nitrogen. Anhydrous THF (50 mL) was added to the flask, and n-butyllithium (1.6 M, 7.5 mL, 12 mmol) was added dropwise at -78 °C. The reaction system was stirred at -78 °C for 30 minutes, and then a THF (10 mL) solution of compound 38-1 (2 g, 10 mmol) was added. The mixture was then slowly brought to room temperature and reacted for 16 hours. After the reaction was completed, the mixture was quenched with ice water (10 mL), extracted with EtOAc (50 mL × 3), the organic phases were combined, dried and concentrated to obtain the crude product, which was purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-10%) to obtain the title compound 38-2 (1.2 g, 60% yield) as a pale yellow liquid. 1 H NMR (400MHz, Chloroform-d) δ4.74(s,2H),3.42(m,4H),2.18(m,4H),1.47(s,9H).

[0653] Preparation of compound 38-3

[0654] Compound 38-2 (1.2 g, 6.1 mmol) was added to a three-necked flask and purged three times with nitrogen. Anhydrous DCM (20 mL) was then added sequentially to the flask, and the mixture was cooled to 0 °C. Subsequently, m-CPBA (85% purity, 1.84 g, 9.15 mmol) was added. After stirring the reaction system for 3 hours, the reaction was quenched with a saturated sodium sulfite aqueous solution, filtered, and the filtrate was evaporated to dryness. Then, petroleum ether (20 mL) was added, the mixture was stirred, filtered, and the filtrate was concentrated to obtain the title compound 38-3 (800 mg, yield 26.8%) as a pale yellow liquid. 1 H NMR (400MHz, Chloroform-d) δ3.74(m,2H),3.46–3.40(m,2H),2.70(s,2H),1.84–1.77(m,2H),1.58(s,9H),1.50–1.42(m,2H).

[0655] Preparation of compound 38-4

[0656] Compound 38-3 (35 mg, 0.16 mmol) was dissolved in DMF solution (1.5 mL), and compound 20 (50 mg, 0.11 mmol) and cesium carbonate (72 mg, 0.22 mmol) were added. The reaction system was stirred at 60 °C for 16 hours. After cooling, the reaction solution was poured into water (20 mL), extracted with EtOAc (50 mL × 3), and the organic phases were combined and concentrated to obtain the title compound 38-4 (68 mg, crude product) as a yellow oil. This crude compound was used directly as a starting material for the next reaction. LC-MS (ESI): m / z 648.3 [M+H] + .

[0657] Preparation of compound 38-5

[0658] Compound 38-4 (68 mg, crude) was added to a three-necked flask and purged three times with nitrogen. Hydrochloric acid-methanol solution (4.0 M, 10 mL) was added to the flask, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated to obtain the title compound 38-5 (60 mg, crude) as a yellow oil. This crude compound was used directly as a starting material for the next reaction. LC-MS (ESI): m / z 548.2 [M+H] + .

[0659] Preparation of compound 38

[0660] Compound 38-5 (60 mg, crude) was dissolved in MeOH (3.0 mL), and formaldehyde aqueous solution (40%, 0.5 mL, 8.3 mmol) was added. After stirring at room temperature for 1 hour, sodium cyanoborohydride (20.7 mg, 0.33 mmol) was added. The reaction system was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was filtered, and the crude product of the filtrate was purified by preparative separation (chromatographic column: Welch). C18 21.2x250mm; column temperature: 25℃; mobile phase: water (10mM / L NH4HCO3)-acetonitrile; mobile phase acetonitrile ratio 15%-45% in 12min; flow rate 30mL / min) yielded title compound 38 (6.4mg, yield 49.6%, containing a pair of enantiomers) as a white solid.

[0661] Compound 38: LC-MS (ESI): m / z 562.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ9.14(s,1H),7.57-7.52(m,1H),7.32–7.29(m,1H) ),7.26(s,1H),7.15–6.98(m,3H),6.83–6.81(m,2H),5.43(d,J=12Hz,1H) ,5.01(d,J=12Hz,1H),4.67(br.s,1H),3.70(s,2H),2.54–2.53(m,2H),2. 50–2.48(m,2H),1.98–1.96(m,4H),1.77–1.74(m,6H),1.73–1.57(m,3H). 19 F NMR(376MHz, DMSO-d6)δ-102.95–-103.19(m,1F),-109.21–-109.31(m,2F),-109.64(m,1F).

[0662] Example 39: Preparation of compound 39

[0663]

[0664] Preparation of compound 39-2

[0665] Compound 39-1 (500 mg, 2.84 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), and lithium aluminum hydride (140 mg, 3.69 mmol) was added in portions at 0 °C. The reaction was carried out at room temperature for 2 hours. The reaction was monitored by TLC until complete, and then quenched dropwise with ice water. The reaction mixture was extracted with EtOAc (20 mL × 3). The organic phases were combined, dried, and concentrated to obtain 380 mg of the crude title compound, which was used directly as a starting material for the next reaction. LC-MS (ESI): m / z 196.2 [M + NH4] + .

[0666] Preparation of compound 39-3

[0667] Compound 39-2 (380 mg, 2.13 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (0.74 mL) was added dropwise at 0 °C. After reacting for 10 minutes, p-toluenesulfonyl chloride (816 mg, 4.27 mmol) was added, and the reaction was carried out at room temperature for 4 hours. The reaction was monitored by TLC until complete, and the reaction system was extracted with DCM (20 mL × 3). The organic phases were combined, dried, and concentrated to obtain the crude product, which was then purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-10%) to obtain the title compound 39-3 (260 mg, yield 37%). 1H NMR(400MHz,DMSO-d6)δ7.82–7.73(m,2H),7.52–7.43(m,2H),7.38–7.22(m,5H),4.55–4.42 (m,1H),4.31(s,2H),3.71–3.56(m,1H),2.59–2.51(m,2H),2.42(s,3H),1.98–1.89(m,2H).

[0668] Preparation of compound 39-4

[0669] Compound 39-3 (100 mg, 0.23 mmol) was dissolved in DMF (5.0 mL), and cesium carbonate (150 mg, 0.46 mmol) was added with stirring. After reacting for 5 minutes, compound 20 (99 mg, 0.3 mmol) was added, and the reaction was stirred at 50 °C for 4 hours. The reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparation method: column: Agilent 10 Prep-C18 250 x 21.2 mm; column temperature: 25 °C; mobile phase: water (0.1% TFA)-acetonitrile; acetonitrile ratio 45%-65% in 12 min; flow rate 30 mL / min) to obtain the title compound 39-4 (280 mg, yield 20%). LC-MS (ESI): m / z 595.2 [M+H] + .

[0670] Preparation of compound 39

[0671] Compound 39-4 (28 mg, 0.05 mmol) was dissolved in a mixed solvent of methanol (5 mL) and formic acid (0.5 mL), and 10% wet palladium on carbon (5 mg) was added. After purging with nitrogen three times, the reaction was carried out at room temperature for 16 hours. The reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparation method: column: Agilent 10 Prep-C18 250 x 21.2 mm; column temperature: 25 °C; mobile phase: water (0.1% TFA)-acetonitrile; acetonitrile ratio 50%-70% in 12 min; flow rate 30 mL / min) to give title compound 39 (10 mg, yield: 42%, containing two pairs of enantiomers).

[0672] Compound 39: LC-MS (ESI): m / z 505.2 [M+H] + . 1H NMR(400MHz, DMSO-d6)δ9.13(s,1H),7.53(td,J=9.0,6.8Hz,1H),7.28(ddd,J=12.0, 9.1,2.6Hz,1H),7.15(s,1H),7.05–6.95(m,3H),6.73–6.63(m,2H),5.42(d,J=14.6Hz ,1H),5.15(d,J=5.4Hz,1H),5.01(d,J=14.6Hz,1H),4.81–4.69(m,1H),4.39–4.23(m ,1H),2.24(t,J=5.6Hz,4H),1.96(dd,J=9.5,1.6Hz,3H),1.75(dd,J=9.4,1.6Hz,3H). 19 F NMR (376MHz, DMSO-d6) δ-102.97–-103.19(m,1F),-109.20–-109.30(m,2F),-109.65(d,J=9.6Hz,1F).

[0673] Example 40: Preparation of compounds 40A and 40B

[0674]

[0675] Preparation of compound 40-2

[0676] Compound 40-1 (500 mg, 5.68 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (1 mL) was added dropwise at 0 °C. After reacting for 10 minutes, p-toluenesulfonyl chloride (1.19 g, 6.25 mmol) was added, and the reaction was carried out at room temperature for 4 hours. The reaction system was extracted with DCM (20 mL × 3), the organic phases were combined, dried, and concentrated to give the title compound 40-2 (1 g, crude product). This crude compound was used directly in the next reaction.

[0677] Preparation of compound 40

[0678] Compound 20 (120 mg, 0.28 mmol) was dissolved in DMF (5 mL) solvent. Cesium carbonate (180 mg, 0.55 mmol) was added with stirring, and the reaction was allowed to proceed for 5 minutes. Then, compound 40-2 (134 mg, 0.55 mmol) was added, and the reaction was stirred at 50 °C for 4 hours. The reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparation method: column: Agilent 10 Prep-C18 250 x 21.2 mm; column temperature: 25 °C; mobile phase: water (0.1% FA)-acetonitrile; acetonitrile ratio 45%-65% in 12 min; flow rate 30 mL / min) to obtain title compound 40 (54 mg, yield: 39%, containing a pair of diastereomers). LC-MS (ESI): m / z 505.2 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ9.13(s,1H),7.54(td,J=9.0,6.7Hz,1H),7.28(ddd,J=12.0 ,9.1,2.6Hz,1H),7.14(s,1H),7.07–6.97(m,3H),6.85–6.76(m,2H),5.42(d,J=14. 5Hz,1H),5.02(d,J=14.5Hz,1H),4.99–4.93(m,1H),3.90–3.67(m,4H),2.24–2.10( m,1H),1.97(dd,J=9.4,1.7Hz,3H),1.94–1.86(m,1H),1.76(dd,J=9.4,1.6Hz,3H). 19 F NMR (376MHz, DMSO-d6) δ-102.97–-103.19(m,1F),-109.21–-109.32(m,2F),-109.65(d,J=9.6Hz,1F).

[0679] Preparation of compounds 40A and 40B

[0680] Compound 40 (50 mg) was chirally separated by SFC (preparative separation method, instrument model: MGⅡpreparative SFC (SFC-14); column model: ChiralPak IC, 250×30 mm ID10 μm; mobile phase: A: CO2, B: ethanol (0.1% NH3H2O); elution gradient: B 30%; flow rate: 70 mL / min; column pressure: 100 bar; column temperature: 38℃; detection wavelength: 220 nm; cycle: ~7 min) to obtain title compounds 40A (25 mg, single enantiomer) and 40B (23 mg, single enantiomer).

[0681] Compound 40A: LC-MS (ESI): 505.0 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ9.13(s,1H),7.54(td,J=9.0,6.7Hz,1H),7.28(ddd,J=12.0 ,9.1,2.6Hz,1H),7.14(s,1H),7.06–6.96(m,3H),6.83–6.76(m,2H),5.42(d,J=14. 5Hz,1H),5.02(d,J=14.5Hz,1H),4.99–4.93(m,1H),3.91–3.65(m,4H),2.23–2.11( m,1H),1.97(dd,J=9.5,1.7Hz,3H),1.94–1.85(m,1H),1.76(dd,J=9.5,1.7Hz,3H). 19 F NMR(376MHz, DMSO-d6)δ-102.97 –-103.18(m,1F),-109.20–-109.31(m,2F),-109.64(d,J=9.2Hz,1F).

