Bicyclic compound as well as preparation method and application thereof

Abstract

The invention discloses a compound as shown in a formula (I), an optical isomer, a tautomer or a pharmacologically acceptable salt thereof, and a pharmaceutical composition containing the compound and the optical isomer, the tautomer or the pharmacologically acceptable salt thereof, which can be used for treating diseases related to ER positive or ER alpha positive.

Description

Bicyclic compounds and their preparation methods and uses

[0001] This application claims priority to:

[0002] CN202310162492.3, application date February 23, 2023;

[0003] CN202410176445.9, application date February 7, 2024;

[0004] CN202410195592.0, application date February 21, 2024. Technical Field

[0005] The present invention relates to a compound represented by formula (I), its optical isomers, tautomers or pharmaceutically acceptable salts thereof, and a pharmaceutical composition containing them, which can be used to treat diseases associated with ER positivity or ERα positivity. Background Art

[0006] The latest 2020 global cancer burden data released by the World Health Organization's International Agency for Research on Cancer (IARC) show that breast cancer surpassed lung cancer for the first time to become the most common cancer. In 2020 alone, over 2.26 million new cases were reported, accounting for 11.7% of all cancer cases. Globally, breast cancer caused over 680,000 deaths that year, making it the fifth leading cause of cancer deaths. In China, there were approximately 420,000 new cases of breast cancer in 2020, making it the leading cancer among Chinese women. Breast cancer also caused nearly 120,000 deaths, making it the fourth leading cause of cancer deaths among women.

[0007] Breast cancer is a phenomenon in which breast epithelial cells undergo uncontrolled proliferation under the action of multiple carcinogenic factors; the most common of these is the estrogen receptor α (ERα) positive type, which accounts for approximately 75% of all breast cancers, and mainly drives the proliferation and survival of cancer cells through the interaction between estrogen and ERα. Commonly used treatments include aromatase inhibitors, selective estrogen modulators (SERMs) and degraders (SERDs). Endocrine therapy can effectively reduce the recurrence and death of patients with ERα-positive breast cancer, but a large number of patients still develop resistance to these treatments, and cancer cell mutations, cancer recurrence, disease progression, and metastasis also occur. There is still a huge unmet clinical need for the treatment of ERα-positive breast cancer; the treatment of other ERα-positive diseases, including ovarian cancer and endometrial cancer, faces the same unmet clinical needs.

[0008] Summary of the Invention

[0009] In one aspect of the present invention, the present invention provides a compound represented by formula (I), its optical isomers, tautomers or pharmaceutically acceptable salts thereof,

[0010] in,

[0011] Ring A is selected from heterocyclyl and heteroaryl;

[0012] Ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0013] X1, X2 and X3 are independently selected from C(R3) and N;

[0014] X4 is selected from O and a single bond;

[0015] X5 is selected from CH(R5), S(=O)2, C(=NR5) and C(=O);

[0016] X6 is selected from CH(R5) and N(R5);

[0017] Y1 is selected from N(R4), CH(R4) and O;

[0018] Y2 is selected from O, S and N(R6);

[0019] R1 is independently selected from H, halogen, OH, CN, NH2, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloheteroalkyl, C 1-6 Alkyl-O-, C 1- 6-alkyl-S-, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-C(=O)O-, C 1-6 Alkyl-OC(=O)-, C 1-6 Alkyl-NH-, -N(C 1-6 Alkyl)2, C 1- 6-alkyl-NH-C 1-6 Alkyl-, C 1-6 Alkyl-C(=O)NH-, C 3-6 Cycloalkyl-C(=O)NH-, C 3-6 Cycloheteroalkyl-C(=O)NH-, C 1-6 Alkyl-NH-C(=O)-, C 3-6 Cycloalkyl-NH-C(=O)-, C 3-6 Cycloheteroalkyl-NH-C(=O)-, C 1-6 Alkyl-S(=O)2-, C 1-6 Alkyl-S(=O)2NH- and C 1-6 Alkyl-NHS(=O)2-, the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloheteroalkyl, C 1-6 Alkyl-O-, C 1-6Alkyl-S-, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-C(=O)O-, C 1-6 Alkyl-OC(=O)-, C 1-6 Alkyl-NH-, -N(C 1-6 Alkyl)2, C 1-6 Alkyl-NH-C 1-6 Alkyl-, C 1-6 Alkyl-C(=O)NH-, C 3-6 Cycloalkyl-C(=O)NH-, C 3-6 Cycloheteroalkyl-C(=O)NH-, C 1-6 Alkyl-NH-C(=O)-, C 3- 6-cycloalkyl-NH-C(=O)-, C 3-6 Cycloheteroalkyl-NH-C(=O)-, C 1-6 Alkyl-S(=O)2-, C 1-6 Alkyl-S(=O)2NH- or C 1-6 Alkyl-NHS(=O)2- is optionally substituted with 1, 2 or 3 R;

[0020] R2 are independently selected from H, halogen, OH, CN, NH2, C 1-6 Alkyl, C 3-6 Cycloalkyl, the C 1-6 Alkyl, C 3-6 Cycloalkyl is optionally substituted with 1, 2 or 3 R;

[0021] R3 is selected from H, halogen, CN, OH, NH2, -C(=O)OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloheteroalkyl, C 1-6 Alkyl-O-, C 1-6 Alkyl-S-, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-C(=O)O-, C 1-6 Alkyl-OC(=O)-, C 1-6 Alkyl-C(=O)NH-, C 1-6 Alkyl-NH-C(=O)-, C 1-6 Alkyl-S(=O)2-, C 1-6 Alkyl-S(=O)2NH- and C 1-6 Alkyl-NHS(=O)2-, the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloheteroalkyl, C 1-6 Alkyl-O-, C 1-6Alkyl-S-, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-C(=O)O-, C 1-6 Alkyl-OC(=O)-, C 1-6 Alkyl-C(=O)NH-, C 1-6 Alkyl-NH-C(=O)-, C 1-6 Alkyl-S(=O)2-, C 1-6 Alkyl-S(=O)2NH- or C 1-6 Alkyl-NHS(=O)2- is optionally substituted with 1, 2 or 3 R;

[0022] R4 is selected from H, halogen, OH, CN, NH2, C 1-6 Alkyl, C 3-6 Cycloalkyl, the C 1-6 Alkyl, C 3-6 Cycloalkyl is optionally substituted with 1, 2 or 3 R;

[0023] R5 is selected from H, halogen, OH, CN, NH2, C 1-6 Alkyl, C 3-6 Cycloalkyl and C 1-6 Alkoxy, the C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 The alkoxy group is optionally substituted with 1, 2 or 3 R;

[0024] R6 are independently selected from H, halogen, OH, CN, NH2 and C 1-6 Alkyl, C 3-6 Cycloalkyl, the C 1-6 The alkyl group is optionally substituted with 1, 2 or 3 R groups;

[0025] R is independently selected from H, F, Cl, Br, I, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1- 6-alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl and C 3-6 Cycloheteroalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl or C 3-6 Cycloheteroalkyl is optionally substituted with 1, 2 or 3 R';

[0026] R' is selected from F, Cl, Br, I, OH, NH2, CN, CH3, CH2F, CHF2 and CF3;

[0027] n is 0, 1, 2, 3 or 4;

[0028] m is 0, 1, 2 or 3.

[0029] In some embodiments of the present invention, the above structural unit Selected from Other variables are as defined in the present invention.

[0030] In some embodiments of the present invention, the above R4 is selected from H, OH, C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R groups, and the other variables are as defined herein.

[0031] In some embodiments of the present invention, the ring A is selected from Other variables are as defined in the present invention.

[0032] In some embodiments of the present invention, the above R2 are independently selected from H, halogen, OH, CN, NH2, C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R groups, and the other variables are as defined herein.

[0033] In some embodiments of the present invention, the above R2 is independently selected from H, F, Cl, Br, I, OH, CN, NH2, methyl, CHF2, CH2OH, CH2CH2OH, and other variables are as defined in the present invention.

[0034] In some embodiments of the present invention, the above structural unit Selected from Other variables are as defined in the present invention.

[0035] In some embodiments of the present invention, the ring B is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, furanyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thienopyridinyl, C 3-7 Cycloalkyl and C 3-6 cycloheteroalkyl, and other variables are as defined herein.

[0036] In some embodiments of the present invention, the above R1 is independently selected from H, halogen, OH, CN, C 1-3 Alkyl, C 1-3Alkyl-O-, C 1- 3-alkyl-S-, C 1-3 Alkyl-C(=O)-, C 1-3 Alkyl-OC(=O)-, C 1-3 Alkyl-C(=O)O-, C 1-3 Alkyl-NH-, -N(C 1-3 Alkyl)2, C 1- 3-alkyl-NH-C 1-3 Alkyl-, C 1-3 Alkyl-C(=O)NH-, C 3-6 Cycloalkyl-C(=O)NH-, C 3-6 Cycloheteroalkyl-C(=O)NH-, C 1-3 Alkyl-NH-C(=O)-, C 1-3 Alkyl-S(=O)2-, C 1-3 Alkyl-S(=O)2NH- and C 1-3 Alkyl-NHS(=O)2-, the C 1-3 Alkyl, C 1-3 Alkyl-O-, C 1-3 Alkyl-S-, C 1-3 Alkyl-C(=O)-, C 1-3 Alkyl-OC(=O)-, C 1-3 Alkyl-C(=O)O-, C 1-3 Alkyl-NH-, -N(C 1-3 Alkyl)2, C 1-3 Alkyl-NH-C 1-3 Alkyl-, C 1-3 Alkyl-C(=O)NH-, C 3-6 Cycloalkyl-C(=O)NH-, C 3-6 Cycloheteroalkyl-C(=O)NH-, C 1-3 Alkyl-NH-C(=O)-, C 1-3 Alkyl-S(=O)2-, C 1-3 Alkyl-S(=O)2NH- or C 1-3 Alkyl-NHS(=O)2- is optionally substituted with 1, 2 or 3 R, and the other variables are as defined herein.

[0037] In some embodiments of the present invention, the above R1 are independently selected from H, F, Cl, Br, I, OH, CN, Me, Other variables are as defined in the present invention.

[0038] In some embodiments of the present invention, the above structural unit Selected from Other variables are as defined in the present invention.

[0039] In some embodiments of the present invention, the above structural unit Selected from Other variables are as defined in the present invention.

[0040] In some embodiments of the present invention, the above R3 is selected from H, halogen, OH, CN, -C(=O)OH, C 1-3 Alkyl, C 3-6 Cycloheteroalkyl, C 1-3 Alkyl-O-, C 1-3 Alkyl-C(=O)-, C 1-3 Alkyl-C(=O)O-, C 1-3 Alkyl-OC(=O)-, C 1-3 Alkyl-C(=O)NH-, C 1-3 Alkyl-NH-C(=O)-, C 1-3 Alkyl-S(=O)2-, C 1-3 Alkyl-S(=O)2NH- and C 1-3 Alkyl-NHS(=O)2-, the C 1-3 Alkyl, C 3-6 Cycloheteroalkyl, C 1-3 Alkyl-O-, C 1-3 Alkyl-C(=O)-, C 1-3 Alkyl-C(=O)O-, C 1-3 Alkyl-OC(=O)-, C 1-3 Alkyl-C(=O)NH-, C 1-3 Alkyl-NH-C(=O)-, C 1-3 Alkyl-S(=O)2-, C 1-3 Alkyl-S(=O)2NH- or C 1-3 Alkyl-NHS(=O)2- is optionally substituted with 1, 2 or 3 R, and the other variables are as defined herein.

[0041] In some embodiments of the present invention, the above R3 is selected from H, F, Cl, Br, -C(=O)OH, -CH3, -OCH3, -OCF3, -CF3, Other variables are as defined in the present invention.

[0042] In some embodiments of the present invention, the above R5 is selected from H and OH, and other variables are as defined in the present invention.

[0043] In some embodiments of the present invention, the above structural unit Selected from Other variables are as defined in the present invention.

[0044] In some embodiments of the present invention, the above-mentioned compound, its optical isomers and pharmaceutically acceptable salts thereof are selected from:

[0045] Ring A, Ring B, X1, X2, X3, X4, X5, X6, R1, R2, R4, n and m are as defined above.

[0046] In some embodiments of the present invention, the above-mentioned compound, its optical isomers and pharmaceutically acceptable salts thereof are selected from:

[0047] Ring B, X1, X2, X3, X4, X5, X6, R1 and n are as defined above.

[0048] In some embodiments of the present invention, the above-mentioned compound, its optical isomers and pharmaceutically acceptable salts thereof are selected from:

[0049] Ring A, Ring B, X1, X2, X3, X4, X5, X6, Y1, Y2, R1, R2, n and m are as defined above.

[0050] In some embodiments of the present invention, the above-mentioned compound, its optical isomers and pharmaceutically acceptable salts thereof are selected from:

[0051] Ring A, Ring B, X1, X2, X3, X4, X5, X6, R1, R2, R4, n and m are as defined above.

[0052] In some embodiments of the present invention, the above-mentioned compound, its optical isomers and pharmaceutically acceptable salts thereof are selected from:

[0053] Ring B, X1, X2, X3, X4, X5, X6, R1 and n are as defined above.

[0054] In another aspect of the present invention, the present invention also provides a compound of the following formula, its optical isomers, tautomers or pharmaceutically acceptable salts thereof, which is selected from:

[0055] In yet another aspect of the present invention, the present invention further provides a compound of the following formula, its optical isomers, tautomers or pharmaceutically acceptable salts thereof, which is selected from:

[0056] In yet another aspect of the present invention, the present invention also provides a pharmaceutical composition comprising the aforementioned compound, its optical isomers, tautomers or pharmaceutically acceptable salts thereof.

[0057] In some embodiments of the present invention, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers, diluents or excipients.

[0058] In another aspect of the present invention, the present invention also provides the use of the aforementioned compound or its pharmaceutically acceptable salt or the aforementioned pharmaceutical composition in the preparation of drugs for treating breast cancer, ovarian cancer, and endometrial cancer.

[0059] In another aspect of the present invention, the present invention also provides the use of the aforementioned compound or its pharmaceutically acceptable salt or the aforementioned pharmaceutical composition in the preparation of drugs for treating uterine cancer and cervical cancer.

[0060] In another aspect of the present invention, the present invention also proposes the use of the aforementioned compound or its pharmaceutically acceptable salt or the aforementioned pharmaceutical composition in the preparation of drugs for treating myeloma, head and neck cancer, thyroid cancer, prostate cancer, testicular cancer, esophageal cancer, lung cancer, liver cancer, gastric cancer, kidney cancer, bile duct cancer, gallbladder cancer, pancreatic cancer, colorectal cancer, bladder cancer, bone cancer, skin cancer, brain tumors, neuroblastoma, lymphoma, and leukemia.

[0061] In yet another aspect of the present invention, the present invention further provides the use of the aforementioned compound or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition in the preparation of a drug for treating ERα-positive related diseases.

[0062] In yet another aspect of the present invention, the present invention further provides the use of the aforementioned compound or its pharmaceutically acceptable salt or the aforementioned pharmaceutical composition in the preparation of a drug for treating ER-positive related diseases.

[0063] Definition and Description

[0064] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as indefinite or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0065] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0066] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, prepared by reacting the compounds of the present invention with relatively nontoxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts, or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, bisulfate, hydroiodic acid, phosphorous acid, and the like; and organic acid salts such as acetic acid, propionic acid, isobutyric acid, trifluoroacetic acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; and salts of amino acids (such as arginine) and organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and can be converted into either base or acid addition salts.

[0067] The pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of the two.

[0068] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are encompassed within the scope of the present invention.

[0069] The compounds of the present invention may exist in specific forms. Unless otherwise indicated, the term "tautomer" or "tautomeric form" refers to isomers with different functional groups that are in dynamic equilibrium at room temperature and can quickly convert into each other. If tautomerism is possible (such as in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions that occur through proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions that occur through the reorganization of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between two tautomers, pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0070] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C). For example, deuterated drugs can be formed by replacing hydrogen with heavy hydrogen. The bond between deuterium and carbon is stronger than that between ordinary hydrogen and carbon. Compared to undeuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, enhanced therapeutic efficacy, and prolonged biological half-life. All isotopic variations of the compounds of this invention, whether radioactive or not, are encompassed by this invention. "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs as well as instances where it does not.

[0071] The term "substituted with" means that any one or more hydrogen atoms on a particular atom are replaced with a substituent, including deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. The term "optionally substituted with" means that the atom may or may not be substituted. Unless otherwise specified, the type and number of substituents may be any chemically feasible.

[0072] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, with each occurrence of R being an independent choice. Furthermore, combinations of substituents and / or their variants are permitted only if such combinations result in stable compounds. For example, Can be selected from wait.

[0073] A hyphen ("-") that is not between two letters or symbols indicates the site of attachment of a substituent. For example, C 1-6 Alkylcarbonyl - refers to a C-alkyl group attached to the rest of the molecule through a carbonyl group. 1-6 However, when the attachment point of the substituent is obvious to those skilled in the art, for example, a halogen substituent, the "-" may be omitted.

[0074] When one of the variables is selected from a single bond, it means that the two groups it connects are directly connected, such as When L1 represents a single bond, it means that the structure is actually

[0075] Unless otherwise indicated, when a group bond is indicated by a dashed line When, for example, In the example, the dashed line indicates the point of attachment of the group to the rest of the molecule.

[0076] When the substituents listed do not specify through which atom they are connected to the substituted group, such substituents can be bonded through any atom thereof. For example, a pyridyl substituent can be connected to the substituted group through any carbon atom on the pyridine ring.

[0077] When the linking group is listed without specifying its linking direction, its linking direction is arbitrary, for example, The connecting group L is at this time Phenyl and cyclopentyl groups can be connected in the same direction as reading from left to right to form It is also possible to connect phenyl and cyclopentyl groups in the opposite direction of reading from left to right to form Combinations of linkers, substituents, and / or variations thereof are permissible only if such combinations result in stable compounds.

[0078] Unless otherwise specified, the number of atoms in a ring is generally defined as the number of members of the ring, for example, a "4-6 membered ring" refers to a "ring" having 4 to 6 atoms arranged around it.

[0079] Unless otherwise specified, the term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, and more preferably an alkyl group containing 1 to 6 carbon atoms. It can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethyl Pentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, methylene (-CH2-), 1,1-ethylene (- CH(CH3)-), 1,2-ethylene (-CH2CH2-), 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), 1,4-butylene (-CH2CH2CH2CH2-), and various branched-chain isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like.The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, OH, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo.

[0080] The term "heteroalkyl" by itself or in combination with another term refers to a stable straight or branched chain alkyl radical or combination thereof consisting of a certain number of carbon atoms and at least one heteroatom or heteroatom group. In some embodiments, the heteroatom is selected from B, O, N and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternized. In other embodiments, the heteroatom group is selected from -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O)2-, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)- and -S(=O)N(H)-. In some embodiments, the heteroalkyl group is C 1-6 In other embodiments, the heteroalkyl group is C 1- 3. Heteroalkyl. The heteroatom or heteroatom group may be located at any interior position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule, but the term "alkoxy" is used as a convention to refer to those alkyl groups that are attached to the remainder of the molecule through 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 up to two heteroatoms can be consecutive, for example, -CH2-NH-OCH3.

[0081] Unless otherwise specified, the term “C 1-6 "Alkoxy" refers to an alkyl group containing 1 to 6 carbon atoms which is attached to the rest of the molecule via an oxygen atom. 1-6 Alkoxy groups include C 1-4 、C 1-3 、C 1-2 、C 2-6 、C2-4 , C6, C5, C4 and C3 alkoxy, etc. 1-6 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), pentoxy (including n-pentoxy, isopentoxy and neopentoxy), hexyloxy, and the like.

[0082] Unless otherwise specified, the term “C 1-3 "Alkoxy" refers to those alkyl groups containing 1 to 3 carbon atoms which are attached to the rest of the molecule via an oxygen atom. The C 1-3 Alkoxy groups include C 1-3 、C 1-2 、C 2-3 , C1, C2 and C3 alkoxy, etc. 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.

[0083] Unless otherwise specified, the term “C 1-6 "Alkylamino" means an alkyl group containing 1 to 6 carbon atoms which is attached to the rest of the molecule via an amino group. 1-6 Alkylamino groups include C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 , C6, C5, C4, C3 and C2 alkylamino, etc. 1-6 Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -N(CH2CH3)(CH2CH3), -NHCH2CH2CH3, -NHCH2(CH3)2, -NHCH2CH2CH2CH3, and the like.

[0084] Unless otherwise specified, the term “C 1-3 "Alkylamino" means an alkyl group containing 1 to 3 carbon atoms which is attached to the rest of the molecule via an amino group. 1-3 Alkylamino groups include C 1-3 、C 1-2 、C 2-3 , C1, C2 and C3 alkylamino, etc. 1-3 Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -NHCH2CH2CH3, -NHCH2(CH3)2, and the like.

[0085] Unless otherwise specified, the term “C 1-6"Alkylthio" refers to those alkyl groups containing 1 to 6 carbon atoms which are linked to the rest of the molecule via a sulfur atom. 1-6 Alkylthio includes C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 , C6, C5, C4, C3 and C2 alkylthio, etc. 1-6 Examples of alkylthio groups include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, and the like.

[0086] Unless otherwise specified, the term “C 1-3 "Alkylthio" refers to those alkyl groups containing 1 to 3 carbon atoms which are linked to the rest of the molecule via a sulfur atom. 1-3 Alkylthio includes C 1-3 、C 1-2 、C 2-3 , C1, C2 and C3 alkylthio, etc. 1-3 Examples of alkylthio groups include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, and the like.

[0087] Unless otherwise specified, the term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms (which can be a specific point or an interval consisting of two points, such as 3, 4, 5, 6 ring atoms, 4 to 11 ring atoms, 6 to 12 ring atoms, etc.), more preferably 3 to 8 carbon atoms, and most preferably 3 to 6 (e.g., 3, 4, 5 or 6) carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc., preferably cycloalkyl; polycyclic cycloalkyls include spirocyclic, fused ring and bridged ring cycloalkyls.

[0088] Unless otherwise specified, the term "spiroalkyl" refers to a polycyclic group having a carbon atom (called a spiro atom) shared between 5 to 20 monocyclic rings, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiro atoms shared between the rings, the spiroalkyl group is divided into a single spiroalkyl group, a double spiroalkyl group or a multi-spiroalkyl group, preferably a single spiroalkyl group and a double spiroalkyl group. More preferably, it is a 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiroalkyl group. Non-limiting examples of spiroalkyl groups include: wait.

[0089] Unless otherwise specified, the term "fused cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with the other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl. Non-limiting examples of fused cycloalkyl include: wait.

[0090] Unless otherwise specified, the term "bridged cycloalkyl" refers to a 5-20 membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6-14 members, more preferably 7-10 members. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged cycloalkyl groups include: wait.

[0091] The cycloalkyl ring includes the above-mentioned cycloalkyl groups (such as monocyclic, condensed, spirocyclic and bridged cycloalkyl groups) fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl and the like; preferably phenylcyclopentyl and tetrahydronaphthyl.

[0092] The cycloalkyl group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from one or more substituents selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, OH, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo.

[0093] Unless otherwise specified, the term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m(wherein m is an integer from 0 to 2) heteroatoms, but excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms (which can be specific points or an interval consisting of any two points, such as 3, 4, 5, 6 ring atoms, 4 to 11 ring atoms, 6 to 12 ring atoms, etc.), of which 1 to 4 are heteroatoms; preferably, it contains 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; more preferably, it contains 3 to 6 ring atoms, of which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include azetidinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc., preferably tetrahydropyranyl, piperidinyl, pyrrolidinyl, etc. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.

[0094] Unless otherwise specified, the term "spiroheterocyclyl" refers to a polycyclic heterocyclic group of 5 to 20 members in which the monocyclic rings share one atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer 0 to 2) heteroatom, and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated π electron system. It is preferably 6 to 14 members, more preferably 7 to 11 members. According to the number of shared spiral atoms between the rings, the spiro heterocyclic group is divided into a single spiral heterocyclic group, a double spiral heterocyclic group or a multi-spiro heterocyclic group, preferably a single spiral heterocyclic group and a double spiral heterocyclic group. More preferably 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiral heterocyclic group. Non-limiting examples of spiro heterocyclic groups include: wait.

[0095] Unless otherwise specified, the term "fused heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 20 members, wherein each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system, and one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, the remaining ring atoms being carbon. Preferably, it is 6 to 14 members, more preferably 7 to 11 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include: wait.

[0096] Unless otherwise specified, the term "bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds but no ring has a completely conjugated π electron system, and in which one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, the remaining ring atoms being carbon. Preferably, it is 6 to 14 members, more preferably 7 to 11 members. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged heterocyclic groups include: wait.

[0097] The heterocyclyl ring includes the above-mentioned heterocyclyls (such as monocyclic, fused, spirocyclic and bridged heterocyclyls) fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclyl, non-limiting examples of which include: wait.

[0098] The heterocyclic group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, OH, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo.

[0099] Unless otherwise specified, the term "aryl" refers to a 6- to 20-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 10-membered, more preferably 6-membered, such as phenyl and naphthyl. The aryl ring includes the above-mentioned aryl fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, non-limiting examples of which include: wait.

[0100] The aryl group may be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from one or more substituents of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, OH, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio and heterocycloalkylthio.

[0101] Unless otherwise specified, the term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 20 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5-10-membered and contains 1 to 3 heteroatoms; more preferably 5-membered or 6-membered and contains 1 to 3 heteroatoms; non-limiting examples include pyrazolyl, imidazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazinyl and the like. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include: wait.

[0102] The heteroaryl group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from one or more substituents of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, OH, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio and heterocycloalkylthio.

[0103] Unless otherwise specified, the term "alkylthio" refers to -S-(alkyl) and -S-(unsubstituted cycloalkyl), wherein alkyl or cycloalkyl are as defined above. Non-limiting examples of alkylthio include: methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio. Alkylthio can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, OH, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio and heterocycloalkylthio.

[0104] Unless otherwise specified, the term "cycloalkyloxy" refers to an -O-cycloalkyl group, wherein cycloalkyl is as defined above.

[0105] Unless otherwise specified, the term "haloalkyl" refers to an alkyl group substituted with a halogen, wherein alkyl is as defined above.

[0106] Unless otherwise specified, the term "haloalkoxy" refers to an alkoxy group substituted with a halogen, wherein alkoxy is as defined above.

[0107] Unless otherwise specified, the term "hydroxyalkyl" refers to an alkyl group substituted with OH, wherein alkyl is as defined above.

[0108] Unless otherwise specified, the term "hydroxy" refers to an -OH group.

[0109] Unless otherwise specified, the term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0110] Unless otherwise specified, the term "aldehyde" refers to -C(O)H.

[0111] Unless otherwise specified, the term "carboxy" refers to -C(O)OH.

[0112] Unless otherwise specified, the term "carboxylate" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.

[0113] Unless otherwise specified, the term “C 1-6 "Alkyl" is used to represent a straight or branched chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms. 1-6 Alkyl groups include C 1-5 、C 1-4 、C 2-6 Alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1-5 Examples of alkyl groups include, but are not limited to, methyl ("Me"), ethyl ("Et"), propyl such as n-propyl ("n-Pr") or isopropyl ("i-Pr"), butyl such as n-butyl ("n-Bu"), isobutyl ("i-Bu"), sec-butyl ("s-Bu") or tert-butyl ("t-Bu"), pentyl, hexyl, and the like.

[0114] Unless otherwise specified, the term “C 1-3 "Alkyl" is used to represent a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms. 1-3 Alkyl groups include C 1-2 and C 2-3 Alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.

[0115] Unless otherwise specified, “C 2-6 "Alkenyl" is used to refer to a linear or branched hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon double bond, which may be located at any position of the group. 2-6 Alkenyl groups include C 2-4 、C 2-3 , C4, C3 and C2 alkenyl, etc.; which may be monovalent, divalent or polyvalent. 2-6 Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, piperyl, hexadienyl, and the like.

[0116] Unless otherwise specified, “C 2-3"Alkenyl" is used to refer to a linear or branched hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon double bond, which may be located at any position of the group. 2-3 Alkenyl includes C3 and C2 alkenyl; the C 2-3 Alkenyl groups can be monovalent, divalent, or polyvalent. 2-3 Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, and the like.

[0117] Unless otherwise specified, “C 4-8 "Cycloalkyl" refers to a saturated monovalent monocyclic or bicyclic hydrocarbon group having 4 to 8 ring carbon atoms, such as 4 to 7 ring carbon atoms, such as 4 to 6 ring carbon atoms, such as 4 to 5 ring carbon atoms. For example, "C 4-8 "Cycloalkyl" means a cycloalkyl group having 4 to 8 ring carbon atoms. Similarly, "C 4-7 "Cycloalkyl" means a cycloalkyl group having 4 to 7 ring carbon atoms; "C 4-6 "Cycloalkyl" means a cycloalkyl group having 4 to 6 ring carbon atoms; "C 4-5 "Cycloalkyl" refers to a cycloalkyl group having 4-5 ring carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0118] Unless otherwise specified, “C 4-6 "Cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 4 to 6 carbon atoms, which is a monocyclic or bicyclic system. 4-6 Cycloalkyl groups include C 4-5 、C 5-6 , C4, C5 and C6 cycloalkyl, etc.; which may be monovalent, divalent or polyvalent. 4-6 Examples of cycloalkyl groups include, but are not limited to, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0119] Unless otherwise specified, the term "3-10 membered heterocyclyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 3 to 10 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p, p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spirocyclic, fused and bridged rings. In addition, with respect to the "3-10 membered heterocycloalkyl", a heteroatom may occupy the position at which the heterocycloalkyl is connected to the rest of the molecule. The 3-10 membered heterocyclyl includes 6-9 membered, 3-6 membered, 3-5 membered, 4-6 membered, 5-6 membered, 4 membered, 5 membered, 6 membered, 7 membered, 8 membered, 9 membered, 10 membered heterocyclyl, etc. Examples of 3-10 membered heterocyclic groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl, etc.), oxadiazinyl (including oxadiazinyl, ... alkyl, 1,2-dioxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl, dioxepanyl, 2,6-diazaspiro[3.3]heptane, octahydropyrrolo[3,4-c]pyrrolyl or hexahydro-1H-furo[3,4-c]pyrrole, 2,7-diazaspiro[3.5]nonane, and 2,5-diazabicyclo[2.2.1]heptane. The present invention also uses the term "5-9 membered bicycloalkyl" to refer to a bicyclic ring with 5-9 ring atoms in a bicyclic ring system, such as bicyclo[1.1.1]pentane and 2,5-diazabicyclo[2.2.1]heptane.

[0120] Unless otherwise specified, the term "3-6 membered heterocyclyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 3 to 6 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p, p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spirocyclic, fused and bridged rings. In addition, with respect to the "3-6 membered heterocyclyl", a heteroatom may occupy the position at which the heterocycloalkyl group is connected to the rest of the molecule. The 3-6 membered heterocycloalkyl group includes 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyl groups. Examples of 4-6 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl or homopiperidinyl, etc.

[0121] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and that the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0122] "Substituted" means that one or more H groups, preferably up to 5, more preferably 1 to 3 H groups, in a group are independently replaced by a corresponding number of substituents, wherein each substituent has an independent option (i.e., the substituents can be the same or different). It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) which substitutions are possible or impossible without undue effort. For example, an amino group or an OH group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0123] It will be appreciated by those skilled in the art that some compounds of formula (I) may contain one or more chiral centers and therefore exist as two or more stereoisomers. Therefore, the compounds of the present invention may exist as single stereoisomers (e.g., enantiomers, diastereomers) and mixtures thereof in any proportion, such as racemates, and, where appropriate, as tautomers and geometric isomers.

[0124] As used herein, the term "stereoisomers" refers to compounds that have identical chemical constitution but differ in the arrangement of the atoms or groups in space. Stereoisomers include enantiomers, diastereomers, and conformers, among others.

[0125] As used herein, the term "enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another.

[0126] As used herein, the term "diastereomer" refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, or biological activities. Mixtures of diastereomers can be separated using high-resolution analytical methods such as electrophoresis and chromatography, such as HPLC.

[0127] Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of plane polarized light. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to its chiral center. The prefixes d and l or (+) and (-) are used to indicate the sign of the compound's rotation of plane polarized light, where (-) or l indicate that the compound is left-handed. Compounds with a prefix of (+) or d are right-handed. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers can also be referred to as enantiomers, and mixtures of such isomers are commonly referred to as enantiomeric mixtures. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which can occur in chemical reactions or methods without stereoselectivity or stereospecificity. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers that do not have optical activity.

[0128] The racemic mixture can be used as is or resolved into its individual isomers. Resolution can yield a stereochemically pure compound or a mixture enriched in one or more isomers. Methods for separating isomers are well known and include physical methods, such as chromatography using chiral adsorbents. Individual isomers can be prepared in chiral form from chiral precursors. Alternatively, the individual isomers can be chemically separated from the mixture by forming diastereomeric salts with chiral acids (e.g., individual enantiomers of 10-camphorsulfonic acid, camphoric acid, α-bromocamphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, etc.), fractionally crystallizing the salts, then liberating one or both of the resolved bases, and optionally repeating this process to obtain one or both isomers substantially free of the other isomer, i.e., the desired stereoisomer having an optical purity of, for example, at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 99.5% by weight. Alternatively, as is well known to those skilled in the art, the racemates can be covalently linked to chiral compounds (auxiliaries) to obtain diastereomers.