[0682] Compound 40B: LC-MS (ESI): 505.0 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ9.14(s,1H),7.54(td,J=9.0,6.7Hz,1H),7.29(ddd,J=12.0 ,9.1,2.6Hz,1H),7.14(s,1H),7.07–6.97(m,3H),6.85–6.76(m,2H),5.42(d,J=14. 5Hz,1H),5.02(d,J=14.5Hz,1H),4.99–4.93(m,1H),3.93–3.66(m,4H),2.24–2.11( m,1H),1.98(dd,J=9.5,1.7Hz,3H),1.95–1.85(m,1H),1.76(dd,J=9.5,1.7Hz,3H). 19 F NMR (376MHz, DMSO-d6) δ-102.97–-103.18(m,1F),-109.20–-109.31(m,2F),-109.64(d,J=9.2Hz,1F).

[0683] Example 41: Preparation of compounds 41A and 41B

[0684]

[0685] Preparation of compound 41-2

[0686] Compound 41-1 (500 mg, 5.68 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (1 mL) was added dropwise at 0 °C. The reaction system was stirred for 10 minutes, and then p-toluenesulfonyl chloride (1.19 g, 6.25 mmol) was added. The reaction was carried out at room temperature for 4 hours. The reaction system was extracted with DCM (20 mL × 3), and the organic phases were combined, dried, and concentrated to give the title compound 41-2 (1 g, crude product). This crude compound was used directly in the next step of the reaction.

[0687] Preparation of compound 41

[0688] Compound 20 (120 mg, 0.28 mmol) was dissolved in DMF (5 mL), and cesium carbonate (180 mg, 0.55 mmol) was added with stirring. After reacting for 5 minutes, compound 41-2 (134 mg, 0.55 mmol) was added, and the reaction was stirred at 50 °C for 4 hours. The reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparation method: column: Agilent 10 Prep-C18 250 x 21.2 mm; column temperature: 25 °C; mobile phase: water (0.1% FA)-acetonitrile; acetonitrile ratio 45%-65% in 12 min; flow rate 30 mL / min) to obtain title compound 41 (88 mg, yield: 63%, containing a pair of diastereomers). LC-MS (ESI): m / z 505.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.06 (s, 1H), 7.47 (td, J=9.0, 6.7Hz, 1H), 7.21 (ddd, J= 12.0,9.1,2.6Hz,1H),7.08(s,1H),7.02–6.88(m,3H),6.79–6.67(m,2H),5.15( dd,J=167.1,14.5Hz,2H),4.92–4.86(m,1H),3.84–3.60(m,4H),2.17–2.03(m,1 H),1.90(dd,J=9.4,1.7Hz,3H),1.87–1.78(m,1H),1.69(dd,J=9.5,1.7Hz,3H). 19 F NMR (376MHz, DMSO-d6) δ-102.97–-103.18(m,1F),-109.21–-109.31(m,2F),-109.64(d,J=9.2Hz,1F).

[0689] Preparation of compounds 41A and 41B

[0690] Compound 41 (88 mg) was chirally separated by SFC (preparative separation method, instrument model: MGⅡpreparative SFC (SFC-14); column model: ChiralPak IC, 250×30 mm ID10 μm; mobile phase: A: CO2 B: ethanol (0.1% NH3H2O); elution gradient: B 30%; flow rate: 70 mL / min; column pressure: 100 bar; column temperature: 38 ℃; detection wavelength: 220 nm; cycle: ~10 min) to obtain title compounds 41A (38 mg, single diastereomer) and 41B (41 mg, single diastereomer).

[0691] Compound 41A: LC-MS (ESI): 505.2 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ9.13(s,1H),7.54(td,J=9.0,6.7Hz,1H),7.28(ddd,J=12.1,9.1,2.6Hz,1H),7.14(s,1H),7.06–6.96(m,3H),6.84–6.7 6(m,2H),5.51–4.90(m,3H),3.92–3.64(m,4H),2.24–2.11(m,1H),1.97 (dd,J=9.4,1.7Hz,3H),1.94–1.84(m,1H),1.76(dd,J=9.4,1.7Hz,3H). 19 F NMR (376MHz, DMSO-d6) δ-102.97–-103.18(m,1F),-109.19–-109.30(m,2F),-109.64(d,J=9.2Hz,1F).

[0692] Compound 41B: LC-MS (ESI): 505.2 [M+H] + . 1H NMR(400MHz, DMSO-d6)δ9.13(s,1H),7.54(td,J=9.0,6.7Hz,1H),7.28(ddd,J=12.0,9.1,2.6Hz,1H),7.14(s,1H),7.06–6.97(m,3H),6.84–6.7 7(m,2H),5.53–4.89(m,3H),3.93–3.66(m,4H),2.23–2.11(m,1H),1.97 (dd,J=9.5,1.7Hz,3H),1.94–1.85(m,1H),1.76(dd,J=9.5,1.7Hz,3H). 19 F NMR (376MHz, DMSO-d6) δ-102.97–-103.18(m,1F),-109.19–-109.30(m,2F),-109.64(d,J=9.2Hz,1F).

[0693] Example 42: Preparation of compound 42

[0694]

[0695] Preparation of compound 42-2

[0696] Compound 42-1 (574 mg, 5.68 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (1 mL) was added dropwise at 0 °C. After reacting for 10 minutes, p-toluenesulfonyl chloride (1.19 g, 6.25 mmol) was added, and the reaction was carried out at room temperature for 4 hours. The reaction was monitored by TLC until complete, and the reaction system was extracted with DCM (20 mL × 3). The organic phases were combined, dried, and concentrated to obtain 800 mg of the crude title compound, which was used directly as the starting material for the next reaction.

[0697] Preparation of compound 42

[0698] Compound 20 (120 mg, 0.28 mmol) was dissolved in DMF (5 mL), and cesium carbonate (180 mg, 0.55 mmol) was added with stirring. After reacting for 5 minutes, compound 42-2 (140 mg, 0.55 mmol) was added, and the reaction was stirred at 50 °C for 4 hours. The reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparation method: chromatographic column: Agilent 10 Prep-C18 250 x 21.2 mm; column temperature: 25 °C; mobile phase: water (0.1% NH4HCO3)-acetonitrile; acetonitrile ratio 40%-60% in 12 min; flow rate 30 mL / min) to obtain title compound 42 (74 mg, yield: 52%, containing a pair of diastereomers).

[0699] Compound 42: LC-MS (ESI): m / z 518.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.13(s,1H),7.54(td,J=9.0,6.7Hz,1H),7.28(ddd,J=12.0,9 .1,2.6Hz,1H),7.14(s,1H),7.00(dt,J=8.0,2.8Hz,3H),6.82–6.68(m,2H),5.42(d,J =14.6Hz,1H),5.01(d,J=14.6Hz,1H),4.86–4.71(m,1H),2.75–2.52(m,3H),2.36–2.1 7(m,5H),1.97(dd,J=9.4,1.7Hz,3H),1.75(dd,J=9.4,1.7Hz,3H),1.73–1.65(m,1H). 19 F NMR (376MHz, DMSO-d6) δ-102.97–-103.19(m,1F),-109.20–-109.30(m,2F),-109.65(d,J=9.6Hz,1F).

[0700] Example 43: Preparation of compound 43

[0701]

[0702] Preparation of compound 43-2

[0703] Compound 43-1 (574 mg, 5.68 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (1 mL) was added dropwise at 0 °C. After reacting for 10 minutes, p-toluenesulfonyl chloride (1.19 g, 6.25 mmol) was added, and the reaction was carried out at room temperature for 4 hours. The reaction was monitored by TLC until complete. The reaction system was extracted with DCM (20 mL × 3), the organic phases were combined, dried and concentrated to obtain 700 mg of the crude title compound, which was used directly as the starting material for the next reaction.

[0704] Preparation of compound 43

[0705] Compound 20 (120 mg, 0.28 mmol) was dissolved in DMF (5 mL), and cesium carbonate (180 mg, 0.55 mmol) was added with stirring. After reacting for 5 minutes, compound 43-2 (140 mg, 0.55 mmol) was added, and the reaction was stirred at 50 °C for 4 hours. The reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparation method: column: Agilent 10 Prep-C18 250 x 21.2 mm; column temperature: 25 °C; mobile phase: water (0.1% NH4HCO3)-acetonitrile; acetonitrile ratio 40%-60% in 12 min; flow rate 30 mL / min) to obtain title compound 43 (82 mg, yield: 57%, containing a pair of diastereomers).

[0706] Compound 43: LC-MS (ESI): m / z 518.2 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ9.13(s,1H),7.53(td,J=9.0,6.7Hz,1H),7.28(ddd,J=12 .0,9.1,2.6Hz,1H),7.14(s,1H),7.05–6.95(m,3H),6.79–6.72(m,2H),5.43(d,J =14.6Hz,1H),5.01(d,J=14.6Hz,1H),4.88–4.73(m,1H),2.83–2.55(m,3H),2.43 –2.35(m,1H),2.30–2.21(m,4H),1.97(dd,J=9.4,1.7Hz,3H),1.79–1.69(m,4H). 19 F NMR (376MHz, DMSO-d6) δ-102.97–-103.19(m,1F),-109.21–-109.31(m,2F),-109.64(d,J=9.6Hz,1F).

[0707] Example 44: Preparation of compound 44

[0708]

[0709] Preparation of compound 44-2

[0710] Compound 44-1 (500 mg, 2.89 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (321 mg, 3.18 mmol) was added dropwise at 0 °C. After reacting for 10 minutes, p-toluenesulfonyl chloride (550 mg, 2.89 mmol) was added, and the reaction was carried out at room temperature for 24 hours. The reaction was monitored by TLC until complete, and the reaction system was extracted with DCM. The organic phases were combined, dried, concentrated, and the crude product was filtered through silica gel to obtain the title compound 44-2 (0.9 g, 95% yield). 1 H NMR(400MHz,Chloroform-d)δ7.88–7.71(m,2H),7.48–7.31(m,2H),5.05–4.96(m,1H),4.12–4.07(m,2H),3.95–3.91(m,2H),2.47(s,3H),1.41(s,9H).

[0711] Preparation of compound 44-3

[0712] Compound 20 (100 mg, 0.23 mmol) was dissolved in DMF (5 mL), and cesium carbonate (97 mg, 0.299 mmol) was added with stirring. After reacting for 5 minutes, compound 44-2 (150 mg, 0.460 mmol) was added, and the reaction was stirred at 50 °C for 24 hours. The reaction solution was filtered, and the filtrate was concentrated to obtain a crude product. After preparative separation and purification, the crude product was filtered through silica gel to obtain the title compound 44-3 (70 mg, yield 52%, containing a pair of enantiomers). LC-MS (ESI): m / z 590.2 [M+H] + .

[0713] Preparation of compound 44

[0714] Compound 44-3 (70 mg, 0.119 mmol) was dissolved in dichloromethane (5 mL), and dioxane hydrochloride (4.0 M, 1 mL) was added with stirring. After reacting for 15 minutes, the mixture was concentrated to obtain the crude product, which was then purified by preparative separation (chromatographic column: Welch). C18 21.2 x 250 mm; column temperature: 25 °C; mobile phase: water (10 mM / L NH4HCO3) - acetonitrile; acetonitrile ratio in the mobile phase 35%-55% in 12 min; flow rate 30 mL / min) yielded title compound 44 (30 mg, yield 51%, containing a pair of enantiomers).