[0129] The compounds disclosed herein may have one or more chiral centers, each independently having an R configuration or an S configuration. The chiral centers of some compounds disclosed herein are marked with *R, *S, R*, or S*, indicating that the absolute configuration of the chiral center of the compound has not been identified, but the compound has been chirally resolved and the chiral center is a chiral center of a single configuration, the compound is a single-configuration enantiomer monomer, a single-configuration diastereomer monomer, or a diastereomer mixture with a single configuration of the chiral center (for example, the configuration of other chiral centers has not been resolved). When the absolute configuration (R configuration or S configuration) of the chiral center of a compound disclosed herein has not been identified, such compound can be confirmed based on its corresponding retention time (RT or Rt) under corresponding chromatographic column conditions (for example, chromatographic column model, chromatographic column packing, chromatographic column size, mobile phase, etc.).

[0130] The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention.

[0131] Technical and scientific terms used herein without specific definition have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0132] Abbreviations:

[0133] CD3OD or MeOD stands for deuterated methanol; DMSO-d6 stands for deuterated dimethyl sulfoxide; Chloroform-d or CDCl3 stands for deuterated chloroform; AcOH stands for acetic acid; N2 stands for nitrogen; Ar stands for argon; BBr3 stands for boron tribromide; BH3 stands for borane; (Boc)2O stands for di-tert-butyl dicarbonate; Et3SiH stands for triethylsilane; HATU stands for 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; HOBt stands for 1-hydroxybenzotriazole; K2 CO3 represents potassium carbonate; KOAc represents potassium acetate; MeONa represents sodium methoxide; LDA represents lithium diisopropylamide; i-PrMgCl represents isopropylmagnesium chloride; LiHMDS represents lithium bis(trimethylsilyl)amide; LiOH represents lithium hydroxide; m-CPBA represents m-chloroperbenzoic 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; KI represents potassium iodide; n-Bu Li represents n-butyllithium; NH4Cl represents ammonium chloride; NMP represents N-methyl-2-pyrrolidone; Cs2CO3 represents cesium carbonate; CuCl represents cuprous chloride; CuI represents cuprous iodide; DCE represents dichloroethane; DCM represents dichloromethane; Dioxane or 1,4-dioxane represents 1,4-dioxane; MeCN, ACN or CH3CN represents acetonitrile; MeOH or methanol represents methanol; EtOH or ethanol represents ethanol; DEA represents diethylamine; DIPEA or DIEA represents N,N-diisopropyl ethyl amine; DMAP stands for 4-dimethylaminopyridine; DMF stands for N,N-dimethylformamide; NH3H2O ​​stands for aqueous ammonia; DMSO stands for dimethyl sulfoxide; EA or EtOAc stands for ethyl acetate; Et2O stands for diethyl ether; PE stands for petroleum ether; THF stands for tetrahydrofuran; Toluene or tol. stands for toluene; SOCl2 stands for dichlorothionyl; TFA stands for trifluoroacetic acid; TfOH stands for trifluoromethanesulfonic acid; TMSI stands for trimethylsilyl iodide; TMSCl stands for trimethylsilyl chloride; FA stands for formic acid; H2O stands for water; HCl stands for hydrogen chloride gas; HCl aq. stands for aqueous hydrochloric acid; °C stands for degrees Celsius; rt stands for room temperature; h stands for hour; min stands for minute; kg or KG stands for kilogram; g stands for gram; mg stands for milligram; μg stands for microgram; L stands for liter; mL stands for milliliter; mmol stands for millimole; M stands for mole; cm stands for centimeter; mm stands for millimeter; μm stands for micrometer; nm stands for nanometer; mL / min stands for milliliter per minute; 1 H NMR stands for nuclear magnetic resonance; 19F NMR stands for nuclear magnetic resonance fluorine; br.s broad singlet; s singlet; d doublet; t triplet; m multiplet; J coupling constant; Hz hertz; MHz megahertz; bar bar; psi pounds per square inch; N2 nitrogen; HPLC high-performance liquid chromatography; ID inner diameter; Rt or RT retention time; LCMS or LC-MS liquid chromatography-mass spectrometry; m / z mass-to-charge ratio; ESI electrospray ionization; CO2 carbon dioxide; TLC thin-layer chromatography; UV ultraviolet; ATCC American type culture collection; PK pharmacokinetic; NADPH nicotinamide adenine dinucleotide phosphate; CYP cytochrome P450; PBS (pH 7.4) phosphate buffered saline (PBS) pH 7.4; FaSSIF fasting simulated intestinal fluid; FeSSIF fed simulated intestinal fluid; PPB plasma protein binding; GSH Trapping stands for glutathione trapping experiment. DETAILED DESCRIPTION

[0134] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention and are not intended to limit the scope of the invention. In the following examples, the experimental methods without specifying specific conditions are generally based on the conventional conditions of this type of reaction, or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and parts by weight. Unless otherwise stated, the ratio of liquid is volume ratio.

[0135] Unless otherwise specified, the experimental materials and reagents used in the following examples can be obtained from commercial channels.

[0136] Example 1: Preparation of Compound 1

[0137] Preparation of compound 1-2

[0138] 4-Bromo-2-methoxypyridine (1.75 g, 9.30 mmol) was added to anhydrous Et2O (10.0 mL), and the reaction system was cooled to -65°C. At this temperature, n-BuLi (2.5 M in tetrahydrofuran, 3.72 mL, 9.3 mmol) was slowly added dropwise to the reaction system, and the reaction was stirred at this temperature for 30 minutes. A solution of compound 1-1 (1 g, 4.65 mmol) in anhydrous tetrahydrofuran (3.0 mL) was slowly added dropwise to the reaction system, and the reaction was stirred at -65°C for one hour. TLC analysis indicated the reaction was complete. After the reaction system was warmed to 0°C, saturated aqueous ammonium chloride (5.0 mL) was added to quench the reaction, followed by the addition of water (20.0 mL). The reaction system was extracted three times with ethyl acetate (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (0-15% ethyl acetate / petroleum ether) to obtain the title compound 1-2 (400 mg, 26.7% yield). LC-MS (ESI): m / z [M+H] + :325.2. 1 H NMR (400MHz, DMSO-d6) δ11.06(br.s,1H),8.09(d,J=5.4Hz,1H),7.58(d,J=8.0Hz,1H),7.38(d,J=7 .3Hz,1H),7.16(t,J=7.7Hz,1H),7.09(br.s,1H),6.74(s,1H),6.71(d,J=5.4Hz,1H),3.84(s,3H). 19 F NMR(376MHz,DMSO-d6)δ-59.97(s,3F).

[0139] Preparation of Compounds 1-3

[0140] Under nitrogen protection at 0°C, compound 1-2 (300 mg, 0.93 mmol) and trifluoromethoxybenzene (194.4 mg, 1.20 mmol) were dissolved in DCM (10.0 mL) and TfOH (1.4 g, 9.26 mmol) was slowly added to the reaction system. After the reaction was completed, ice water (20.0 mL) was added to quench the reaction. The reaction system was extracted three times with ethyl acetate (20 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The concentrated residue was purified by preparative separation (preparative method: mobile phase: A: 0.1% TFA / H2O; B: ACN; chromatographic column: Pursuit XRs10C18, 19×250 mm, 10 μm; column temperature: 25°C; gradient: 49% to 59% acetonitrile over 9.0-9.5 min; flow rate: 20 mL / min) to obtain the title compound 1-3 (145 mg, yield 33.4%). LC-MS(ESI):m / z[M+H] + :469.3. 1 H NMR (400MHz, DMSO-d6) δ11.49(br.s,1H),8.16(d,J=5.6Hz,1H),7.69(d,J=7.6Hz,1H),7.61(d,J=7.6Hz,1H),7.38(d,J=8.4 Hz, 2H), 7.28 (d, J = 8.4 Hz, 2H), 7.26 (m, 1H), 6.81 (dd, J = 5.5, 1.6 Hz, 1H), 6.51 (s, 1H), 3.83 (s, 3H). 19 F NMR(376MHz, DMSO-d6)δ-56.78(s,3F),-60.05(s,3F).

[0141] Preparation of Compounds 1-4

[0142] To a solution of compound 1-3 (500 mg, 1.06 mmol) in CHCl₃ (5.0 mL) was added m-CPBA (276.6 mg, 1.60 mmol). The reaction temperature was raised to 60°C and stirred for 1 hour. After completion, the reaction was quenched by adding cold saturated aqueous sodium sulfite solution (10.0 mL). The mixture was extracted three times with DCM (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (0-25% ethyl acetate / petroleum ether) to obtain the title compound 1-4 (240 mg, 46.3% yield). LC-MS (ESI): m / z [M+H] + :485.0.

[0143] Preparation of compound 1

[0144] Compound 1-4 (200 mg, 0.413 mmol) was dissolved in acetyl chloride (5.0 mL) and stirred at room temperature for 12 h. After the reaction was complete, the reaction solution was dried, and MeOH (6.0 mL) and K2CO3 (93 mg) were added to the reaction residue in sequence, and the reaction was stirred for 2 hours. After the reaction was completed, water (3.0 mL) was added to the reaction system, and EtOAc (5.0 mL) was extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (0-25% ethyl acetate / petroleum ether) to obtain the title compound 1 (23 mg, yield 12%). LC-MS (ESI): m / z[M+H] + :471.3. 1 H NMR (400MHz, DMSO-d6) δ11.55(br.s,1H),11.49(br.s,1H),7.87(d,J=7.4Hz,1H),7.69(d,J=7.6Hz,1H),7.63(d,J=8.0Hz, 1H), 7.39 (d, J = 8.6Hz, 2H), 7.33 (d, J = 8.9Hz, 2H), 7.26 (t, J = 7.8Hz, 1H), 6.16 (d, J = 2.4Hz, 1H), 5.99 (dd, J = 7.4, 2.4Hz, 1H). 19 F NMR(376MHz, DMSO-d6)δ-56.78(s,3F),-60.07(s,3F).

[0145] Example 2: Preparation of Compound 2

[0146] Preparation of compound 2-2

[0147] Compound 2-1 (2.46 g, 9.30 mmol) was added to tetrahydrofuran (10.0 mL) and the temperature was lowered to -65°C. At this temperature, n-BuLi (3.72 mL, 9.3 mmol) was slowly added to the reaction mixture. After the addition was complete, the reaction was stirred at this temperature for half an hour. Compound 1-1 (1 g, 4.65 mmol) was dissolved in tetrahydrofuran (3.0 mL) and slowly added dropwise to the reaction mixture at -65°C. After the addition was complete, the reaction was stirred for one hour. LCMS monitoring indicated the reaction was complete. The reaction was quenched by the addition of saturated ammonium chloride solution (5.0 mL) at low temperature. Water (20 mL) was added, and the reaction system was extracted three times with ethyl acetate (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (0-15% ethyl acetate / petroleum ether) to obtain the title compound 2-2 (550 mg, yield 29.5%). LC-MS (ESI): m / z [M+H] + :401.1.

[0148] Preparation of compound 2

[0149] Compound 2-2 (500 mg, 1.25 mmol) and trifluoromethoxybenzene (264.3 mg, 1.63 mmol) were dissolved in DCM (10.0 mL). Under nitrogen protection, the temperature was controlled in an ice-water bath, and TfOH (938.2 mg, 6.25 mmol) was slowly added. After the reaction was completed, water (10.0 mL) was added, and the reaction system was extracted three times with ethyl acetate (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by preparative separation (preparative method: mobile phase: A: 0.1% TFA / H2O; B: ACN; chromatographic column: Pursuit XRs10 C18, 19×250 mm, 10 μm; column temperature: 25°C; gradient: 49% to 59% acetonitrile over 9.3-10.0 min; flow rate: 20 mL / min) to obtain the title compound 2 (85.85 mg, yield 15.1%). LC-MS(ESI):m / z[M+H] + :455.2. 1 H NMR(400MHz,DMSO-d6)δ11.51(br.s,1H),11.41 (br.s,1H),7.65(d,J=7.7Hz,1H),7.60(d,J=7.7Hz,1H),7.42–7.33(m,3H),7. 31 (d, J = 8.9 Hz, 2H), 7.23 (t, J = 7.8 Hz, 1H), 6.90 (s, 1H), 6.37 (d, J = 9.7 Hz, 1H). 19 F NMR(376MHz, DMSO-d6)δ-56.78(s,3F),-60.01(s,3F).

[0150] Example 3: Preparation of Compounds 3A and 3B

[0151] Preparation of compound 3

[0152] Compound 1-3 (100 mg, 0.23 mmol) was dissolved in DCM (3.0 mL) and TMSI (59.1 mg, 0.34 mmol) was added under nitrogen. The reaction temperature was raised to 60°C and allowed to react for one hour, after which the reaction was complete. Water (10 mL) was added and the reaction system was extracted three times with ethyl acetate (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by preparative separation (preparative method: mobile phase: A: 0.1% TFA / H2O; B: ACN; column: Pursuit XRs10 C18, 19×250 mm, 10 μm; column temperature: 25°C; gradient: 49% to 59%; acetonitrile at 9.0-9.5 min; flow rate: 20 mL / min) to afford the title compound 3 (29.14 mg, 30.1% yield). LC-MS (ESI): m / z [M+H] + :455.3. 1 H NMR (400MHz, DMSO-d6) δ11.67(br.s,1H),11.48(s,1H),7.68(d,J=7.7Hz,1H),7.64(d,J=7.7Hz,1H),7.40(d,J=8. 9Hz, 2H), 7.37–7.31 (m, 1H), 7.33 (d, J = 8.9Hz, 2H), 7.27 (t, J = 7.7Hz, 1H), 5.98 (s, 1H), 5.97 (dd, J = 6.0, 2.0Hz, 1H). 19 F NMR(376MHz, DMSO-d6)δ-56.78(s,3F),-60.09(s,3F).

[0153] Preparation of compounds 3A and 3B

[0154] Compound 3 was subjected to SFC chiral preparative separation (preparative separation method, instrument model: Water 150 preparative SFC (SFC-26); chromatographic column model: ChiralPak IG, 250×30 mm ID, 10 μm; mobile phase: A: CO2, B: ethanol; elution gradient: B 15%; flow rate: 70 mL / min; column pressure: 100 bar; column temperature: 38°C; detection wavelength: 220 nm; cycle: ~7 min) to obtain the title compounds 3A (16 mg) and 3B (17 mg).

[0155] Compound 3A: LC-MS (ESI): m / z 455.0 [M+H] +Chiral analysis method (instrument model: Waters UPC2 analytical SFC (SFC-H); chromatographic column model: ChiralPak IG, 100×4.6 mm ID, 3 μm; mobile phase: A: CO2B: ethanol (0.05% DEA); elution gradient: B 20%; flow rate: 2.5 mL / min; column temperature: 35°C; column pressure: 100 bar; detection wavelength: 220 nm; RT = 1.349 min). 1 H NMR (400MHz, DMSO-d6) δ11.67(br.s,1H),11.48(s,1H),7.68(d,J=7.7Hz,1H),7.64(d,J=7.7Hz,1H),7.40(d,J=8. 9Hz, 2H), 7.37–7.31 (m, 1H), 7.33 (d, J = 8.9Hz, 2H), 7.27 (t, J = 7.7Hz, 1H), 5.98 (s, 1H), 5.97 (dd, J = 6.0, 2.0Hz, 1H). 19 F NMR(376MHz, DMSO-d6)δ-56.78(s,3F),-60.09(s,3F).

[0156] Compound 3B: LC-MS (ESI): m / z 455.0 [M+H] + Chiral analysis method (instrument model: Waters UPC2 analytical SFC (SFC-H); chromatographic column model: ChiralPak IG, 100×4.6 mm ID, 3 μm; mobile phase: A: CO2 B: ethanol (0.05% DEA); elution gradient: B 20%; flow rate: 2.5 mL / min; column temperature: 35°C; column pressure: 1500 psi; detection wavelength: 220 nm; RT = 1.855 min). 1 H NMR (400MHz, DMSO-d6) δ11.67(br.s,1H),11.48(s,1H),7.68(d,J=7.7Hz,1H),7.64(d,J=7.7Hz,1H),7.40(d,J=8. 9Hz, 2H), 7.37–7.31 (m, 1H), 7.33 (d, J = 8.9Hz, 2H), 7.27 (t, J = 7.7Hz, 1H), 5.98 (s, 1H), 5.97 (dd, J = 6.0, 2.0Hz, 1H). 19 F NMR(376MHz, DMSO-d6)δ-56.78(s,3F),-60.09(s,3F).

[0157] Example 4: Preparation of Compound 4

[0158] Preparation of compound 4-2

[0159] Under nitrogen, i-PrMgCl (1.3 M tetrahydrofuran solution, 6.3 mL, 8.19 mmol) was added dropwise to a solution of compound 4-1 (1.54 g, 6.51 mmol) in tetrahydrofuran (10.0 mL) at -78°C. The reaction was stirred at this temperature for 30 min. A solution of compound 1-1 (700 mg, 3.25 mmol) in tetrahydrofuran (5.0 mL) was added dropwise to the reaction system, and the mixture was stirred at this temperature for 2 h. The reaction was monitored by LCMS for completion. The reaction solution was quenched by addition of saturated aqueous ammonium chloride (10.0 mL), and water (10.0 mL) was added. The reaction system was extracted three times with ethyl acetate (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (EA:PE = 0-20%) to give the title compound 4-2 (500 mg, 47% yield). LC-MS (ESI): m / z [M+H] + =326.0.

[0160] Preparation of compound 4

[0161] TfOH (4.62 g, 30.76 mmol) was added to a mixture of compound 4-2 (500 mg, 1.54 mmol) in toluene (1.42 g, 15.38 mmol) and DCE (5.0 mL). The reaction system was heated to 70°C and stirred for 2 h. LCMS monitored the reaction for completion. The pH of the reaction solution was adjusted to a weakly alkaline state with saturated aqueous sodium bicarbonate. The reaction system was extracted three times with DCM (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by preparative separation (mobile phase: A: 0.1% aqueous TFA; B: acetonitrile; column: Agilent C18, 19 × 250 mm × 10 μm, flow rate: 20 mL / min, column temperature: 25°C; gradient: 52%-52%, retention time: 8-9.5 min) to afford the title compound 4 (148.36 mg, 26% yield). LC-MS(ESI):m / z[M+H] + =386.1. 1 H NMR (400MHz, DMSO-d6) δ12.58(br.s,1H),11.24(br.s,1H),8.12(d,J=0.8Hz,1H),7.66(d, J=7.4Hz,1H),7.59(d,J=8.0Hz,1H),7.25–7.15(m,5H),6.06(d,J=0.8Hz,1H),2.29(s,3H). 19F NMR(376MHz,DMSO-d6)δ-60.00(s,3F).

[0162] Example 5: Preparation of Compound 5

[0163] Preparation of compound 5

[0164] Compound 3 (260 mg, 0.572 mmol) was added to a single-necked flask. A mixture of acetonitrile and water (1:1, 5.0 mL) was added to the reaction flask, followed by sodium hydroxide (92 mg, 2.29 mmol). The reaction system was cooled to 0°C, and bromodifluoromethyl diethylphosphonate (230 mg, 0.858 mmol) was added. The reaction was continued for 3 hours. After completion of the reaction, water (10 mL) was added to the reaction system, and the product was extracted three times with ethyl acetate (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by preparative separation (preparative column: Pursuit XRs C18 21.2 × 250 mm × 10 μm; flow rate: 20 mL / min; mobile phase: A-0.1% TFA in water, B-acetonitrile; gradient: 79-79% acetonitrile content, retention time: 6.5-8.9 min) to afford the title compound 5 (34.47 mg, 11.9% yield). LCMS (ESI): m / z = 505.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.61(br.s,1H),7.97–7.62(m,4H),7.45–7.34(m,4H),7.27(t,J=7.8Hz, 1H), 6.23 (dd, J=7.6, 2.0Hz, 1H), 6.13 (d, J=1.7Hz, 1H). 19 F NMR(376MHz, DMSO-d6)δ-56.78(s,3F),-60.09(s,3F),-103.36(s,2F).

[0165] Example 6: Preparation of Compound 6

[0166] Preparation of compound 6-2

[0167] Under nitrogen, n-BuLi (1.6 M tetrahydrofuran solution, 35 mL, 56 mmol) was added dropwise to a solution of compound 6-1 (13.4 g, 55.78 mmol) in tetrahydrofuran (40 mL) at -78°C and stirred for 30 min. Then, a solution of 1-1 (6.0 g, 27.89 mmol) in tetrahydrofuran (20 mL) was added dropwise and stirring continued at -78°C for 30 min. The reaction system was allowed to warm to room temperature and stirred for 30 min. LC-MS monitored the reaction for completion. Saturated aqueous ammonium chloride (30 mL) was added to quench the reaction, and the mixture was extracted three times with ethyl acetate (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (EA:PE = 0-30%) to afford the title compound 6-2 (5.1 g, 55% yield). LC-MS (ESI): m / z [M+H] + 331.1.

[0168] Preparation of compound 6-3

[0169] Compound 6-2 (2.5 g, 7.57 mmol) and trifluoromethoxybenzene (1.6 g, 9.84 mmol) were dissolved in DCM (20 mL). TfOH (5.7 g, 37.85 mmol) was slowly added dropwise in an ice-water bath under N2 protection. The mixture was stirred for 30 min in an ice-water bath and the reaction was monitored by LC-MS for completeness. The reaction solution was spin-dried and quenched with saturated aqueous sodium bicarbonate solution (30 mL). The mixture was extracted three times with ethyl acetate (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (EA:PE = 0-30%) to give the title compound 6-3 (900 mg, yield 25%). LC-MS (ESI): m / z [M+CH3CN+H] + :516.3. 1 H NMR (400MHz, DMSO-d6) δ11.58(br.s,1H),8.09(d,J=5.2Hz,1H),7.68(d,J=8.0Hz,1H), 7.58(d,J=7.5Hz,1H),7.45-7.37(m,4H),7.28(t,J=7.8Hz,1H),7.05(t,J=5.1Hz,1H). 19 F NMR(376MHz, DMSO-d6)δ-56.78(s,3F),-60.13(s,3F),-89.41(d,1F),-139.36(d,1F).

[0170] Preparation of compound 6

[0171] Compound 6-3 (400 mg, 0.82 mmol) was dissolved in 1,4-dioxane (1.5 mL), and a solution of NaOH (300 mg, 7.5 mmol) in H₂O (1.5 mL) was added. The mixture was heated to 100°C and stirred for 3 h. The reaction was monitored for completion by LC-MS. The reaction solution was adjusted to pH 1 with concentrated hydrochloric acid, filtered, and the filter cake was rinsed with water before being purified using preparative purification (preparative method: mobile phase: A: 0.1% TFA aqueous solution; B: acetonitrile; column: SunFire Sunfire C₁₈, 19×250 mm×10 μm, flow rate: 20 mL / min, column temperature: 25°C; gradient: 50%-60%) to obtain the title compound 6 (133.9 mg, 34% yield). LC-MS (ESI): m / z [M+CH₃CN+H] + :514.3. 1 H NMR (400MHz, DMSO-d6) δ12.30(br.s,1H),11.41(br.s,1H),7.67(d,J=8.0Hz,1H),7.56(d,J=7. 4Hz, 1H), 7.42 (d, J = 8.6Hz, 2H), 7.35 (d, J = 9.0Hz, 2H), 7.30-7.25 (m, 2H), 5.70 (t, J = 6.4Hz, 1H). 19 F NMR(376MHz, DMSO-d6)δ-56.79(s,3F),-60.15(s,3F),-129.92(s,1F).

[0172] Example 7: Preparation of Compounds 7A and 7B

[0173] Preparation of compound 7-2

[0174] Compound 7-1 (4.00 g, 18.02 mmol) was dissolved in anhydrous DMF (50 mL). Cs2CO3 (8.81 g, 27.03 mmol) and BnBr (3.70 g, 21.63 mmol) were added to the reaction system in sequence. The reaction was stirred at room temperature for 3 h. Water (30 mL) was added directly, and the mixture was extracted three times with ethyl acetate (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (0-100% ethyl acetate / petroleum ether) to obtain the title compound 7-2 (3.2 g, 56.9% yield). LC-MS (ESI): m / z [M+H] + =313.0.

[0175] Preparation of compound 7-3

[0176] At -78°C, n-BuLi (2.5M tetrahydrofuran solution, 64 mL, 160 mmol) was slowly added dropwise to a solution of 4-trifluoromethoxybromobenzene (42.4 g, 176.8 mmol) in anhydrous tetrahydrofuran (200 mL) under argon protection (careful to control the internal temperature of the reaction system below -60°C). After completion of the addition, the reaction mixture was stirred for one hour. Subsequently, a solution of 1-1 (19.0 g, 88.4 mmol) in tetrahydrofuran (100 mL) was added dropwise to the reaction system, and stirring was continued for one hour. The reaction mixture was poured into saturated aqueous ammonium chloride (500 mL), extracted twice with ethyl acetate (500 mL), washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 7-3 (43.0 g). LC-MS (ESI): m / z [M-H2O+H] + =360.0.

[0177] Preparation of compound 7-4

[0178] Compound 7-3 (3.0 g, 8.0 mmol) was added to a single-necked flask, followed by acetic acid (20 mL), concentrated hydrochloric acid (2 mL), and stannous chloride dihydrate (4.5 g, 20.0 mmol). The reaction system was heated to 120°C and stirred for 3 hours. The reaction system was cooled to room temperature, adjusted to alkalinity with saturated aqueous sodium bicarbonate, and filtered through a thin layer of celite. The filter cake was rinsed with a 5 / 1 EA / THF solution. The filtrate was extracted three times with ethyl acetate (100 mL). The organic phase was washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. The concentrated residue was purified by column chromatography (EtOAc / PE = 0-20%) to afford the title compound 7-4 (2.2 g, 75.9% yield). LCMS (ESI): m / z [MH] - =359.9.

[0179] Preparation of compound 7-5

[0180] Compound 7-4 (500 mg, 1.38 mmol) was added to a single-necked flask, followed by the addition of 2-butanone (10 mL), compound 7-2 (518 mg, 1.66 mmol), potassium carbonate (571 mg, 4.14 mmol), and potassium iodide (42 mg, 0.25 mmol). The reaction system was heated to 90°C and stirred for 16 hours. The reaction solution was cooled to room temperature, water (30 mL) was added, and the mixture was extracted three times with ethyl acetate (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified on a silica gel column (EA / PE = 0-30%) to obtain the title compound 7-5 (240 mg, yield 31.8%). LC-MS (ESI): m / z [MH] - =544.0.

[0181] Preparation of compound 7

[0182] Compound 7-5 (240 mg, 0.44 mmol) was dissolved in DCE (2.0 mL). TfOH (1.0 mL) was added at room temperature, and the reaction mixture was heated to 65°C and stirred for 1 hour. The reaction system was cooled to room temperature, and the pH was adjusted to alkaline with aqueous sodium bicarbonate solution. The mixture was extracted three times with DCM (20 mL). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated, and purified on a reverse phase column (ACN / 0.1% ammonia water = 10-50%) to obtain the title compound 7 (123.28 mg, yield 61.6%). LCMS (ESI): m / z [M+H] + =456.2, 1 H NMR(400MHz,DMSO-d6)δ13.20(br.s,1H),11.62(s,1H),7.81(d,J=7.6Hz,1H),7.76(d,J=2.2Hz,1H),7 .66(d,J=8.0Hz,1H),7.42(d,J=8.5Hz,2H),7.35(d,J=8.9Hz,2H),7.29(t,J=7.8Hz,1H),6.45(m,1H). 19 F NMR(376MHz, DMSO-d6)δ-56.78(s,3F),-60.04(s,3F).

[0183] Preparation of compounds 7A and 7B

[0184] Compound 7 was subjected to SFC chiral preparative separation (preparative separation method, instrument model: MG II preparative SFC (SFC-14); chromatographic column model: ChiralPak AD, 250×30 mm ID, 10 μm; mobile phase: A is CO2, B is ethanol (0.1% NH3H2O); elution gradient: B 20%; flow rate: 80 mL / min; column pressure: 100 bar; column temperature: 38°C; detection wavelength: 220 nm; cycle: ~8 min) to obtain the title compounds 7A (45 mg) and 7B (49 mg).

[0185] Compound 7A: Chiral analysis method (instrument model: Waters UPC2 analytical SFC (SFC-H); chromatographic column model: ChiralPak AD, 50×4.6 mm ID, 3 μm; mobile phase: A: CO2 B: ethanol (0.05% DEA); elution gradient: B 5-40%; flow rate: 3 mL / min; column temperature: 35°C; column pressure: 100 bar; detection wavelength: 220 nm; RT = 1.469 min). LC-MS (ESI): m / z 456.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ13.21(br.s,1H),11.63(s,1H),7.81(d,J=7.6Hz,1H),7.77(d,J=2.2Hz,1H),7. 66(d,J=8.0Hz,1H),7.42(d,J=8.5Hz,2H),7.35(d,J=8.9Hz,2H),7.7.29(t,J=7.8Hz,1H),6.45(m,1H). 19 F NMR(376MHz, DMSO-d6)δ-56.80(s,3F),-60.06(s,3F).

[0186] Compound 7B: Chiral analysis method (instrument model: Waters UPC2 analytical SFC (SFC-H); chromatographic column model: ChiralPak AD, 50×4.6 mm ID, 3 μm; mobile phase: A: CO2 B: ethanol (0.05% DEA); elution gradient: B 5-40%; flow rate: 3 mL / min; column temperature: 35°C; column pressure: 100 bar; detection wavelength: 220 nm; RT = 2.221 min). LC-MS (ESI): m / z 456.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ13.21(br.s,1H),11.63(s,1H),7.81(d,J=7.6Hz,1H),7.77(d,J=2.2Hz,1H),7. 66(d,J=8.0Hz,1H),7.42(d,J=8.5Hz,2H),7.35(d,J=8.9Hz,2H),7.7.29(t,J=7.8Hz,1H),6.45(m,1H). 19 F NMR(376MHz, DMSO-d6)δ-56.80(s,3F),-60.06(s,3F).

[0187] Example 8: Preparation of Compounds 8A and 8B

[0188] Preparation of compound 8-1

[0189] Compound 1-2 (900 mg, 2.78 mmol) was dissolved in DCM (10 mL). The air in the reaction system was replaced with nitrogen. SOBr2 (1.2 g, 5.56 mmol) and pyridine (439 mg, 5.56 mmol) were slowly added dropwise to the reaction solution in an ice-water bath. Stirring was continued in an ice-water bath for 2 hours. The reaction solution was concentrated to obtain the title compound 8-1 (1.03 g, crude product, 96.3% yield). LC-MS (ESI): m / z [MH] - =384.9.

[0190] Preparation of compound 8-2

[0191] Compound 8-1 (900 mg, 2.33 mmol) and 4,4-difluoropiperidine (564 mg, 4.66 mmol) were added to DMF (10 mL) followed by cesium carbonate (2.27 g, 6.98 mmol). The reaction system was replaced with nitrogen and allowed to react at room temperature for 2 hours. Water (40 mL) was added and the mixture was extracted three times with ethyl acetate (50 mL). The organic phase was washed three times with saturated sodium chloride solution (10 mL) and dried over anhydrous sodium sulfate. The concentrated residue was purified by column chromatography (0-15% ethyl acetate / petroleum ether) to yield the title compound 8-2 (450 mg, 40.1%). LC-MS (ESI): m / z [MH] - =426.1.

[0192] Preparation of compound 8

[0193] Compound 8-2 (400 mg, 0.94 mmol) was dissolved in DMF (5.0 mL), and lithium chloride (220 mg, 5.19 mmol) and p-toluenesulfonic acid (876 mg, 5.09 mmol) were added. The reaction system was heated to 120°C for 1 hour. The reaction solution was cooled to room temperature and purified by reverse phase column chromatography (10-55%, acetonitrile / 0.1 TFA%) to obtain the title compound 8 (234.75 mg, 60.7% yield). LC-MS (ESI): [M+H] + =414.3. 1H NMR (400MHz, DMSO-d6) δ11.64(br.s,1H),11.32(br.s,1H),7.61(t,J=8.0Hz,2H),7.41(d,J=7.0Hz,1H),7.2 3(t,J=7.8Hz,1H),6.54(dd,J=6.9,1.8Hz,1H),6.07(d,J=1.8Hz,1H),2.75–2.53(m,4H),2.12–1.82(m,4H). 19 F NMR(376MHz,DMSO-d6)δ-60.03(s,3F),-96.14(s,2F).

[0194] Preparation of compounds 8A and 8B

[0195] Compound 8 was subjected to SFC chiral preparative separation (preparative separation method, instrument model: Waters 150 preparative SFC (SFC-26); chromatographic column model: ChiralPak AD, 250×30 mm ID, 10 μm; mobile phase: A: CO2, B: ethanol (0.1% NH3H2O); elution gradient: B 15%; flow rate: 150 mL / min; column pressure: 100 bar; column temperature: 38°C; detection wavelength: 220 nm; cycle: ~4 min) to obtain the title compounds 8A (106 mg) and 8B (112 mg).

[0196] Compound 8A: Chiral analysis method (instrument model: Waters UPC2 analytical SFC (SFC-H); chromatographic column model: ChiralPak AD, 50×4.6 mm ID, 3 μm; mobile phase: A: CO2, B: ethanol (0.05% DEA); elution gradient: B 5-40%; flow rate: 3 mL / min; column temperature: 35°C; column pressure: 100 bar; detection wavelength: 220 nm; RT = 1.547 min). LC-MS (ESI): m / z 414.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.64(br.s,1H),11.32(br.s,1H),7.61(t,J=8.0Hz,2H),7.41(d,J=7.0Hz,1H),7.2 3(t,J=7.8Hz,1H),6.54(dd,J=6.9,1.8Hz,1H),6.07(d,J=1.8Hz,1H),2.75–2.53(m,4H),2.12–1.82(m,4H). 19F NMR(376MHz, DMSO-d6)δ-60.03(s,3F),-96.14(s,2F).