[0715] Compound 44: LC-MS (ESI): m / z 490.0 [M+H] + . 1H NMR(400MHz, DMSO-d6)δ9.14(s,1H),7.59–7.48(m,1H),7.31–7.25(m,1H),7.19(s,1H),7.08–6.96(m,3H),6.72–6.64(m,2H),5.43(d, J=14.6Hz,1H),5.01(d,J=14.6Hz,1H),4.94–4.84(m,1H),3.74–3.70(m,2H),3.46–3.42(m,2H),1.98–1.95(m,3H),1.76–1.74(m,3H). 19 F NMR (376MHz, DMSO-d6) δ-102.95–-103.16(m,1F),-109.18–-109.31(m,2F),-109.64(d,J=9.6Hz,1F).

[0716] Example 45: Preparation of compound 45

[0717]

[0718] Preparation of compound 45

[0719] Compound 44 (60 mg, 0.122 mmol) was dissolved in methanol (6 mL), and formaldehyde (37 mg, 38% aqueous solution) was added with stirring. After stirring for 15 minutes, sodium triacetylborohydride (78 mg, 0.367 mmol) was added, and the reaction was stirred for 1 hour. Most of the methanol solution was removed by concentration, and the residue was purified by preparative separation (chromatographic column: Welch). C18 21.2x250mm; column temperature: 25℃; mobile phase: water (10mM / L NH4HCO3)-acetonitrile; acetonitrile ratio in mobile phase 45%-65% in 12 min; flow rate 30 mL / min) to give title compound 45 (25 mg, yield: 40%, one enantiomer).

[0720] Compound 45: LC-MS (ESI): m / z 490.0 [M+H] + . 1H NMR(400MHz, DMSO-d6)δ9.13(s,1H),7.58–7.49(m,1H),7.31–7.25(m,1H),7.14(s,1H),7.02–6.98(m,3H),6.72–6.68(m,2H),5.42(d,J=14.6H z,1H),5.01(d,J=14.6Hz,1H),4.67(t,J=5.6Hz,1H),3.73–3.65(m,2H) ,2.95–2.85(m,2H),2.25(s,3H),1.98–1.95(m,3H),1.76–1.74(m,3H). 19 F NMR (376MHz, DMSO-d6) δ-102.98–-103.19(m,1F),-109.21–-109.32(m,2F),-109.64(d,J=9.6Hz,1F).

[0721] Example 46: Preparation of compounds 46A and 46B

[0722]

[0723] Preparation of compound 46-2

[0724] Compound 13-1 (500 mg, 1.26 mmol) was dissolved in cyclopentyl methyl ether (10 mL). Compound n-butyldi(1-adamantyl)phosphine (cataCXium A, CAS: 321921-71-5, 90 mg, 0.25 mmol), cesium carbonate (1.23 g, 3.77 mmol), cuprous oxide (179 mg, 1.26 mmol), palladium acetate (159 mg, 1.15 mmol), compound 46-1 (482 mg, 1.88 mmol), and water (2 mL) were added separately. The reaction was carried out under argon protection and microwaved at 120 °C for 16 hours. After the reaction system cooled and the reaction was complete, a saturated ammonium chloride solution (5 mL) was added to quench the reaction. Extraction was performed using EtOAc (20 mL × 3). The organic phases were combined, dried, and concentrated to obtain the crude product. Purification was achieved by normal-phase silica gel column chromatography (EtOAc / PE = 0-10%) to obtain the title compound 46-2 (280 mg, yield 49%) as a brown oil. LC-MS (ESI): m / z 448.0 [M+H] + . 1H NMR(400MHz,Chloroform-d)δ7.91(d,J=2.4Hz,1H),7.65–7.51(m,1H),7.50–7.38(m,1H),7.03–6.90(m,1H),6.90–6 .81(m,1H),6.78(d,J=8.4Hz,1H),4.73(q,J=8.6Hz,2H),3.40(d,J=5.2Hz,1H),3.00–2.89(m,1H),2.17–2.04(m,6H).

[0725] Preparation of compound 46

[0726] Compound 46-2 (180 mg, 0.4 mmol) was dissolved in DMF (3 mL), and 1-H tetrazolium (141 mg, 2.0 mmol) and potassium carbonate (278 mg, 2.0 mmol) were added. The reaction mixture was sealed at 80 °C for 16 hours. After the reaction system cooled, the reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparation method: chromatographic column: Agilent 10 Prep-C18 250 x 21.2 mm; mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; column temperature: 25 °C; gradient: 60%-80% acetonitrile in 12 min; flow rate: 30 mL / min) to obtain the title compound 46 (110 mg, yield 24%, containing a pair of enantiomers) and the corresponding regioisomer compound 46-3 (15 mg, yield 7%, containing a pair of enantiomers).

[0727] Compound 46: LC-MS (ESI): m / z 518.0 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ9.14(s,1H),7.96(d,J=2.4Hz,1H),7.70–7.48(m,2H),7.35–7.24(m,1H),7.21(s,1H),7.10–6.96(m,1H),6.89(d,J =8.4Hz,1H),5.43(d,J=14.6Hz,1H),5.02(d,J=14.6Hz,1H),4.94(q,J=9.1Hz,2H),2.05(dd,J=9.4,1.7Hz,3H),1.84(dd,J=9.4,1.7Hz,3H). 19 F NMR(376MHz, DMSO-d6)δ-72.35(s,3F),-102.53–-103.49(m,1F),-108.89–-109.97(m,3F).

[0728] Compound 46-3: LC-MS (ESI): m / z 518.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.76(s,1H),7.96(d,J=2.4Hz,1H),7.65–7.48(m,2H),7.25(d,J=12.8Hz,2H),6.99(d,J=2.4Hz,1H),6.88(d,J=8 .4Hz,1H),5.61(d,J=14.2Hz,1H),5.24(d,J=14.2Hz,1H),4.94(q,J=9.1Hz,2H),2.04(dd,J=9.5,1.7Hz,3H),1.83(dd,J=9.5,1.7Hz,3H). 19 F NMR(376MHz, DMSO-d6)δ-72.34(s,3F),-102.15–-103.52(m,1F),-108.66–-109.53(m,2F),-109.67–-110.90(m,1F).

[0729] Preparation of compounds 46A and 46B

[0730] Compound 46 (40 mg) was chirally separated by SFC (preparative separation method, instrument model: MGⅡpreparative SFC (SFC-14); column model: ChiralPak AD, 250×30mm ID, 10μm; mobile phase: A:CO2, B:ethanol (0.1% NH3H2O); elution gradient: B 20%; flow rate: 60 mL / min; column pressure: 100 bar; column temperature: 38℃; detection wavelength: 220 nm; cycle: ~2.8 min) to obtain title compounds 46A (18 mg, single enantiomer) and 46B (17 mg, single enantiomer).

[0731] Compound 46A: LC-MS (ESI): m / z 518.0 [M+H] + Chiral analysis method (column type: AD-3 150×4.6mm ID, 3um; mobile phase: A:CO2, B:ethanol (0.05% DEA); elution gradient: B 40%; flow rate: 2.5mL / min; column temperature: 35℃; column pressure: 100bar; detection wavelength: 220nm; Rt=1.456min). 1H NMR (400MHz, DMSO-d6) δ9.13 (s, 1H), 7.96 (d, J = 2.4Hz, 1H), 7.70–7.57 (m, 1H),7.55–7.48(m.1H),7.35–7.24(m,1H),7.21(s,1H),7.10–6.96(m,1H), 6.89(d,J=8.4Hz,1H),5.43(d,J=14.6Hz,1H),5.02(d,J=14.6Hz,1H),4.94 (q, J=9.1Hz, 2H), 2.05 (dd, J=9.4, 1.7Hz, 3H), 1.84 (dd, J=9.4, 1.7Hz, 3H). 19 F NMR(376MHz, DMSO-d6)δ-72.35(s,3F),-102.53–-103.49(m,1F),-108.89–-109.97(m,3F).

[0732] Compound 46B: LC-MS (ESI): m / z 518.0 [M+H] + Chiral analysis method (Column type: ChiralCel OD, 150×4.6mm ID, 3μm; Mobile phase: A:CO2, B:ethanol (0.05% DEA); Elution gradient: B 40%; Flow rate: 2.5mL / min; Column temperature: 35℃; Column pressure: 100bar; Detection wavelength: 220nm; Rt = 1.133min). 1 H NMR (400MHz, DMSO-d6) δ9.14 (s, 1H), 7.96 (d, J = 2.4Hz, 1H), 7.70–7.57 (m, 1H),7.55–7.48(m.1H),7.35–7.24(m,1H),7.21(s,1H),7.10–6.96(m,1H), 6.89(d,J=8.4Hz,1H),5.43(d,J=14.6Hz,1H),5.02(d,J=14.6Hz,1H),4.94 (q, J=9.1Hz, 2H), 2.05 (dd, J=9.4, 1.7Hz, 3H), 1.84 (dd, J=9.4, 1.7Hz, 3H). 19 F NMR(376MHz, DMSO-d6)δ-72.35(s,3F),-102.53–-103.49(m,1F),-108.89–-109.97(m,3F).

[0733] Example 47: Preparation of Compound 47

[0734]

[0735] Preparation of compound 47

[0736] Compound 1,2,4-triazole (77 mg, 1.12 mmol) was dissolved in DMF solution (2 mL) and cooled to 0 °C. Sodium hydride (60%, 27 mg, 1.12 mmol) was added, and the reaction was allowed to proceed for half an hour. Compound 46-2 (100 mg, 0.22 mmol) was then added. The reaction mixture was stirred at 80 °C for 2 hours. After the reaction mixture cooled, the reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10 Prep-C18 250 × 21.2 mm; column temperature: 25 °C; gradient: 70%-90% acetonitrile in 12 min; flow rate: 30 mL / min) to give title compound 47 (25 mg, yield 21%, containing a pair of enantiomers).

[0737] Compound 47: LC-MS (ESI): m / z 517.0 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ8.38(br.s,1H),7.96(d,J=2.4Hz,1H),7.71(br.s,1H),7.62–7.51(m,2H),7.25–7.13(m,1H),7.03–6.94(m,1H),6.94 –6.84(m,2H),5.14(d,J=14.5Hz,1H),4.94(q,J=9.2Hz,2H),4.76(d,J=14.5Hz,1H),2.04(dd,J=9.4,1.7Hz,3H),1.82(dd,J=9.4,1.7Hz,3H). 19 F NMR(376MHz, DMSO-d6)δ-72.34(m,3F),-101.77–-103.67(m,1F),-109.02–-109.95(m,2F),-109.86–-111.01(m,1F).

[0738] Example 48: Preparation of compounds 48, 48A and 48B

[0739]

[0740] Preparation of compound 48-2

[0741] Compound 1-1 (200 g, 0.68 mol) was added to a three-necked flask, purged three times with nitrogen, and then anhydrous diethyl ether (500 mL) was added. Methyllithium (1.6 M, 850 mL, 1.36 mol) was then added dropwise to the reaction system at -78 °C. After reacting for 5 minutes, the reaction system was transferred to 0 °C and stirred for 3 hours. Ethyl iodoacetate (73 g, 0.34 mol) was then added, and the reaction was carried out at room temperature for 16 hours. Extraction was performed using EtOAc (20 mL × 3), the organic phases were combined, dried, and concentrated to obtain a crude product. Purification was achieved by normal column chromatography (EtOAc / PE = 0-5%) to obtain the title compound 48-2 (32 g, yield 16.8%) as a pale yellow liquid. 1 H NMR (400MHz, DMSO-d6) δ4.05 (q, J = 7.2Hz, 2H), 2.58 (s, 2H), 2.28 (s, 6H), 1.18 (t, J = 7.2Hz, 3H).