[0197] Compound 8B: Chiral analysis method (instrument model: Waters UPC2 analytical SFC (SFC-H); chromatographic column model: ChiralPak AD, 50×4.6 mm ID, 3 μm; mobile phase: A: CO2 B: ethanol (0.05% DEA); elution gradient: B 5-40%; flow rate: 3 mL / min; column temperature: 35°C; column pressure: 100 bar; detection wavelength: 220 nm; RT = 1.888 min). LC-MS (ESI): m / z 414.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.64(br.s,1H),11.32(br.s,1H),7.61(t,J=8.0Hz,2H),7.41(d,J=7.0Hz,1H),7.2 3(t,J=7.8Hz,1H),6.54(dd,J=6.9,1.8Hz,1H),6.07(d,J=1.8Hz,1H),2.75–2.53(m,4H),2.12–1.82(m,4H). 19 F NMR(376MHz, DMSO-d6)δ-60.03(s,3F),-96.14(s,2F).

[0198] Example 9: Preparation of Compound 9

[0199] Preparation of compound 9-1

[0200] Compound 1-2 (700.00 mg, 2.16 mmol) and fluorobenzene (2.10 mg, 21.60 mmol) were dissolved in DCE (10 mL) and replaced with nitrogen. TfOH (3.20 g, 21.60 mmol) was slowly added dropwise at room temperature and heated to 65°C with stirring for one hour. The reaction system was quenched with saturated aqueous sodium bicarbonate solution (5.0 mL), water (10 mL) was added, and the mixture was extracted three times with dichloromethane (15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the organic phase was dried by spin drying. The residue was purified by column chromatography (0-25% ethyl acetate / petroleum ether) to obtain the title compound 9-1 (650 mg, 74.8%). LC-MS (ESI): m / z [MH] - =401.0.

[0201] Preparation of compound 9

[0202] Compound 9-1 (300 mg, 0.75 mmol) was dissolved in can (8.0 mL), and TMSI (450.1 mg, 2.25 mmol) was added to the reaction mixture, which was heated to 60°C and stirred for one hour. Water (6.0 mL) was added to the reaction system, and the mixture was extracted three times with ethyl acetate (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The resulting mixture was purified by preparative separation (preparative method: mobile phase: A: 0.05% NH₄OH / H₂O; B: acetonitrile; column: Xbridge C₁₈, 250 × 19 mm × 10 μm; column temperature: 25°C; gradient: 36%-36%; retention time: 9.0-12.0 min; flow rate: 20 mL / min) to obtain the title compound 9 (153.71 mg, 52.8% yield). LCMS (ESI): m / z [M+H] + =389.2. 1 H NMR (400MHz, DMSO-d6) δ11.64(s,1H),11.43(s,1H),7.68–7.59(m,2H),7.34(d,J=6.7Hz,1H),7.29–7.19(m,5H),5.95(d,J=7.1Hz,2H). 19 F NMR(376MHz, DMSO-d6)δ-60.07(s,3F),-114.29(s,1F).

[0203] Preparation of compounds 9A and 9B

[0204] Compound 9 was subjected to SFC chiral preparative separation (preparative separation method, instrument model: WATERS 150 preparative SFC (SFC-26); chromatographic column model: ChiralPak AD, 250×30 mm ID, 10 μm; mobile phase: A: CO2, B: Ethanol (0.1% NH3H2O); elution gradient: B 30%; flow rate: 150 mL / min; column pressure: 100 bar; column temperature: 38°C; detection wavelength: 220 nm; cycle: ~5 min) to obtain the title compounds 9A (75 mg) and 9B (74 mg).

[0205] Compound 9A: Chiral analysis method (instrument model: Waters UPC2 analytical SFC (SFC-H); column model: ChiralPak AD, 50×4.6 mm ID, 3 μm; mobile phase: A: CO2, B: ethanol (0.05% DEA); elution gradient: B from 5-40% in 4 minutes, from 40-5% in 0.2 minutes, then maintained at 5% for 1.8 minutes; flow rate: 3 mL / min; column temperature: 35°C; column pressure: 100 bar; detection wavelength: 220 nm; RT = 2.083 min). LCMS (ESI): m / z [M+H] + :389.0. 1 H NMR (400MHz, DMSO-d6) δ11.64(br.s,1H),11.43(s,1H),7.68–7.59(m,2H),7.34(dd,J=6.6,1.0Hz,1H),7.29–7.19(m,5H),5.97–5.93(m,2H). 19 F NMR (376MHz, DMSO) δ-60.07 (s, 3F), -114.29 (s, 1F).

[0206] Compound 9B: Chiral analysis method (instrument model: Waters UPC2 analytical SFC (SFC-H); column model: ChiralPak AD, 50×4.6 mm ID, 3 μm; mobile phase: A: CO2 B: ethanol (0.05% DEA); elution gradient: B from 5-40% in 4 minutes, from 40-5% in 0.2 minutes, then maintained at 5% for 1.8 minutes; flow rate: 3 mL / min; column temperature: 35°C; column pressure: 100 bar; detection wavelength: 220 nm; RT = 2.946 min). LCMS (ESI): m / z [M+H] + :389.0. 1 H NMR (400MHz, DMSO-d6) δ11.64(br.s,1H),11.43(s,1H),7.63(m,2H),7.34(dd,J=6.6,1.0Hz,1H),7.29–7.19(m,5H),5.95(m,2H). 19 F NMR (376MHz, DMSO) δ-60.08 (s, 3F), -114.28 (s, 1F).

[0207] Example 10: Preparation of Compound 10

[0208] Preparation of compound 10-1

[0209] Compound 1-2 (800 mg, 2.5 mmol) was dissolved in DCE (20 mL), and toluene (2.3 g, 25 mmol) was added to the reaction. TfOH (3.75 g, 25.00 mmol) was added at room temperature, and the mixture was stirred at 70°C for 1 h. Saturated aqueous sodium bicarbonate (20 mL) was added to the reaction system to quench the reaction. Water (40 mL) was added, and the mixture was extracted three times with DCM (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrate was purified by column chromatography (0-25% EA / PE) to yield the title compound 10-1 (700 mg, 72.0%). LC-MS (ESI): m / z [MH] - =397.0.

[0210] Preparation of compound 10

[0211] Compound 10-1 (200 mg, 0.5 mmol) was dissolved in CH3CN (5.0 mL), followed by the addition of TMSI (301.5 mg, 1.5 mmol) to the reaction mixture, which was heated to 60°C and stirred for 2 h. Water (15 mL) was added to the reaction system to quench the reaction, which was then extracted three times with ethyl acetate (10 mL). The combined organic phases were dried over anhydrous sodium sulfate, and the concentrate was purified via a reverse-phase column (ACN / 0.1% aqueous ammonia = 5-95%) to afford the title compound 10 (41.66 mg, 21.7%). LCMS (ESI): m / z [M+H] + =385.2. 1 H NMR (400MHz, DMSO-d6) δ11.60(s,1H),11.36(s,1H),7.60(d,J=7.9Hz,2H),7.32(d,J=7.4Hz,1H),7. 23(t,J=7.8Hz,1H),7.19(d,J=8.2Hz,2H),7.09(d,J=8.2Hz,2H),5.95(d,J=6.3Hz,2H),2.28(s,3H). 19 F NMR(376MHz,DMSO-d6)δ-60.05(s,3F).

[0212] Example 11: Preparation of Compound 11

[0213] Preparation of compound 11-2

[0214] Compound 11-1 (3.81 g, 13.95 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL), then cooled to -78°C. n-BuLi (2.5 M tetrahydrofuran solution, 12.6 mL, 31.5 mmol) was slowly added dropwise to the reaction mixture and stirred at -78°C for 30 minutes. A solution of compound 1-1 (1.5 g, 6.98 mmol) in tetrahydrofuran (10 mL) was added dropwise to the reaction system, stirred at -78°C for 30 minutes, then gradually warmed to room temperature and allowed to react for 12 hours. The reaction system was quenched with saturated aqueous ammonium chloride (8.0 mL), water (40 mL) was added, and the mixture was extracted three times with ethyl acetate (40 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrate was purified by column chromatography (0-100% EA / PE) to obtain the title compound 11-2 (800 mg, 28.0%). LC-MS (ESI): m / z [M+H] + =410.1.

[0215] Preparation of compound 11

[0216] Compound 11-2 (300 mg, 0.73 mmol) was dissolved in DCE (8.0 mL), and toluene (676 mg, 7.33 mmol) was added to the solvent. TfOH (1.10 g, 7.33 mmol) was added at room temperature, the nitrogen atmosphere was replaced, and the mixture was stirred at 70°C for 1 h. The reaction system was quenched with saturated aqueous sodium bicarbonate (5 mL), water (10 mL) was added, and the mixture was extracted three times with DCM (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrate was purified by preparative separation (preparative method: mobile phase: A: 0.05% NH4OH / H2O; B: acetonitrile; column: Xbridge C18, 250 × 19 mm × 10 μm; column temperature: 25°C; gradient: 45%-50%; retention time: 9.1-10.1; flow rate: 20 mL / min) to obtain the title compound 11 (54.71 mg, 19.6%). LCMS (ESI): m / z [M+H] + =384.2. 1 H NMR (400MHz, DMSO-d6) δ11.27(s,1H),7.83(d,J=5.4Hz,1H),7.55(dd,J=18.4,7.7Hz,2H ),7.25–7.13(m,3H),7.06(d,J=8.2Hz,2H),6.25–6.18(m,2H),5.97(s,2H),2.27(s,3H). 19 F NMR(376MHz,DMSO-d6)δ-60.01(s,3F).

[0217] Example 12: Preparation of Compounds 12A and 12B

[0218] Preparation of compound 12-1

[0219] Compound 7-2 (2.9 g, 9.29 mmol) was dissolved in anhydrous tetrahydrofuran (40 mL). The reaction system was replaced with nitrogen. i-PrMgCl (1.3 M tetrahydrofuran solution, 7.2 mL, 9.29 mmol) was added dropwise at -10°C and stirred for 0.5 hours. A solution of compound 1-1 (0.80 g, 3.72 mmol) in anhydrous tetrahydrofuran (5 mL) was added dropwise to the reaction mixture and stirred at -10°C for 2 hours. The reaction system was quenched with saturated aqueous ammonium chloride (10 mL), water (40 mL) was added, and the mixture was extracted three times with ethyl acetate (40 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the organic phase was evaporated to dryness. The residue was purified by reverse-phase chromatography (5%-95% H2O (0.05% NH4OH) / ACN) to obtain the title compound 12-1 (350 mg). LC-MS (ESI): m / z [M+H] + =402.0.

[0220] Preparation of compound 12

[0221] The compound (0.35 g, 1.63 mmol) and toluene (1.49 g, 16.30 mmol) were dissolved in anhydrous DCE (3.0 mL). The atmosphere was replaced with nitrogen, and TfOH (2.45 g, 16.30 mmol) was added to the reaction mixture at room temperature. The mixture was heated to 70°C and stirred for 1 hour. The reaction was quenched with saturated aqueous sodium bicarbonate (5 mL), and water (10 mL) was added. The mixture was extracted three times with dichloromethane (15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrate was purified by preparative separation (mobile phase: A: 0.1% TFA / H2O; B: acetonitrile; column: Pursuit XRs C18, 250 × 21.2 mm × 10 μm; column temperature: 25°C; gradient: 49%-59%; retention time: 7.4-8.4 min; flow rate: 20 mL / min) to afford the title compound 12 (6.48 mg, 1.03% yield). LCMS (ESI): m / z[M+1] + =386.2. 1H NMR(400MHz,DMSO-d6)δ13.14 (s,1H),11.50(s,1H),7.73(d,J=7.6Hz,1H),7.71(d,J=2.2Hz,1H),7.62(d,J=8.0Hz,1H),7 .26(t,J=7.8Hz,1H),7.21(d,J=8.0Hz,2H),7.10(d,J=8.1Hz,2H),6.41(s,1H),2.28(s,3H). 19 F NMR(376MHz,DMSO-d6)δ-60.05(s,3F).

[0222] Preparation of compounds 12A and 12B

[0223] Compound 12 (1.0 g) was subjected to SFC preparative chiral separation (preparative separation method, instrument model: MGⅡ preparative SFC (SFC-14); chromatographic column model: ChiralPak AD, 250×30 mm ID, 10 μm; mobile phase: A is CO2, B is ethanol (0.1% NH3H2O); elution gradient: B 30%; flow rate: 80 mL / min; column pressure: 100 bar; column temperature: 38°C; detection wavelength: 220 nm; cycle: ~8.12 min) to obtain the title compounds 12A (493 mg) and 12B (472 mg).

[0224] Compound 12A: LC-MS (ESI): m / z 386.2 [M+H] + Chiral analysis method (chromatographic column model: Waters UPC2 analytical SFC (SFC-H); mobile phase: A is CO2, B is ethanol (0.05% DEA); flow rate: 3 mL / min; column temperature: 35°C; column pressure: 100 bar; detection wavelength: 220 nm; RT = 2.038 min). 1 H NMR (400MHz, DMSO-d6) δ13.14(s,1H),11.50(s,1H),7.73(d,J=7.6Hz,1H),7.71(d,J=2.2Hz,1H),7.62(d,J =8.0Hz, 1H), 7.26 (t, J = 7.8Hz, 1H), 7.21 (d, J = 8.0Hz, 2H), 7.10 (d, J = 8.1Hz, 2H), 6.41 (s, 1H), 2.28 (s, 3H). 19 F NMR(376MHz,DMSO-d6)δ-60.05(s,3F).

[0225] Compound 12B: LC-MS (ESI): m / z 386.2 [M+H] + Chiral analysis method (chromatographic column model: Waters UPC2 analytical SFC (SFC-H); mobile phase: A is CO2, B is ethanol (0.05% DEA); flow rate: 3 mL / min; column temperature: 35°C; column pressure: 100 bar; detection wavelength: 220 nm; RT = 3.166 min). 1 H NMR (400MHz, DMSO-d6) δ13.14(s,1H),11.50(s,1H),7.73(d,J=7.6Hz,1H),7.71(d,J=2.2Hz,1H),7.62(d,J =8.0Hz, 1H), 7.26 (t, J = 7.8Hz, 1H), 7.21 (d, J = 8.0Hz, 2H), 7.10 (d, J = 8.1Hz, 2H), 6.41 (s, 1H), 2.28 (s, 3H). 19 F NMR(376MHz,DMSO-d6)δ-60.05(s,3F).

[0226] Example 13: Preparation of Compound 13

[0227] Preparation of compound 13-1

[0228] Compound 12-1 (2 g, 4.99 mmol) and fluorobenzene (959 mg, 9.98 mmol) were dissolved in DCE (20 mL). TfOH (7.49 g, 49.9 mmol) was slowly added dropwise at room temperature, and the temperature was raised to 60°C and stirred for 1 hour. The reaction system was quenched with saturated aqueous NH4Cl (10 mL), water (10 mL) was added, and the mixture was extracted three times with dichloromethane (15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrate was purified by column chromatography (0-100% ethyl acetate / petroleum ether) to obtain compound 13-1 (380 mg, 16% yield). LC-MS (ESI): m / z [M+H] + =479.9.

[0229] Preparation of compound 13

[0230] Compound 13-1 (380 mg, 0.79 mmol) and fluorobenzene (0.3 mL) were dissolved in DCE (4 mL), and TfOH (2 mL) was slowly added dropwise. The reaction system was heated to 80°C for 1 hour. The reaction solution was quenched with saturated aqueous NH4Cl (3 mL) and extracted three times with dichloromethane (15 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The concentrate was purified by preparative separation (chromatographic column: Pursuit XRs C18, 19.5×250 mm, 10 μm; mobile phase A: 0.1% TFA / H2O, mobile phase B: ACN; flow rate: 20 mL / min; gradient: 42% to 52%; retention time: 9.2-10.2 min) to obtain the title compound 13 (6.27 mg, 2% yield). LC-MS (ESI): [M+H] + =390.1. 1 H NMR(400MHz,DMSO-d6)δ 13.17(br.s,1H),11.60(br.s,1H),7.77(d,J=7.5Hz,1H),7.73(d,J=2.1Hz,1H),7.64(d,J=8.0Hz,1H),7.28–7.23(m,5H),6.42(d,J=2.0Hz,1H). 19 F NMR(376MHz, DMSO-d6)δ-60.03(s,3F),-113.83(s,1F).

[0231] Example 14: Preparation of Compound 14

[0232] Preparation of compound 14-1

[0233] 1-Bromo-4-(2,2,2-trifluoro-ethoxy)benzene (3.0 g, 11.76 mmol) was dissolved in tetrahydrofuran (20 mL). The mixture was cooled to -78°C and n-BuLi (2.5 M tetrahydrofuran solution, 5.88 mL, 14.7 mmol) was slowly added dropwise to the reaction mixture. The mixture was stirred at -78°C for 30 minutes. Subsequently, a solution of compound 1-1 (1.26 g, 5.88 mmol) in tetrahydrofuran (5 mL) was slowly added dropwise to the reaction mixture. The mixture was stirred at -78°C for 1 hour. The reaction mixture was quenched with saturated ammonium chloride solution (10 mL), water (30 mL) was added, and the mixture was extracted three times with ethyl acetate (40 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrate was purified by column chromatography (0-30% EA / PE) to obtain compound 14-1 (1.2 g, 52.2% yield). LC-MS (ESI): m / z [MH] - =390.0.

[0234] Preparation of compound 14-2

[0235] Compound 14-1 (1.10 g, 2.81 mmol) was dissolved in a mixture of acetic acid (15 mL) and concentrated hydrochloric acid (1.5 mL). Stannous chloride dihydrate (1.59 g, 7.03 mmol) was then added, and the reaction mixture was stirred at 120°C for 1 h. The reaction system was quenched with saturated aqueous sodium bicarbonate (20 mL), and water (20 mL) was added. The mixture was extracted three times with dichloromethane (40 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrate was purified by column chromatography (0-20% EA / PE) to yield the title compound 14-2 (970 mg, 92.1% yield). LC-MS (ESI): m / z [MH] - =374.0.

[0236] Preparation of compound 14-3

[0237] Compound 7-2 (870 mg, 2.32 mmol) and compound 14-2 (867 mg, 2.78 mmol) were dissolved in butanone (10 mL). KI (77 mg, 0.46 mmol) and K2CO3 (641.29 mg, 4.64 mmol) were added sequentially to the reaction mixture, and the mixture was stirred under reflux at 90°C for 12 h. Water (15 mL) was added to the reaction system, and the mixture was extracted three times with EtOAc (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrate was purified by column chromatography (0-40% EA / PE) to obtain the title compound 14-3 (800 mg, 61.7% yield). LC-MS (ESI): m / z [MH] - =557.9.

[0238] Preparation of compound 14

[0239] Compound 14-3 (300 mg, 0.54 mmol) was dissolved in DCE (2 mL), and TfOH (1 mL) was added dropwise to the reaction mixture at room temperature and stirred at 70°C for 1 h. Saturated aqueous sodium bicarbonate (5 mL) was added to the reaction mixture, followed by water (5 mL) and extraction with DCM (20 mL) three times. The organic phases were combined and dried over anhydrous sodium sulfate. The concentrate was purified by preparative separation (preparative method: mobile phase: A: 0.1% TFA / H2O; B: ACN; column: SunFire Sunfire C18, 250×19 mm×10 μm; column temperature: 25°C; gradient: 49%-59%; retention time: 8.2-9.4 min; flow rate: 20 mL / min) to obtain the title compound 14 (105.98 mg, 41.8% yield). LCMS (ESI): m / z [M+H] + =470.2. 1H NMR (400MHz, DMSO-d6) δ13.17(s,1H),11.54(br.s,1H),7.76(d,J=7.6Hz,1H),7.71(d,J=2.1Hz,1H),7.64(d,J=8.1Hz ,1H),7.28(t,J=7.8Hz,1H),7.19(d,J=8.9Hz,2H),7.09(d,J=8.9Hz,2H),6.42(d,J=1.5Hz,1H),4.77(q,J=8.9Hz,2H). 19 F NMR(376MHz, DMSO-d6)δ-60.03(s,3F),-72.57(s,3F).

[0240] Example 15: Preparation of Compound 15

[0241] Preparation of compound 15-1

[0242] Compound 1-2 (2 g, 6.17 mmol) was added to a round-bottom flask, followed by dichloromethane (50 mL), pyridine (975 mg, 12.34 mmol), and thionyl chloride (1.47 g, 12.34 mmol). The reaction mixture was stirred at room temperature for 2 hours. Tetrahydrofuran (20 mL), acetic acid (5 mL), and zinc powder (4 g, 61.68 mmol) were then added, and the reaction mixture was allowed to react at 70°C for 3 hours. The reaction mixture was filtered through celite, and the filtrate was extracted three times with water (30 mL) and ethyl acetate (40 mL). The organic phase was washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. The concentrate was purified by normal phase column chromatography (petroleum ether / ethyl acetate = 0-100%) to obtain the title compound 15-1 (700 mg, yield 36.82%). LC-MS (ESI): m / z [MH] - =307.0.

[0243] Preparation of compound 15-3

[0244] Compound 15-1 (300 mg, 0.973 mmol) was added to a round-bottom flask, followed by the addition of 2-butanone (15 mL), compound 15-2 (290 mg, 1.46 mmol), potassium carbonate (269 mg, 1.95 mmol), and potassium iodide (32 mg, 0.197 mmol). The reaction system was purged with nitrogen and allowed to react at 90°C for 16 hours. Water (20 mL) and ethyl acetate (20 mL) were added to the reaction solution, which was extracted twice. The organic phase was washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. The concentrate was purified by normal phase column chromatography (ethyl acetate / petroleum ether = 0-100%) to afford the title compound 15-3 (46 mg, 11.1% yield). LC-MS (ESI): m / z [MH] - =425.0.

[0245] Preparation of compound 15

[0246] Compound 15-3 (46 mg, 0.107 mmol) was added to a single-necked flask. DMF (3 mL), anhydrous p-toluenesulfonic acid (93 mg, 0.539 mmol), and lithium chloride (23 mg, 0.539 mmol) were added sequentially to the reaction flask. The reaction mixture was reacted at 120°C for 3 hours. Water (10 mL) was added to the reaction system, and the mixture was extracted three times with ethyl acetate (10 mL). The organic phase was washed with saturated brine (30 mL). The mixture was dried over anhydrous sodium sulfate, and the concentrate was purified by preparative separation (preparative method: mobile phase: A: 10 mmol formic acid solution; B: acetonitrile; column: Pursuit XRs C18 250 × 19.5 mm × 10 μm; column temperature: 25°C; gradient: 40%-45% acetonitrile over 8.0-9.2 min; flow rate: 20 mL / min) to obtain the title compound 15 (11 mg, 22.2% yield). LC-MS (ESI): m / z [M+H] + =413.2. 1 H NMR (400MHz, DMSO-d6) δ11.62(br.s,1H),11.24(br.s,1H),7.67(d,J=7.5Hz,1H),7.60(d,J=8.1Hz,1H),7.38(d,J=7.0Hz,1H) ,7.26(t,J=7.8Hz,1H),6.35(dd,J=7.0,1.7Hz,1H),6.12(d,J=1.4Hz,1H),2.66(m,1H),1.85(m,4H),1.40(m,3H),1.15(m,1H). 19F NMR (376MHz, DMSO-d6) δ -60.13 (s), -89.69 (d, J = 232.7Hz, 1F), -100.90 (d, J = 232.7, 1F).

[0247] Example 16: Preparation of Compound 16

[0248] Preparation of compound 16-2

[0249] 4-Bromo-2-methoxypyridine (1.5 g, 8.19 mmol) was added to anhydrous tetrahydrofuran (20 mL). The reaction mixture was cooled to -60°C and n-butyllithium (2.5 M tetrahydrofuran solution, 3.93 mL, 9.83 mmol) was slowly added dropwise. The reaction system was stirred for 30 minutes. A solution of compound 16-1 (600 mg, 3.28 mmol) in tetrahydrofuran (5 mL) was slowly added dropwise to the reaction system, and the reaction was continued for 2 hours. The reaction mixture was extracted three times with saturated aqueous ammonium chloride (10 mL), water (30 mL), and ethyl acetate (60 mL). The organic phase was washed with saturated aqueous sodium chloride (60 mL). The organic phase was concentrated and purified by normal phase column chromatography (petroleum ether / ethyl acetate = 0-60%) to obtain the title compound 16-2 (400 mg, yield 41.77%). LC-MS (ESI): m / z 293.0 [M+H] + .

[0250] Preparation of compound 16-3

[0251] Compound 16-2 (400 mg, 1.37 mmol) was added to a round-bottom flask, followed by the addition of dichloromethane (5 mL), pyridine (217 mg, 2.74 mmol), and thionyl chloride (326 mg, 2.74 mmol). The reaction mixture was stirred for 2 hours. Tetrahydrofuran (15 mL), acetic acid (2 mL), and zinc powder (447 mg, 6.84 mmol) were then added, and the reaction mixture was allowed to react at 70°C for 3 hours. The reaction mixture was filtered through celite, and the filtrate was extracted three times with water (15 mL) and ethyl acetate (20 mL). The organic phase was washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. The concentrate was purified by normal phase column chromatography (petroleum ether / ethyl acetate = 0-100%) to afford the title compound 16-3 (230 mg, 60.83% yield). LC-MS (ESI): m / z 275.0 [MH] - .

[0252] Preparation of compound 16-5

[0253] Compound 16-3 (230 mg, 0.832 mmol) was added to a round-bottom flask, followed by the addition of 2-butanone (15 mL), compound 16-4 (177 mg, 0.999 mmol), potassium carbonate (230 mg, 1.67 mmol), and potassium iodide (28 mg, 0.166 mmol). The reaction mixture was reacted at 80°C for 5 hours. Water (30 mL) was then added to the reaction system, and the mixture was extracted twice with ethyl acetate (30 mL). The mixture was washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. The concentrate was purified by normal phase column chromatography (ethyl acetate / petroleum ether = 0-100%) to obtain the title compound 16-5 (26 mg, yield 8.39%). LC-MS (ESI): m / z 371.1 [MH] - .

[0254] Preparation of compound 16

[0255] Compound 16-5 (20 mg, 0.053 mmol) was added to a single-necked flask. DMF (3 mL), anhydrous p-toluenesulfonic acid (50 mg, 0.290 mmol), and lithium chloride (13 mg, 0.295 mmol) were then added sequentially. The reaction mixture was allowed to react at 120°C for 3 hours. Water (10 mL) was added to the reaction system, and the mixture was extracted three times with ethyl acetate (10 mL). The organic phase was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The concentrate was purified by preparative separation (preparative method: mobile phase: A: 10 mmol formic acid solution; B: acetonitrile; column: Pursuit XRs C18 250 × 19.5 mm × 10 μm; column temperature: 25°C; gradient: 46%-56% acetonitrile over 8.0-9.2 min; flow rate: 20 mL / min) to afford the title compound 16 (11.17 mg, 58.04% yield). LCMS (ESI): 359.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.55(br.s,1H),11.41(s,1H),7.34(d,J=7.0Hz,1H),7.19(dd,J=8.3,4.2Hz,1H),7.07( dt,J=11.2,7.7Hz,1H),6.36(dd,J=7.0,1.7Hz,1H),5.99(d,J=1.4Hz,1H),1.75–1.12(m,12H),1.00–0.86(m,1H). 19 F NMR (376MHz, DMSO-d6) δ -138.56 (d, J = 21.8Hz, 1F), -156.52 (d, J = 21.8Hz, 1F).

[0256] Example 17: Preparation of Compound 17

[0257] Preparation of compound 17-2

[0258] Compound 17-1 (4.9 g, 20.46 mmol) was dissolved in tetrahydrofuran (20 mL). The atmosphere was replaced with nitrogen three times, and the mixture was cooled to approximately 0°C in an ice bath. i-PrMgCl (1.3 M tetrahydrofuran solution, 15.74 mL, 20.46 mmol) was slowly added dropwise, and stirred at approximately 0°C for 0.5 hours. A solution of compound 1-1 (2 g, 9.3 mmol) in tetrahydrofuran (15 mL) was slowly added dropwise to the reaction mixture, and the reaction system was gradually warmed to room temperature and stirred for 1 hour. The reaction mixture was quenched with saturated aqueous NH4Cl (10 mL), and water (10 mL) was added. The mixture was extracted three times with ethyl acetate (15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (0-100% ethyl acetate / petroleum ether) to afford the title compound 17-2 (1.5 g, 49% yield). LC-MS (ESI): m / z [MH] - =326.9.

[0259] Preparation of compound 17-3

[0260] Compound 17-2 (800 mg, 2.44 mmol) was added to a mixed solution of toluene (2.24 g, 24.4 mmol) and DCE (8 mL). The reaction system was purged with nitrogen three times, and trifluoromethanesulfonic acid (3.66 g, 24.4 mmol) was added dropwise at room temperature, followed by reaction for 1 hour. The reaction solution was quenched with saturated aqueous NaHCO3 (5 mL), water (5 mL) was added, and the mixture was extracted three times with dichloromethane (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrate was purified by column chromatography (0-100% ethyl acetate / petroleum ether) to obtain the title compound 17-3 (700 mg, 71.1% yield). LC-MS (ESI): m / z [MH] - =400.9.

[0261] Preparation of compound 17

[0262] Compound 17-3 (300 mg, 0.75 mmol) and thiourea (228.36 mg, 3 mmol) were dissolved in n-butanol (3 mL). The reaction system was heated to 120°C for 12 h. The reaction solution was cooled to room temperature, filtered, and the filter cake was washed with n-butanol. The filtrate concentrate was purified by preparative separation (chromatographic column: Pursuit XRs C18, 19.5×250 mm, 10 μm; mobile phase A: 0.1% TFA / H2O, mobile phase B: ACN; flow rate: 20 mL / min; gradient: 52% to 62%; retention time: 8.4-10 min) to obtain the title compound 17 (54 mg, 9% yield). LC-MS (ESI): [2M+H] + =799.5. 1 H NMR (400MHz, DMSO-d6) δ13.44(s,1H),11.40(s,1H),7.81–7.50(m,2H),7.32–7.14(m,5H),7.14–7.06(m,3H),2.27(s,3H). 19 F NMR(376MHz,DMSO-d6)δ-59.99(s,3F).

[0263] Example 18: Preparation of Compound 18

[0264] Preparation of compound 18

[0265] Compound 18-1 (180 mg, 0.45 mmol) was dissolved in n-butanol (10 mL), followed by the addition of thiourea (136 mg, 1.79 mmol). After the addition, the atmosphere was replaced with nitrogen, and the temperature was raised to 120°C for 12 h. The reaction system was cooled to room temperature, and water (20 mL) was added. Extraction was performed three times with ethyl acetate (20 mL). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The concentrate was purified by preparative chromatography (mobile phase: A: 0.1% TFA / H2O; B: acetonitrile; column: Atlantis™ T3 Prep OBD™, 19×250 mm, 10 μm; gradient: 52%-60% retention time: 8.5-9.2 min; flow rate: 20 mL / min) to obtain the title compound 18 (14.03 mg, 3.9% yield). LC-MS (ESI): m / z [2M+H] + =799.5. 1H NMR (400MHz, DMSO-d6) δ13.56(s,1H),11.45(s,1H),7.66–7.57(m,3H),7.26(t,J=7.9Hz,1H),7.20(d ,J=8.1Hz,2H),7.09(d,J=8.2Hz,2H),6.92(d,J=1.5Hz,1H),6.49(dd,J=6.7,1.8Hz,1H),2.29(s,3H). 19 F NMR(376MHz,DMSO-d6)δ-60.07(s,3F).

[0266] Example 19: Preparation of Compound 19

[0267] Preparation of compound 19-1

[0268] Compound 12 (250 mg, 0.649 mmol) was added to a single-necked flask. Acetonitrile (5 mL) and tribromophosphine oxide (223 mg, 0.778 mmol) were added to the reaction flask, and the reaction system was reacted at 80°C for 2 hours. The reaction system was cooled in an ice-water bath and quenched with saturated aqueous sodium bicarbonate (15 mL). The reaction was extracted three times with dichloromethane (20 mL). The organic phase was washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. The concentrate was purified by preparative separation (preparative column: Pursuit XRs C18 19.5 × 250 mm × 10 μm; flow rate: 20 mL / min; mobile phase: A-0.1% TFA aqueous solution, B-acetonitrile; gradient: 26-36% acetonitrile content, retention time: 14.0-14.6 min) to obtain the title compound 19-1 (150 mg, yield: 51.58%). LCMS (ESI): m / z = 448.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.59(br.s,1H),9.11(d,J=2.0Hz,1H),7.81(d,J=7.5Hz,1H),7.67– 7.60(m,2H),7.26(t,J=7.8Hz,1H),7.20(d,J=8.2Hz,2H),7.06(d,J=8.2Hz,2H),2.28(s,3H). 19 F NMR(376MHz,DMSO-d6)δ-59.96(s,3F).

[0269] Preparation of compound 19

[0270] Compound 19-1 (136 mg, 0.303 mmol), aqueous ammonia (30%, 212 mg, 6.07 mmol), and dioxane (5 mL) were added sequentially to a sealed container. Nitrogen was introduced for 5 seconds, then the container was closed and the reaction system was allowed to react at 120°C for 16 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted twice with ethyl acetate (20 mL). The organic phase was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The concentrate was purified by preparative separation (preparative column: Pursuit XRs C18 19.5 × 250 mm × 10 μm; flow rate: 20 mL / min; mobile phase: A-0.1% TFA aqueous solution, B-acetonitrile; gradient: 26-36% acetonitrile content, retention time: 9.0-13.6 min) to obtain the title compound 19 (14.54 mg, yield: 12.47%). LC-MS (ESI): m / z = 385.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.42(s,1H),8.18(d,J=2.0Hz,1H),7.63(dd,J=15.3,7.7Hz,2H),7.25(t,J=7. 8Hz, 1H), 7.20 (d, J = 8.1Hz, 2H), 7.06 (d, J = 8.2Hz, 2H), 6.52 (d, J = 2.0Hz, 1H), 6.46 (s, 2H), 2.28 (s, 3H). 19 F NMR(376MHz,DMSO-d6)δ-60.05(s,3F).