[0742] Preparation of compound 48-3

[0743] Ferric triacetylacetone (7.7 g, 0.02 mol) was added to a three-necked flask, and under nitrogen protection, THF (300 mL), compound 48-2 (32 g, 0.11 mol), and TMEDA (5.2 g, 0.05 mol) were added separately. After stirring for 5 minutes, a Grignard reagent solution of 4-methoxyphenyl magnesium bromide in THF (1-5 M, 176 mL, 0.18 mol) was slowly added dropwise to the reaction system, and the reaction was carried out at room temperature for 16 hours. Extraction was performed with EtOAc (20 mL × 3), the organic phases were combined, dried and concentrated to obtain a crude product. The crude product was purified by normal column chromatography (EtOAc / PE = 0-10%) to obtain the title compound 48-3 (17 g, yield 57%) as a pale yellow liquid. 1 H NMR(400MHz, DMSO-d6)δ7.13-7.07(dd,J=6.6,2.2Hz,2H),6.87–6.82(dd,J=6.6,2.2Hz, 2H), 4.08 (q, J = 7.2Hz, 2H), 3.71 (s, 3H), 2.55 (s, 2H), 1.93 (s, 6H), 1.20 (t, J = 7.2Hz, 3H).

[0744] Preparation of compound 48-4

[0745] Compound 48-3 (17.0 g, 65.4 mmol) and anhydrous tetrahydrofuran (150 mL) were sequentially added to a single-necked reaction flask. The reaction mixture was then partially added to lithium aluminum hydride (3.2 g, 85.1 mmol) at 0 °C, and reacted at room temperature for 2 hours. The reaction was quenched with ice water (5.0 mL), extracted with EtOAc (20 mL × 3), and the organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was purified by normal column chromatography (EtOAc / PE = 0-10%) to obtain the title compound 48-4 (7.1 g, 50% yield) as a colorless oil. LC-MS (ESI): m / z 219.2 [M+H] + .

[0746] Preparation of compound 48-5

[0747] Compound 48-4 (7.1 g, 32.5 mmol) was added to a three-necked flask, purged three times with nitrogen, and then 100 mL of dichloromethane was added. Dys-Martin oxidant (15.2 g, 78.5 mmol) was slowly added at 0 °C, and the reaction mixture was stirred at room temperature for 2 hours. Extraction was performed with dichloromethane (20 mL × 3). The organic phases were combined, dried, and concentrated to obtain a crude product. Purification was achieved by normal column chromatography (EtOAc / PE = 0-10%) to give the title compound 48-5 (4.5 g, 64% yield) as a pale yellow liquid. LC-MS (ESI): m / z 217.2 [M+H]+.

[0748] Preparation of compound 48-6

[0749] 1-Bromo-2,4-difluorobenzene (12.1 g, 62.4 mmol) was added to a three-necked flask, and the mixture was purged three times with nitrogen. Anhydrous diethyl ether (150 mL) was added to the flask, and n-butyllithium (1.6 M, 39 mL, 62.4 mmol) was added dropwise at -78 °C. The reaction mixture was stirred at -78 °C for 2 hours, followed by the dropwise addition of anhydrous diethyl ether solution (10 mL) containing compound 48-5 (4.5 g, 20.8 mmol) and stirring for another hour. After the reaction was complete, the mixture was quenched with saturated ammonium chloride solution (20 mL), extracted with EtOAc (20 mL × 3), and the organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-15%) to obtain the title compound 48-6 (3.5 g, 50% yield) as a yellow solid. LC-MS (ESI): m / z 313.2 [M-H2O+H] + .

[0750] Preparation of compound 48-7

[0751] Compound 48-6 (3.5 g, 10.6 mmol) was added to a three-necked flask, purged three times with nitrogen, and then dichloromethane (50 mL) and Dys-Martin oxidant (9.1 g, 21.2 mmol) were added at 0 °C. The reaction system was stirred at room temperature for 2 hours. Extraction was performed with dichloromethane (20 mL × 3), the organic phases were combined, dried, and concentrated to obtain a crude product. Purification was achieved by normal column chromatography (EtOAc / PE = 0-10%) to give the title compound 48-7 (3.2 g, 91% yield) as a pale yellow liquid. LC-MS (ESI): m / z 329.2 [M+H] + .

[0752] Preparation of compound 48-8

[0753] Compound 48-7 (3.2 g, 9.7 mmol), acetic acid (15 mL), and hydrobromic acid aqueous solution (15 mL) were sequentially added to a sealed reaction tube, and the reaction system was reacted at 100 °C for 60 hours. Extraction was performed with dichloromethane (20 mL × 3), the organic phases were combined, dried, and concentrated to obtain a crude product. Purification was achieved by normal column chromatography (EtOAc / PE = 0-10%) to give the title compound 48-8 (2.4 g, 78% yield) as a pale yellow liquid. LC-MS (ESI): m / z 313.0 [MH] - .

[0754] Preparation of Compounds 48-9

[0755] Compound 48-8 (2.4 g, 7.1 mmol) was dissolved in DCM (5 mL) solvent, and potassium carbonate (3.5 g, 10.8 mmol) and 2,2,2-trifluoroethyltrifluoromethanesulfonate (2.5 g, 10.8 mmol) were added. The reaction system was reacted in sealed test tubes at 65 °C for 16 hours. After the reaction system was cooled, it was extracted with EtOAc (20 mL × 3), the organic phases were combined, dried and concentrated to obtain the crude product, which was purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-15%) to obtain the title compound 48-9 (1.2 g, 40% yield) as a light yellow oil. 1 H NMR (400MHz, DMSO-d6) δ7.99–7.84(m,1H),7.53–7.36(m,1H),7.34–7.19(m,1H),7.19–7.06(dd,J=6.6, 2.2Hz, 2H), 7.04–6.87 (dd, J=6.6, 2.2Hz, 2H), 4.71 (q, J=8.8Hz, 2H), 3.21 (d, J=2.4Hz, 2H), 1.93 (s, 6H).

[0756] Preparation of compound 48-10

[0757] Trimethyl sulfoxide (1.98 g, 9.0 mmol), NaH (216 mg, 9.0 mmol), and DMSO (10 mL) were added to separate three-necked flasks. The reaction system was stirred at room temperature for 1 hour, followed by the addition of 3 mL of DMSO solution containing compound 48-9 (1.2 g, 3.0 mmol) to the reaction system, and the reaction was continued at 50 °C for 2 hours. The reaction system was cooled to room temperature, extracted with DCM (20 mL × 3), the organic phases were combined, dried, and concentrated to obtain the crude product, which was then purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-15%) to obtain a pale yellow oily substance of the title compound 48-9 (456 mg, yield 36%). 1 H NMR (400MHz, DMSO-d6) δ7.55–7.46(m,1H),7.32–7.23(m,1H),7.13–7.06(m,1H),7.07–7.02(m,2H),6.98–6.86(m,2H),4.76–4 .62(q,J=8Hz,2H),2.96(d,J=5.1Hz,1H),2.81(d,J=5.1Hz,1H),2.29–2.20(m,1H),1.99(d,J=14.7Hz,1H),1.78–1.64(m,6H).

[0758] Preparation of compound 48

[0759] Compound 48-10 (70 mg, 0.17 mmol) was dissolved in DMF (2.5 mL), followed by the sequential addition of 1-H tetrazolium (60 mg, 0.85 mmol) and potassium carbonate (277 mg, 0.85 mmol). The reaction system was sealed at 80 °C and reacted for 16 hours. After cooling, the reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparation method: chromatographic column: Agilent 10 Prep-C18 250 x 21.2 mm; mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; column temperature: 25 °C; gradient: 60%-80% acetonitrile in 12 min; flow rate: 30 mL / min) to obtain title compound 48 (29.5 mg, yield 36%, containing one enantiomer) and the corresponding regioisomer compound 48-11 (11.7 mg, yield 14%, containing one enantiomer). Compound 48: LC-MS (ESI): m / z 481.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ9.09(s,1H),7.43–7.32(m,1H),7.28–7.19(m,1H),7.03–6.94(m,3H),6.93–6.86(m,2H),5.86(s,1H) ,4.79(d,J=14.2Hz,1H),4.72–4.63(m,3H),2.46–2.38(m,1H),1.96(d,J=14.8Hz,1H),1.71–1.61(m,3H),1.56–1.45(m,3H). 19 F NMR(376MHz, DMSO-d6)δ-72.59(s,3F),-108.56(m,2F),-111.88(m,2F).

[0760] Compound 48-11: LC-MS (ESI): m / z 481.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.79(s,1H),7.44–7.37(m,1H),7.25–7.18(m,1H),7.00–6.95(m,3H),6.91–6.86(m,2H),5.83(s,1 H),5.02–4.87(m,2H),4.72–4.63(m,2H),2.47–2.41(m,1H),2.04(d,J=14.8Hz,1H),1.68–1.62(m,3H),1.51–1.45(m,3H). 19 F NMR(376MHz, DMSO-d6)δ-72.60(s,3F),-108.82(d,2F),-112.19(d,2F).

[0761] Preparation of compounds 48A and 48B

[0762] Compound 48 (26 mg) was chirally separated by SFC (preparative separation method, instrument model: Thar80 preparative SFC (SFC-17); column model: ChiralCel OJ, 250×30mm ID, 10μm; mobile phase: A: CO2, B: ethanol (0.1% NH3H2O); elution gradient: B 20%; flow rate: 80 mL / min; column pressure: 100 bar; column temperature: 38℃; detection wavelength: 254 nm; cycle: ~7 min) to obtain title compounds 48A (7.9 mg) and 48B (7.9 mg).

[0763] Compound 48A: Chiral analysis method (Column: Chiralcel OJ-3 150×4.6mm ID, 3µm; Mobile phase: A: CO2, B: ethanol (0.05% DEA); Elution gradient: B 25%; Flow rate: 2.5mL / min; Column temperature: 35℃; Column pressure: 1500psi; Rt = 1.435min). LC-MS (ESI): m / z 481.2 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ8.56(s,1H),7.43–7.32(m,1H),6.96–6.88(m,2H),6.84–6.69(m,4H),4.69(d,J=3.2Hz,2H),4.22(q,J =8.0Hz,2H),2.76(s,1H),2.58(dd,J=15.2,2.2Hz,1H),1.86(d,J=12Hz,1H),1.71(d,J=9.6,1.7Hz,3H),1.57(d,J=9.6,1.7Hz,3H). 19 F NMR(376MHz, DMSO-d6)δ-74.00(s,3F),-108.80–-108.82(d,1F),-109.28–-109.30(d,1F).

[0764] Compound 48B: Chiral analysis method (Column: Chiralcel OJ-3 150×4.6mm ID, 3µm; Mobile phase: A: CO2, B: ethanol (0.05% DEA); Elution gradient: B 25%; Flow rate: 2.5mL / min; Column temperature: 35℃; Column pressure: 1500psi; Rt = 1.663min). LC-MS (ESI): m / z 481.2 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ8.55(s,1H),7.43–7.32(m,1H),6.96–6.89(m,2H),6.84–6.69(m,4H),4.69(d,J=2.8Hz,2H),4.22(q, J=8.1Hz,2H),2.74(br.s,1H),2.58(dd,J=15.2,2.3Hz,1H),1.86(d,J=12Hz,1H),1.71(d,J=9.6,1.7Hz,3H),1.58(d,J=1.6Hz,3H). 19F NMR(376MHz, DMSO-d6)δ-74.00(s,3F),-108.80–-108.82(d,1F),-109.28–-109.30(d,1F).