[0271] Example 20: Preparation of Compound 20

[0272] Preparation of compound 20

[0273] Compound 19-1 (50 mg, 0.112 mmol) was added to a single-necked flask. n-Butanol (10 mL) and thiourea (11 mg, 0.134 mmol) were added to the reaction flask, respectively. The reaction system was reacted at 120°C for 3 hours. Water (15 mL) was added to the reaction solution, and the mixture was extracted twice with ethyl acetate (20 mL). The organic phase was washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. The concentrate was purified by preparative separation (preparative column: SunFire C18 19×250 mm×10 μm; flow rate: 20 mL / min; mobile phase: A-0.1% TFA aqueous solution, B-acetonitrile; gradient: 55-65% acetonitrile content, retention time 7.7-9.6 min) to obtain the title compound 20 (7.47 mg, yield 16.68%). LC-MS (ESI): m / z = 402.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ14.85(s,1H),11.58(s,1H),8.13(d,J=2.2Hz,1H),7.77(d,J=7.5Hz, 1H), 7.64 (d, J = 8.0Hz, 1H), 7.28 (t, J = 7.8Hz, 1H), 7.22 (d, J = 8.1Hz, 2H), 7.16 (d, J = 1.9Hz, 1H), 7.11 (d, J = 8.2Hz, 2H), 2.29 (s, 3H). 19 F NMR(376MHz,DMSO-d6)δ-60.02(s,3F).

[0274] Example 21: Preparation of Compound 21

[0275] Preparation of compound 21-1

[0276] Compound 12-1 (500 mg, 1.25 mmol) was added to a single-necked flask, followed by DCM (10 mL) and pyridine (197 mg, 2.49 mmol). The reaction system was cooled to 0°C, and thionyl chloride (296 mg, 2.49 mmol) was slowly added dropwise. The reaction solution was stirred at room temperature for 2 hours. Most of the solvent in the reaction solution was evaporated, and DMF (5 mL), sodium bicarbonate (524 mg, 6.23 mmol), and 4,4-difluoropiperidine (300 mg, 2.49 mmol) were added sequentially. The reaction solution was allowed to react at room temperature for 30 minutes. Water (20 mL) was added to the reaction system, and the mixture was extracted three times with ethyl acetate (20 mL). The organic phase was washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. The concentrate was purified by normal phase column chromatography (petroleum ether / ethyl acetate = 0-100%) to obtain the title compound 21-1 (130 mg, yield 24.86%). LCMS (ESI): m / z = 503.0 [MH] - .

[0277] Preparation of compound 21

[0278] Compound 21-1 (130 mg, 0.257 mmol) was added to a single-necked flask, followed by dichloroethane (5 mL) and TfOH (193 mg, 1.29 mmol). The reaction mixture was allowed to react at 60°C for 1 hour. The reaction system was quenched with saturated aqueous sodium bicarbonate (5 mL) in an ice-water bath, extracted three times with dichloromethane (20 mL), and the organic phase was washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. The concentrate was purified by preparative HPLC (preparative column: Pursuit XRs C18, 19.5 × 250 × 10 μm; flow rate: 20 mL / min; mobile phase: A-0.1% aqueous TFA, B-acetonitrile; gradient: 45%-55% acetonitrile content, retention time 7.9-8.4 min) to obtain the title compound 21 (26.18 mg, yield 24.52%). LC-MS (ESI): m / z = 415.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ13.18(s,1H),11.43(s,1H),8.33(d,J=2.0Hz,1H),7.74(d,J=7.5H z, 1H), 7.65 (d, J = 8.1Hz, 1H), 7.29 (t, J = 7.8Hz, 1H), 6.38 (s, 1H), 2.56 (m, 4H), 1.99 (m, 4H). 19 F NMR(376MHz, DMSO-d6)δ-60.02(s,3F),-77.75(s,2F).

[0279] Example 22: Preparation of Compound 22

[0280] Preparation of compound 22-2

[0281] Compound 22-1 (1.3 g, 4.46 mmol) was added to a single-necked flask, followed by the addition of 2-butanone (30 mL), 2,4-dichloropyrimidine (800 mg, 5.36 mmol), potassium carbonate (1.23 g, 8.93 mmol), and potassium iodide (150 mg, 0.892 mmol). The reaction system was purged with nitrogen and heated to 80°C for 16 hours. After completion, the reaction was quenched with water (40 mL) and extracted three times with ethyl acetate (40 mL). The organic phase was washed with saturated brine (40 mL) and dried over anhydrous sodium sulfate. The concentrate was purified by normal phase column chromatography (petroleum ether / ethyl acetate = 0-100%) to obtain the title compound 22-2 (140 mg, 7.7% yield). LC-MS (ESI): m / z 401.9 [MH] - .

[0282] Preparation of compound 22

[0283] Compound 22-2 (140 mg, 0.347 mmol) was added to a single-necked flask. Tetrahydrofuran (5 mL) and aqueous sodium hydroxide (4.0 M, 0.35 mL, 1.39 mmol) were then added to the reaction flask. The reaction system was allowed to react at 70°C for 16 hours. The reaction solution was quenched with saturated aqueous ammonium chloride (20 mL) and extracted twice with ethyl acetate (20 mL). The organic phase was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The concentrate was purified by preparative separation (preparative column: Agilent C18 19×250 mm×10 μm; flow rate: 20 mL / min; mobile phase: A: 0.1% aqueous TFA; B: acetonitrile; gradient: 51-51% acetonitrile content, retention time: 8.0-9.2 min) to obtain the title compound 22 (31.93 mg, yield: 24.7%). LC-MS (ESI): m / z 386.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.99(br.s,1H),11.27(br.s,1H),7.93(d,J=6.5Hz,1H),7.60( t,J=7.7Hz,2H),7.21(m,3H),7.10(d,J=8.3Hz,2H),6.23(d,J=6.5Hz,1H),2.29(s,3H). 19 F NMR(376MHz,DMSO-d6)δ-60.01(s,3F).

[0284] Example 23: Preparation of Compound 23

[0285] Preparation of compound 23-1

[0286] Under nitrogen, i-PrMgCl (1.3 M tetrahydrofuran solution, 26 mL, 33.8 mmol) was added dropwise to a solution of 5-bromo-2-methoxypyrimidine (5.27 g, 27.89 mmol) in tetrahydrofuran (30 mL) at -78°C and stirred for 30 min. Compound 1-1 (3.0 g, 13.95 mmol) in tetrahydrofuran (20 mL) was then added dropwise, and the reaction system was stirred at room temperature for 16 hours. The reaction solution was quenched with saturated aqueous ammonium chloride (20 mL), extracted twice with ethyl acetate (20 mL), and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and the concentrate was purified by column chromatography (EA:PE = 0-30%) to afford the title compound 23-1 (700 mg, 16% yield). LC-MS (ESI): m / z [M+H] + =326.1.

[0287] Preparation of compound 23-2

[0288] Compound 23-1 (700 mg, 2.15 mmol) was dissolved in a mixture of toluene (1.98 g, 21.54 mmol) and DCE (5 mL). TfOH (3.23 g, 21.54 mmol) was then slowly added, and the reaction mixture was stirred at room temperature for 2 h. The pH of the reaction mixture was adjusted to a weakly alkaline state with saturated aqueous sodium bicarbonate solution, and the mixture was extracted twice with DCM (20 mL). The organic phase was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The concentrate was purified on a C18 column (ACN:0.1% NH3.H2O aqueous solution = 5%-50%) to obtain the title compound 23-2 (300 mg, 35% yield). LC-MS (ESI): m / z [M+H] + =400.1.

[0289] Preparation of compound 23

[0290] Compound 23-2 (100 mg, 0.25 mmol), TMSCl (82 mg, 0.75 mmol), and KI (125 mg, 0.75 mmol) were sequentially dissolved in ACN (2 mL). The reaction mixture was heated to 60°C and stirred for 1 h. Water (10 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (20 mL). The organic phase was washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The concentrate was purified by preparative purification (preparative method: mobile phase: A: 0.1% NH4HCO3 aqueous solution; B: acetonitrile; column: Xbridge C18, 19×250 mm×10 μm, flow rate: 20 mL / min, column temperature: 25°C; gradient: 35%-35%, retention time: 9.6-11.5 min) to obtain the title compound 23 (17.34 mg, yield 18%). LC-MS (ESI): m / z [M+H] + =386.2. 1 H NMR (400MHz, MeOD) δ8.09(s,2H),7.62–7.50(m,2H),7.26-7.14(m,5H),2.32(s,3H). 19 F NMR (376MHz, MeOD) δ-63.04 (s, 3F).

[0291] Example 24: Preparation of Compound 24

[0292] Preparation of compound 24-2

[0293] Under N₂ protection, n-BuLi (2.5 M tetrahydrofuran solution, 1.67 mL, 4.18 mmol) was added dropwise to 24-1 (506 mg, 1.86 mmol) dissolved in tetrahydrofuran (3 mL) at -78°C, and the mixture was stirred for 30 min. A solution of 1-1 (200 mg, 0.97 mmol) dissolved in tetrahydrofuran (2 mL) was then added dropwise to the reaction system, and the mixture was stirred at -78°C for 2 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (15 mL), extracted three times with ethyl acetate (20 mL), and the organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and the concentrate was purified by column chromatography (EA:PE = 0-20%) to afford the title compound 24-2 (100 mg, 26% yield). LC-MS (ESI): m / z [MH] - =408.1.

[0294] Preparation of compound 24

[0295] Compound 24-2 (100 mg, 0.24 mmol) was dissolved in a mixture of toluene (225 mg, 2.44 mmol) and DCM (1 mL). TfOH (367 mg, 2.44 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 2 h. The pH of the reaction mixture was adjusted to a weak base with saturated sodium bicarbonate, extracted three times with ethyl acetate (20 mL), and the organic phase was washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The concentrate was purified by preparative purification (preparative method: mobile phase: A: 0.1% NH4HCO3 aqueous solution; B: acetonitrile; column: Xbridge C18, 19 × 250 mm × 10 μm, flow rate: 20 mL / min, column temperature: 25°C; gradient: 46%-46%) to obtain the title compound 24 (17.02 mg, 18% yield). LC-MS (ESI): m / z [M+H] + =384.2. 1 H NMR (400MHz, DMSO-d6) δ11.20(s,1H),7.61(d,J=1.8Hz,1H),7.54(t,J=7.5Hz,2H),7.2 2–7.12(m,4H),7.04(d,J=8.1Hz,2H),6.42(d,J=8.7Hz,1H),6.03(s,2H),2.27(s,3H). 19 F NMR(376MHz,DMSO-d6)δ-59.99(s,3F).

[0296] Example 25: Preparation of Compound 25

[0297] Preparation of compound 25-2

[0298] Compound 25-1 (500 mg, 1.63 mmol) was dissolved in DCM (5 mL). Pyridine (257.9 mg, 3.26 mmol) and thionyl chloride (387.8 mg, 3.26 mmol) were slowly added dropwise at room temperature. The reaction mixture was stirred for 1 hour. The reaction mixture was concentrated to give compound 25-2 (500 mg, crude product). LC-MS (ESI): m / z [MH] - =324.0.

[0299] Preparation of compound 25

[0300] Compound 25-2 (500 mg, 1.54 mmol) was dissolved in DMF (5 mL), and K2CO3 (1.28 g, 9.24 mmol) and piperazin-2-one (308.37 mg, 3.08 mmol) were added, respectively. The reaction mixture was allowed to react at room temperature for 1 hour. The reaction was quenched with water (5 mL) and extracted three times with ethyl acetate (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrate was purified by preparative separation (chromatographic column: Agilent C18, 19×250 mm, 10 μm; mobile phase A: 0.1% TFA / H2O, mobile phase B: ACN; flow rate: 20 mL / min; gradient: 56% to 56%; retention time: 9-10 min) to obtain the title compound 25 (52.66 mg, 8.7% yield). LC-MS (ESI): [M+H] + =390.2. 1 H NMR(400MHz, DMSO-d6) δ11.25(s,1H),7.88(s,1H),7.59(m,2H),7.37(d,J=8.2Hz,2H),7.21(m,3H),3.13(s,2H),2.94(m,2H),2.65(m,2H),2.28(s,3H). 19 F NMR (376MHz, DMSO-d6) δ-60.00 (s, 3F).

[0301] Example 26: Preparation of Compound 26

[0302] Preparation of compound 26-2

[0303] Compound 26-1 (5.2 g, 25.5 mmol) was dissolved in tetrahydrofuran (50 mL). The reaction system was purged with nitrogen and the temperature was maintained at approximately 0°C in an ice-water bath. i-PrMgCl (19.6 mL, 25.5 mmol) was added dropwise to the reaction solution, and the reaction was then maintained in an ice-water bath for 30 min. A solution of compound 1-1 (2.2 g, 10.2 mmol) in anhydrous tetrahydrofuran (15 mL) was added dropwise to the reaction solution, and the reaction system was naturally warmed to room temperature and reacted for 12 h. Water (15 mL) was added to the reaction solution, and the reaction solution was extracted three times with ethyl acetate (30 mL). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The concentrate was purified by column chromatography (EA / PE = 0-30%) to obtain the title compound 26-2 (1.71 g, 49% yield). LC-MS (ESI): m / z = 339.9 [MH] - .

[0304] Preparation of compound 26-3

[0305] Compound 26-2 (1.71 g, 5.01 mmol) and toluene (4.62 g, 50.1 mmol) were dissolved in DCE (15 mL). The atmosphere was replaced with nitrogen, and TfOH (7.53 g, 50.1 mmol) was added. After addition, the temperature was raised to 60°C and the reaction mixture was allowed to react for 12 h. The reaction solution was slowly poured into a saturated sodium bicarbonate ice-water solution and extracted three times with DCM (50 mL). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The concentrate was purified by column chromatography (EA / PE = 0-35%) to obtain the title compound 26-3 (260 mg, yield 12.5%). LC-MS (ESI): m / z = 416.0 [M+H] + .

[0306] Preparation of compound 26-4

[0307] Compound 26-3 (260 mg, 0.63 mmol) was dissolved in DCM (3 mL) and m-CPBA (270 mg, 1.57 mmol) was added in an ice-water bath at approximately 0°C. After addition, the mixture was allowed to react for 20 minutes while maintaining the ice-water bath, then naturally warmed to room temperature and reacted for 12 hours. Water (15 mL) was added to the reaction solution, and the mixture was extracted three times with DCM (20 mL). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The concentrate was purified by column chromatography (EA / PE = 0-50%) to obtain the title compound 26-4 (110 mg, 39% yield). LC-MS (ESI): m / z = 445.9 [MH] - .

[0308] Preparation of compound 26

[0309] Compound 26-4 (110 mg, 0.25 mmol) was dissolved in 1,4-dioxane (1.5 mL), followed by the addition of NH4OH (1 mL). After the addition, the reaction system was purged with nitrogen and heated to 80°C for 1 h. Water (15 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (30 mL). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The concentrate was purified by preparative chromatography (mobile phase: A: 0.05% NH3H2O / H2O; B: acetonitrile; column: XBridge C18 19×250 mm, 10 μm; gradient: 42%-47% retention time: 8.21-9.90 min; flow rate: 20 mL / min) to obtain the title compound 26 (1.38 mg, 1.5% yield). LC-MS (ESI): m / z = 385.2 [M+H] + . 1 H NMR (400MHz, MeOD) δ8.06 (s, 2H), 7.56-7.54 (d, J = 8.0Hz, 1H), 7.50-7.48 (d, J = 7.5Hz, 1H), 7.24-7.16 (m, 3H), 7.12-7.10 (m, 2H), 2.31 (s, 3H). 19 F NMR (376MHz, MeOD) δ-63.03 (s, 3F).

[0310] Example 27: Preparation of Compound 27

[0311] Preparation of compound 27-2

[0312] NaHMDS (2.0 M tetrahydrofuran solution, 7.1 mL, 14.12 mmol) was added dropwise to a solution of compound 27-1 (1.0 g, 4.71 mmol) in tetrahydrofuran (5.0 mL) under an ice bath, and stirring was continued for 30 min. A solution of di-tert-butyl dicarbonate (1.0 g, 4.65 mmol) in tetrahydrofuran (2 mL) was added dropwise, and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (10 mL) and extracted three times with EtOAc (30 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was evaporated to dryness. The residue was purified by column chromatography (EA:PE = 0-20%) to obtain the title compound 27-2 (900 mg, 70% yield). LC-MS (ESI): m / z [M+H] + 276.0.

[0313] Preparation of compound 27-3

[0314] n-BuLi (2.5 M tetrahydrofuran solution, 3.4 mL, 8.37 mmol) was added dropwise to a solution of N2-protected compound 27-2 (1.03 g, 3.72 mmol) in tetrahydrofuran (5 mL) at -78°C, and the mixture was stirred at this temperature for 30 min. Subsequently, a solution of compound 1-1 (400 mg, 1.86 mmol) in tetrahydrofuran (5 mL) was added dropwise, and the mixture was stirred at -78°C for 1 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (10 mL) and extracted three times with EtOAc (30 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was evaporated to dryness. The residue was purified by column chromatography (EA:PE = 0-50%) to obtain the title compound 27-3 (40 mg, 5% yield). LC-MS (ESI): m / z [M+H] + 413.1.

[0315] Preparation of compound 27

[0316] Compound 27-3 (40 mg, 0.10 mmol) and toluene (90 mg, 0.99 mmol) were dissolved in DCE (2 mL), and TfOH (3.23 g, 21.54 mmol) was added. The mixture was stirred at room temperature for 2 h. The pH of the reaction mixture was adjusted to a weak base with saturated sodium bicarbonate, and the mixture was extracted three times with DCM (30 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then spin-dried. The residue was purified using preparative purification (mobile phase: A: 0.1% NH3H2O ​​aqueous solution; B: acetonitrile; column: Xbridge C18, 19×250 mm×10 μm, flow rate: 20 mL / min, column temperature: 25°C; gradient: 42%-42%, retention time: 9-10.2 min) to obtain the title compound 27 (2.79 mg, 8% yield). LC-MS (ESI): m / z [M+H] + =387.2. 1 H NMR(400MHz, CDCl3) δ7.69(d,J=7.4Hz,1H),7.44(d,J=8.0Hz,1H),7.19–7.13(m ,3H),7.08(d,J=8.2Hz,2H),6.45(s,1H),4.04(s,2H),3.35(s,3H),2.29(s,3H). 19 F NMR (376MHz, CDCl3) δ-60.37 (s, 3F).

[0317] Example 28: Preparation of Compound 28

[0318] Preparation of Compound 28-2 / 28-3

[0319] Under nitrogen, n-BuLi (2.5 M tetrahydrofuran solution, 3.4 mL, 8.37 mmol) was added dropwise to a solution of compound 28-1 (1.04 g, 3.72 mmol) in tetrahydrofuran (5 mL) at -78°C. The mixture was stirred at -78°C for 30 min, followed by a solution of 1-1 (400 mg, 1.86 mmol) in tetrahydrofuran (5 mL) added dropwise, and the mixture was stirred at this temperature for 1 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (15 mL) and extracted three times with EtOAc (30 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was evaporated to dryness. The residue was purified by column chromatography (EA:PE = 0-25%) to give the title compounds 28-2 (260 mg) and 28-3 (140 mg). Compound 28-2: LC-MS (ESI): m / z [M+H] + 416.1; Compound 28-3: LC-MS (ESI): m / z [M+H] + 416.1.

[0320] Preparation of compound 28-4

[0321] Compound 28-3 (140 mg, 0.34 mmol) and toluene (310 mg, 3.37 mmol) were dissolved in DCM (2 mL). TfOH (506 g, 3.37 mmol) was slowly added under N2 protection in an ice-water bath and stirred at room temperature for 2 h. The reaction mixture was adjusted to a weakly alkaline pH with saturated sodium bicarbonate and extracted three times with DCM (30 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then spin-dried to dryness. The residue was purified by preparative purification (preparative method: mobile phase: A: 0.1% NH3H2O ​​aqueous solution; B: acetonitrile; column: Xbridge C18, 19×250 mm×10 μm, flow rate: 20 mL / min, column temperature: 25°C; gradient: 50%-50%, retention time: 6.7-7.8 min) to obtain the title compound 28-4 (44.94 mg, 34% yield). LC-MS (ESI): m / z [M+H] + 390.2. 1 H NMR (400MHz, DMSO-d6) δ11.29(s,1H),7.56(d,J=8.0Hz,1H),7.50(d,J=7.4Hz,1H),7.22–7.12(m,3H),7.09–6.93(m,4H),6.62(s,1H),2.26(s,3H). 19 F NMR (376MHz, DMSO-d6) δ-60.00 (s, 3F).

[0322] Preparation of compound 28

[0323] Compound 28-2 (260 mg, 0.63 mmol) and toluene (577 mg, 6.27 mmol) were dissolved in DCM (3 mL). TfOH (940 mg, 6.27 mmol) was slowly added in an ice-water bath under N2 protection and stirred at room temperature for 2 h. The reaction mixture was adjusted to a weakly alkaline pH with saturated sodium bicarbonate and extracted three times with DCM (30 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then spin-dried to dryness. The residue was purified using preparative purification (mobile phase: A: 0.1% NH3H2O ​​aqueous solution; B: acetonitrile; column: Xbridge C18, 19×250 mm×10 μm, flow rate: 20 mL / min, column temperature: 25°C; gradient: 50%-50%, retention time: 10.1-11 min) to obtain the title compound 28 (23.70 mg, 10% yield). LC-MS (ESI): m / z [M+H] + =390.2. 1 H NMR (400MHz, DMSO-d6) δ11.04(s,1H),7.61(d,J=7.4Hz,1H),7.54(d,J=8.0Hz,1H) ,7.20(t,J=7.7Hz,1H),7.14-7.06(m,4H),7.00(s,2H),6.22(s,1H),2.26(s,3H). 19 F NMR(376MHz,DMSO-d6)δ-59.88(s,3F).

[0324] Example 29: Preparation of Compound 29

[0325] Preparation of compound 29-2

[0326] Compound 22-1 (600 mg, 2.06 mmol) was added to a single-necked flask, along with 2-butanone (10 mL), compound 29-1 (434 mg, 2.47 mmol), potassium carbonate (570 mg, 4.12 mmol), and potassium iodide (68 mg, 0.411 mmol). After nitrogen replacement, the mixture was stirred at 80°C for 16 hours. The reaction mixture was quenched by adding water (20 mL). The product was extracted twice with ethyl acetate (20 mL), and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and the concentrate was purified by preparative separation (preparative method: mobile phase: A: 10 mmol formic acid solution; B: acetonitrile; preparative column: Pursuit XRs C18 250×19.5×10 μm; flow rate: 20 mL / min; gradient: 54-64% acetonitrile content, retention time 7.6-8.6 min) to obtain the title compound 29-2 (9.32 mg, yield 6.20%). LCMS (ESI): m / z 387.2 [M+H]+ . 1 H NMR (400MHz, DMSO-d6) δ11.18(d,J=54.1Hz,2H),7.65(dd,J=20.3,7.7Hz,2H),7.26(t ,J=7.8Hz,1H),7.19(d,J=8.2Hz,2H),7.11(d,J=8.3Hz,2H),6.39(s,1H),2.28(s,3H). 19 F NMR(376MHz,DMSO-d6)δ-59.96(s,3F).

[0327] Preparation of compound 29

[0328] Compound 29-2 (40 mg, 0.103 mmol) was added to a single-necked flask, followed by methanol (10 mL) and palladium-on-carbon (10 mg). After replacing the hydrogen atmosphere, the mixture was reacted at 60°C for 16 hours. The reaction solution was filtered through celite, and the filtrate was concentrated and purified by preparative separation (preparative method: mobile phase: A: 5 mmol ammonia solution; B: acetonitrile; preparative column: XBridge C18 250×21.2 mm×10 μm; flow rate: 20 mL / min; gradient: 31-31% acetonitrile content, retention time 10.0-13.0 min) to obtain the title compound 29 (10 mg, yield 24.97%). LC-MS (ESI): m / z 389.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.92(s,2H),7.66–7.43(m,2H),7.25(d,J=8.3Hz,1H),7.21– 7.09(m,3H),7.02(d,J=8.3Hz,1H),4.34–4.16(m,1H),2.92–2.52(m,2H),2.26(s,3H). 19 F NMR(376MHz, DMSO-d6)δ-59.88(s),-60.11(s,3F).

[0329] Example 30: Preparation of Compound 30

[0330] Preparation of compound 30

[0331] CrO₃ (497 mg, 4.98 mmol) was added to a solution of compound 12 (400 mg, 0.99 mmol) in AcOH (4 mL). The system was then heated to 110°C and stirred for 16 hours. LCMS confirmed the reaction was complete. The system was cooled to 0°C and quenched with saturated aqueous sodium bicarbonate (20.0 mL). The reaction was extracted three times with ethyl acetate (20 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The reaction solution was concentrated to dryness, and the residue was purified by preparative separation (preparative method: mobile phase: A: 0.05% NH₄OH / H₂O; B: ACN; column: Xbridge Xbridge C₁₈, 19×250 mm, 10 μm; column temperature: 25°C; gradient: 37% to 40%; acetonitrile in 7.8-10.5 min; flow rate: 20 mL / min) to afford the title compound 30 (31 mg, 7% yield). LC-MS (ESI): m / z [M+H] + :402.2. 1 H NMR (400MHz, DMSO-d6) δ13.28(br.s,1H),10.17(br.s,1H),7.86(d,J=1.8Hz,1H),7.78(d,J=7.8Hz,1H ),7.31–7.26(m,3H),7.20(d,J=7.8Hz,1H),7.08(d,J=8.0Hz,2H),6.08(d,J=1.8Hz,1H),2.34(s,3H). 19 F NMR(376MHz,DMSO-d6)δ-59.17(s,3F).

[0332] Example 31: Preparation of Compound 31

[0333] Preparation of compound 31-2

[0334] At room temperature, compound 22-1 (1.7 g, 5.84 mmol) was dissolved in 2-butanone (34 mL) solvent, and compound 31-1 (1.0 g, 6.21 mmol), potassium carbonate (2.42 g, 17.51 ​​mmol), and potassium iodide (194 mg, 1.17 mmol) were added in sequence. The system was heated to 90°C and stirred for 16 hours. LCMS detected that the reaction was complete. After the system was cooled to room temperature, saturated brine (50 mL) was added to quench the reaction, followed by water (50 mL). The reaction system was extracted three times with ethyl acetate (100 mL), the organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (0-15% ethyl acetate / petroleum ether) to give the title compound 31-2 (1.3 g, yellow-brown solid, yield 34%). LC-MS (ESI): m / z [MH] -:370.0. 1 H NMR(400MHz,DMSO-d6)δ11.38(br.s,1H),7.64(dd,J=14.1,7.7Hz,2H),7.28–7.23(m,1H),7.23– 7.18(m,2H),7.16–7.10(m,2H),5.94(s,1H),2.69–2.55(m,2H),2.45–2.35(m,2H),2.29(s,3H). 19 F NMR(376MHz,DMSO-d6)δ-60.06(s,3F).

[0335] Preparation of compound 31

[0336] Compound 31-2 (1.3 g, 3.50 mmol) was dissolved in DCM (25 mL) at room temperature, and methanesulfonic acid (5.38 g, 56.01 mmol) was slowly added to the reaction system. Sodium azide (455 mg, 7.00 mmol) was added portionwise at 0°C under nitrogen protection. The mixture was slowly warmed to room temperature and stirred for 16 hours. LCMS analysis confirmed the reaction was complete. The reaction solution was slowly poured into a cold 10% aqueous NaOH solution (30 mL) to quench the reaction. The mixture was extracted three times with DCM (25 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by preparative separation (preparative method: mobile phase: A: 0.1% ammonia / H2O; B: ACN; column: Xbridge Xbridge C18, 19×250 mm, 10 μm; column temperature: 25°C; gradient: 47% to 47%; acetonitrile in 6.5-7.5 min; flow rate: 20 mL / min) to obtain the title compound 31 (264 mg, yield 46%). LC-MS (ESI): m / z [M+H] + :387.2. 1 H NMR(400MHz,DMSO-d6)δ11.25(br.s,1H),7.63–7.55(m,3H),7.27–7.22(m,1H),7.22–7.19 (m,2H),7.19–7.15(m,2H),5.41(s,1H),3.26–3.09(m,2H),2.28(s,3H),2.27–2.10(m,2H). 19 F NMR(376MHz,DMSO-d6)δ-60.08(s,3F).

[0337] Example 32: Preparation of Compound 32-1 / 32-2

[0338] Preparation of Compound 32-1 and Compound 32-2

[0339] Compound 31 (400 mg, 1.02 mmol) was dissolved in methanol (60 mL) at room temperature. Under nitrogen, Pd / C (400 mg, 10%) was added, and the atmosphere was replaced with hydrogen three times. The mixture was stirred at room temperature for 16 hours. The reaction was complete by LCMS. The reaction mixture was filtered, the filtrate dried, and the residue purified by preparative separation (preparative method: mobile phase: A: 0.05% NH₄OH / H₂O; B: ACN; column: Xbridge C₁₈, 19×250 mm, 10 μm; column temperature: 25°C; gradient: 42% to 42%; acetonitrile in 7.7-9 min to give compound 32-1 (56 mg, yield: 15%); acetonitrile in 9-10.3 min to give compound 32-2 (56 mg, yield: 15%); flow rate: 20 mL / min).

[0340] Compound 32-1: LC-MS (ESI): m / z [M+H] + :389.2,RT=9.785min. 1 H NMR(400MHz, DMSO-d6)δ11.14(s,1H),7.72(d,J=7.5Hz,1H),7.59–7.49(m,2H),7.31–7.26(m,2H),7.25–7.19(m, 1H),7.19–7.14(m,2H),3.10–2.98(m,3H),2.27(s,3H),2.02–1.80(m,2H),1.52–1.42(m,1H),1.30–1.16(m,1H). 19 F NMR(376MHz,DMSO-d6)δ-60.06(s,3F).

[0341] Compound 32-2: LC-MS (ESI): m / z [M+H] + :389.2,RT=10.005min. 1 H NMR (400MHz, DMSO-d6) δ11.12(br.s,1H),7.67(d,J=7.4Hz,1H),7.59–7.53(m,2H),7.34–7.28(m,2H),7. 26–7.20(m,1H),7.20–7.15(m,2H),3.13–2.99(m,3H),2.27(s,3H),1.94–1.86(m,2H),1.48–1.32(m,2H). 19 F NMR(376MHz,DMSO-d6)δ-60.05(s,3F).

[0342] Example 33: Preparation of Compound 33

[0343] Preparation of compound 33-1

[0344] Under nitrogen, 2,6-difluoro-4-iodopyridine (7.84 g, 32.54 mmol) was added to anhydrous THF (25.0 mL). After stirring for 5 minutes, a solution of n-BuLi (2.5 M in THF, 16.5 mL, 40.67 mmol) was slowly added dropwise to the reaction system at -65°C, and stirring was continued for 30 minutes. Subsequently, a solution of compound 1-1 (3.5 g, 16.27 mmol) in anhydrous THF (10 mL) was slowly added dropwise to the reaction system, and stirring was continued at -65°C for one hour. LCMS analysis indicated the reaction was complete. Saturated aqueous ammonium chloride (25 mL) was added to the reaction system to quench the reaction, followed by addition of water (25 mL) and extraction three times with ethyl acetate (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (0-25% ethyl acetate / petroleum ether) to afford the title compound 33-1 (2.0 g, orange-yellow solid, 37% yield). LC-MS (ESI): m / z [MH] - :329.0.

[0345] Preparation of compound 33-2

[0346] Under nitrogen, compound 33-2 (2.0 g, 6.06 mmol) and toluene (5.58 g, 60.60 mmol) were dissolved in DCE (20.0 mL). After cooling to 0°C, TfOH (9.10 g, 60.60 mmol) was slowly added dropwise and stirred for 2 hours. LCMS confirmed the reaction was complete. The reaction solution was slowly poured into saturated aqueous sodium bicarbonate solution (100 mL) to quench the reaction. The mixture was extracted three times with ethyl acetate (100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the residue was concentrated and purified by column chromatography (0-25% ethyl acetate / petroleum ether) to obtain the title compound 33-2 (722 mg, white solid, 29% yield). LC-MS (ESI): m / z [M+H] + :405.2. 1 H NMR (400MHz, DMSO-d6) δ11.50 (s, 1H), 7.76 (d, J = 7.4Hz, 1H), 7.63 (d, J = 8.0Hz, 1H), 7.29–7.23(m,1H),7.22–7.17(m,2H),7.07–7.02(m,2H),6.92(s,2H),2.28(s,3H). 19F NMR(376MHz,DMSO-d6)δ-60.00(s,3F),-68.65(s,2F).

[0347] Preparation of compound 33

[0348] To a solution of compound 33-2 (100 mg, 0.25 mmol) in dioxane (1.0 mL) was added 20% aqueous NaOH (1 mL), followed by heating to 110°C and stirring for 16 hours. LCMS confirmed the reaction was complete. The system was cooled to room temperature and adjusted to pH 1 with concentrated hydrochloric acid (2 mL). After stirring at room temperature for 30 minutes, crude compound 33 was obtained by filtration. The crude product was purified by preparative separation (preparative method: mobile phase: A: 0.05% NH4OH / H2O; B: ACN; column: Xbridge C18, 19×250 mm, 10 μm; column temperature: 25°C; gradient: 26% to 26%; acetonitrile in 8.6-10.6 min; flow rate: 20 mL / min) to afford the title compound 33 (23 mg, 24% yield). LC-MS (ESI): m / z [M+H] + :403.2. 1 H NMR(400MHz,DMSO-d6)δ11.20(br.s,2H),7.61(dd,J=14.0,7.8Hz,2H),7.26–7.19 (m,1H),7.19–7.14(m,2H),7.08–7.03(m,2H),6.20(d,J=29.2Hz,2H),2.28(s,3H). 19 F NMR(376MHz, DMSO-d6)δ-60.04(s, 3F),-70.11(s, 1F).

[0349] Example 34: Preparation of Compound 34

[0350] Preparation of compound 34-2

[0351] Compound 34-1 (2.0 g, 6.87 mmol), compound 22-1 (1.4 g, 7.558 mol), KI (228 mg, 1.37 mmol), K2CO3 (2.8 g, 20.61 mmol), and 2-Butanone (40 mL) were added to a reaction flask, heated to 90°C, and stirred for 2 hours. LCMS confirmed the reaction was complete. The system was cooled to room temperature, and water (40 mL) was added. The mixture was extracted three times with ethyl acetate (40 mL), dried over anhydrous sodium sulfate, and concentrated to yield the title compound 34-2 (2 g, light yellow oil, yield 65%) using a normal phase column chromatography (0-30% ethyl acetate / petroleum ether). LC-MS (ESI): m / z [MH] - :441.8.

[0352] Preparation of compound 34-3

[0353] Compound 34-2 (1.8 g, 4.35 mmol) was dissolved in anhydrous ethanol (100 mL). Pd / C (180 mg, 10%) was added under nitrogen. The gas was replaced with hydrogen three times and the mixture was stirred at room temperature for 2 hours. LCMS confirmed the reaction was complete. The filtrate was filtered, and the residue was concentrated and purified by normal phase column chromatography (0-40% ethyl acetate / petroleum ether) to obtain the title compound 34-3 (1.5 g, white oil, 80% yield). LC-MS (ESI): m / z [MH] - :411.8.

[0354] Preparation of compound 34-4

[0355] Compound 34-3 (1.3 g, 3.13 mmol) and H2SO4 (2M, 6.4 mL, 12.87 mmol) were added to a reaction flask. After cooling to 0°C, NaNO2 (238 mg, 3.45 mmol) was added portionwise. After stirring for 30 minutes, 1M H2SO4 aqueous solution (6.44 mL, 6.43 mmol) was added. The system was heated to 70°C and stirred for 2 hours. The reaction was complete as determined by LCMS. After cooling to room temperature, saturated ammonium chloride (30 mL) was added to quench the reaction. The reaction system was extracted twice with ethyl acetate (30 mL), dried over anhydrous sodium sulfate, and the residue was purified by reverse phase column chromatography (NH3.H2O:ACN = 5-95%) to obtain the title compound 34-4 (115 mg, yellow oil, yield 9%). LC-MS (ESI): [M+H] + :415.2. 1H NMR (400MHz, DMSO-d6) δ11.09(br.s,1H),9.65(br.s,1H),7.70(d,J=7.4Hz,1H),7.53(d,J=7.9Hz,1H),7.21–7.16( m,1H),7.15–7.09(m,2H),7.07(d,J=7.9Hz,1H),7.01–6.95(m,2H),6.86(d,J=7.9Hz,1H),3.68(s,3H),2.26(s,3H). 19 F NMR(376MHz,DMSO-d6)δ-59.96(s,3F).

[0356] Preparation of compound 34

[0357] Under nitrogen, compound 34-4 (64 mg, 0.16 mmol) was dissolved in anhydrous dichloroethane (2 mL), and BBr3 (0.64 mL, 1 M in DCM, 0.64 mmol) was slowly added dropwise at 0°C. The mixture was heated to 50°C and stirred for 1 hour. LCMS confirmed the reaction was complete. The mixture was quenched with aqueous NaHCO3 (10 mL) and extracted twice with dichloromethane (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by preparative separation (mobile phase: A: 0.1% FA / H2O; B: ACN; column: Agilent C18, 19*250 mm, 10 μm; column temperature: 25°C; gradient: 55% to 55%; acetonitrile in 5.5-6.5 min; flow rate: 20 mL / min) to afford the title compound 34 (15 mg, 24% yield). LC-MS (ESI): [M+H] + :401.2. 1 H NMR (400MHz, DMSO-d6) δ11.04(br.s,1H),9.45(br.s,1H),7.75(d,J=7.4Hz,1H),7.58(d,J= 8.0Hz,1H),7.25–7.15(m,3H),7.03(d,J=8.1Hz,2H),6.69(s,1H),5.86(s,1H),2.28(s,3H). 19 F NMR(376MHz,DMSO-d6)δ-59.93(s,3F).

[0358] Example 35: Preparation of Compound 35

[0359] Preparation of compound 35-2

[0360] Compound 22-1 (400.0 mg, 1.37 mmol) was dissolved in 2-butanone (6 mL). Compound 35-1 (287.01 mg, 1.64 mmol), potassium carbonate (568.04 mg, 4.11 mmol), and potassium iodide (45.48 mg, 0.27 mmol) were added sequentially under stirring at room temperature. The mixture was then heated to 90°C and stirred for 16 hours. The reaction was complete by LCMS. After cooling the reaction system to 0°C, ice water (8 mL) was added to quench the reaction and the mixture was extracted three times with ethyl acetate (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by preparative separation (preparative method: mobile phase: A: 0.05% NH3H2O / H2O; B: ACN; column: XBridge XBridge C18, 19×250 mm, 10 μm; column temperature: 25°C; gradient: 65% to 65%; acetonitrile in 9.7-10.3 min; flow rate: 20 mL / min) to obtain the title compound 35-2 (3.5 mg, white solid, yield 0.6%). LC-MS (ESI): m / z [M+H] + :430.2. 1 H NMR(400MHz, Methanol-d4)δ7.65(d,J=7.5Hz,1H),7.55(d,J=8.0Hz,1H),7.25–7.16(m,1H) ,7.19–7.12(m,3H),7.14–7.07(m,2H),6.44(s,1H),3.93(s,4H),3.85(s,4H),2.32(s,4H). 19 F NMR (376MHz, Methanol-d4) δ-62.95 (s, 3F).

[0361] Preparation of compound 35

[0362] Compound 35-2 (50 mg, 0.12 mmol) was dissolved in DMF (2.0 mL) at room temperature, followed by the addition of LiCl (25.43 mg, 0.60 mmol) and TsOH (103.32 mg, 0.60 mmol). The mixture was heated to 120°C and stirred for one hour. LCMS confirmed the reaction was complete. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated to dryness. The residue was then purified by preparative separation (preparative method: mobile phase: A: 0.1% TFA / H2O; B: ACN; column: Atlantis™ T3 Prep OBD™, C18, 19×250 mm, 10 μm; column temperature: 25°C; gradient: 43% to 48%; acetonitrile in 8.3-9.0 min; flow rate: 20 mL / min) to afford the title compound 35 (11 mg, 23% yield). LC-MS (ESI): m / z [M+ACN] + =443.2. 1 H NMR (400MHz, DMSO-d6) δ11.34(br.s,1H),11.17(br.s,1H),10.85(br.s,1H),7.85(d,J=7.6Hz,1H),7. 64(d,J=8.0Hz,1H),7.29-7.25(m,1H),7.24–7.17(m,2H),7.17–7.08(m,2H),5.11(s,1H),2.30(s,3H). 19 F NMR(376MHz,DMSO-d6)δ-59.99(s,3F).

[0363] Example 36: Preparation of Compound 36

[0364] Preparation of compound 36-2

[0365] Under nitrogen, compound 36-1 (5.78 g, 27.90 mmol) was dissolved in anhydrous THF (50.0 mL). After cooling to -65°C, a solution of n-BuLi (2.5 M in THF, 13.95 mL, 34.88 mmol) was slowly added dropwise to the reaction system. After stirring for 30 minutes, a solution of compound 1-1 (3.00 g, 13.95 mmol) in anhydrous THF (20 mL) was slowly added dropwise to the reaction system and stirred for 1 hour. LCMS confirmed the reaction was complete. Saturated aqueous ammonium chloride (10 mL) was added to the reaction system to quench the reaction, followed by water (30 mL). The system was extracted three times with ethyl acetate (40 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (0-15% ethyl acetate / petroleum ether) to afford the title compound 36-2 (3 g, yellow solid, 52% yield). LC-MS (ESI): m / z [MH] - :342.0.

[0366] Preparation of compound 36-3

[0367] At room temperature, compound 36-2 (2.00 g, 5.83 mmol) and stannous chloride dihydrate (3.29 g, 14.57 mmol) were dissolved in glacial acetic acid (20.0 mL) solvent, and concentrated hydrochloric acid (2.0 mL) was slowly added to the reaction system. The system was heated to 120°C and stirred for one hour. LCMS detected that the reaction was complete. After cooling to 0°C, saturated sodium bicarbonate solution (30 mL) was slowly added dropwise to quench the reaction, followed by addition of water (50 mL) and extraction with ethyl acetate (100 mL) three times. The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was separated and purified by column chromatography (0-100% ethyl acetate / petroleum ether) to obtain the title compound 36-3 (1.4 g, white solid, yield 70%). LC-MS (ESI): m / z [MH] - :326.0.

[0368] Preparation of compound 36-4

[0369] Compound 7-2 (573.03 mg, 1.84 mmol), potassium iodide (50.80 mg, 0.31 mmol), and potassium carbonate (634.38 mg, 4.59 mmol) were added sequentially to a solution of compound 36-3 (500 mg, 1.53 mmol) in 2-butanone (10.0 mL). The system was heated to 90°C and stirred for 16 hours. LCMS confirmed the completion of the reaction. The system was cooled to 0°C and then slowly added with ice water (10 mL) to quench the reaction. The mixture was extracted three times with ethyl acetate (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (0-25% ethyl acetate / petroleum ether) to obtain the title compound 36-4 (240 mg, light yellow solid, yield 29%). LC-MS (ESI): m / z [MH] - :510.0.

[0370] Preparation of compound 36

[0371] Compound 36-4 (240 mg, 0.47 mmol) was dissolved in DCE (3.0 mL), and TfOH (1.5 mL, ρ = 1.7 mol / L) was slowly added dropwise to the reaction system with stirring at room temperature. The temperature was raised to 65°C and stirred for one hour. LCMS confirmed the reaction was complete. The reaction system was cooled to 0°C and quenched with saturated sodium bicarbonate solution (6 mL). Water (4 mL) was then added and the mixture was extracted three times with dichloromethane (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by preparative separation (preparative method: mobile phase: A: 0.1% FA / H2O; B: ACN; column: Atlantis™ T3 Prep OBD™, C18, 19×250 mm, 10 μm; column temperature: 25°C; gradient: 50% to 55%; acetonitrile in 9.3-10.2 min; flow rate: 20 mL / min) to obtain the title compound 36 (101 mg, 51% yield). LC-MS (ESI): m / z [M+H+ACN] + :463.2. 1 H NMR (400MHz, DMSO-d6) δ13.17(br.s,1H),11.57(br.s,1H),7.96(d,J=8.7Hz,1H),7.95–7.88(m,2H),7.82(d,J=7.6Hz,1H),7.79(d,J=2.1 Hz,1H),7.74–7.70(m,1H),7.66(d,J=8.1Hz,1H),7.58–7.51(m,2H),7.38(dd,J=8.7,1.8Hz,1H),7.32–7.26(m,1H),6.49(d,J=2.1Hz,1H). 19F NMR(376MHz, DMSO-d6)δ-56.78(s,3F),-59.94(s,3F).

[0372] Example 37: Preparation of Compound 37

[0373] Preparation of compound 37-1

[0374] Under nitrogen, magnesium turnings (1.2 g, 46.48 mmol) and two iodine particles were added to anhydrous tetrahydrofuran (10 mL). 3,4-Difluorobromobenzene (4.5 g, 23.24 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) to prepare Solution A. Solution A (2 mL) was slowly added dropwise to the reaction system, heated to 50°C with vigorous stirring. After the brown color disappeared, the remaining Solution A (18 mL) was slowly added dropwise while maintaining the reaction temperature at 50°C. After the addition was complete, the reaction solution was allowed to cool naturally to room temperature to obtain 3,4-difluorophenylmagnesium bromide in tetrahydrofuran (Solution B). Under nitrogen, compound 1-1 (2.0 g, 9.30 mmol) and anhydrous tetrahydrofuran (20 mL) were added to the reaction flask. Solution B (20 mL) was slowly added dropwise to the reaction system at 0°C. Stirring was continued for 1 hour after the addition was complete. LCMS confirmed the reaction was complete. The reaction was quenched by adding water (50 mL) and extracted twice with ethyl acetate (60 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The concentrated residue was purified by column chromatography (0-50% ethyl acetate / petroleum ether) to afford the title compound 37-1 (2.5 g, yellow oil, 81% yield). LC-MS (ESI): m / z [MH] - :328.0.

[0375] Preparation of compound 37-2

[0376] Under nitrogen, compound 37-1 (2.5 g, 7.59 mmol), acetic acid (20 mL), stannous chloride dihydrate (4.3 g, 18.97 mmol), and hydrochloric acid (2 mL) were added to a reaction flask. The system was heated to 120°C and stirred for 2 hours. LCMS confirmed the completion of the reaction. After cooling to 0°C, saturated sodium bicarbonate (60 mL) was slowly added dropwise to quench the reaction. The system was extracted twice with ethyl acetate (60 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (0-20% ethyl acetate / petroleum ether) to obtain the title compound 37-2 (2.0 g, yellow solid, 84% yield). LC-MS (ESI): m / z [MH] - :311.9.

[0377] Preparation of compound 37-3

[0378] Under nitrogen, compound 37-2 (2.0 g, 6.39 mmol) was dissolved in 2-butanone (50 mL), followed by the addition of compound 7-2 (2.2 g, 7.02 mmol), potassium iodide (212 mg, 1.28 mmol), and potassium carbonate (1.76 g, 12.77 mmol). The system was heated to 90°C and stirred for 16 hours. LCMS confirmed the reaction was complete. After cooling to room temperature, water (60 mL) was added and the mixture was extracted twice with ethyl acetate (60 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (0-25% ethyl acetate / petroleum ether) to afford the title compound 37-3 (700 mg, yellow solid, 22% yield). LC-MS (ESI): m / z [MH] - :496.0.

[0379] Preparation of compound 37

[0380] Under nitrogen, compound 37-3 (200 mg, 0.402 mmol) was dissolved in DCE (10 mL) and TfOH (603 mg, 4.02 mmol) was added. The system was heated to 60°C and stirred for 2 hours. LCMS confirmed the reaction was complete. After cooling to 0°C, saturated sodium bicarbonate (20 mL) was slowly added to quench the reaction. The mixture was extracted twice with dichloromethane (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by preparative separation (preparative method: mobile phase: A: 10 mmol formic acid solution; B: acetonitrile; column: XBridge C18 250*19 mm*10 μm; column temperature: 25°C; gradient: 40%-48% acetonitrile in 7.32-7.86 min; flow rate: 20 mL / min) to obtain the title compound 37 (70 mg, 44% yield). LCMS (ESI): m / z [M+H] + :408.1. 1 H NMR (400MHz, DMSO-d6) δ10.47(br.s,1H),7.76(d,J=7.5Hz,1H),7.72(d,J=2.1Hz,1H),7.62(d,J=8.0Hz ,1H),7.53–7.42(m,1H),7.38–7.29(m,1H),7.28–7.19(m,1H),7.15–7.03(m,1H),6.42(d,J=2.1Hz,1H). 19 F NMR(376MHz,DMSO-d6)δ-60.02(s,3F),-136.77(d,1F),-138.94(d,1F).

[0381] Example 38: Preparation of Compound 38

[0382] Preparation of compound 38-1

[0383] Compound 22-1 (1.5 g, 5.15 mmol), 2-butanone (30 mL), 2,4-dichloropyrimidine (844 mg, 5.66 mmol), potassium carbonate (2.1 g, 15.45 mmol), and potassium iodide (170 mg, 1.03 mmol) were added to a reaction flask and stirred at 90°C for 2 hours. LCMS confirmed the completion of the reaction. The reaction system was cooled to room temperature, water (50 mL) was added, and the mixture was extracted twice with ethyl acetate (80 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified on a reverse phase column (10-75% ACN / 0.1% FA in H2O) to obtain the title compound 38-1 (240 mg, white solid, 11% yield). LC-MS (ESI): m / z [MH] - :401.9.

[0384] Preparation of compound 38

[0385] Compound 38-1 (216 mg, 0.53 mmol) was dissolved in 1,4-dioxane (0.5 mL) and then added with methanolic ammonia (1 mL, 7 mol / L in MeOH, 7.00 mmol). The mixture was heated to 110°C and stirred for 20 hours under a sealed tube. The reaction was confirmed by LCMS, and the system was concentrated. The residue was purified by preparative separation (mobile phase: A: 0.1% TFA / H2O; B: ACN; column: Pursuit XRs10 C18 19*250mm*10μm, 10μm; column temperature: 25°C; gradient: 51% to 51%; acetonitrile in 8.5-9.5 min; flow rate: 20 mL / min) to obtain the title compound 38 (76.64 mg, 33% yield). LC-MS (ESI): m / z [M+H] + :385.2. 1 H NMR (400MHz, DMSO-d6) δ11.13(s,1H),8.22(d,J=5.1Hz,1H),7.64(d,J=7.5Hz,1H),7.57(d,J=8.0Hz,1H), 7.25–7.19(m,1H),7.19–7.14(m,2H),7.08–7.02(m,2H),6.66(s,2H),6.42(d,J=5.1Hz,1H),2.28(s,3H). 19 F NMR(376MHz,DMSO-d6)δ-59.91(s,3F).

[0386] Example 39: Preparation of Compound 39

[0387] Preparation of compound 39-2

[0388] Under nitrogen, compound 39-1 (1.48 g, 6.23 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL) and then warmed to -65°C. A solution of n-BuLi (2.74 mL, 2.5 M in THF, 6.85 mmol) was slowly added dropwise to the reaction system. After stirring for 30 minutes, a solution of compound 1-1 (670 mg, 3.115 mmol) in anhydrous tetrahydrofuran (10 mL) was slowly added dropwise to the reaction system. After stirring for one hour, LCMS confirmed the reaction was complete. Saturated aqueous ammonium chloride (25 mL) was added to quench the reaction, followed by water (20 mL). The reaction system was extracted three times with ethyl acetate (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the residue was concentrated and purified by column chromatography (0-25% ethyl acetate / petroleum ether) to afford the title compound 39-2 (750 mg, yellow oil, 64% yield). LC-MS(ESI):m / z:[MH] - :372.8.

[0389] Preparation of compound 39-3

[0390] Compound 39-2 (300 mg, 0.802 mmol) and toluene (369 mg, 4.010 mmol) were dissolved in dichloroethane (6 mL), and trifluoromethanesulfonic acid (602 mg, 4.010 mmol) was added. The mixture was heated to 65°C and stirred for 2 hours. LCMS confirmed the reaction was complete. The reaction system was cooled to room temperature and quenched with saturated aqueous NaHCO₃ (10 mL). The reaction system was extracted three times with dichloromethane (20 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The residue was purified by column chromatography (0-30% ethyl acetate / petroleum ether) to afford the title compound 39-3 (200 mg, yellow oil, 55.6% yield). LC-MS (ESI): m / z [MH] - :446.9.

[0391] Preparation of compound 39

[0392] Compound 39-3 (200 mg, 0.446 mmol) and TMSI (268 mg, 1.339 mmol) were dissolved in acetonitrile (2 mL). The temperature was raised to 60°C and stirred for 1 hour. LCMS confirmed the reaction was complete. The reaction system was cooled to room temperature and saturated aqueous sodium chloride solution (10 mL) was added. The reaction system was extracted three times with ethyl acetate (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by preparative separation (preparative method: mobile phase: A: 10 mmol NH4HCO3 / H2O; B: ACN; column: XBridge C18, 19*250 mm, 10 μm; column temperature: 25°C; gradient: 48% to 48%; acetonitrile in 9.0-11.3 min; flow rate: 20 mL / min) to obtain the title compound 39 (97 mg, 50% yield). LC-MS (ESI): [M+H] + :435.2. 1 H NMR (400MHz, DMSO-d6) δ11.76(s,1H),11.22(br.s,1H),7.87(d,J=9.6Hz,1H),7.62–7.54(m,2H),7.43–7.37(m,1H ),7.34–7.26(m,2H),7.25–7.19(m,1H),7.18–7.13(m,2H),7.07–7.00(m,2H),6.45(d,J=9.6Hz,1H),2.27(s,3H). 19 F NMR(376MHz,DMSO-d6)δ-59.95(s,3F).

[0393] Example 40: Preparation of Compound 40

[0394] Preparation of compound 40-3

[0395] Under nitrogen, compound 40-1 (4.0 g, 33.01 mmol) was added to water (200 mL), followed by chloral hydrate (8.19 g, 49.51 mmol), hydroxylamine hydrochloride (8.26 g, 118.83 mmol), and sodium sulfate (37.51 g, 264.06 mmol). The mixture was stirred at 50°C for 16 hours. After cooling the reaction system to room temperature, 2N aqueous hydrochloric acid (10 mL) was added and stirred for 10 minutes. The mixture was filtered, and the filter cake was rinsed with water (50 mL). The filter cake was dried at 50°C, concentrated sulfuric acid (80 mL) was added, and the temperature was raised to 80°C, followed by stirring for 3 hours. The reaction mixture was cooled to room temperature and slowly poured into ice water (200 mL). The mixture was filtered, and the filter cake was rinsed with water (80 mL). The filter cake was dried at 50°C to obtain the title compound 40-3 (700 mg, yellow solid, yield 12%). LC-MS(ESI):m / z[MH] - :174.1.

[0396] Preparation of compound 40-4

[0397] 4-Bromotrifluoromethoxybenzene (2.4 g, 9.99 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL). A solution of n-BuLi (2.5 M in THF, 4.79 mL, 11.99 mmol) was slowly added dropwise to the reaction system at -65°C. After stirring for 30 minutes, a solution of compound 40-3 (700 mg, 4.00 mmol) in anhydrous tetrahydrofuran (3 mL) was slowly added dropwise to the reaction system. After stirring for one hour, the reaction was complete as determined by LCMS. Saturated aqueous ammonium chloride (5 mL) was added to quench the reaction, followed by water (20 mL). The reaction system was extracted three times with ethyl acetate (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (0-25% ethyl acetate / petroleum ether) to afford the title compound 40-4 (800 mg, yellow solid, 59% yield). LC-MS (ESI): m / z [MH] - :336.0.

[0398] Preparation of compound 40-5

[0399] Under nitrogen, compound 40-4 (800 mg, 2.37 mmol), acetic acid (5 mL), hydrochloric acid (0.5 mL), and stannous chloride dihydrate (1.3 g, 5.93 mmol) were added to a reaction flask. The temperature was raised to 120°C and stirred for 2 hours. LCMS confirmed the reaction was complete. The mixture was cooled to room temperature and quenched with saturated sodium bicarbonate (20 mL). The mixture was extracted three times with ethyl acetate (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (0-25% ethyl acetate / petroleum ether) to obtain the title compound 40-5 (600 mg, yellow solid, 78% yield). LC-MS (ESI): m / z [MH] - :320.0.

[0400] Preparation of compound 40-6

[0401] Under nitrogen, compound 40-5 (600 mg, 1.87 mmol), dibutyl ketone (30 mL), compound 7-2 (641 mg, 2.05 mmol), potassium iodide (62 mg, 0.373 mmol), and potassium carbonate (516 mg, 3.73 mmol) were added to a reaction flask. The temperature was raised to 90°C and stirred for 16 hours. LCMS confirmed the reaction was complete. After cooling to room temperature, water (20 mL) was added and the system was extracted three times with ethyl acetate (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (0-35% ethyl acetate / petroleum ether) to obtain the title compound 40-6 (200 mg, yellow solid, yield 21%). LC-MS (ESI): m / z [MH] - :504.0.

[0402] Preparation of compound 40

[0403] Compound 40-6 (200 mg, 0.395 mmol) was dissolved in DCE (5 mL) and TfOH (592 mg, 3.95 mmol) was slowly added dropwise. The mixture was heated to 60°C and stirred for 3 hours. LCMS confirmed the reaction was complete. After cooling to room temperature, the mixture was quenched with ice water (10 mL) and extracted three times with dichloromethane (15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by preparative separation (preparative method: mobile phase: A: 10 mmol formic acid solution; B: acetonitrile; column: Pursuit XRs10 C18, 19×250 mm, 10 μm; column temperature: 25°C; gradient: 54%-64% acetonitrile in 7.8-9.0 min; flow rate: 20 mL / min) to obtain the title compound 40 (59 mg, 36% yield). LCMS (ESI): m / z [M+H] + :416.2. 1H NMR (400MHz, DMSO-d6) δ13.13(br.s,1H),11.07(br.s,1H),7.72(d,J=2.1Hz,1H),7.39(d,J=8.6Hz,2H),7.33( d,J=8.6Hz,2H),7.17(d,J=7.7Hz,1H),6.92(d,J=7.7Hz,1H),6.44(d,J=2.1Hz,1H),2.24(s,3H),2.19(s,3H). 19 F NMR(376MHz,DMSO-d6)δ-56.79(s,3F).

[0404] Example 41: Preparation of Compound 41

[0405] Preparation of compound 41-3

[0406] Under nitrogen, compound 41-1 (5.0 g, 35.31 mmol) was added to water (200 mL), followed by chloral hydrate (8.76 g, 52.97 mmol), hydroxylamine hydrochloride (8.83 g, 127.12 mmol), and sodium sulfate (40.12 g, 282.49 mmol). The mixture was stirred at 50°C for 16 hours. After cooling to room temperature, 2N hydrochloric acid (10 mL) was added to the reaction system and stirred for 10 minutes. The system was filtered, and the filter cake was rinsed with water (50 mL). The filter cake was dried at 50°C, and concentrated sulfuric acid (80 mL) was added. The mixture was stirred at 80°C for 3 hours. After cooling to room temperature, the reaction solution was slowly poured into ice water (200 mL). Filtered with suction, the filter cake was rinsed with water (80 mL). The filter cake was dried at 50°C to obtain the title compound 41-3 (3.0 g, yellow solid, 43% yield). LC-MS(ESI):m / z[MH] - :194.0.

[0407] Preparation of compound 41-4

[0408] 4-Bromotrifluoromethoxybenzene (4.62 g, 19.17 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL). A solution of n-BuLi (2.5 M in THF, 9.20 mL, 23.01 mmol) was slowly added dropwise to the reaction system at -65°C. After stirring for 30 minutes, a solution of compound 41-3 (1.5 g, 7.67 mmol) in anhydrous tetrahydrofuran (10 mL) was slowly added dropwise to the reaction system and stirred at -65°C for one hour. LCMS confirmed the reaction was complete. Saturated aqueous ammonium chloride (10 mL) was added to quench the reaction, followed by water (30 mL). The reaction system was extracted three times with ethyl acetate (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the residue was concentrated and purified by column chromatography (0-25% ethyl acetate / petroleum ether) to afford the title compound 41-4 (1.1 g, yellow solid, 40% yield). LC-MS(ESI):m / z[MH] - :355.9.

[0409] Preparation of compound 41-5

[0410] Under nitrogen, compound 41-4 (1.1 g, 3.08 mmol), acetic acid (10 mL), hydrochloric acid (1 mL), and stannous chloride dihydrate (1.73 g, 7.70 mmol) were added to a reaction flask. The temperature was raised to 120°C and stirred for 2 hours. LCMS confirmed the reaction was complete. The mixture was cooled to room temperature and quenched with saturated sodium bicarbonate (30 mL). The mixture was extracted three times with ethyl acetate (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (0-25% ethyl acetate / petroleum ether) to obtain the title compound 41-5 (760 mg, yellow solid, 72.3% yield). LC-MS (ESI): m / z [MH] - :339.9.

[0411] Preparation of compound 41-6

[0412] Under nitrogen protection, compound 41-5 (350 mg, 1.02 mmol), dibutyl ketone (30 mL), compound 7-2 (352 mg, 1.13 mmol), potassium iodide (34 mg, 0.205 mmol), and potassium carbonate (283 mg, 2.05 mmol) were added to a reaction flask. The temperature was raised to 90°C and stirred for 16 hours. LCMS confirmed the reaction was complete. Aqueous solution (20 mL) was added and the system was extracted three times with ethyl acetate (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (0-35% ethyl acetate / petroleum ether) to obtain the title compound 41-6 (180 mg, yellow solid, yield 33%). LC-MS (ESI): m / z [MH] - :523.9.

[0413] Preparation of compound 41

[0414] Compound 41-6 (180 mg, 0.342 mmol) was dissolved in DCE (5 mL) and TfOH (513 mg, 3.42 mmol) was slowly added dropwise. The mixture was heated to 60°C and stirred for 3 hours. LCMS confirmed the reaction was complete. After cooling to room temperature, ice water (10 mL) was added to quench the reaction. The mixture was extracted three times with dichloromethane (15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by preparative separation (preparative method: mobile phase: A: 10 mmol formic acid solution; B: acetonitrile; column: Pursuit XRs C18, 19×250 mm, 10 μm; column temperature: 25°C; gradient: 56%-66% acetonitrile in 7.8-8.4 min; flow rate: 20 mL / min) to obtain the title compound 41 (64 mg, 42% yield). LCMS (ESI): m / z [M+H] + :436.1. 1 H NMR (400MHz, DMSO-d6) δ13.16(s,1H),11.47(s,1H),7.74(d,J=1.6Hz,1H),7.40(d,J=8.8Hz,2H),7. 37(d,J=7.7Hz,1H),7.34(d,J=8.8Hz,2H),7.10(d,J=7.7Hz,1H),6.46(d,J=1.6Hz,1H),2.35(s,3H). 19 F NMR(376MHz,DMSO-d6)δ-56.78(s,3F).

[0415] Preparation of compounds 41A and 41B

[0416] Compound 41 was subjected to SFC chiral preparative separation (preparative separation method, instrument model: WATERS 150 preparative SFC (SFC-29); chromatographic column model: ChiralPak AD, 250×30 mm ID, 10 μm; mobile phase: A: CO2, B: ethanol (0.1% NH3H2O); elution gradient: B 20%; flow rate: 150 mL / min; column pressure: 100 bar; column temperature: 38°C; detection wavelength: 220 nm; cycle: ~8 min) to obtain the title compounds 41A (14 mg) and 41B (12 mg).

[0417] Compound 41A: Chiral analysis method (instrument model: Waters UPC2 analytical SFC (SFC-H); chromatographic column model: ChiralPak AD, 50×4.6 mm ID, 3 μm; mobile phase: A: CO2, B: ethanol (0.05% DEA); elution gradient: B 40%; flow rate: 3 mL / min; column temperature: 35°C; column pressure: 100 bar; detection wavelength: 220 nm; RT = 0.681 min). LCMS (ESI): m / z [M+H] + :435.8.

[0418] Compound 41B: Chiral analysis method (instrument model: Waters UPC2 analytical SFC (SFC-H); chromatographic column model: ChiralPak AD, 50×4.6 mm ID, 3 μm; mobile phase: A: CO2, B: ethanol (0.05% DEA); elution gradient: B 40%; flow rate: 3 mL / min; column temperature: 35°C; column pressure: 100 bar; detection wavelength: 220 nm; RT = 1.819 min). LCMS (ESI): m / z [M+H] + :435.9.

[0419] Example 42: Preparation of Compound 42

[0420] Preparation of compound 42-1

[0421] Under nitrogen, 2-fluoro-4-bromo-toluene (3.9 g, 20.46 mmol) was added to anhydrous THF (40 mL). A solution of n-BuLi (2.5 M in THF, 8.2 mL, 20.46 mmol) was slowly added dropwise to the reaction system at -65°C. After stirring for 30 minutes, a solution of compound 1-1 (2.0 g, 9.30 mmol) in anhydrous THF (10 mL) was slowly added dropwise to the reaction system. After stirring for one hour, HPLC analysis indicated the reaction was complete. Saturated aqueous ammonium chloride (50 mL) was added to the reaction system to quench the reaction. Water (50 mL) was then added and the mixture was extracted three times with ethyl acetate (100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (0-25% ethyl acetate / petroleum ether) to afford the title compound 42-1 (1.6 g, yellow solid, 34% yield). LC-MS (ESI): m / z [MH] - :324.0.

[0422] Preparation of compound 42-2

[0423] Compound 42-1 (1.3 g, 4.0 mmol), stannous chloride dihydrate (2.3 g, 9.99 mmol), glacial acetic acid (15 mL), and concentrated hydrochloric acid (1.5 mL) were added to a reaction flask. The temperature was raised to 120°C and stirred for 1 hour. LCMS confirmed the completion of the reaction. The system was cooled to room temperature and adjusted to alkalinity with saturated aqueous sodium bicarbonate solution. The mixture was extracted three times with ethyl acetate (40 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (0-20% ethyl acetate / petroleum ether) to afford the title compound 42-2 (900 mg, yellow oil, 72.8% yield). LC-MS (ESI): m / z [MH] - :307.7.