[0765] Example 49: Preparation of compounds 49, 49A and 49B

[0766]

[0767] Preparation of compound 49

[0768] 1,2,4-triazole (38 mg, 0.55 mmol) was dissolved in DMF (2 mL), and NaH (60%, 22 mg, 0.55 mmol) was added at 0 °C. After reacting for 30 minutes, compound 48-10 (45 mg, 0.11 mmol) was added to the reaction system, and the reaction system was sealed at 70 °C for 16 hours. After the reaction system cooled, the reaction solution was filtered, and the crude filtrate was purified by preparative separation (chromatographic column: Agilent 10 Prep-C18 250 x 21.2 mm; column temperature: 25 °C; mobile phase: water (0.1% FA)-acetonitrile; acetonitrile ratio 50%-70% in 12 min; flow rate 30 mL / min) to give title compound 49 (9.5 mg, yield 21%, containing a pair of enantiomers).

[0769] Compound 49: LC-MS (ESI): m / z 480.2 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ8.28(s,1H),7.78(s,1H),7.49–7.41(m,1H),7.23–7.14(m,1H),7.03–6.95(m,3H),6.91–6.86(m,2H),5. 65(s,1H),4.67(q,J=8Hz,2H),4.45(d,J=3.4Hz,2H),2.38(m,1H),1.89(d,J=14.8Hz,1H),1.67–1.62(m,3H),1.51–1.45(m,3H). 19 F NMR (376MHz, DMSO-d6) δ -72.60 (s, 3F), -108.50 (d, J = 7.5Hz, 2F), -112.48 (d, J = 7.5Hz, 2F).

[0770] Preparation of compounds 49A and 49B

[0771] Compound 49 (90 mg) was chirally separated by SFC (preparative separation method, instrument model: MGⅡpreparative SFC (SFC-14); column model: ChiralPak IC, 250×30 mm ID 10 μm; mobile phase: A: CO2 B: ethanol; elution gradient: B 15%; flow rate: 60 mL / min; column pressure: 100 bar; column temperature: 38 ℃; detection wavelength: 220 nm; cycle: ~16 min) to obtain title compounds 49A (48 mg) and 49B (22 mg).

[0772] Compound 49A: LC-MS (ESI): m / z 480.6 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.29(s,1H),7.78(s,1H),7.59-7.39(m,1H),7.30-7.11(m,1H),7.11-6.78(m,5H),5.66(s,1H),4. 67(q,J=8.9Hz,2H),4.55-4.35(m,2H),2.43-2.30(m,1H),1.94-1.79(m,1H),1.65(d,J=9.6Hz,3H),1.48(d,J=9.6Hz,3H). 19 F NMR(376MHz, DMSO-d6)δ-72.59(s,3F),-108.50(d,1F),-112.47(d,1F).

[0773] Compound 49B: LC-MS (ESI): m / z 480.6 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.29(s,1H),7.78(s,1H),7.59-7.39(m,1H),7.30-7.11(m,1H),7.11-6.78(m,5H),5.66(s,1H),4. 67(q,J=8.9Hz,2H),4.55-4.35(m,2H),2.43-2.30(m,1H),1.94-1.79(m,1H),1.65(d,J=9.6Hz,3H),1.48(d,J=9.6Hz,3H). 19 F NMR(376MHz, DMSO-d6)δ-72.59(s,3F),-108.50(d,1F),-112.47(d,1F).

[0774] Example 50: Preparation of compounds 50, 50A and 50B

[0775]

[0776] Preparation of compound 50-2

[0777] Compound 50-1 (400 mg, 3.57 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (433 mg, 4.28 mmol) was added dropwise at 0 °C. After reacting for 10 minutes, p-toluenesulfonyl chloride (816 mg, 4.28 mmol) was added, and the reaction was carried out at room temperature for 24 hours. The reaction was monitored by TLC until complete, and the reaction system was extracted with DCM (20 mL × 3). The organic phases were combined, dried, and concentrated to give 1 g of crude product, which was filtered through silica gel to give the title compound 50-2 (300 mg, yield 31%). 1 H NMR (400MHz, Chloroform-d) δ7.84–7.79(m,2H),7.41–7.36(m,2H),4.27(t,J=12.4Hz,2H),3.85(t,J=12.4Hz,2H),2.47(s,3H),2.08(br,1H).

[0778] Preparation of Compound 50

[0779] Compound 20 (80 mg, 0.184 mmol) was dissolved in DMF (2 mL), and cesium carbonate (120 mg, 0.386 mmol) was added with stirring. After reacting for 5 minutes, compound 50-2 (73 mg, 0.276 mmol) was added, and the reaction was stirred at 50 °C for 24 hours. The reaction solution was filtered, and the filtrate was concentrated to obtain the crude product. The crude product was then purified by preparative separation (preparation method: column: Agilent 10 Prep-C18 250 x 21.2 mm; column temperature: 25 °C; mobile phase: water (0.1% FA) - acetonitrile; acetonitrile ratio 45%-65% in 12 min; flow rate 30 mL / min) to obtain title compound 50 (6 mg, yield: 6%, containing a pair of enantiomers).

[0780] Compound 50: LC-MS (ESI): m / z 529.2 [M+H] + . 1H NMR(400MHz, DMSO-d6)δ9.13(s,1H),7.57–7.51(m,1H),7.31–7.25(m,1H),7.16(s,1H),7.09–6.97(m,3H),6.93–6.87(m,2H),5.65(t,J=6.2Hz, 1H),5.43(d,J=14.5Hz,1H),5.01(d,J=14.6Hz,1H),4.25(t,J=13.8Hz, 2H),3.72(td,J=13.8,6.2Hz,2H),2.00–1.97(m,3H),1.78–1.76(m,3H). 19 F NMR (376MHz, DMSO-d6) δ-102.95–-103.17(m,1F),-109.21–-109.32(m,2F),-109.62(d,J=9.6Hz,1F),-114.06(s,1F).

[0781] Preparation of compounds 50A and 50B

[0782] Compound 50 (160 mg) was chirally separated by SFC (preparative separation method, instrument model: MGⅡpreparative SFC (SFC-1); column model: Cellulose-2, 250×30mm ID, 10μm; mobile phase: A:CO2, B:ethanol; elution gradient: B 40%; flow rate: 70mL / min; column pressure: 100bar; column temperature: 35℃; detection wavelength: 220nm; cycle: ~8min) to obtain title compounds 50A (37 mg) and 50B (68 mg).

[0783] Compound 50A: Chiral analysis method (Column type: Cellulose-2 150×4.6mm ID, 3µm; Mobile phase: A: CO2, B: Methanol (0.05% DEA); Elution gradient: 5% B to 40% B within 5 minutes, maintain 40% B for 2.5 minutes, then equilibrate with 5% B for 2.5 minutes; Flow rate: 2.5 mL / min; Column temperature: 35℃; Column pressure: 1500 psi; Detection wavelength: 220 nm; RT = 1.817 min). LC-MS (ESI): m / z 529.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ9.13(s,1H),7.57-7.51(m,1H),7.31-7.25(m,1H),7.14(s,1H),7.07-6.98(m,3H),6.92-6.88(m,2H),5.63(t,J=6.2Hz ,1H),5.43(d,J=14.6Hz,1H),5.01(d,J=14.6Hz,1H),4.25(t,J=13.8Hz ,2H),3.72(td,J=13.8,6.2Hz,2H),2.0-1.97(m,3H),1.78-1.76(m,3H). 19 F NMR(376MHz,Chloroform-d)δ-102.95–-103.16(m,1F),-109.20–-109.30(m,2F),-109.63(d,J=9.7Hz,1F),-114.05(s,2F).

[0784] Compound 50B: Chiral analysis method (Column type: Cellulose-2 150×4.6mm ID, 3µm; Mobile phase: A: CO2, B: Methanol (0.05% DEA); Elution gradient: 5% B to 40% B within 5 minutes, maintain 40% B for 2.5 minutes, then equilibrate with 5% B for 2.5 minutes; Flow rate: 2.5 mL / min; Column temperature: 35℃; Column pressure: 1500 psi; Detection wavelength: 220 nm; RT = 1.342 min). LC-MS (ESI): m / z 529.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.13(s,1H),7.55-7.51(m,1H),7.31-7.25(m,1H),7.14(s,1H),7.09-6.97(m,3H),6.93-6.87(m,2H),5.63(t,J=6.2Hz, 1H),5.43(d,J=14.6Hz,1H),5.01(d,J=14.6Hz,1H),4.25(t,J=13.8Hz, 2H),3.72(td,J=13.8,6.2Hz,2H),2.00-1.97(m,3H),1.78-1.76(m,3H). 19 F NMR(376MHz,Chloroform-d)δ-102.95–-103.16(m,1F),-109.20–-109.30(m,2F),-109.63(d,J=9.7Hz,1F),-114.05(s,2F).

[0785] Example 51: Preparation of compounds 51, 51A, 51B, 51C and 51D

[0786]

[0787] Preparation of compound 51

[0788] Compound 20 (80 mg, 0.18 mmol) was dissolved in acetonitrile (5 mL), and potassium carbonate (51 mg, 0.37 mmol) was added with stirring. After reacting for 5 minutes, compound 1,1,1-trifluoro-2,3-epoxypropane (31 mg, 0.28 mmol) was added, and the reaction was stirred at 50 °C for 16 hours. The reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparation method: column: Agilent 10Prep-C18 250 x 21.2 mm; column temperature: 25 °C; mobile phase: water (0.1% TFA)-acetonitrile; acetonitrile ratio 50%-70% in 12 min; flow rate 30 mL / min) to obtain title compound 51 (62 mg, yield: 62%, containing two pairs of enantiomers).

[0789] Compound 51: LC-MS (ESI): m / z 547.2 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ9.13(s,1H),7.54(td,J=9.0,6.7Hz,1H),7.28(ddd,J=12.0 ,9.0,2.6Hz,1H),7.15(s,1H),7.09–6.96(m,3H),6.92–6.82(m,2H),6.63(d,J=6.6H z,1H),5.42(d,J=14.5Hz,1H),5.01(d,J=14.5Hz,1H),4.35(dt,J=11.3,6.8Hz,1H) ,4.12(m,1H),4.01(m,1H),1.98(dd,J=9.4,1.7Hz,3H),1.76(dd,J=9.4,1.7Hz,3H). 19 F NMR(376MHz, DMSO-d6)δ-76.06(s,3F),-102.96–-103.17(m,1F),-109.22–-109.32(m,2F),-109.63(d,J=9.2Hz,1F).

[0790] Preparation of compounds 51A, 51B, 51C and 51D

[0791] Compound 51 (62 mg) was chirally separated by SFC (preparative separation method, instrument model: MGⅡpreparative SFC (SFC-14); column model: ChiralPak AD, 250×30mm ID, 5μm; mobile phase: A:CO2, B:isopropanol; elution gradient: B 20%; flow rate: 70mL / min; column pressure: 100bar; column temperature: 38℃; detection wavelength: 220nm; cycle: ~4min) to obtain title compounds 51A (11 mg), 51B (10 mg), 51C (12 mg) and 51D (9 mg).