[0424] Preparation of compound 42-3

[0425] Compound 42-2 (300 mg, 0.971 mmol), compound 7-2 (303 mg, 0.971 mmol), KI (32 mg, 0.914 mmol), K2CO3 (403 mg, 2.913 mmol), and 2-Butanone (5 mL) were added to a reaction flask. The temperature was raised to 90°C and stirred for 16 hours. LCMS confirmed the completion of the reaction. The temperature was lowered to room temperature, water (5 mL) was added, and the mixture was extracted three times with ethyl acetate (10 mL). The organic phases were combined, concentrated, and purified by normal phase column chromatography (0-30% ethyl acetate / petroleum ether) to obtain the title compound 42-3 (140 mg, white oil, yield 29%). LC-MS (ESI): m / z [MH] - :491.9.

[0426] Preparation of compound 42

[0427] Compound 42-3 (100 mg, 0.203 mmol) was dissolved in dichloroethane (2 mL), and trifluoromethanesulfonic acid (122 mg, 0.812 mmol) was slowly added. The mixture was heated to 120°C and stirred for 1 hour. LCMS confirmed the reaction was complete. After cooling to room temperature, saturated aqueous NaHCO₃ (10 mL) was slowly added dropwise to quench the reaction. The reaction system was extracted three times with dichloromethane (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by preparative separation (preparative method: mobile phase: A: 0.1% FA / H₂O; B: ACN; column: SunFire C₁₈, 19×250 mm, 10 μm; column temperature: 25°C; gradient: 47% to 57%; acetonitrile in 7.4-9.3 min; flow rate: 20 mL / min) to obtain the title compound 42 (34.13 mg, 41% yield). LC-MS(ESI):m / z[M+H] + :404.2. 1H NMR (400MHz, DMSO-d6) δ13.08(br.s,1H),11.58(br.s,1H),7.78(d,J=7.5Hz,1H),7.72(d,J=2.1Hz, 1H),7.64(d,J=8.0Hz,1H),7.37–7.23(m,2H),7.04–6.94(m,2H),6.41(d,J=2.1Hz,1H),2.21(s,3H). 19 F NMR(376MHz,DMSO-d6)δ-60.02(s,3F),-115.72(s,1F).

[0428] Example 43: Preparation of Compound 43

[0429] Preparation of compound 43-2

[0430] Under nitrogen, compound 43-1 (6.28 g, 27.90 mmol) was added to anhydrous THF (50 mL). The reaction system was cooled to -65°C, and a solution of n-BuLi (2.5 M in THF, 13.95 mL, 34.88 mmol) was slowly added dropwise to the reaction system. After stirring for 30 minutes, a solution of compound 1-1 (3.00 g, 13.95 mmol) in anhydrous THF (20 mL) was slowly added dropwise to the reaction system. After stirring for 1 hour, the reaction was complete by LCMS. Saturated aqueous ammonium chloride (10 mL) was added to the reaction system to quench the reaction. Water (30 mL) was then added, and the mixture was extracted three times with ethyl acetate (40 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the residue was concentrated and purified by column chromatography (0-20% ethyl acetate / petroleum ether) to afford the title compound 43-2 (2.0 g, yellow solid, 30% yield). LC-MS(ESI):m / z[MH] - :359.9.

[0431] Preparation of compound 43-3

[0432] At room temperature, compound 43-2 (1.80 g, 4.98 mmol), tetrahydrofuran (20 mL), and pyridine (0.79 g, 9.96 mmol) were added to a reaction flask. After the reaction system was cooled to 0°C, thionyl chloride (1.18 g, 9.96 mmol) was slowly added dropwise and stirred for 1 hour. LCMS showed that the reaction was complete. Water (10 mL) was added to the system to quench the reaction, and the mixture was extracted three times with ethyl acetate (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give the title compound 43-3 (2.1 g, yellow oil, yield 71%). LC-MS (ESI): m / z [MH] -:378.0.

[0433] Preparation of compound 43-4

[0434] Under nitrogen, compound 43-3 (2.10 g, 5.50 mmol) was dissolved in anhydrous methanol (40 mL), followed by the addition of Pd / C (300 mg, 10%). The mixture was replaced with hydrogen and stirred at room temperature for 16 hours. LCMS confirmed the reaction was complete, and the mixture was filtered and the filtrate was concentrated to obtain the crude target compound. The crude product was purified by column chromatography (0-23% ethyl acetate / petroleum ether) to afford the title compound 43-4 (1.00 g, white solid, 40% yield). LC-MS (ESI): m / z [MH] - :344.0.

[0435] Preparation of compound 43-5

[0436] Compound 7-2 (554.31 mg, 1.78 mmol), cesium carbonate (1.69 g, 5.18 mmol) and 2-butanone (5 mL) were added to the reaction flask. At 90°C, a solution of compound 43-4 (510 mg, 1.48 mmol) in 2-butanone (5 mL) was slowly added dropwise to the reaction system. After stirring for 16 hours, the reaction was completed by LCMS. The reaction system was cooled to 0°C and quenched with water (10 mL). The reaction was extracted three times with ethyl acetate (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (0-30% ethyl acetate / petroleum ether) to obtain the title compound 43-5 (100 mg, yellow oil, yield 8%). LC-MS (ESI): m / z [MH] - :528.0.

[0437] Preparation of compound 43

[0438] Under nitrogen protection, compound 43-5 (90 mg, 0.17 mmol) was dissolved in DCE (2.0 mL), and TfOH (1.0 mL, ρ=1.7 mol / L) was slowly added dropwise to the reaction system. The mixture was stirred at 65° C. for 1 hour. The reaction was complete after LCMS analysis. After the system was cooled to 0°C, saturated sodium bicarbonate solution (3 mL) was slowly added to quench the reaction. Water (5 mL) was then added and the mixture was extracted three times with dichloromethane (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by preparative separation (preparative method: mobile phase: A: 0.05% NH4OH / H2O; B: ACN; column: XBridge XBridge C18, 19×250 mm, 10 μm; column temperature: 25°C; gradient: 40% to 40%; acetonitrile in 7.7-12.1 min; flow rate: 20 mL / min) to obtain the title compound 43 (9 mg, yield 12%). LC-MS (ESI): m / z [M+H+ACN] + :481.2. 1 H NMR(400MHz,DMSO-d6)δ13.20(br.s,1H),11.56(br.s,1H),7.82–7.77(m,4H),7.67( d,J=8.0Hz,1H),7.45(d,J=8.2Hz,2H),7.29(t,J=7.8Hz,1H),6.48(d,J=2.2Hz,1H). 19 F NMR(376MHz, DMSO-d6)δ-60.04(s,3F),-61.22(s,3F).

[0439] Example 44: Preparation of Compound 44

[0440] Preparation of compound 44-1

[0441] Compound 12-1 (700 mg, 1.74 mmol) and pyridine (275 mg, 3.48 mmol) were dissolved in DCM (15 mL). At 0°C, dichlorothionyl (414 mg, 3.48 mmol) was slowly added dropwise to the system. The reaction system was warmed to room temperature and stirred for one hour. LCMS detected the completion of the reaction. Saturated aqueous sodium bicarbonate solution (20 mL) was added to the reaction system to quench the reaction, followed by addition of water (20 mL) and extraction with ethyl acetate (40 mL) three times. The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (0-30% ethyl acetate / petroleum ether) to give the title compound 44-1 (530 mg, yellow solid, yield 56%). LC-MS (ESI): m / z [MH] - :417.9.

[0442] Preparation of compound 44-2

[0443] Under nitrogen, compound 44-1 (500 mg, 1.19 mmol) was dissolved in anhydrous methanol (8 mL), followed by the addition of 10% Pd / C (200 mg). The mixture was replaced with hydrogen and stirred at room temperature for 16 hours. LCMS confirmed the reaction was complete. The mixture was filtered and the filtrate was concentrated to obtain the crude target compound. This crude product was purified by column chromatography (0-23% ethyl acetate / petroleum ether) to afford the title compound 44-2 (390 mg, yellow solid, 53% yield). LC-MS (ESI): m / z [MH] - :384.1.

[0444] Preparation of compound 44-3

[0445] Compound 44-2 (300 mg, 0.78 mmol), bromocyclohexane (152 mg, 0.93 mmol), KI (26 mg, 0.16 mmol), K2CO3 (323 mg, 2.34 mmol), and 2-Butanone (5 mL) were added to a reaction flask. The temperature was raised to 90°C and stirred for 16 hours. LCMS confirmed the completion of the reaction. The reaction solution was cooled to room temperature, added with water (10 mL), and extracted three times with ethyl acetate (10 mL). The mixture was dried over anhydrous sodium sulfate, and the organic phases were combined and concentrated. The residue was purified by column chromatography (0-30% ethyl acetate / petroleum ether) to afford the title compound 44-3 (27 mg, yellow oil, 7% yield). LC-MS (ESI): m / z [MH] - :466.0.

[0446] Preparation of compound 44

[0447] Compound 44-3 (27 mg, 0.058 mmol) was dissolved in dichloroethane (0.5 mL), and trifluoromethanesulfonic acid (0.2 mL) was slowly added. The mixture was heated to 65°C and stirred for 1 hour. LCMS confirmed the reaction was complete, and the reaction solution was cooled to room temperature. Aqueous sodium bicarbonate (5 mL) was slowly added to quench the reaction. The reaction system was extracted three times with dichloromethane (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by preparative separation (preparative method: mobile phase: A: 0.05% NH3H2O / H2O, B: ACN; column: XBridge XBridge C18, 19*250 mm, 10 μm; 25°C; gradient: 35% to 40%; retention time: 5.98-8.57 min of 16 min; flow rate: 20 mL / min) to obtain the title compound 44 (7 mg, 32% yield). LC-MS(ESI):m / z[M+H+ACN] + :419.2.1 H NMR (400MHz, DMSO-d6) δ8.17(d,J=2.1Hz,1H),7.76(d,J=7.4Hz,1H),7.61(d,J=8.0Hz,1H),7.28(t,J=7.7Hz,1 H), 6.46 (d, J = 2.1Hz, 1H), 3.29-3.28 (m, 1H), 1.62 (m, 3H), 1.39 (m, 2H), 1.19 (m, 3H), 0.97 (m, 1H), 0.81 (m, 1H). 19 F NMR(376MHz,DMSO-d6)δ-60.11(s,3F).

[0448] Example 45: Preparation of Compound 45

[0449] Preparation of compound 45-2

[0450] Compound 45-1 (11 g, 87.96 mmol), hydroxylamine hydrochloride (15.27 g, 219.75 mmol), and H₂O (60 mL) were added to a reaction flask. Concentrated hydrochloric acid (4 mL) was then added dropwise, followed by anhydrous sodium sulfate (62.43 g, 439.51 mmol). The system was heated to 120°C, and a solution of chloral hydrate (11.63 g, 70.32 mmol) in H₂O (10 mL) was added to the reaction system. After stirring for one hour, the reaction was complete as determined by LCMS. The system was cooled to room temperature, filtered, and the filtrate was discarded. Water (70 mL) was added to the filter cake, and the mixture was extracted three times with ethyl acetate (140 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain the crude product of the title compound 45-2 (17.4 g, yellow oil). LC-MS (ESI): m / z [MH] - :195.1.

[0451] Preparation of compound 45-3

[0452] Compound 45-2 (17.4 g, 88.75 mmol) and concentrated sulfuric acid (80 mL) were added to a reaction flask and stirred at 80°C for one hour. LCMS confirmed the reaction was complete. After cooling to room temperature, saturated aqueous sodium bicarbonate solution (160 mL) was slowly added dropwise to quench the reaction. Water (160 mL) was then added, and the reaction system was extracted three times with ethyl acetate (200 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (0-40% ethyl acetate / petroleum ether) to afford the title compound 45-3 (1.57 g, yellow solid, 10% yield). LC-MS (ESI): m / z [MH] - :178.1.

[0453] Preparation of compound 45-4

[0454] Under nitrogen, p-bromotrifluoromethoxybenzene (4.04 g, 16.75 mmol) was added to anhydrous THF (8 mL). After cooling to -65°C, a solution of n-BuLi (2.5 M in THF, 6.7 mL, 16.75 mmol) was slowly added dropwise to the reaction system and stirred for 30 minutes. Compound 45-3 (1.2 g, 6.70 mmol) in anhydrous THF (4 mL) was then slowly added dropwise to the reaction system. After stirring for one hour, the reaction was complete by LCMS. Saturated aqueous ammonium chloride (12 mL) was added to the reaction system to quench the reaction, followed by the addition of water (12 mL). The system was extracted three times with ethyl acetate (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (0-40% ethyl acetate / petroleum ether) to afford the title compound 45-4 (1.7 g, yellow oil, 68% yield). LC-MS (ESI): m / z [MH] - :340.0.

[0455] Preparation of compound 45-5

[0456] Compound 45-4 (1.7 g, 4.99 mmol), stannous chloride dihydrate (2.8 g, 12.46 mmol), glacial acetic acid (15.0 mL), and concentrated hydrochloric acid (1.5 mL) were added to a reaction flask. The temperature was raised to 120°C and stirred for 1 hour. LCMS confirmed the completion of the reaction. The reaction system was cooled to room temperature and adjusted to alkalinity with saturated sodium bicarbonate aqueous solution. The mixture was extracted three times with ethyl acetate (40 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (0-30% ethyl acetate / petroleum ether) to afford the title compound 45-5 (590 mg, light yellow solid, 36% yield). LC-MS (ESI): m / z [MH] - :324.0.

[0457] Preparation of compound 45-6

[0458] Compound 45-5 (300 mg, 0.92 mmol), compound 7-2 (318 mg, 1.02 mmol), 2-Butanone (5 mL) and K2CO3 (382 mg, 2.77 mmol) were added to a reaction flask. The temperature was raised to 90°C and stirred for 16 hours. LCMS confirmed the completion of the reaction. The reaction solution was cooled to room temperature and extracted three times with water (5 mL) and ethyl acetate (5 mL). The organic phases were combined and the concentrated residue was purified by normal phase column chromatography (0-30% ethyl acetate / petroleum ether) to obtain the title compound 45-6 (360 mg, light yellow solid, yield 67%). LC-MS (ESI): m / z [M+H] +:510.1.

[0459] Preparation of compound 45

[0460] Compound 45-6 (360 mg, 0.71 mmol), dichloroethane (4 mL), and trifluoromethanesulfonic acid (2 mL) were added to a reaction flask and stirred at 65°C for 1 hour. The reaction was complete as determined by LCMS. The reaction solution was cooled to room temperature and then slowly quenched with saturated aqueous sodium bicarbonate (10 mL). The reaction system was extracted three times with dichloromethane (10 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The concentrated residue was purified by preparative separation (preparative method: mobile phase: A: 0.05% NH3H2O / H2O, B: ACN; column: XBridge XBridge C18, 19*250 mm, 10 μm; 25°C; gradient: 41% to 47%; retention time: 9.25-11.25 min of 16 min; flow rate: 20 mL / min) to afford the title compound 45 (136 mg, 45% yield). LC-MS(ESI):m / z[M+H+ACN] + :461.2. 1 H NMR (400MHz, DMSO-d6) δ11.87(br.s,2H),7.73(d,J=1.9Hz,1H),7.39(d,J=8.7Hz,2H),7.3 4(m,1H),7.33(d,J=8.7Hz,2H),6.89(t,J=8.8Hz,1H),6.44(d,J=1.8Hz,1H),2.20(s,3H). 19 F NMR(376MHz, DMSO-d6)δ-56.78(s,3F),-116.42(s,F).

[0461] Example 46: Preparation of Compound 46

[0462] Preparation of compound 46-2

[0463] Compound 46-1 (4.5 g, 34.85 mmol), hydroxylamine hydrochloride (6.05 g, 87.13 mmol), anhydrous sodium sulfate (24.75 g, 174.25 mmol), and water (30 mL) were added to a reaction flask, followed by the slow dropwise addition of concentrated hydrochloric acid (3 mL). The temperature was raised to 120°C, and a 20 mL solution of chloral hydrate (4.61 g, 27.88 mmol) was added dropwise to the reaction flask. The mixture was stirred for 2 hours, and the reaction was complete by LCMS. The system was cooled to room temperature, and ice water (30 mL) was added. THF (20 mL) was then added to dissolve the oil. The system was extracted three times with ethyl acetate (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give the crude product 46-2 (6.9 g, brown solid), which was used directly in the next step. LC-MS (ESI): m / z [MH] - :199.1.

[0464] Preparation of compound 46-3

[0465] Compound 46-2 (6.40 g, 31.98 mmol) and concentrated sulfuric acid (50 mL) were added to a reaction flask. The system was heated to 80°C and stirred for two hours. LCMS confirmed the reaction was complete. After cooling to room temperature, ice water (50 mL) was added to quench the reaction. The mixture was extracted three times with ethyl acetate (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (0-30% ethyl acetate / petroleum ether) to obtain the title compound 46-3 (3.9 g, brown solid, 43% yield). LC-MS (ESI): m / z [MH] - :182.1.

[0466] Preparation of compound 46-4

[0467] Under nitrogen, p-bromotrifluoromethoxybenzene (8.69 g, 36.04 mmol) and anhydrous THF (40 mL) were added to a reaction flask. A solution of n-BuLi (2.5 M in THF, 16.40 mL, 40.95 mmol) was slowly added dropwise to the reaction system at -65°C. After stirring for 30 minutes, a solution of compound 46-3 (3.00 g, 16.38 mmol) in anhydrous THF (20 mL) was slowly added dropwise to the reaction system. After stirring for one hour, the reaction was complete as determined by LCMS. Saturated aqueous ammonium chloride (10 mL) was added to the reaction system to quench the reaction, followed by the addition of water (30 mL). The reaction system was extracted three times with ethyl acetate (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the residue was concentrated and purified by column chromatography (0-35% ethyl acetate / petroleum ether) to afford the target compound 46-4 (2.1 g, yellow solid, 27% yield). LC-MS(ESI):m / z[MH] -:343.9.

[0468] Preparation of compound 46-5

[0469] Compound 46-4 (1.00 g, 2.90 mmol) and stannous chloride dihydrate (1.64 g, 7.25 mmol) were dissolved in glacial acetic acid (10 mL) and concentrated hydrochloric acid (1.0 mL) was slowly added to the reaction system. The temperature was raised to 120°C and stirred for one hour. The reaction was complete after LCMS analysis. The reaction system was cooled to 0°C and quenched by slowly adding saturated sodium bicarbonate solution (10 mL). Water (10 mL) was added and the reaction system was extracted three times with ethyl acetate (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (0-32% ethyl acetate / petroleum ether) to obtain the target compound 46-5 (720 mg, white solid, yield 74%). LC-MS (ESI): m / z [MH] - :327.9.

[0470] Preparation of compound 46-6

[0471] Compound 46-5 (300 mg, 0.91 mmol), compound 7-2 (340 mg, 1.09 mmol), 2-butanone (5 mL), potassium carbonate (377.31 mg, 2.73 mmol) and potassium iodide (30.21 mg, 0.18 mmol) were added to a reaction flask. The system was heated to 90°C and stirred for 16 hours. LCMS detected the completion of the reaction. After the reaction system was cooled to 0°C, water (10 mL) was added to quench the reaction, and then extracted three times with ethyl acetate (15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (0-30% ethyl acetate / petroleum ether) to obtain the target compound 46-6 (260 mg, brown solid, yield 47%). LC-MS (ESI): m / z [MH] - :511.9.

[0472] Preparation of compound 46

[0473] Compound 46-6 (260 mg, 0.51 mmol), DCE (3 mL) and TfOH (1.5 mL, ρ = 1.7 mol / L) were added to a reaction flask. The system was heated to 65 ° C and stirred for 1 hour. LCMS detected that the reaction was complete. After the reaction system was cooled to 0 ° C, a saturated sodium bicarbonate solution (5 mL) was slowly added to quench the reaction. Water (6 mL) was then added and extracted three times with dichloromethane (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by normal column chromatography (0-100% ethyl acetate / petroleum ether) to obtain the title compound 46 (117 mg, yield 54%). LC-MS (ESI): m / z [M + H + ACN]+ :465.1. 1 H NMR (400MHz, DMSO-d6) δ13.17(s,1H),11.91(s,1H),7.74(d,J=2.1Hz,1H),7.40(d,J =8.8Hz,2H),7.36(m,1H),7.35(d,J=8.8Hz,2H),7.14(m,1H),6.46(t,J=2.0Hz,1H). 19 F NMR(376MHz, DMSO-d6)δ-56.78(s,3F),-137.02(d,1F),-154.97(d,1F).

[0474] Example 47: Preparation of Compound 47

[0475] Preparation of compound 47-2

[0476] Compound 47-1 (8.5 g, 61.96 mmol), hydroxylamine hydrochloride (10.76 g, 154.90 mmol), anhydrous sodium sulfate (44.0 g, 309.80 mmol), and water (80 mL) were added to a reaction flask, followed by the slow dropwise addition of concentrated hydrochloric acid (4 mL). The reaction system was heated to 120°C, and a solution of chloral hydrate (8.2 g, 49.57 mmol) in water (20 mL) was added dropwise to the reaction flask and stirred for 2 hours. LCMS confirmed the reaction was complete. The system was cooled to room temperature, and ice water (50 mL) was added, followed by THF (20 mL) to dissolve the oil. The system was extracted three times with ethyl acetate (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give the crude product 47-2 (13.0 g, brown solid), which was used directly in the next step. LC-MS (ESI): m / z [M+H] + :209.2.

[0477] Preparation of compound 47-3

[0478] Compound 47-2 (12.0 g, 57.63 mmol) and concentrated sulfuric acid (80 mL) were added to a reaction flask. The system was heated to 80°C and stirred for two hours. LCMS confirmed the reaction was complete. After cooling to room temperature, ice water (50 mL) was added to quench the reaction. The mixture was extracted three times with ethyl acetate (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (0-50% ethyl acetate / petroleum ether) to afford the title compound 47-3 (1.4 g, orange-yellow solid, 11.4% yield). 1H NMR (400MHz, DMSO-d6) δ11.05(s,1H),7.43(d,J=8.4Hz,1H),6.67(d,J=8.4Hz,1H),3.90(s,3H),2.01(s,3H).

[0479] Preparation of compound 47-4

[0480] Under nitrogen, p-bromotrifluoromethoxybenzene (3.61 g, 14.96 mmol) and anhydrous THF (40 mL) were added to a reaction flask. A solution of n-BuLi (2.5 M in THF, 6.8 mL, 17.0 mmol) was slowly added dropwise to the reaction system at -65°C. After stirring for 30 minutes, a solution of compound 47-3 (1.30 g, 6.80 mmol) in anhydrous THF (10 mL) was slowly added dropwise to the reaction system. After stirring for one hour, the reaction was complete as determined by LCMS. Saturated aqueous ammonium chloride (10 mL) was added to the reaction system to quench the reaction, followed by the addition of water (30 mL). The reaction system was extracted three times with ethyl acetate (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the residue was concentrated and purified by column chromatography (0-40% ethyl acetate / petroleum ether) to afford the target compound 47-4 (1.8 g, yellow solid, 35.1% yield). LC-MS(ESI):m / z[MH] - :352.0.

[0481] Preparation of compound 47-5

[0482] Compound 47-4 (1.70 g, 4.81 mmol) and stannous chloride dihydrate (2.71 g, 12.02 mmol) were dissolved in glacial acetic acid (15 mL) and concentrated hydrochloric acid (1.5 mL) was slowly added to the reaction system. The temperature was raised to 120°C and stirred for one hour. The reaction was complete after LCMS detection. After the system was cooled to 0°C, a saturated sodium bicarbonate solution (10 mL) was slowly added to quench the reaction. Water (10 mL) was added and the mixture was extracted three times with ethyl acetate (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (0-40% ethyl acetate / petroleum ether) to obtain the target compound 47-5 (610 mg, white solid, yield 27%). LC-MS (ESI): m / z [MH] - :336.0.

[0483] Preparation of compound 47-6

[0484] Compound 47-5 (550 mg, 1.60 mmol), compound 7-2 (599 mg, 1.92 mmol), 2-butanone (5 mL), potassium carbonate (1.69 g, 5.18 mmol) and potassium iodide (53.12 mg, 0.32 mmol) were added to a reaction flask. The system was heated to 90°C and stirred for 8 hours. LCMS detected the completion of the reaction. After the system was cooled to 0°C, water (10 mL) was added to quench the reaction, followed by extraction three times with ethyl acetate (15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (0-30% ethyl acetate / petroleum ether) to obtain the target compound 47-6 (180 mg, yellow oil, yield 10%). LC-MS (ESI): m / z [MH] - :519.9.

[0485] Preparation of compound 47

[0486] Compound 47-6 (170 mg, 0.33 mmol), DCE (2 mL), and TfOH (1.0 mL, ρ = 1.7 mol / L) were added to a reaction flask, and the system was heated to 65°C and stirred for 1 hour. LCMS confirmed the reaction was complete, and the system was cooled to 0°C and slowly quenched with saturated sodium bicarbonate solution (5 mL). Water (6 mL) was then added and the mixture was extracted three times with dichloromethane (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by preparative separation (preparative method: mobile phase: A: 0.05% NH4OH / H2O; B: ACN; column: XBridge XBridge C18, 19×250 mm, 10 μm; column temperature: 25°C; gradient: 42% to 42%; acetonitrile in 9.0-10.1 min; flow rate: 20 mL / min) to obtain the title compound 47 (9 mg, 6% yield). LC-MS(ESI):m / z[M+H+ACN] + :473.2. 1 H NMR (400MHz, DMSO-d6) δ13.11(s,1H),11.11(s,1H),7.72(d,J=2.0Hz,1H),7.39(d,J=8.8Hz,2H),7.33(d,J =8.8Hz,2H),7.24(d,J=8.4Hz,1H),6.68(d,J=8.4Hz,1H),6.44(d,J=2.0Hz,1H),3.79(s,3H),2.10(s,3H). 19 F NMR(376MHz,DMSO-d6)δ-56.77(s,3F).

[0487] Example 48: Preparation of Compound 48

[0488] Preparation of compound 48-3

[0489] Under nitrogen, compound 48-1 (10.0 g, 72.90 mmol), water (200 mL), chloral hydrate (18.1 g, 109.34 mmol), hydroxylamine hydrochloride (18.2 g, 262.43 mmol), and sodium sulfate (82.8 g, 583.17 mmol) were added to a reaction flask. The system was heated to 95°C and stirred for 3 hours. 2N hydrochloric acid (20 mL) was then added to the reaction system and stirred for 10 minutes. The reaction mixture was filtered, the filter cake was washed with water (100 mL), and after drying, sulfuric acid (100 mL) was added. The temperature was raised to 80°C and stirred for 3 hours. LCMS confirmed the reaction was complete. After cooling the system to room temperature, it was slowly poured into ice water (200 mL). The reaction mixture was filtered, the filter cake was washed with water (80 mL), and dried to afford the title compound 48-3 (1.5 g, yellow solid, 10% yield). LC-MS(ESI):m / z[MH] - :190.0.

[0490] Preparation of compound 48-4

[0491] Under nitrogen, p-bromotrifluoromethoxybenzene (4.73 g, 19.61 mmol) and anhydrous THF (20 mL) were added to a reaction flask. A solution of n-BuLi (2.5 M in THF, 9.4 mL, 23.5 mmol) was slowly added dropwise to the reaction system at -65°C. After stirring for 30 minutes, a solution of compound 48-3 (1.5 g, 7.85 mmol) in anhydrous THF (10 mL) was slowly added dropwise to the reaction system. After stirring for one hour, the reaction was complete as determined by LCMS. The reaction was quenched by the addition of saturated aqueous ammonium chloride (10 mL), followed by the addition of water (30 mL). The mixture was extracted three times with ethyl acetate (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the residue was concentrated and purified by column chromatography (0-40% ethyl acetate / petroleum ether) to afford the target compound 48-4 (500 mg, yellow solid, 18% yield). LC-MS (ESI): m / z [MH] - :352.0.

[0492] Preparation of compound 48-5

[0493] Compound 48-4 (500 mg, 1.42 mmol) and stannous chloride dihydrate (799 mg, 3.55 mmol) were dissolved in glacial acetic acid (10 mL). Concentrated hydrochloric acid (1 mL) was then slowly added to the reaction system. The temperature was raised to 120°C and stirred for 2 hours. LCMS confirmed the reaction was complete. The reaction system was cooled to 0°C and saturated sodium bicarbonate solution (10 mL) was slowly added to quench the reaction. Water (10 mL) was added, and the reaction system was extracted three times with ethyl acetate (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (0-40% ethyl acetate / petroleum ether) to obtain the target compound 48-5 (270 mg, yellow solid, yield 56.6%). LC-MS (ESI): m / z [MH] - :336.1.

[0494] Preparation of compound 48-6

[0495] Compound 48-5 (270 mg, 0.80 mmol), compound 7-2 (275 mg, 0.88 mmol), 2-butanone (10 mL), and potassium carbonate (221 mg, 1.60 mmol) were added to a reaction flask. The system was heated to 90°C and stirred for 16 hours. LCMS detected the completion of the reaction. After the system was cooled to room temperature, water (10 mL) was added to quench the reaction, followed by extraction three times with ethyl acetate (15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (0-30% ethyl acetate / petroleum ether) to obtain the target compound 48-6 (180 mg, yellow solid, yield 43.1%). LC-MS (ESI): m / z [MH] - :520.1.

[0496] Preparation of compound 48

[0497] Compound 48-6 (180 mg, 0.35 mmol), DCE (5 mL), and TfOH (518 mg, 3.45 mmol) were added to a reaction flask. The system was heated to 60°C and stirred for 3 hours. LCMS confirmed the reaction was complete. The reaction system was cooled to 0°C and slowly quenched with saturated sodium bicarbonate solution (5 mL). Water (6 mL) was added and the mixture was extracted three times with dichloromethane (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by preparative separation (preparative method: mobile phase: A: 10 mmol ammonia solution; B: acetonitrile; column: XBridge C18, 19×250 mm, 10 μm; column temperature: 25°C; gradient: 40%-45% acetonitrile in 7.56-8.05 min; flow rate: 20 mL / min) to obtain the title compound 48 (15 mg, 10% yield). LCMS (ESI): m / z [M+41+H] + :473.3.1 H NMR(400MHz, DMSO-d6)δ11.02(br.s,1H),7.74(d,J=2.1Hz,1H),7.42–7.37(m,2H),7.37–7.32(m, 2H), 6.93 (d, J = 2.0Hz, 1H), 6.77 (d, J = 2.0Hz, 1H), 6.46 (d, J = 2.1Hz, 1H), 3.69 (s, 3H), 2.26 (s, 3H). 19 F NMR(376MHz,DMSO-d6)δ-56.76(s,3F).

[0498] Example 49: Preparation of Compound 49

[0499] Preparation of compound 49-1

[0500] Compound 44-2 (540 mg, 1.40 mmol), bromocycloheptane (298 mg, 1.68 mmol), KI (46 mg, 0.28 mmol), K2CO3 (580 mg, 4.20 mmol), and 2-Butanone (6 mL) were added to a reaction flask. The mixture was stirred at 90°C for 16 hours. LCMS confirmed the completion of the reaction. The reaction solution was cooled to room temperature, added with water (10 mL), and extracted three times with ethyl acetate (10 mL). The mixture was dried over anhydrous sodium sulfate, and the organic phases were combined, concentrated, and purified by column chromatography (0-30% ethyl acetate / petroleum ether) to afford the title compound 49-1 (270 mg, yellow oil, 40.2% yield). LC-MS (ESI): m / z [MH] - :480.2.

[0501] Preparation of compound 49

[0502] Compound 49-1 (150 mg, 0.31 mmol) was dissolved in dichloroethane (3 mL), and trifluoromethanesulfonic acid (1.2 mL) was slowly added. The temperature was raised to 65°C and stirred for 1 hour. LCMS confirmed the reaction was complete. The reaction solution was cooled to room temperature and quenched with aqueous sodium bicarbonate (5 mL). The reaction system was extracted three times with dichloromethane (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by preparative separation (preparative method: mobile phase: A: 0.05% NH3H2O / H2O, B: ACN; column: XBridge XBridge C18, 19*250 mm, 10 μm; 25°C; gradient: 47% to 52%; retention time: 7.92-8.67 min of 16 min; flow rate: 20 mL / min) to obtain the title compound 49 (13 mg, 11% yield). LC-MS (ESI): m / z [M+H]+ :392.2. 1 H NMR (400MHz, DMSO-d6) δ13.13(s,1H),11.28(s,1H),8.18(d,J=1.8Hz,1H),7.76(d,J=7.5Hz,1H),7.62(d,J=8. 0Hz,1H),7.27(m,1H),6.38(s,1H),2.71–2.62(m,1H),1.67–1.46(m,5H),1.44–1.29(m,6H),1.03–0.88(m,1H). 19 F NMR(376MHz,DMSO-d6)δ-60.11(s,3F).

[0503] Example 50: Preparation of Compound 50

[0504] Preparation of compound 50-2

[0505] Under nitrogen, compound 50-1 (23 g, 132.19 mmol) and 1-(trifluoromethyl)-1,2-benzidoxyl-3(1H)-one (12.5 g, 39.66 mmol) were added to anhydrous DCE (100 mL). The system was heated to 90°C and stirred for 16 hours. LCMS confirmed the reaction was complete. The temperature was then lowered to 0°C and stirred for 1 hour, resulting in the precipitation of a solid. The filtrate was concentrated and purified by column chromatography (0-15% ethyl acetate / petroleum ether) to afford the title compound 50-2 (3.0 g, colorless oil, 9% yield). 1 H NMR (400MHz, DMSO-d6) δ8.55(d,J=2.6Hz,1H),8.28(dd,J=8.7,2.6Hz,1H),7.33(d,J=8.7Hz,1H).

[0506] Preparation of compound 50-3

[0507] Under nitrogen, compound 50-2 (3.0 g, 12.40 mmol) was added to anhydrous tetrahydrofuran (50 mL). A solution of n-BuLi (2.5 M in THF, 6.20 mL, 15.50 mmol) was slowly added dropwise to the reaction system at -65°C and stirred for 30 minutes. Subsequently, a solution of compound 1-1 (1.3 g, 6.20 mmol) in anhydrous THF (5 mL) was slowly added dropwise to the reaction system. After stirring for 2 hours, LCMS confirmed the reaction was complete. The reaction was quenched by adding saturated aqueous ammonium chloride (5 mL), followed by addition of water (20 mL) and extraction with ethyl acetate (20 mL) three times. The organic phases were combined, dried over anhydrous sodium sulfate, and the residue was concentrated and purified by column chromatography (0-50% ethyl acetate / petroleum ether) to afford the title compound 50-3 (750 mg, yellow solid, 32% yield). LC-MS (ESI): m / z [MH] - :377.1.

[0508] Preparation of compound 50-5

[0509] Under nitrogen, compound 50-3 (730 mg, 1.93 mmol) was dissolved in DCM (5 mL) and then pyridine (305 mg, 3.86 mmol) and thionyl chloride (459 mg, 3.86 mmol) were added. The mixture was stirred at room temperature for 2 hours. TLC confirmed the reaction was complete. The reaction solution was dried and methanol (10 mL) and palladium carbon (20 mg, 10%) were added under nitrogen. The gas was replaced with hydrogen three times and the mixture was stirred at room temperature for 16 hours. The reaction was completed by LCMS. The mixture was filtered, the filtrate was concentrated to dryness, and the residue was purified by column chromatography (0-25% ethyl acetate / petroleum ether) to obtain the title compound 50-5 (300 mg, yellow solid, 42% yield). LC-MS (ESI): m / z [MH] - :361.4.

[0510] Preparation of compound 50-6

[0511] Compound 50-5 (300 mg, 0.83 mmol), compound 7-2 (284 mg, 0.91 mmol), 2-butanone (10 mL), and potassium carbonate (229 mg, 1.66 mmol) were added to a reaction flask. The system was heated to 90°C and stirred for 16 hours. LCMS detected the completion of the reaction. After the reaction system was cooled to room temperature, water (10 mL) was added to quench the reaction, followed by extraction three times with ethyl acetate (15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (0-35% ethyl acetate / petroleum ether) to obtain the title compound 50-6 (80 mg, yellow solid, yield 17%). LC-MS (ESI): m / z [MH] - :545.5.

[0512] Preparation of compound 50

[0513] Compound 50-6 (80 mg, 0.146 mmol), DCE (5 mL), and TfOH (110 mg, 0.730 mmol) were added to a reaction flask, and the system was heated to 60°C and stirred for 2 hours. The reaction was completed by LCMS. After cooling the reaction system to 0°C, saturated sodium bicarbonate solution (10 mL) was slowly added to quench the reaction. Water (10 mL) was then added and the mixture was extracted three times with dichloromethane (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by preparative separation (preparative method: mobile phase: A: 10 mmol formic acid solution; B: acetonitrile; column: ECLIPSE PLUS C18 40 g; gradient: 5%-60% acetonitrile; flow rate: 30 mL / min) to obtain the title compound 50 (21 mg, 32% yield). LCMS (ESI): m / z [M+H] + :457.1. 1 H NMR (400MHz, DMSO-d6) δ13.21(s,1H),11.76(br.s,1H),8.21(d,J=2.6Hz,1H),7.91(dd,J=8.6,2.6Hz,1H),7.85(d,J =7.6Hz,1H),7.79(d,J=2.2Hz,1H),7.67(d,J=8.0Hz,1H),7.34(d,J=8.6Hz,1H),7.29(t,J=7.6Hz,1H),6.48(s,1H). 19 F NMR(376MHz,DMSO-d6)δ-55.25(s,3F),-60.01(s,3F).

[0514] Example 51: Preparation of Compound 51

[0515] Preparation of compound 51-2

[0516] Compound 51-1 (11 g, 87.96 mmol), hydroxylamine hydrochloride (15.27 g, 219.75 mmol), and H₂O (60 mL) were added to a reaction flask. Hydrochloric acid (6 mol / L, 4 mL) was then added dropwise to the reaction system, followed by anhydrous sodium sulfate (62.43 g, 439.51 mmol). A solution of chloral hydrate (11.63 g, 70.32 mmol) in H₂O (10 mL) was added to the reaction system at 120°C. After stirring for one hour, the system was cooled to room temperature, filtered, and the filtrate was discarded. Water (70 mL) was added to the filter cake, and the mixture was extracted three times with ethyl acetate (70 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the residue was concentrated to obtain the crude product of the title compound 51-2 (15.5 g, yellow oil).

[0517] Preparation of compound 51-3

[0518] Compound 51-2 (11.5 g, 58.62 mmol) and concentrated sulfuric acid (50 mL) were added to a reaction flask and stirred at 80°C for one hour. LCMS confirmed the reaction was complete. The reaction solution was slowly added dropwise to a saturated aqueous sodium bicarbonate solution (160 mL) at 0°C to quench the reaction. Water (160 mL) was then added, and the reaction system was extracted three times with ethyl acetate (300 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (0-40% ethyl acetate / petroleum ether) to afford the title compound 51-3 (4.8 g, yellow solid, 45% yield). LC-MS (ESI): m / z [MH] - :178.1.

[0519] Preparation of compound 51-4

[0520] Under nitrogen, p-bromotrifluoromethoxybenzene (10.09 g, 41.88 mmol) was added to anhydrous THF (25 mL). A solution of n-BuLi (2.5 M in THF, 16.7 mL, 41.88 mmol) was slowly added dropwise to the reaction system at -65°C and stirred for 30 minutes. Compound 51-3 (3 g, 16.75 mmol) in anhydrous THF (5 mL) was then slowly added dropwise to the reaction system. After stirring for one hour, the reaction was complete by LCMS. Saturated aqueous ammonium chloride (12 mL) was added to the reaction system to quench the reaction, followed by water (12 mL). The system was extracted three times with ethyl acetate (24 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the residue was concentrated and purified by column chromatography (0-40% ethyl acetate / petroleum ether) to afford the title compound 51-4 (3.05 g, yellow oil, 53% yield). LC-MS (ESI): m / z [MH] - :340.1

[0521] Preparation of compound 51-5

[0522] Compound 51-4 (2 g, 5.86 mmol), stannous chloride dihydrate (3.3 g, 14.65 mmol), glacial acetic acid (20 mL), and concentrated hydrochloric acid (5 mL) were added to a reaction flask. The temperature was raised to 120°C and stirred for 1 hour. LCMS confirmed the completion of the reaction. The reaction system was cooled to room temperature and adjusted to alkalinity with saturated aqueous sodium bicarbonate solution. The mixture was extracted three times with ethyl acetate (40 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (0-30% ethyl acetate / petroleum ether) to afford the title compound 51-5 (1.78 g, light yellow solid, 93% yield). LC-MS (ESI): m / z [MH] - :324.4.

[0523] Preparation of compound 51-6

[0524] Compound 51-5 (300 mg, 0.92 mmol), compound 7-2 (345 mg, 1.10 mmol), 2-Butanone (5 mL) and K2CO3 (382 mg, 2.77 mmol) were added to a reaction flask. The temperature was raised to 90°C and stirred for 16 hours. LCMS confirmed the completion of the reaction. The reaction solution was cooled to room temperature, added with water (5 mL), and extracted three times with ethyl acetate (10 mL). The organic phases were combined and the concentrated residue was purified by normal phase column chromatography (0-30% ethyl acetate / petroleum ether) to obtain the title compound 51-6 (200 mg, light yellow solid, yield 42%). LC-MS (ESI): m / z [MH] - :508.1.

[0525] Preparation of compound 51

[0526] Compound 51-6 (200 mg, 0.39 mmol), dichloroethane (3 mL), and trifluoromethanesulfonic acid (1.5 mL) were added to a reaction flask and stirred at 65°C for 1 hour. The reaction was completed by LCMS. The reaction solution was cooled to room temperature and then slowly quenched with saturated aqueous sodium bicarbonate (10 mL). The reaction system was extracted three times with dichloromethane (10 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The concentrated residue was purified by preparative separation (preparative method: mobile phase: A: 0.05% NH3H2O / H2O, B: ACN; column: XBridge XBridge C18, 19*250 mm, 10 μm; 25°C; gradient: 41% to 46%; retention time: 7.81-10.38 min of 16 min; flow rate: 20 mL / min) to obtain the title compound 51 (11 mg, 7% yield). LC-MS(ESI):m / z[M+H] +:420.2. 1 H NMR(400MHz,DMSO-d6)δ13.06(br.s,1H),11.64(br.s,1H),7.71(d,J=2.1Hz,1H),7.42–7.36(m,2H) ,7.36–7.30(m,2H),7.17(d,J=7.6Hz,1H),6.94(t,J=7.1Hz,1H),6.44(d,J=2.1Hz,1H),2.26(s,3H). 19 F NMR(376MHz,DMSO-d6)δ-56.78(s,3F),-135.24(s,1F).

[0527] Example 52: Preparation of Compound 52

[0528] Preparation of compound 52-1

[0529] Under nitrogen, 1,3-dibromobenzene (30.0 g, 127.83 mmol) was dissolved in anhydrous tetrahydrofuran (200 mL). After cooling to -65°C, a solution of n-BuLi (2.5 M in THF, 51 mL, 127.83 mmol) was slowly added dropwise to the reaction system and stirred for 30 minutes. A solution of compound 1-1 (11.0 g, 51.13 mmol) in anhydrous tetrahydrofuran (50 mL) was slowly added dropwise to the reaction system. After stirring for 2 hours, the reaction was complete as determined by LCMS. The system was quenched by the addition of saturated aqueous ammonium chloride (50 mL), followed by the addition of water (200 mL) and extraction with ethyl acetate (300 mL) twice. The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (0-40% ethyl acetate / petroleum ether) to afford the title compound 52-1 (12 g, yellow solid, 63% yield). LC-MS (ESI): m / z [MH] - :370.9.

[0530] Preparation of compound 52-2

[0531] Compound 52-1 (12 g, 32.25 mmol), stannous chloride dihydrate (18 g, 80.61 mmol), glacial acetic acid (100 mL), and concentrated hydrochloric acid (10 mL) were added to a reaction flask. The temperature was raised to 120°C and stirred for 3 hours. LCMS confirmed the completion of the reaction. The reaction system was cooled to room temperature and adjusted to alkalinity with saturated aqueous sodium bicarbonate solution. The mixture was extracted three times with ethyl acetate (300 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (0-30% ethyl acetate / petroleum ether) to obtain the title compound 52-2 (8.7 g, yellow solid, 75% yield). LC-MS (ESI): m / z [MH] - :353.9.

[0532] Preparation of compound 52-3

[0533] Compound 52-2 (2.7 g, 7.58 mmol), compound 7-2 (2.6 g, 8.34 mmol), 2-Butanone (50 mL), and K2CO3 (2.1 g, 15.16 mmol) were added to a reaction flask. The reaction system was heated to 90°C and stirred for 16 hours. LCMS confirmed the completion of the reaction. The reaction solution was cooled to room temperature, water (5 mL) was added, and the mixture was extracted three times with ethyl acetate (10 mL). The organic phases were combined, and the concentrated residue was purified by normal phase column chromatography (0-30% ethyl acetate / petroleum ether) to obtain the title compound 52-3 (900 mg, yellow solid, yield 22%). LC-MS (ESI): m / z [MH] - :537.9.

[0534] Preparation of compound 52-4

[0535] Compound 52-3 (200 mg, 0.370 mmol) was dissolved in toluene (10 mL), followed by the addition of palladium acetate (8.3 mg, 0.037 mmol), Xantphos (21.4 mg, 0.037 mmol), and triethylamine (75 mg, 0.740 mmol). A drop of water was added to the reaction system to displace the carbon monoxide atmosphere three times. The system was heated to 90°C and stirred for 16 hours. LCMS confirmed the completion of the reaction. After cooling to room temperature, water (20 mL) was added, and the pH was adjusted to acidic with 1 M aqueous hydrochloric acid. The mixture was then extracted three times with ethyl acetate (30 mL). The residue was dried over anhydrous sodium sulfate and concentrated to afford the title compound 52-4 (50 mg, yellow solid, 26% yield). LC-MS (ESI): m / z [MH] - :504.4.

[0536] Preparation of compound 52-5

[0537] Under nitrogen, compound 52-4 (50 mg, 0.099 mmol) was dissolved in DMF (3 mL) and then 2-methoxyethylamine (8.17 mg, 0.108 mmol) and HATU (56 mg, 0.148 mmol) were added. After stirring at room temperature for 30 minutes, DIEA (18 mg, 0.148 mmol) was added to the reaction system. The mixture was stirred at room temperature for 2 hours. LCMS confirmed the completion of the reaction. Water (20 mL) and ethyl acetate (20 mL) were added twice, and the organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (0-45% ethyl acetate / petroleum ether) to obtain the title compound 52-5 (40 mg, light yellow solid, yield 71%). LC-MS (ESI): m / z [MH] - :561.5.

[0538] Preparation of compound 52

[0539] Compound 52-5 (40 mg, 0.071 mmol), dichloroethane (5 mL), and trifluoromethanesulfonic acid (106.5 mg, 0.71 mmol) were added to a reaction flask. The mixture was stirred at 50°C for 2 hours. LCMS confirmed the reaction was complete. The reaction solution was cooled to room temperature and then slowly quenched with saturated aqueous sodium bicarbonate (10 mL). The mixture was extracted three times with dichloromethane (10 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The concentrated residue was purified by preparative separation (preparative method: mobile phase: A: 10 mmol formic acid solution; B: acetonitrile; column: ECLIPSE PLUS C18 40 g; gradient: 5%-65% acetonitrile; flow rate: 30 mL / min) to obtain the title compound 52 (14 mg, 43% yield). LCMS (ESI): m / z [M+H] + :473.2. 1 H NMR(400MHz, DMSO-d6)δ13.22(br.s,1H),8.64(s,1H),7.86(d,J=7.6Hz,1H),7.82–7.59(m,4H),7.51 (t,J=7.8Hz,1H),7.39(d,J=7.7Hz,1H),7.26(t,J=7.7Hz,1H),6.44(s,1H),3.42(m,4H),3.25(s,3H). 19 F NMR(376MHz,DMSO-d6)δ-59.99(s,3F).

[0540] Example 53: Preparation of Compound 53

[0541] Preparation of compound 53-1

[0542] Under nitrogen, 5-bromo-2-trifluoromethylpyridine (7.5 g, 33.20 mmol) was dissolved in anhydrous THF (40 mL). After cooling to -15°C, a solution of isopropylmagnesium chloride and lithium chloride (1.3 M in THF, 30.7 mL, 39.91 mmol) was slowly added dropwise. After stirring for 40 minutes, a solution of compound 1-1 (3.57 g, 16.60 mmol) in anhydrous THF (20 mL) was slowly added dropwise to the reaction system and stirred at -15°C for one hour. LCMS confirmed the reaction was complete. Water (60 mL) was added to the system to quench the reaction. The mixture was extracted three times with ethyl acetate (120 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (0-40% ethyl acetate / petroleum ether) to afford the title compound 53-1 (4.3 g, yellow solid, 71% yield). LC-MS (ESI): m / z [MH] - :361.1

[0543] Preparation of compound 53-2

[0544] Compound 53-1 (2.2 g, 6.07 mmol), pyridine (0.96 g, 12.14 mmol) and DCM (20 mL) were added to a reaction flask. Thionyl chloride (1.44 g, 12.14 mmol) was added dropwise at 0°C, then the temperature was slowly raised to room temperature and stirred for one hour. LCMS confirmed the reaction was complete. Water (20 mL) was added to quench the reaction, and the mixture was extracted three times with DCM (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain a crude product of compound 53-2 (3 g, yellow oil). LC-MS (ESI): m / z [MH] - :379.4.

[0545] Preparation of compound 53-3

[0546] Under nitrogen, compound 53-5 (3 g, 7.88 mmol), palladium on carbon (1.12 g, 10%), and anhydrous methanol (30 mL) were added to a reaction flask. The gas was replaced with hydrogen three times and the mixture was stirred at room temperature for 16 hours. LCMS confirmed the completion of the reaction. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by column chromatography (ethyl acetate / petroleum ether 0-60%) to give compound 53-3 (1.05 g, yellow solid, yield 38%). LC-MS (ESI): m / z [MH] - :345.4.

[0547] Preparation of compound 53-4

[0548] Compound 53-3 (800 mg, 2.31 mmol), compound 7-2 (865.17 mg, 2.77 mmol), 2-Butanone (8 mL), and K2CO3 (957.80 mg, 6.93 mmol) were added to a reaction flask. The reaction system was heated to 90°C and stirred for 16 hours. LCMS confirmed the completion of the reaction. The reaction solution was cooled to room temperature, water (5 mL) was added, and the mixture was extracted three times with ethyl acetate (10 mL). The organic phases were combined, and the concentrated residue was purified by normal phase column chromatography (0-30% ethyl acetate / petroleum ether) to obtain the title compound 53-4 (260 mg, yellow oil, yield 21%). LC-MS (ESI): m / z [MH] - :529.2.

[0549] Preparation of compound 53

[0550] Compound 53-4 (130 mg, 0.25 mmol), dichloroethane (1.5 mL), and trifluoromethanesulfonic acid (0.5 mL) were added to a reaction flask and stirred at 65°C for 1 hour. LCMS confirmed the reaction was complete. The reaction solution was cooled to room temperature and then slowly quenched with saturated aqueous sodium bicarbonate (4 mL). The mixture was extracted three times with dichloromethane (4 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by preparative separation (preparative method: mobile phase: A: 0.1% FA / H2O; B: acetonitrile; column: Atlantis™ T3 Prep OBD™ 19*250 mm, 10 μm; gradient: 44%-50% retention time: 8.4-9.4 min of 16 min; flow rate: 20 mL / min) to afford compound 53 (34 mg, yield 32%). LC-MS (ESI): m / z [MH] - :LC-MS(ESI):m / z[M+H] + :441.2. 1 H NMR(400MHz,DMSO-d6)δ13.24(s,1H),11.78(br.s,1H),8.68–8.63(m,1H),7.98–7.91(m,2H),7.87(d ,J=7.5Hz,1H),7.81(d,J=2.2Hz,1H),7.69(d,J=8.0Hz,1H),7.32(t,J=7.8Hz,1H),6.53–6.48(m,1H). 19 F NMR(376MHz,DMSO-d6)δ-60.01(s,3F),-66.51(s,3F).

[0551] Example 54: Preparation of Compound 54

[0552] Preparation of compound 54-2

[0553] Under nitrogen, m-bromophenol (6.0 g, 34.68 mmol), triphenylphosphine (13.6 g, 52.02 mmol), and 1-methyl-2-pyrrolidinemethanol (4.4 g, 38.15 mmol) were dissolved in anhydrous tetrahydrofuran (100.0 mL). DIAD (10.5 g, 52.02 mmol) was slowly added dropwise to the reaction system at 0°C. Stir for 2 hours, and the reaction was complete by TLC. Water (50 mL) was then added, and the mixture was extracted twice with ethyl acetate (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (0-15% methanol / dichloromethane) to obtain the title compound 54-2 (3.5 g, light yellow solid, 37% yield). LC-MS (ESI): m / z [M+H] + :270.2

[0554] Preparation of compound 54-3

[0555] Under nitrogen, compound 54-2 (3.5 g, 13.94 mmol) was dissolved in anhydrous THF (25 mL). After cooling to -65°C, n-BuLi (2.5 M in THF, 6.97 mL, 17.43 mmol) was slowly added dropwise. After stirring for 40 minutes, a solution of compound 1-1 (1.1 g, 6.97 mmol) in anhydrous THF (5 mL) was slowly added dropwise to the reaction system. Stirring was continued for one hour. LCMS confirmed the reaction was complete. Water (10 mL) was added to the system to quench the reaction. The mixture was extracted with ethyl acetate (10 mL) three times. The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (0-40% ethyl acetate / petroleum ether) to obtain the title compound 54-3 (1.1 g, yellow solid, 38% yield). LC-MS (ESI): m / z [MH] - :405.1.

[0556] Preparation of compound 54-4

[0557] Compound 54-3 (1 g, 2.46 mmol), stannous chloride dihydrate (1.67 g, 7.38 mmol), glacial acetic acid (10 mL), and concentrated hydrochloric acid (1 mL) were added to a reaction flask. The temperature was raised to 120°C and stirred for 2 hours. LCMS confirmed the completion of the reaction. The reaction system was cooled to room temperature and the pH was adjusted to alkaline with saturated aqueous sodium bicarbonate solution. The mixture was extracted three times with ethyl acetate (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (0-30% ethyl acetate / petroleum ether) to give the title compound 54-4 (400 mg, yellow solid, 37% yield). LC-MS (ESI): m / z [MH] - :389.2.

[0558] Preparation of compound 54-5

[0559] Compound 54-4 (400 mg, 1.02 mmol), compound 7-2 (352 mg, 1.13 mmol), 2-Butanone (10 mL), and K2CO3 (283 mg, 2.05 mmol) were added to a reaction flask. The reaction system was heated to 90°C and stirred for 16 hours. LCMS confirmed the completion of the reaction. The reaction solution was cooled to room temperature, water (10 mL) was added, and the mixture was extracted three times with ethyl acetate (10 mL). The organic phases were combined, and the concentrated residue was purified by normal phase column chromatography (0-30% ethyl acetate / petroleum ether) to obtain the title compound 54-5 (150 mg, yellow solid, yield 25%). LC-MS (ESI): m / z [MH] - :573.3.

[0560] Preparation of compound 54

[0561] Compound 54-5 (150 mg, 0.261 mmol), dichloroethane (1.5 mL), and trifluoromethanesulfonic acid (391.5 mg, 2.61 mmol) were added to a reaction flask, heated to 60°C, and stirred for 1 hour. The reaction was complete as determined by LCMS. The reaction solution was cooled to room temperature and then slowly quenched with saturated aqueous sodium bicarbonate (10 mL). The reaction solution was extracted three times with dichloromethane (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by preparative separation (preparative method: mobile phase: A: 10 mmol formic acid solution; B: acetonitrile; column: ECLIPSE PLUS C18 40 g; gradient: 5%-50% acetonitrile; flow rate: 30 mL / min) to obtain the title compound 54 (16.23 mg, yield 12.8%). LCMS (ESI): m / z [M+H] + :485.3. 1H NMR (400MHz, DMSO-d6) δ13.17(s,1H),8.28(s,1H),7.79(d,J=7.6Hz,1H),7.7 2(d,J=2.2Hz,1H),7.64(d,J=8.0Hz,1H),7.36–7.24(m,2H),6.97(dd,J=8.2,2 .5Hz,1H),6.82–6.68(m,2H),6.48–6.36(m,1H),3.96–3.91(m,1H),3.80–3.76 (m,1H),2.97–2.89(m,1H),2.31(s,3H),2.24–1.75(m,3H),1.75–1.48(m,3H). 19 F NMR(376MHz,DMSO-d6)δ-60.02(s,3F).

[0562] Example 55: Preparation of Compound 55

[0563] Preparation of compound 55-2

[0564] Under nitrogen, compound 55-1 (1.90 g, 8.86 mmol) was added to anhydrous tetrahydrofuran (20 mL). A solution of n-BuLi (2.5 M in THF, 3.54 mL, 8.86 mmol) was slowly added dropwise to the reaction system at -65°C and stirred for 30 minutes. A solution of compound 1-1 (0.95 g, 4.43 mmol) in anhydrous THF (10 mL) was then slowly added dropwise to the reaction system. After stirring for 2 hours, the reaction was complete as determined by LCMS. The reaction was then quenched by addition of saturated aqueous ammonium chloride (10 mL), followed by addition of water (20 mL) and extraction with ethyl acetate (20 mL) three times. The organic phases were combined, dried over anhydrous sodium sulfate, and the residue was concentrated and purified by column chromatography (0-50% ethyl acetate / petroleum ether) to afford the title compound 55-2 (800 mg, light-colored solid, 39% yield). LC-MS (ESI): m / z [MH] - :349.1.

[0565] Preparation of compound 55-3

[0566] Compound 55-2 (750 mg, 2.14 mmol), stannous chloride dihydrate (1.21 g, 5.35 mmol), glacial acetic acid (15 mL), and concentrated hydrochloric acid (1.5 mL) were added to a reaction flask. The temperature was raised to 120°C and stirred for 1 hour. LCMS confirmed the completion of the reaction. The reaction system was cooled to room temperature and the pH was adjusted to alkaline with saturated aqueous sodium bicarbonate solution. The mixture was extracted three times with ethyl acetate (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (0-30% ethyl acetate / petroleum ether) to give the title compound 55-3 (500 mg, yellow solid, 60% yield). LC-MS (ESI): m / z [MH] - :333.0.

[0567] Preparation of compound 55-4

[0568] Compound 55-4 (450 mg, 1.35 mmol), compound 7-2 (632.02 mg, 2.03 mmol), 2-Butanone (5 mL), and K2CO3 (559 mg, 4.05 mmol) were added to a reaction flask. The reaction system was heated to 90°C and stirred for 16 hours. LCMS confirmed the completion of the reaction. The reaction solution was cooled to room temperature and extracted three times with water (5 mL) and ethyl acetate (10 mL). The organic phases were combined and the concentrated residue was purified by normal phase column chromatography (0-50% ethyl acetate / petroleum ether) to obtain the title compound 55-4 (100 mg, yellow solid, 7% yield). LC-MS (ESI): m / z [MH] - :517.0.

[0569] Preparation of compound 55

[0570] Compound 55-4 (80.00 mg, 0.15 mmol), dichloroethane (3 mL), and trifluoromethanesulfonic acid (1 mL) were added to a reaction flask and stirred at 65°C for 1 hour. The reaction was completed by LCMS. The reaction solution was cooled to room temperature and then slowly quenched with saturated aqueous sodium bicarbonate (10 mL). The mixture was extracted three times with dichloromethane (10 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The concentrated residue was purified by preparative separation (preparative method: mobile phase: A: 0.1% FA / H2O; B: ACN; column: Atlantis™ T3 Prep OBD™ C18, 19×250 mm, 10 μm; column temperature: 25°C; gradient: 40% to 40%; acetonitrile in 8.0-8.9 min; flow rate: 20 mL / min) to obtain the title compound 55 (18.15 mg, 27% yield). LC-MS(ESI):m / z[M+H+ACN] + :470.2. 1H NMR(400MHz,DMSO-d6) δ13.26(s,1H),11.77(s,1H),8.57(dd,J=4.6,1.6Hz,1H),8.26(dd,J=8.1,1.6Hz,1H),7.98(d,J=7.6Hz,1H),7.90(d,J =2.2Hz,1H),7.72(d,J=8.1Hz,1H),7.46(dd,J=8.1,4.6Hz,1H),7.42(s,1H),7.36(t,J=7.9Hz,1H),6.61–6.57(m,1H). 19 F NMR(376MHz,DMSO-d6)δ-60.02(s,3F).

[0571] Example 56: Preparation of Compound 56

[0572] Preparation of compound 56-1

[0573] Under nitrogen protection, compound 52-3 (2.8 g, 5.18 mmol), benzophenone imine (1.13 g, 6.22 mmol), Xantphos (0.30 g, 0.52 mmol), cesium carbonate (3.38 g, 10.36 mmol), Pd2(dba)3 (0.47 g, 0.52 mmol) and toluene (30 mL) were added to a reaction flask. The temperature was raised to 90 ° C and stirred for 16 hours. LCMS detection showed that the reaction was complete. After cooling to room temperature, water (30 mL) was added and extracted three times with ethyl acetate (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (0-50% ethyl acetate / petroleum ether) to give the title compound 56-1 (2 g, yellow solid, yield 60%). LC-MS (ESI): m / z [MH] - :639.2.

[0574] Preparation of compound 56-2

[0575] Compound 56-1 (2 g, 3.12 mmol) was dissolved in THF (20 mL) and then an aqueous HCl solution (1 mol / L, 5 mL) was added. The mixture was stirred at room temperature for one hour. LCMS confirmed the reaction was complete. Saturated aqueous sodium bicarbonate solution (30 mL) was added to quench the reaction. The mixture was extracted three times with ethyl acetate (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and purified by column chromatography (0-60% ethyl acetate / petroleum ether) to afford compound 56-2 (1.3 g, yellow solid, yield 76%). LC-MS (ESI): m / z [MH] - :475.1.

[0576] Preparation of compound 56-4

[0577] Under nitrogen, compound 56-2 (1.3 g, 2.73 mmol), compound 56-3 (0.75 g, 3.00 mmol), and HATU (1.56 g, 4.09 mmol) were dissolved in DMF (15 mL) and stirred at room temperature for 20 minutes before adding DIEA (0.53 g, 4.09 mmol). After stirring for 16 hours, the reaction was complete as determined by LCMS. Water (15 mL) was added, and the mixture was extracted three times with ethyl acetate (15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (0-100% ethyl acetate / petroleum ether) to give compound 56-4 (1.7 g, white solid, yield 85%). LC-MS (ESI): m / z [MH] - :708.1.

[0578] Preparation of compound 56-5

[0579] Compound 56-4 (1.7 g, 0.13 mmol) was dissolved in DCM (20 mL), cooled to 0°C in an ice-water bath, and then TFA (6.7 mL) was added. The system was slowly warmed to room temperature and stirred for 1 hour. LCMS confirmed the completion of the reaction. Saturated aqueous sodium bicarbonate solution (20 mL) was added to quench the reaction, and the mixture was extracted three times with DCM (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give a crude product of compound 56-5 (1.3 g, off-white solid, yield 89%). LC-MS (ESI): m / z [MH] - :608.0.

[0580] Preparation of compound 56-6

[0581] Compound 56-5 (1.3 g, 2.13 mmol), aqueous formaldehyde solution (0.4 g, 37%, 4.26 mmol), and acetic acid (1 mL) were added to methanol (15 mL) and stirred at room temperature for 20 minutes. Then, sodium cyanoborohydride (0.27 g, 4.26 mmol) was added. After stirring for 2 hours, the reaction was confirmed to be complete by LCMS. Saturated aqueous ammonium chloride solution (20 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (20 mL) three times. The organic phases were combined, dried over anhydrous sodium sulfate, and the residue was concentrated and purified by column chromatography (0-60% ethyl acetate / petroleum ether) to obtain compound 56-6 (900 mg, white solid, yield 67%). LC-MS (ESI): m / z [MH] - :622.1.

[0582] Preparation of compound 56

[0583] Compound 56-6 (300 mg, 0.048 mmol), dichloroethane (4 mL) and trifluoromethanesulfonic acid (1.5 mL) were added to a reaction flask and stirred at 65°C for 1 hour. LCMS confirmed the completion of the reaction. The reaction solution was cooled to room temperature and then slowly quenched with saturated aqueous sodium bicarbonate solution (10 mL). The product was extracted three times with dichloromethane (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by C18 reverse phase chromatography (5-60% acetonitrile / 0.1% aqueous FA solution) to give compound 56 (23 mg, yield 9%). LC-MS (ESI): m / z [M+H] + :534.3. 1 H NMR(400MHz,DMSO-d6)δ13.19(s,1H),11.56(s,1H),10.05(s,1H),7.81–7.76( m,2H),7.72(d,J=7.5Hz,1H),7.65(d,J=8.1Hz,1H),7.48(s,1H),7.35(t,J=8. 0Hz,1H),7.29(t,J=7.8Hz,1H),6.90(d,J=7.8Hz,1H),6.43(s,1H),3.48–3.39 (m,1H),2.82–2.75(m,1H),2.69–2.55(m,2H),2.41–2.36(m,1H),2.30(s,3H). 19 F NMR(376MHz, DMSO-d6)δ-60.00(s,3F),-91.37–-93.41(m,2F).

[0584] Example 57: Preparation of Compound 57

[0585] Preparation of compound 57-2

[0586] At -65°C, n-BuLi (2.5M tetrahydrofuran solution, 64 mL, 160 mmol) was slowly added dropwise to a solution of 4-trifluoromethoxybromobenzene (3.36 g, 13.94 mmol) in anhydrous tetrahydrofuran (30 mL) under argon protection (carefully keeping the internal temperature of the reaction system below -60°C). After completion of the addition, the reaction mixture was stirred for one hour. Subsequently, a solution of 57-1 (1.50 g, 6.97 mmol) in tetrahydrofuran (15 mL) was added dropwise to the reaction mixture, and stirring was continued for another hour. The reaction mixture was poured into saturated aqueous ammonium chloride (50 mL), extracted twice with ethyl acetate (50 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to afford the title compound 57-2 (2.80 g, light yellow solid, 93% yield). LC-MS (ESI): m / z [MH] -:376.1.

[0587] Preparation of compound 57-3

[0588] Compound 57-2 (2.30 g, 6.10 mmol) was added to a single-necked flask, followed by acetic acid (25 mL), concentrated hydrochloric acid (2.5 mL), and stannous chloride dihydrate (3.44 g, 15.25 mmol). The reaction system was heated to 120°C and stirred for 3 hours. The reaction system was cooled to room temperature, adjusted to alkalinity with saturated aqueous sodium bicarbonate solution, and filtered through a thin layer of celite. The filter cake was rinsed with a 5 / 1 EA / tetrahydrofuran solution. The filtrate was extracted three times with ethyl acetate (30 mL), dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (EtOAc / PE = 0-20%) to obtain the title compound 57-3 (2.5 g, light yellow solid, yield 98%). LC-MS (ESI): m / z [MH] - :360.1.