[0792] Compound 51A: LC-MS (ESI): 547.2 [M+H] + Chiral analysis method (Column type: ChiralPakAD-3, 150×4.6mm ID, 3μm; Mobile phase: A: CO2, B: isopropanol (0.05% DEA); Elution gradient: 5% B to 40% B in the mobile phase over 5 minutes, then maintain 40% B for 2.5 minutes, followed by equilibration with 5% B for 2.5 minutes; Flow rate: 2.5 mL / min; Column temperature: 35℃; Column pressure: 100 bar; Detection wavelength: 220 nm; RT = 4.257 min). 1 H NMR(400MHz, DMSO-d6)δ9.13(s,1H),7.54(td,J=9.0,6.6Hz,1H),7.36–7.19(m,1H),7.15 (s,1H),7.06–7.03(m,2H),7.03–6.98(m,1H),6.93–6.79(m,2H),6.63(d,J=6.6Hz,1H),5. 42(d,J=14.6Hz,1H),5.01(d,J=14.6Hz,1H),4.44–4.25(m,1H),4.11(dd,J=10.6,4.2Hz,1 H), 4.01 (dd, J=10.6, 6.4Hz, 1H), 1.98 (dd, J=9.4, 1.6Hz, 3H), 1.76 (dd, J=9.4, 1.6Hz, 3H). 19 F NMR(376MHz, DMSO-d6)δ-76.06(s,3F),-102.96–-103.17(m,1F),-109.22–-109.32(m,2F),-109.64(d,J=9.6Hz,1F).

[0793] Compound 51B: LC-MS (ESI): 547.2 [M+H] +Chiral analysis method (Column type: ChiralPakAD-3, 150×4.6mm ID, 3μm; Mobile phase: A: CO2, B: isopropanol (0.05% DEA); Elution gradient: elution from 5% B to 40% B over 5 minutes and maintaining 40% B for 2.5 minutes, followed by equilibration with 5% B for 2.5 minutes; Flow rate: 2.5 mL / min; Column temperature: 35℃; Column pressure: 100 bar; Detection wavelength: 220 nm; RT = 3.764 min). 1 H NMR(400MHz,DMSO-d6)δ9.13(s,1H),7.60–7.48(m,1H),7.33–7.22(m,1H),7.14(s ,1H),7.06–7.03(m,2H),7.01–6.98(m,1H),6.91–6.81(m,2H),6.62(d,J=6.6Hz,1 H),5.42(d,J=14.6Hz,1H),5.01(d,J=14.6Hz,1H),4.42–4.25(m,1H),4.13–4.09( m,1H),4.03–3.99(m,1H),1.98(dd,J=9.4,1.6Hz,3H),1.77(dd,J=9.4,1.6Hz,3H). 19 F NMR(376MHz, DMSO-d6)δ-76.06(s,3F),-102.95–-103.16(m,1F),-109.19–-109.29(m,2F),-109.64(d,J=9.6Hz,1F).

[0794] Compound 51C: LC-MS (ESI): 547.2 [M+H] + Chiral analysis method (Column type: ChiralPakAD-3, 150×4.6mm ID, 3μm; Mobile phase: A: CO2, B: isopropanol (0.05% DEA); Elution gradient: elution of 5% B to 40% B over 5 minutes and maintaining 40% B for 2.5 minutes, followed by equilibration with 5% B for 2.5 minutes; Flow rate: 2.5 mL / min; Column temperature: 35℃; Column pressure: 100 bar; Detection wavelength: 220 nm; RT = 4.090 min). 1H NMR(400MHz,DMSO-d6)δ9.13(s,1H),7.59–7.49(m,1H),7.33–7.22(m,1H),7.14(s ,1H),7.06–7.03(m,2H),7.02–6.98(m,1H),6.90–6.82(m,2H),6.62(d,J=6.4Hz,1 H),5.42(d,J=14.6Hz,1H),5.01(d,J=14.6Hz,1H),4.42–4.25(m,1H),4.33–4.09( m,1H),4.03–3.99(m,1H),1.98(dd,J=9.5,1.6Hz,3H),1.77(dd,J=9.5,1.6Hz,3H). 19 F NMR(376MHz, DMSO-d6)δ-76.06(s,3F),-102.95–-103.16(m,1F),-109.19–-109.29(m,2F),-109.64(d,J=9.6Hz,1F).

[0795] Compound 51D: LC-MS (ESI): 547.2 [M+H] + Chiral analysis method (Column type: ChiralPakAD-3, 150×4.6mm ID, 3μm; Mobile phase: A: CO2, B: isopropanol (0.05% DEA); Elution gradient: 5% B to 40% B in the mobile phase over 5 minutes, then maintain 40% B for 2.5 minutes, followed by equilibration with 5% B for 2.5 minutes; Flow rate: 2.5 mL / min; Column temperature: 35℃; Column pressure: 100 bar; Detection wavelength: 220 nm; RT = 3.761 min). 1 H NMR(400MHz,DMSO-d6)δ9.13(s,1H),7.59–7.48(m,1H),7.33–7.23(m,1H),7.13(s ,1H),7.08–7.03(m,2H),7.01–6.96(m,1H),6.91–6.82(m,2H),6.61(d,J=6.6Hz,1 H),5.42(d,J=14.6Hz,1H),5.01(d,J=14.6Hz,1H),4.41–4.27(m,1H),4.13–4.09( m,1H),4.03–3.99(m,1H),1.98(dd,J=9.4,1.6Hz,3H),1.77(dd,J=9.4,1.6Hz,3H). 19F NMR(376MHz, DMSO-d6)δ-76.06(s,3F),-103.04–-103.16(m,1F),-109.19–-109.29(m,2F),-109.64(d,J=9.6Hz,1F).

[0796]

[0797] Preparation of compound 51E

[0798] Compound 20 (0.2 g, 0.46 mmol) was dissolved in acetonitrile (2 mL), and potassium carbonate (0.127 g, 0.922 mmol) was added with stirring. After reacting for 5 minutes, compound R-(+)-2-trifluoromethyl ethylene oxide (CAS No.: 143142-90-9, 67 mg, 0.6 mmol) was added, and the reaction was stirred at 50 °C for 16 hours. The reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparation method: column: Agilent 10 Prep-C18 250 x 21.2 mm; column temperature: 25 °C; mobile phase: water (0.1% TFA)-acetonitrile; acetonitrile ratio 55%-75% in 12 min; flow rate 30 mL / min) to obtain the title compound 51E (0.14 g, yield: 56%, containing a pair of diastereomers).

[0799] Compound 51E: LC-MS (ESI): m / z 547.2 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ9.13(s,1H),7.54(td,J=9.0,6.6Hz,1H),7.33–7.22(m,1H),7.14 (s,1H),7.06–7.03(m,2H),7.03–6.98(m,1H),6.91–6.82(m,2H),6.62(d,J=6.6Hz,1H),5. 42(d,J=14.6Hz,1H),5.01(d,J=14.6Hz,1H),4.43–4.25(m,1H),4.11(dd,J=10.6,4.2Hz,1 H), 4.01 (dd, J=10.6, 6.4Hz, 1H), 1.98 (dd, J=9.4, 1.6Hz, 3H), 1.77 (dd, J=9.4, 1.6Hz, 3H). 19 F NMR(376MHz, DMSO-d6)δ-76.06(s,3F),-102.95–-103.16(m,1F),-109.19–-109.29(m,2F),-109.64(d,J=9.6Hz,1F).

[0800] Preparation of compounds 51A and 51C

[0801] Compound 51E (0.14 g) was chirally separated by SFC (preparative separation method, instrument model: MGⅡpreparative SFC (SFC-14); column model: ChiralPak IC, 250×30 mm ID 10 μm; mobile phase: A: CO2 B: ethanol (0.1% NH3H2O); elution gradient: B 20%; flow rate: 60 mL / min; column pressure: 100 bar; column temperature: 38 ℃; detection wavelength: 220 nm; cycle: ~11 min) to obtain title compounds 51A (60 mg) and 51C (57 mg).

[0802]

[0803] Preparation of compound 51F

[0804] Compound 20 (0.2 g, 0.46 mmol) was dissolved in acetonitrile (2 mL), and potassium carbonate (0.127 g, 0.922 mmol) was added with stirring. After reacting for 5 minutes, compound (S)-(-)-3,3,3-trifluoro-1,2-epoxypropane (CAS No.: 130025-34-2, 67 mg, 0.6 mmol) was added, and the reaction was stirred at 50 °C for 16 hours. The reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparation method: column: Agilent 10 Prep-C18 250 x 21.2 mm; column temperature: 25 °C; mobile phase: water (0.1% TFA)-acetonitrile; acetonitrile ratio 55%-75% in 12 min; flow rate 30 mL / min) to obtain the title compound 51F (0.13 g, yield: 52%, containing a pair of diastereomers). LC-MS(ESI): m / z 547.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ9.13(s,1H),7.61–7.47(m,1H),7.35–7.23(m,1H),7.15(s ,1H),7.06–7.03(m,2H),7.03–6.98(m,1H),6.92–6.79(m,2H),6.62(d,J=6.8Hz,1 H),5.42(d,J=14.6Hz,1H),5.01(d,J=14.6Hz,1H),4.43–4.24(m,1H),4.19–4.11( m,1H),4.09–3.92(m,1H),1.98(dd,J=9.4,1.6Hz,3H),1.77(dd,J=9.4,1.6Hz,3H). 19 F NMR(376MHz, DMSO-d6)δ-76.06(s,3F),-102.95–-103.16(m,1F),-109.19–-109.29(m,2F),-109.64(d,J=9.6Hz,1F).

[0805] Preparation of compounds 51B and 51D

[0806] Compound 51F (0.13 g) was chirally separated by SFC (preparative separation method, instrument model: MGⅡpreparative SFC (SFC-14); column model: ChiralPak IC, 250×30 mm ID 10 μm; mobile phase: A: CO2 B: ethanol (0.1% NH3H2O); elution gradient: B 20%; flow rate: 60 mL / min; column pressure: 100 bar; column temperature: 38 ℃; detection wavelength: 220 nm; cycle: ~11 min) to obtain the title compounds 51B (47 mg) and 51D (48 mg).

[0807]

[0808] Preparation of compound 51A-P1-1

[0809] Compound 51A (1 g, 1.83 mmol) was dissolved in DMF (10 mL), and sodium hydride (81 mg, 2.01 mmol) was added with stirring at 0 °C. After reacting for 15 minutes, benzyl bromide (342 mg, 2.01 mmol) was added, and the reaction was continued at room temperature for 12 hours. The reaction solution was poured into ice water and extracted with EtOAc (20 mL × 3). The organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was purified by normal-phase silica gel column chromatography (EtOAc / PE = 0-30%) to obtain the title compound 51A-P1-1 (760 mg, yield 65%). LC-MS (ESI): m / z 637.2 [M+H]+ .

[0810] Preparation of compound 51A-P1-3

[0811] Compound 51A-P1-1 (320 mg, 0.50 mmol) was dissolved in DMF (8 mL), and cesium carbonate (492 mg, 1.51 mmol) was added with stirring. After reacting for 15 minutes, compound 51A-P1-2 (329 mg, 1.0 mmol) was added, and the reaction was stirred at 50 °C for 12 hours. The reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparation method: column: Agilent 10 Prep-C18 250 x 21.2 mm; column temperature: 25 °C; mobile phase: water (10 mM / L NH4HCO3)-acetonitrile; acetonitrile ratio 60%-90% in 9 min; flow rate 30 mL / min) to obtain the title compound 51A-P1-3 (220 mg, yield 47%). LC-MS (ESI): m / z 927.2 [M+H) + .

[0812] Preparation of compound 51A-P1

[0813] Compound 51A-P1-3 (220 mg, 0.24 mmol) was dissolved in methanol (10 mL), and 10% wet palladium on carbon (22 mg) was added. The mixture was purged three times with nitrogen and twice with hydrogen, and reacted at room temperature for 16 hours. The reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparation method: column: Agilent 10 Prep-C18 250 x 21.2 mm; column temperature: 25 °C; mobile phase: water (10 mM / L NH4HCO3)-acetonitrile; acetonitrile ratio 25%-45% in 12 min; flow rate 30 mL / min) to obtain the title compound 51A-P1 (65 mg, yield: 42%). LC-MS (ESI): m / z 657.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6+D2O (one drop)) δ9.81 (s, 1H), 7.94–7.67 (m, 1H), 7.20 (ddd, J = 12.0, 9.0, 2.6Hz, 1H), 7.10–6.98 (m, 3H), 6.91– 6.83(m,2H),5.73–5.26(m,4H),4.45–4.24(m,1H),4.17–3.95(m,2H),1.97(dd,J=9.4,1.6Hz,3H),1.85(dd,J=9.4,1.6Hz,3H).

[0814]

[0815] Preparation of compound 51A-P2-1

[0816] Compound 51A-P1-1 (300 mg, 0.47 mmol) was added to a sealed tube. Under nitrogen protection, NaH (135 mg, 3.39 mmol) and THF (3 mL) were added at 0 °C. After reacting for 30 minutes, phosphorus oxychloride (0.5 mL) was slowly added, and the reaction was carried out at room temperature for 16 hours. Saturated sodium bicarbonate solution was added dropwise to the reaction solution until the reaction solution became weakly alkaline, and the reaction was carried out at 50 °C for 16 hours. After the reaction system cooled, the reaction solution was filtered. The crude filtrate was purified by preparative separation (chromatographic column: Agilent 10 Prep-C18 250 x 21.2 mm; column temperature: 25 °C; mobile phase: water (0.1% TFA)-acetonitrile; acetonitrile ratio 55%-80% in 12 min; flow rate 30 mL / min) to obtain the title compound 51A-P2-1 (200 mg, yield: 59%). LC-MS (ESI): 717.20 [M+H] + .

[0817] Preparation of compound 51A-P2

[0818] Compound 51A-P2-1 (200 mg, 0.28 mmol) was dissolved in methanol (10 mL), and 10% wet palladium on carbon (20 mg) was added. The mixture was purged three times with nitrogen and twice with hydrogen, and reacted at room temperature for 16 hours. The reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparation method: column: Agilent 10 Prep-C18 250 x 21.2 mm; column temperature: 25 °C; mobile phase: water (10 mM / L NH4HCO3)-acetonitrile; acetonitrile ratio 25%-45% in 12 min; flow rate 30 mL / min) to give the title compound 51A-P2 (82 mg, yield: 46%). LC-MS (ESI): m / z 627.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ10.26(s,1H),8.16–8.04(m,1H),7.20–7.08(m,1H),7.09–7 .01(m,1H),7.05–6.95(m,2H),6.90–6.82(m,2H),6.72–6.50(m,3H),6.17(d,J=14.4 Hz,1H),5.54(d,J=14.4Hz,1H),4.45–4.23(m,1H),4.11(dd,J=10.5,4.2Hz,1H),4. 00(dd,J=10.5,4.2Hz,1H),1.92(dd,J=9.5,1.7Hz,3H),1.76(dd,J=9.5,1.7Hz,3H). 19 F NMR(376MHz)δ-76.07(s,3F),-101.37–-101.99(m,1F),-107.82–-109.04(m,2F),-109.70–-111.38(m,1F).

[0819] Example 52: Preparation of compound 52

[0820]

[0821] Preparation of compound 52-1

[0822] Compound 20 (200 mg, 0.46 mmol) was added to a sealed tube, followed by (S)-(+)-epoxychloropropane (CAS: 67843-74-7, 64 mg, 0.69 mmol), Cs₂CO₃ (225 mg, 0.69 mmol), and DMF (1 mL). The reaction mixture was reacted at 50 °C for 16 hours. After cooling, the mixture was evaporated to dryness to obtain the crude title compound 52-1 (200 mg, 89% yield). LC-MS (ESI): m / z 491.00 [M+H] + .

[0823] Preparation of compound 52

[0824] The crude compound 52-1 (200 mg, 0.41 mmol) was added to a sealing tube, followed by 1.5 mL of ammonia-methanol solution (7.0 M). The reaction was carried out at 50 °C for 16 hours. After the reaction system cooled, the reaction solution was filtered, and the crude filtrate was purified by preparative separation (chromatographic column: Agilent 10 Prep-C18 250 x 21.2 mm; column temperature: 25 °C; mobile phase: water (0.1% FA)-acetonitrile; acetonitrile ratio 35%-55% in 12 min; flow rate 30 mL / min) to obtain the title compound 52 (160 mg, yield 77%).

[0825] Compound 52: LC-MS (ESI): m / z 508.00 [M+H]+. 1 H NMR(400MHz,DMSO-d6)δ9.14(t,J=1.9Hz,1H),7.60–7.47(m,1H),7.35–7.24(m ,1H),7.16(br.s,1H),7.08–6.93(m,3H),6.88–6.76(m,2H),6.67(br.s,1H),5. 42(d,J=14.6Hz,1H),5.01(d,J=14.6Hz,1H),3.93–3.71(m,3H),2.90–2.61(m,2 H),1.97(dd,J=9.5,1.7Hz,3H),1.75(dd,J=9.5,1.6Hz,3H),1.34–1.16(m,2H). 19 F NMR (376MHz, DMSO-d6) δ-102.66–-103.37(m,1F),-108.96–-109.47(m,2F),-109.65(d,J=9.5Hz,1F).

[0826] Example 53: Preparation of compound 53

[0827]

[0828] Preparation of compound 53

[0829] Compound 52-1 (112 mg, 0.23 mmol) was placed in a microwave tube, DMF (5.0 mL) was added, and excess isopropylamine (0.5 mL) was added dropwise. The mixture was reacted in a microwave oven at 100 °C for 2 hours. The reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparation method: chromatographic column: Agilent 10 Prep-C18 250 x 21.2 mm; column temperature: 25 °C; mobile phase: water (0.1% FA)-acetonitrile; acetonitrile ratio 15%-35% in 12 min; flow rate 30 mL / min) to obtain title compound 53 (35 mg, overall yield: 28%, containing a pair of diastereomers).

[0830] Compound 53: LC-MS (ESI): m / z 550.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.16(s,1H),8.31(s,1H),7.54 (td,J=9.0,6.7Hz,1H),7.28(ddd,J=12.0,9.1,2.6Hz,2H),7.07–6.96(m,3H),6.87–6.78(m,2H),5.42(d,J=14.5Hz,1H),5.02(d,J=14.5Hz,1 H),4.01–3.79(m,4H),2.93(m,1H),2.81(m,1H),2.69(m,1H),1.97(dd,J=9.4,1.7Hz,3H),1.75(dd,J=9.4,1.7Hz,3H),1.05(d,J=6.3Hz,6H). 19 F NMR (376MHz, DMSO-d6) δ-102.93–-103.14(m,1F),-109.20–-109.30(m,2F),-109.68(d,J=9.2Hz,1F).

[0831] Example 54: Preparation of compound 54

[0832]

[0833] Preparation of compound 54-1

[0834] Compound 20 (100 mg, 0.23 mmol) was dissolved in DMF (5 mL), and cesium carbonate (150 mg, 0.46 mmol) was added with stirring. After reacting for 5 minutes, compound (R)-(-)-epoxychloropropane (CAS: 51594-55-9, 43 mg, 0.46 mmol) was added, and the reaction was stirred at 50 °C for 2 hours. The reaction was monitored by LC-MS until complete, and the reaction solution was filtered. The crude filtrate was used directly as the starting material for the next reaction. LC-MS (ESI): m / z 491.2 [M+H] + .

[0835] Preparation of compound 54

[0836] The filtrate from the previous step was placed in a microwave tube, and excess isopropylamine (0.5 mL) was added dropwise. The mixture was reacted in a microwave oven at 100°C for 2 hours. The reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparation method: chromatographic column: Agilent 10 Prep-C18 250x21.2 mm; column temperature: 25°C; mobile phase: water (0.1% FA)-acetonitrile; acetonitrile ratio in the mobile phase 15%-35% in 12 min; flow rate 30 mL / min) to obtain the title compound 54 (22 mg, overall yield: 17%, containing a pair of diastereomers).

[0837] Compound 54: LC-MS (ESI): m / z 550.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.17(s,1H),8.31(s,1H),7.54(td,J=9.0,6.7Hz,1H),7.28( ddd,J=12.0,9.1,2.7Hz,2H),7.10–6.95(m,3H),6.88–6.76(m,2H),5.42(d,J=14.5H z,1H),5.02(d,J=14.5Hz,1H),4.04–3.76(m,4H),2.93(m,1H),2.83(m,1H),2.70(m, 1H), 1.97 (dd, J=9.4, 1.7Hz, 3H), 1.76 (dd, J=9.4, 1.6Hz, 3H), 1.07 (d, J=6.3Hz, 6H). 19 F NMR (376MHz, DMSO-d6) δ-102.92–-103.14(m,1F),-109.19–-109.29(m,2F),-109.68(d,J=9.2Hz,1F).

[0838] Example 55: Preparation of compound 55

[0839]

[0840] Preparation of compound 55

[0841] Compound 54-1 (200 mg, 0.41 mmol) was added to a sealing tube, followed by 0.3 mL of 1.0 M NaOH and 1 mL of DMF. The reaction was carried out at 50 °C for 16 hours. After cooling, the reaction mixture was filtered, and the crude product from the filtrate was purified by preparative separation (chromatographic column: Welch). C1821.2x250mm; column temperature: 25℃; mobile phase: water (10mM / L NH4HCO3)-acetonitrile; acetonitrile content in the mobile phase 35%-55% in 12min; flow rate 30mL / min), yielding the title compound 55 (130mg, yield 53%).

[0842] Compound 55: LC-MS (ESI): m / z 536.00 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.13(s,1H),7.59–7.48(m,1H),7.33–7.23(m,1H),7.1 6(s,1H),7.07–6.95(m,3H),6.85–6.77(m,2H),5.42(d,J=14.6Hz,1H),5.01(d ,J=14.6Hz,1H),5.00(br.s,1H),3.97–3.85(m,2H),3.83–3.74(m,1H),2.26(s ,6H),1.97(dd,J=9.5,1.7Hz,3H),1.75(dd,J=9.4,1.7Hz,3H),1.23(br.s,2H). 19 F NMR (376MHz, DMSO-d6) δ-102.81–-103.33(m,1F),-109.25(d,J=37.6Hz,2F),-109.63(d,J=9.4Hz,1F).

[0843] Example 56: Preparation of Compound 56

[0844]

[0845] Preparation of compound 56

[0846] Compound 52-1 (200 mg, 0.41 mmol) was added to a sealing tube, followed by 0.3 mL of 1.0 M NaOH aqueous solution and 1.0 mL of DMF. The reaction was carried out at 50 °C for 16 hours. After the reaction system cooled, the reaction solution was filtered, and the crude product of the filtrate was purified by preparative separation (chromatographic column: Welch). C18 21.2x250mm; column temperature: 25℃; mobile phase: water (10mM / LNH4HCO3)-acetonitrile; acetonitrile content in the mobile phase 35%-55% in 12min; flow rate 30mL / min), to obtain the title compound (130mg, yield 53%).

[0847] Compound 56: LC-MS (ESI): m / z 536.0 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ9.14(d,J=1.5Hz,1H),7.60–7.48(m,1H),7.34–7.22(m ,1H),7.15(s,1H),7.07–6.96(m,3H),6.86–6.78(m,2H),5.42(d,J=14.5Hz,1H ),5.12(br.s,1H),5.01(d,J=14.6Hz,1H),4.01–3.76(m,3H),2.33(d,J=6.2Hz ,6H),1.97(dd,J=9.5,1.7Hz,3H),1.75(dd,J=9.4,1.7Hz,3H),1.23(br.s,2H). 19 F NMR(376MHz, DMSO-d6)δ-102.62–-103.43(m),-108.96–-109.46(m),-109.65(d,J=9.6Hz).

[0848] Example 57: Preparation of Compound 57

[0849]

[0850] Preparation of compound 57-1

[0851] Compound 20 (200 mg, 0.46 mmol) was added to a sealed tube, followed by epichlorohydrin (CAS: 106-89-8, 64 mg, 0.69 mmol), CS₂CO₃ (225 mg, 0.69 mmol), and DMF (1 mL). The reaction mixture was reacted at 50 °C for 16 hours. After cooling, the mixture was evaporated to dryness to give the title compound 57-1 (200 mg, 89% yield). LC-MS (ESI): m / z 491.00 [M+H] + .

[0852] Preparation of compound 57

[0853] Compound 57-1 (200 mg, 0.41 mmol) was added to a sealing tube, followed by morpholine (0.3 mL) and ethanol (1 mL). The reaction was carried out at 80 °C for 16 hours. After the reaction system cooled, the reaction solution was filtered. The crude filtrate was purified by preparative separation (chromatographic column: Agilent 10 Prep-C18 250 x 21.2 mm; column temperature: 25 °C; mobile phase: water (0.1% FA)-acetonitrile; acetonitrile ratio 35%-55% in 12 min; flow rate 30 mL / min), yielding the title compound 57 (147 mg, 60% yield, containing two pairs of enantiomers).

[0854] Compound 57: LC-MS (ESI): m / z 578.20 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.23–9.12(m,1H),7.60–7.48(m,1H),7.38–7.11(m,2 H),7.07–6.95(m,3H),6.86–6.77(m,2H),5.42(d,J=14.4Hz,1H),5.03(d,J=1 4.4Hz,1H),4.88(br.s,1H),4.00–3.83(m,3H),3.83–3.72(m,2H),3.60(m,4H ),2.48–2.22(m,4H),1.97(dd,J=9.3,1.7Hz,3H),1.75(dd,J=9.4,1.7Hz,3H). 19 F NMR (376MHz, DMSO-d6) δ-102.94–-103.15(m,1F),-109.20–-109.30(m,2F),-109.69(d,J=9.4Hz,1F).

[0855] Example 58: Preparation of Compound 58

[0856]

[0857] Preparation of compound 58

[0858] Compound 52-1 (200 mg, 0.41 mmol) was added to a sealing tube, followed by morpholine (0.3 mL) and ethanol (1 mL). The reaction was carried out at 80 °C for 16 hours. After cooling, the reaction solution was filtered, and the crude product from the filtrate was purified by preparative separation (chromatographic column: Welch). C1821.2x250mm; column temperature: 25℃; mobile phase: water (10mM / L NH4HCO3)-acetonitrile; acetonitrile content in the mobile phase 35%-55% in 12min; flow rate 30mL / min), yielded the title compound 58 (147mg, yield 60%).

[0859] Compound 58: LC-MS (ESI): m / z 578.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.14(s,1H),7.60–7.47(m,1H),7.35–7.22(m,1H),7.1 5(s,1H),7.08–6.96(m,3H),6.90–6.73(m,2H),5.42(d,J=14.5Hz,1H),5.01(d, J=14.5Hz,1H),4.86(br.s,1H),4.14–3.78(m,4H),3.61(m,5H),2.76–2.56(m,2 H),2.43–2.25(m,2H),1.97(dd,J=9.5,1.7Hz,3H),1.76(dd,J=9.5,1.7Hz,3H). 19 F NMR(376MHz, DMSO-d6)δ-102.95–-103.16(m,1F),-109.20–-109.30(m,2F),-109.63–-109.66(m,1F).

[0860] Example 59: Preparation of compound 59

[0861]

[0862] Preparation of compound 59

[0863] Compound 54-1 (200 mg, 0.41 mmol) was added to a sealed tube, followed by 1.5 mL of ammonia-methanol solution (7.0 M). The reaction mixture was incubated at 50 °C for 16 hours. After cooling, the reaction mixture was filtered, extracted, and evaporated to dryness to obtain crude compound 59-1. The crude compound 59-1 was transferred directly to a sealed tube without purification. Potassium carbonate (54 mg, 0.40 mmol), CDI (32 mg, 0.40 mmol), and THF (1.5 mL) were added to the sealed tube, and the reaction mixture was incubated at 70 °C for 16 hours. After the reaction system cooled, the reaction solution was filtered, and the crude filtrate was purified by preparative separation (chromatographic column: Agilent 10 Prep-C18 250x21.2mm; column temperature: 25℃; mobile phase: water (0.1% FA)-acetonitrile; acetonitrile ratio in the mobile phase 35%-55% in 12min; flow rate 30mL / min), to obtain the title compound 59 (40mg, yield 38%).

[0864] Compound 59: LC-MS (ESI): m / z 534.0 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ9.13(s,1H),7.69–7.45(m,2H),7.28(m,1H),7.16(s,1H),7.08–6.95(m,3H),6.90–6.80(m,2H),5.42(d,J=1 4.4Hz,1H),5.01(d,J=14.4Hz,1H),4.92–4.80(m,1H),4.22–3.89(m,2H),3.60(m,1H),3.25(m,1H),1.98(m,3H),1.82–1.70(m,3H). 19 F NMR(376MHz, DMSO-d6)δ-102.94(m,1F),-109.25(m,2F),-109.62(m,1F).

[0865] Example 60: Preparation of Compound 60

[0866]

[0867] Preparation of compound 60

[0868] Compound 52 (100 mg, 0.20 mmol) was added to a sealed test tube, and potassium carbonate (54 mg, 0.40 mmol), CDI (32 mg, 0.40 mmol), and THF (1.5 mL) were added to the sealed test tube. The reaction system was reacted at 70 °C for 16 hours. After the reaction system cooled, the reaction solution was filtered, and the crude filtrate was purified by preparative separation (chromatographic column: Agilent 10Prep-C18 250 x 21.2 mm; column temperature: 25 °C; mobile phase: water (0.1% FA)-acetonitrile; acetonitrile ratio 35%-55% in 12 min; flow rate 30 mL / min) to obtain the title compound 60 (40 mg, yield 38%).

[0869] Compound 60: LC-MS (ESI): m / z 534.00 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.13(s,1H),7.63–7.48(m,2H),7.36–7.22(m,1H),7 .14(s,1H),7.10–6.94(m,3H),6.92–6.79(m,2H),5.42(d,J=14.6Hz,1H),5. 01(d,J=14.6Hz,1H),4.93–4.80(m,1H),4.16–4.00(m,2H),3.58(t,J=8.9Hz ,1H),3.25(m,1H),1.98(dd,J=9.5,1.7Hz,3H),1.76(dd,J=9.4,1.7Hz,3H). 19 F NMR (376MHz) δ-102.54–-103.49(m,1F),-109.26(d,J=36.8Hz,2F),-109.64(d,J=9.6Hz,1F).

[0870] Example 61: Preparation of Compound 61

[0871]

[0872] Preparation of compound 61

[0873] Compound 20 (100 mg, 0.23 mmol) was dissolved in DMF (5 mL), and cesium carbonate (90 mg, 0.276 mmol) was added with stirring. After reacting for 5 minutes, compound 1-bromo-3-methoxypropane (42 mg, 0.253 mmol) was added, and the reaction was stirred at 50 °C for 4 hours. The reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparation method: column: Agilent 10Prep-C18 250 x 21.2 mm; column temperature: 25 °C; mobile phase: water (0.1% FA)-acetonitrile; acetonitrile ratio 55%-75% in 12 min; flow rate 30 mL / min) to obtain title compound 61 (60 mg, yield: 50%, containing a pair of enantiomers).

[0874] Compound 61: LC-MS (ESI): m / z 507.2 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ9.13(s,1H),7.57–7.51(m,1H),7.31–7.25(m,1H),7.15(s,1H),7.04–6.97(m,3H),6.87–6.73(m,2H),5.43(d,J=14.6Hz, 1H),5.01(d,J=14.6Hz,1H),3.95(t,J=6.4Hz,2H),3...

Claims

1. The compound represented by formula (I), its optical isomer, or a pharmaceutically acceptable salt thereof, in, Ring A is selected from , and ; Ring B is selected from phenyl; R3 is selected from OH, NH2, and halogens; R2, R4, and R5 are independently selected from H, F, Cl, Br, I, and C, respectively. 1-6 alkyl; m, y, and z are each independently selected from 1; n is selected from 0, 1, 2, or 3; L1 is selected from single bonds, -NH-, CH2. , , , , , , and ; L2 is selected from single bonds, O, S, CH2, NH, NCH3, , , , and ; L3 is selected from single bond, O, NH, CH2, CH2CH2, -C(=O)-, -C(=O)NH-, , , , , , , , , , , , , and ; L4 is selected from H, F, Cl, Br, I, OH, CN, CH3, CH2CF3, NH2, CHF2, CF3, OCH3, OCF3, OCHF2, OCH2CH3, COOH, CONHMe, CONMe2, NMe2, CH2OH. , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 2. The compound according to claim 1, its optical isomer, or a pharmaceutically acceptable salt thereof, wherein, Structural unit Selected from , , ,and .

3. The compound shown in formula (I), its optical isomer, or a pharmaceutically acceptable salt thereof, in, Ring A is selected from , and ; Ring B is selected from phenyl; R3 is selected from OH, NH2, and halogens; R2, R4, and R5 are independently selected from H, F, Cl, Br, I, and C, respectively. 1-6 alkyl; m, y, and z are each independently selected from 1; n is selected from 0, 1, 2, or 3; Structural unit Selected from H, I, CN, OH, CH3, NHCH3, CF3, C(=O)OH, C(=O)NHMe, C(=O)NMe2, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 4. Compounds of the following formula, their optical isomers, or pharmaceutically acceptable salts thereof, selected from... 。 5. A compound of the following formula or a pharmaceutically acceptable salt thereof, selected from... 。 6. Use of the compound of any one of claims 1-5, its optical isomer or a pharmaceutically acceptable salt thereof in the preparation of an antifungal medicament, wherein the fungus is Candida albicans.

7. Use of a compound of the following formula or a pharmaceutically acceptable salt thereof in the preparation of an antifungal drug, wherein the fungus is Aspergillus fumigatus. 。 8. Use of a compound of the following formula or a pharmaceutically acceptable salt thereof in the preparation of an antifungal drug, wherein the fungus is Aspergillus fumigatus. 。

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