[0589] Preparation of compound 57-4

[0590] Compound 57-3 (1.10 g, 3.05 mmol) was added to a single-necked flask, followed by the addition of 2-butanone (10 mL), compound 7-2 (1.14 g, 3.66 mmol), and potassium bicarbonate (0.92 g, 9.13 mmol). The reaction system was heated to 90°C and stirred for 8 hours. The reaction solution was cooled to room temperature, water (10 mL) was added, and the mixture was extracted three times with ethyl acetate (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified on a silica gel column (EA / PE = 0-30%) to obtain the title compound 57-4 (160 mg) as a white solid (yield 9%). LC-MS (ESI): m / z [MH] - :544.4.

[0591] Preparation of compound 57

[0592] Compound 57-4 (150 mg, 0.28 mmol) was dissolved in DCE (3 mL). TfOH (1.0 mL) was added at room temperature, and the reaction mixture was heated to 60°C and stirred for 1 hour. The reaction system was cooled to room temperature, and the pH was adjusted to alkaline with aqueous sodium bicarbonate. The mixture was extracted three times with DCM (20 mL). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated, and purified on a reverse phase column (5-50% acetonitrile / 0.1% aqueous formic acid) to obtain the title compound 57 (80 mg, 64% yield). LC-MS (ESI): m / z [M+H] + :456.1. 1H NMR (400MHz, DMSO-d6) δ13.20(s,1H),11.42(s,1H),7.78–7.73(m,2H),7.48(d,J=7.9Hz,1H),7.43-7.35(m,4H),7.25(s,1H),6.47(m,1H). 19 F NMR(376MHz, DMSO-d6)δ-56.79(s,3F),-61.25(s,3F).

[0593] Example 58: Preparation of Compound 58

[0594] Preparation of compound 58-1

[0595] Compound 44-2 (1.4 g, 3.63 mmol), compound 7-2 (1.13 g, 3.63 mmol), 2-Butanone (15 mL), and K2CO3 (1.51 g, 10.89 mmol) were added to a reaction flask. The reaction system was heated to 90°C and stirred for 16 hours. LCMS confirmed the completion of the reaction. The reaction solution was cooled to room temperature, water (20 mL) was added, and the mixture was extracted three times with ethyl acetate (20 mL). The organic phases were combined and the concentrated residue was purified by normal phase column chromatography (0-50% ethyl acetate / petroleum ether) to obtain the title compound 58-1 (130 mg, yellow oil, yield 6%). LC-MS (ESI): m / z [MH] - :568.1.

[0596] Preparation of compound 58

[0597] Compound 58-1 (130 mg, 0.23 mmol) was dissolved in dichloroethane (1.5 mL), and trifluoromethanesulfonic acid (0.5 mL) was slowly added. The mixture was heated to 60°C and stirred for 1 hour. LCMS confirmed the completion of the reaction. The reaction solution was cooled to room temperature and quenched with aqueous sodium bicarbonate solution (5 mL) was slowly added. The mixture was extracted three times with dichloromethane (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by reverse phase C18 column chromatography (acetonitrile / 0.1% FA / H2O 5-95%) to give compound 58 (7 mg, yield 8%). LC-MS (ESI): m / z [M+H] + :390.2. 1 H NMR (400MHz, DMSO-d6) δ13.25(s,2H),11.75(s,1H),7.88–7.82(m,3H),7.70(d,J=8.1Hz,1H),7.33(t,J=7.8Hz,1H),6.53(s,2H). 19F NMR(376MHz,DMSO-d6)δ-59.99(s,3F).

[0598] Example 59: Preparation of Compound 59

[0599] Preparation of compound 59-1

[0600] Under argon, (4-bromophenyl)sulfur pentafluoride (3.5 g, 12.28 mmol) was dissolved in anhydrous diethyl ether (60.0 mL). After cooling the system to -65°C, a solution of tert-butyllithium (1.3 M in pentane, 9.4 mL, 12.28 mmol) was slowly added dropwise. After stirring at -65°C for one hour, a solution of compound 1-1 (1.2 g, 5.58 mmol) in anhydrous THF (8.0 mL) was slowly added dropwise to the reaction system. Stirring was continued at -65°C for another hour. LCMS confirmed the reaction was complete. The reaction was quenched by adding saturated aqueous ammonium chloride (100 mL), followed by the addition of water (25 mL). The reaction system was extracted three times with ethyl acetate (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The concentrated residue was purified by column chromatography (0-20% ethyl acetate / petroleum ether) to afford the title compound 59-1 (1.3 g, light yellow oil, 55.6% yield). LC-MS (ESI): m / z [MH] - :418.0.

[0601] Preparation of compound 59-2

[0602] Compound 59-1 (1.3 g, 3.10 mmol) was dissolved in acetic acid (5.0 mL), and concentrated hydrochloric acid (0.5 mL) and stannous chloride dihydrate (2.5 g, 10.85 mmol) were added to a reaction flask and stirred at 120°C for 5 hours. LCMS monitored the reaction completion, cooled to room temperature, adjusted to alkalinity with saturated sodium bicarbonate aqueous solution, filtered, and the filtrate was extracted three times with ethyl acetate (200 mL). The organic phase was washed with saturated brine (100 mL). Drying over anhydrous sodium sulfate, filtering, and drying was performed. The residue was concentrated and purified by column chromatography (0-20% ethyl acetate / petroleum ether) to obtain the title compound 59-2 (1.0 g, white solid, 80% yield). LC-MS (ESI): m / z [MH] - :402.1.

[0603] Preparation of compound 59-3

[0604] Compound 59-2 (400 mg, 0.99 mmol), 2-butanone (10 mL), 2-benzyl-5-iodopyridazin-3-one (402 mg, 1.29 mmol), and potassium phosphate (630 mg, 2.97 mmol) were added to a reaction flask, then heated to 90°C and stirred for 16 hours. LCMS confirmed the reaction was complete, and the mixture was cooled to room temperature and quenched with aqueous ammonium chloride (30 mL). The mixture was then extracted twice with ethyl acetate (50 mL), and the organic phase was washed with saturated brine (30 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and dried. The residue was concentrated and purified by column chromatography (0-20% ethyl acetate / petroleum ether) to afford the title compound 59-3 (370 mg, light yellow solid, 63% yield). LC-MS (ESI): m / z [MH] - :586.1.

[0605] Preparation of compound 59

[0606] Compound 59-3 (270 mg, 0.46 mmol), DCE (2.5 mL), and trifluoromethanesulfonic acid (0.5 mL) were added to a reaction flask, then heated to 65°C with stirring for 2 hours. LCMS confirmed the reaction was complete. The reaction system was cooled to room temperature and quenched by slowly adding cold saturated sodium bicarbonate solution (100 mL) dropwise. The system was extracted three times with dichloromethane / isopropanol = 10 / 1 (100 mL). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and dried. The residue was concentrated and purified by reverse-phase C18 column chromatography (5-50% ACN / 0.1% FA) to obtain compound 59 (154.48 mg, 67% yield). LC-MS (ESI): m / z [M+H] + :498.2. 1 H NMR(400MHz,DMSO-d6)δ13.23(s,1H),11.69(s,1H),7.99–7.91(m,2H),7.85–7.77(m,2H),7.68(d,1H),7.50–7.40(m,2H),7 .35–7.26(m,1H),6.49(d,J=2.2Hz,1H).NMR(376MHz,DMSO-d6)δ-87.09-86.28(m,1F),-64.20-63.80(m,4F),-60.06(s,3F).

[0607] Example 60: Preparation of Compound 60

[0608] Preparation of compound 60-2

[0609] Under nitrogen, compound 60-1 (8.4 g, 37.18 mmol) was added to anhydrous THF (100 mL). A solution of isopropylmagnesium chloride-lithium chloride (1.3 M in THF, 35.75 mL, 46.48 mmol) was slowly added dropwise to the reaction system at -20°C. After stirring at -20°C for 30 minutes, a solution of compound 1-1 (4 g, 18.59 mmol) in anhydrous THF (10 mL) was slowly added dropwise to the reaction system. The mixture was stirred at -20°C for one hour. LCMS confirmed the reaction was complete. The reaction was quenched by adding saturated aqueous ammonium chloride (100 mL), extracted three times with EA (100 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried. The concentrated residue was purified by column chromatography (0-40% ethyl acetate / petroleum ether) to give the title compound 60-2 (2.7 g, yellow solid, yield 40%). LC-MS (ESI): m / z [MH]-: 362.0.

[0610] Preparation of compound 60-3

[0611] Compound 60-2 (2.5 g, 6.88 mmol), pyridine (1.09 g, 13.76 mmol) and DCM (30 mL) were added to a reaction flask. After cooling to 0°C, thionyl chloride (1.64 g, 13.76 mmol) was added dropwise. The temperature was slowly raised to room temperature and stirred for one hour. The reaction was complete by LCMS. Water (60 mL) was added to the reaction system and extracted three times with DCM (60 mL). The organic phases were combined and washed with brine (180 mL), dried over anhydrous sodium sulfate, filtered, and dried. The residue was concentrated to give a crude product of compound 60-3 (3 g, yellow oil). LC-MS (ESI): m / z [MH] - :380.0.

[0612] Preparation of compound 60-4

[0613] Under nitrogen, palladium on carbon (1.13 g), methanol (25 mL), and compound 60-3 (2.8 g, 7.34 mmol) were added to a reaction flask. The gas was then replaced with a hydrogen balloon three times and the reaction was stirred for 16 hours. LCMS confirmed the reaction was complete. The product was filtered, dried, and concentrated to dryness. The residue was purified by column chromatography (0-25% ethyl acetate / petroleum ether) to afford compound 60-4 (1.45 g, yellow solid, 56% yield). LC-MS (ESI): m / z [MH] - :346.0.

[0614] Preparation of compound 60-5

[0615] Compound 60-4 (300 mg, 0.86 mmol), 2-benzyl-5-iodopyridazin-3-one (295.26 mg, 12.75 mmol), K2CO3 (356.58 mg, 2.58 mmol) and 2-Butanone (4 mL) were added to a reaction flask. The reaction was stirred at 90°C for 16 hours. LCMS detected the completion of the reaction. The reaction solution was cooled to room temperature, water (20 mL) was added, and the mixture was extracted three times with ethyl acetate (20 mL), dried over anhydrous sodium sulfate, and the organic phases were combined, filtered, and dried. The residue was concentrated and purified by column chromatography (0-60% ethyl acetate / petroleum ether) to obtain compound 60-5 (70 mg, yellow oil, yield 15.2%). LC-MS (ESI): m / z [MH] - :530.2.

[0616] Preparation of Compound 60

[0617] Compound 60-5 (70 mg, 0.13 mmol), DCE (2 mL) and trifluoromethanesulfonic acid (0.7 mL) were added to a reaction flask, and the temperature was raised to 60° C. and stirred for one hour. LCMS detected that the reaction was complete. The reaction system was cooled to room temperature, saturated aqueous sodium bicarbonate solution (20 mL) was added, and the mixture was extracted three times with DCM (20 mL). The organic phases were combined, washed with saturated brine (8 mL), dried over anhydrous sodium sulfate, filtered, and dried by rotary evaporation. The residue was concentrated and purified by preparative separation (preparative method: mobile phase: A: 0.1% FA / H2O; B: ACN; column: Atlantis™ T3 Prep OBD™, C18, 19×250 mm, 10 μm; column temperature: 25°C; gradient: 50% to 55%; acetonitrile in 9.3-10.2 min; flow rate: 20 mL / min) to give the title compound 60 (15 mg, yield 27%). LC-MS (ESI): m / z [M+H] + :442.2. 1 H NMR(400MHz,DMSO-d6)δ13.21(s,1H),11.99(br.s,1H),8.96(s,2H),7.85–7. 80(m,2H),7.66(d,J=8.0Hz,1H),7.26(t,J=7.8Hz,1H),6.56(d,J=2.0Hz,1H). 19 F NMR(376MHz,DMSO-d6)δ-59.96(s,3F),-68.95(s,3F).

[0618] Example 61: Preparation of Compounds 61, 61A and 61B

[0619] Preparation of compound 61-2

[0620] Under nitrogen protection, compound 44-1 (450 mg, 1.07 mmol), compound 61-1 (288.16 mg, 1.60 mmol), sodium bicarbonate (359.56 mg, 4.28 mmol), and DMF (5.0 mL) were added to a reaction flask and stirred at room temperature for 5 hours. LCMS confirmed the completion of the reaction, and ice water (15 mL) was added to quench the reaction. The mixture was extracted three times with ethyl acetate (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (0-25% ethyl acetate / petroleum ether) to obtain compound 61-2 (350 mg, yellow solid, 60% yield). LC-MS (ESI): m / z [MH] - :525.2.

[0621] Preparation of compound 61

[0622] Compound 61-2 (350 mg, 0.66 mmol), DCE (3 mL), and TfOH (1.7 M, 1.5 mL) were added to a reaction flask and stirred at room temperature for one hour. The reaction was complete by LCMS. The system was cooled to 0°C and quenched with saturated sodium bicarbonate solution (5 mL). Water (15 mL) was then added and the mixture was extracted three times with dichloromethane (15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by preparative separation (mobile phase: A: 0.1% FA / H2O; B: ACN; column: Agilent C18, 21.2×250 mm, 10 μm; column temperature: 25°C; gradient: 56% to 56%; acetonitrile in 8.0-9.8 min; flow rate: 20 mL / min) to obtain the title compound 61 (204 mg, 70% yield). LC-MS (ESI): m / z [M+H] + :437.1. 1 H NMR (400MHz, DMSO-d6) δ13.26(s,1H), δ11.65(s,1H),8.11(d,J=2.0Hz,1H),7.83(d,J=8.0Hz ,1H),7.69(d,J=8.0Hz,1H),7.29(t,J=7.8Hz,1H),6.54(d,J=2.0Hz,1H),3.41–3.18(m,4H). 19 F NMR (376MHz, DMSO-d6) δ-59.93 (s, 3F), -117.64 (d, J = 13.1Hz, 4F).

[0623] Preparation of compounds 61A and 61B

[0624] Compound 61 was subjected to SFC preparative chiral separation (preparative separation method, instrument model: WATERS 150 preparative SFC (SFC-26); chromatographic column model: ChiralPak AD, 250×30 mm ID, 10 μm; mobile phase: A: CO2, B: ethanol; elution gradient: B 10%; flow rate: 120 mL / min; column pressure: 100 bar; column temperature: 38°C; detection wavelength: 220 nm; cycle: ~6.2 min) to obtain the title compounds 61A (88 mg) and 61B (84 mg).

[0625] Compound 61A: Chiral analysis method (instrument model: Waters UPC2 analytical SFC (SFC-H); column model: ChiralPak AD, 50×4.6 mm ID, 3 μm; mobile phase: A: CO2, B: ethanol (0.05% DEA); elution gradient: B from 5% to 40% in 4 minutes, from 40% to 5% in 0.2 minutes, then maintained at 5% for 1.8 minutes; flow rate: 3 mL / min; column temperature: 35°C; column pressure: 100 bar; detection wavelength: 220 nm; RT = 0.975 min). LCMS (ESI): m / z [M+H] + :437.0.

[0626] Compound 61B: Chiral analysis method (instrument model: Waters UPC2 analytical SFC (SFC-H); column model: ChiralPak AD, 50×4.6 mm ID, 3 μm; mobile phase: A: CO2 B: ethanol (0.05% DEA); elution gradient: B from 5-40% in 4 minutes, from 40-5% in 0.2 minutes, then maintained at 5% for 1.8 minutes; flow rate: 3 mL / min; column temperature: 35°C; column pressure: 100 bar; detection wavelength: 220 nm; RT = 1.422 min). LCMS (ESI): m / z [M+H] + :437.0.

[0627] Example 62: Preparation of Compound 62

[0628] Preparation of compound 62-1

[0629] Under nitrogen, 2,6-dichloro-4-iodopyridine (5.1 g, 18.59 mmol) and anhydrous THF (15 mL) were added to a reaction flask. A solution of isopropylmagnesium chloride and lithium chloride (1.3 M in THF, 18 mL, 23.24 mmol) was slowly added dropwise to the reaction system at -10°C. After stirring for 30 minutes, a solution of compound 1-1 (2.0 g, 9.30 mmol) in anhydrous THF (10 mL) was slowly added dropwise to the system and stirred at -10°C for one hour. TLC confirmed the reaction was complete. The reaction was quenched by adding saturated aqueous ammonium chloride (25 mL), followed by addition of water (25 mL). The mixture was extracted three times with ethyl acetate (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (0-25% ethyl acetate / petroleum ether) to afford the title compound 62-1 (1.7 g, orange-yellow solid, 30.2% yield). LC-MS(ESI):m / z[MH] - :360.9.

[0630] Preparation of compound 62-2

[0631] At room temperature, compound 62-1 (1.7 g, 4.70 mmol), toluene (4.32 g, 46.96 mmol), DCE (10.0 mL), and TfOH (7.05 g, 46.96 mmol) were added to a reaction flask and reacted at 60°C for 2 hours. LCMS confirmed the completion of the reaction, and the reaction solution was poured into a cold saturated aqueous sodium bicarbonate solution (20 mL) to quench the reaction. The reaction system was extracted three times with DCM (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried by rotary evaporation. The residue was concentrated and purified by column chromatography (0-25% ethyl acetate / petroleum ether) to obtain the title compound 62-2 (440 mg, white solid, 35% yield). LC-MS (ESI): m / z [M+H] + :437.1. 1 H NMR (400MHz, DMSO-d6) δ10.33(s,1H),7.75(d,J=7.5Hz,1H),7.61(d,J=8.0Hz,1 H),7.27–7.22(m,3H),7.19(d,J=8.2Hz,2H),7.06(d,J=8.2Hz,2H),2.28(s,3H). 19 F NMR(376MHz,DMSO-d6)δ-59.97(s,3F).

[0632] Preparation of compound 62

[0633] Compound 62-2 (100 mg, 0.25 mmol) was dissolved in tert-butanol (1.0 mL) and KOH (64 mg, 1.15 mmol) in a reaction flask. The temperature was raised to 100°C and stirred for 16 hours. The reaction was monitored by LCMS. The pH was adjusted to 5-6 with 3M hydrochloric acid, and the mixture was concentrated to dryness. The residue was then purified by preparative separation (mobile phase: A: 0.05% NH4OH / H2O; B: ACN; column: Xbridge C18, 19×250 mm, 10 μm; column temperature: 25°C; gradient: 26% to 26%; acetonitrile in 10-13.2 min; flow rate: 20 mL / min) to afford the title compound 62 (26 mg, 27% yield).

[0634] LC-MS(ESI):m / z[M+H+ACN] + :460.2. 1 H NMR (400MHz, DMSO-d6) δ10.98(s,2H),7.64–7.56(m,2H),7.23–7.16(m,3H),7.08–7.04(m,2H),6.51–6.37(m,1H),6.24–6.15(m,1H),2.28(s,3H). 19 F NMR(376MHz,DMSO-d6)δ-60.03(s,3F).

[0635] Example 63: Preparation of Compound 63

[0636] Preparation of compound 63-2

[0637] Under nitrogen, p-bromotrifluoromethoxybenzene (28.3 g, 117.35 mmol) was added to anhydrous THF (150 mL). A solution of n-BuLi (2.5 M in THF, 46.6 mL, 117.35 mmol) was slowly added dropwise to the reaction system at -65°C and stirred for 30 minutes. A solution of compound 63-1 (13.8 g, 46.94 mmol) in anhydrous THF (50 mL) was slowly added dropwise to the system and stirred for one hour. LCMS confirmed the reaction was complete. Saturated aqueous ammonium chloride (200 mL) was added, and the product was extracted three times with ethyl acetate (400 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (ethyl acetate / petroleum ether 0-60%) to afford compound 63-2 (21.9 g, yellow oil, 71% yield). LC-MS (ESI): m / z [MH] - :455.9.

[0638] Preparation of compound 63-3

[0639] Under nitrogen protection, compound 63-2 (20.9 g, 45.82 mmol), acetic acid (210 mL), stannous chloride dihydrate (25.9 g, 114.55 mmol) and hydrochloric acid (21 mL) were added to a reaction flask and heated to 120°C with stirring for 5 hours. LCMS detection showed that the reaction was complete. The mixture was cooled to room temperature, and a saturated aqueous sodium bicarbonate solution was added to adjust the pH to alkaline. The mixture was extracted three times with ethyl acetate (200 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried. The residue was concentrated and purified by column chromatography (ethyl acetate / petroleum ether 0-60%) to give compound 63-3 (10.2 g, white solid, 48.3% yield). LC-MS (ESI): m / z [MH] - :439.9.

[0640] Preparation of compound 63-4

[0641] Compound 63-3 (5.1 g, 11.59 mmol), 2-benzyl-5-iodopyridazin-3-one (4.0 g, 12.75 mmol), K2CO3 (4.8 g, 34.77 mmol) and 2-Butanone (60 mL) were added to a reaction flask and stirred at 90°C for 16 hours. LCMS confirmed the completion of the reaction. The reaction system was cooled to room temperature, water (60 mL) was added, and the mixture was extracted three times with ethyl acetate (60 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried. The residue was concentrated and purified by column chromatography (ethyl acetate / petroleum ether 0-40%) to obtain compound 63-4 (4.5 g, yellow oil, yield 30%). LC-MS (ESI): m / z [MH] - :623.8.

[0642] Preparation of compound 63-5

[0643] Compound 63-4 (2.2 g, 3.52 mmol), DCE (20 mL), and trifluoromethanesulfonic acid (7 mL) were added to a reaction flask and heated to 60°C with stirring for one hour. LCMS confirmed the completion of the reaction. The reaction solution was cooled to room temperature and slowly poured into an ice-cold sodium bicarbonate solution (20 mL). The mixture was extracted three times with DCM (40 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried. The concentrated residue was purified by C18 column (5-95% ACN / 0.1% FA) to give compound 63-5 (420 mg, white solid, yield 22%). LC-MS (ESI): m / z [MH] - :533.9.

[0644] Preparation of compound 63

[0645] Under nitrogen, compound 63-5 (100 mg, 0.19 mmol), palladium acetate (4.3 mg, 0.019 mmol), Xanphos (11 mg, 0.019 mmol), TEA (38 mg, 0.38 mmol), and toluene (3 mL) were added to a reaction flask. The atmosphere was replaced three times with a carbon monoxide balloon, and the temperature was then raised to 90°C and stirred for 16 hours. The reaction was complete by LCMS. The reaction system was cooled to room temperature, water (6 mL) was added, and the mixture was extracted three times with ethyl acetate (6 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried by rotary evaporation. The residue was concentrated (preparation method: mobile phase: A: 0.1% FA aqueous solution; B: acetonitrile; chromatographic column: Atlantis™ T3 Prep OBD™, 19*250 mm, 10 μm; column temperature: 25°C; gradient: 43%-43% retention time: 9.6-10.6 min of 16 min; flow rate: 20 mL / min) to obtain compound 63 (45 mg, yield 48%). LC-MS (ESI): m / z [M+H] + :500.2. 1 H NMR (400MHz, DMSO-d6) δ13.21(s,1H),12.01(s,1H),8.14(d,J=9.1Hz,2H),7.77(d,J=2.2Hz,1H),7.45–7.38(m,4H),6.47(s,1H). 19 F NMR(376MHz, DMSO-d6)δ-56.76(s,3F),-60.55(s,3F).

[0646] Example 64: Preparation of Compound 64

[0647] Preparation of compound 64-1

[0648] Under nitrogen, compound 1,4-dibromobenzene (13.71 g, 58.10 mmol) and anhydrous THF (50.0 mL) were added to a reaction flask. A solution of n-BuLi (2.5 M in THF, 23.3 mL, 58.10 mmol) was slowly added dropwise to the reaction system at -65°C. After stirring for 30 minutes, a solution of compound 1-1 (5.0 g, 23.24 mmol) in anhydrous THF (10 mL) was slowly added dropwise. The mixture was stirred for 1 hour, and LCMS analysis indicated completion of the reaction. The reaction was quenched by the addition of saturated aqueous ammonium chloride (10 mL), followed by the addition of water (50 mL). The mixture was extracted twice with ethyl acetate (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (0-30% ethyl acetate / petroleum ether) to afford the title compound 64-1 (8.1 g, yellow solid, 93% yield). LC-MS (ESI): m / z [MH] - :370.0.

[0649] Preparation of compound 64-2

[0650] Compound 64-1 (8.0 g, 21.50 mmol), acetic acid (10 mL), hydrochloric acid (10 mL), and stannous chloride dihydrate (14.55 g, 64.5 mmol) were added to a reaction flask, heated to 120°C, and stirred for 2 hours. LCMS confirmed the reaction was complete, and the mixture was slowly quenched by adding cold aqueous sodium bicarbonate (200 mL). The mixture was extracted three times with EA (200 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the residue was concentrated and purified by normal phase chromatography (0-30% ethyl acetate / petroleum ether) to obtain the title compound 64-2 (5.1 g, yellow solid, 66% yield). LC-MS (ESI): m / z [MH] - :354.0.

[0651] Preparation of compound 64-3

[0652] Compound 64-2 (5.0 g, 14.04 mmol), 2-butanone (50 mL), 2-benzyl-5-iodopyridazin-3-one (5.3 g, 16.85 mmol), and potassium carbonate (3.88 g, 28.08 mmol) were added to a reaction flask. The temperature was raised to 90°C and stirred for 16 hours. LCMS confirmed the completion of the reaction, and aqueous solution (50 mL) was added. The mixture was extracted three times with ethyl acetate (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The residue was concentrated and purified by column chromatography (0-50% ethyl acetate / petroleum ether) to obtain the title compound 64-3 (4.5 g, yellow solid, 59% yield). LC-MS (ESI): m / z [MH] - :540.1.

[0653] Preparation of compound 64-4

[0654] Under nitrogen, compound 64-3 (4.0 g, 7.40 mmol), dioxane (50 mL), 1,1-bis(diphenylphosphino)dibrominated iron palladium(II) chloride (541 mg, 0.74 mmol), potassium acetate (1.82 g, 18.50 mmol), and bis(pinacol) borate (2.1 g, 8.14 mmol) were added to a reaction flask and stirred at 100°C for 16 hours. LCMS confirmed the reaction was complete, and aqueous solution (50 mL) was added. The mixture was extracted three times with ethyl acetate (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried. The concentrated residue, acetone (50 mL), water (50 mL), sodium periodate (5.5 g, 25.53 mmol), and ammonium acetate (1.97 g, 25.53 mmol) were added to a reaction flask and stirred at room temperature for 16 hours. The mixture was then extracted three times with ethyl acetate (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried by rotary evaporation. The concentrated residue was purified by column chromatography (0-50% ethyl acetate / petroleum ether) to obtain the title compound 64-4 (1.8 g, yellow solid, yield 41%). LC-MS (ESI): m / z [MH] - :504.2.

[0655] Preparation of compound 64-5

[0656] Under nitrogen, (2,2'-bipyridine) trifluoromethylsulfonate (254 mg, 0.79 mmol), compound 64-4 (400 mg, 0.79 mmol), and N-methylpyrrolidone (10 mL) were added to a reaction flask and stirred at room temperature for 1 hour. LCMS confirmed the reaction was complete, and aqueous solution (10 mL) was added. The mixture was extracted three times with ethyl acetate (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried. The residue was concentrated and purified by column chromatography (0-40% ethyl acetate / petroleum ether) to obtain the title compound 64-5 (224 mg, yellow solid, 50% yield). LC-MS (ESI): m / z [MH] - :560.1.

[0657] Preparation of compound 64

[0658] Compound 64-5 (224 mg, 0.399 mmol), DCE (3.0 mL), and trifluoromethanesulfonic acid (1.0 mL) were added to a reaction flask. The mixture was stirred at 60°C for 2 hours. LCMS confirmed the reaction was complete and the reaction was quenched by adding cold saturated sodium bicarbonate (10 mL). The reaction system was extracted three times with dichloromethane (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried by rotary evaporation. The residue was concentrated and purified by preparative separation (preparative method: mobile phase: A: 10 mmol formic acid solution; B: acetonitrile; column: ECLIPSE PLUS C18 40 g; gradient: 5%-50% acetonitrile; flow rate: 30 mL / min) to obtain the title compound 64 (66.39 mg, 39% yield). LCMS (ESI): m / z [M+H] + :472.2. 1 H NMR(400MHz,DMSO-d6)δ13.21(s,1H),11.70(s,1H),7.82–7.71(m,4H),7.65(d,J =8.1Hz,1H),7.38(d,J=8.4Hz,2H),7.27(t,J=7.8Hz,1H),6.45(d,J=1.9Hz,1H). 19 F NMR(376MHz, DMSO-d6)δ-41.76(s,3F),-60.04(s,3F).

[0659] Example 65: Preparation of Compound 65

[0660] Preparation of compound 65

[0661] Under nitrogen, compound 63-5 (200 mg, 0.37 mmol), 4-methylpiperazine (63.0 mg, 0.63 mmol), RuPhosPd-G3 (24.76 mg, 0.030 mmol), and 2-MeTHF (5 mL) were added to a reaction flask. LiHMDS (1.0 mol / L in THF, 1.5 mL, 1.48 mmol) was then added dropwise. The temperature was raised to 85°C and stirred for 3 hours. The reaction was complete by LCMS. The mixture was cooled to room temperature, and water (10 mL) was added. The mixture was extracted three times with ethyl acetate (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried by rotary evaporation. The residue was concentrated and purified by preparative chromatography (preparative method: mobile phase: A: 0.1% FA aqueous solution; B: acetonitrile; chromatographic column: Atlantis™ T3 Prep OBD™, 19*250 mm, 10 μm; column temperature: 25°C; gradient: 28%-28% retention time: 5.3-8.1 min of 16 min; flow rate: 20 mL / min) to obtain compound 65 (79 mg, yield 38%). LC-MS (ESI): m / z [M+H] + :554.3. 1 H NMR(400MHz, Methanol-d4)δ7.88(d,J=2.0Hz,1H),7.42–7.36(m,2H),7.35–7.29(m,3H),7.1 5(d,J=2.0Hz,1H),6.68(d,J=2.1Hz,1H),3.29–3.24(m,4H),2.92–2.85(m,4H),2.55(s,3H). 19 F NMR(376MHz, Methanol-d4)δ-59.46(s,3F),-62.95(s,3F).

[0662] Example 66: Preparation of Compound 66

[0663] Preparation of compound 66-1

[0664] Compound 1-2 (1.0 g, 3.10 mmol), phenol (580 mg, 6.23 mmol), DCE (15 mL) and trifluoromethanesulfonic acid (2.3 g, 15.42 mmol) were added to a reaction flask and stirred at 60°C for one hour. The reaction was completed by LCMS. The reaction system was adjusted to alkaline with saturated aqueous sodium bicarbonate solution and extracted three times with ethyl acetate (30 mL). The organic phases were combined and washed with brine (60 mL), dried over anhydrous sodium sulfate, filtered, and dried. The residue was concentrated and purified by column chromatography (0-60% ethyl acetate / petroleum ether) to give compound 66-1 (400 mg, yield 32.4%). LC-MS (ESI): m / z [MH] - :399.0.

[0665] Preparation of compound 66

[0666] Compound 66-1 (400 mg, 0.001 mmol) was dissolved in ACN (5 mL) and TMSI (800 mg, 0.004 mmol) was added at room temperature. The reaction system was heated to 60°C and stirred for one hour. LCMS confirmed the completion of the reaction. The reaction system was cooled to room temperature, water (10 mL) was added, and the mixture was extracted three times with ethyl acetate (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried. The residue was concentrated and purified by C18 column (5-60% ACN / 0.1% FA) to obtain compound 66 (158 mg, yield 41%). LC-MS (ESI): m / z [M+H] + :387.2. 1 H NMR (400MHz, DMSO-d6) δ11.60(br.s,1H),11.31(s,1H),9.58(br.s,1H),7.58(dd,J=7.7,3.6Hz,2H),7.3 1(d,J=7.3Hz,1H),7.23(t,J=7.7Hz,1H),7.01(d,J=8.8Hz,2H),6.75(d,J=8.8Hz,2H),6.03–5.86(m,2H). 19 F NMR(376MHz,DMSO-d6)δ-60.05(s,3F).

[0667] Example 67: Preparation of Compound 67

[0668] Preparation of compound 67-2

[0669] Compound 67-1 (10.0 g, 81.88 mmol), water (50 mL), and acetic acid (50 mL) were added to a reaction flask. After cooling to 0°C, sodium nitrite (8.5 g, 122.83 mmol) was added portionwise and stirred for 1 hour. Solid precipitated and was filtered. The filter cake was washed with water (100 mL) and dried to obtain the title compound 67-2 (11.0 g, yellow solid, yield 88%). LC-MS (ESI): m / z [MH] - :150.1.

[0670] Preparation of compound 67-3

[0671] Under nitrogen, compound 67-2 (11.0 g, 72.79 mmol), tetrahydrofuran (100 mL), methanol (100 mL), and palladium on carbon (2 g, 10%) were added to a reaction flask. The hydrogen atmosphere was replaced three times with a hydrogen balloon. The reaction was stirred at room temperature for 5 hours. Filtered and dried to give the crude title compound 67-3 (12.0 g, bluish-brown solid). LC-MS (ESI): m / z [M+H] + :138.2.

[0672] Preparation of compound 67-4

[0673] Compound 67-3 (12.0 g, 87.50 mmol) and hydrobromic acid (40% aqueous solution, 100 mL) were added to a reaction flask. After cooling to -10°C, a solution of sodium nitrite (12.1 g, 175.01 mmol) in water (30 mL) was slowly added dropwise to the reaction system. Stir at room temperature for 16 hours. Water (100 mL) was added and the mixture was extracted three times with ethyl acetate (100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried by rotary evaporation. The concentrated residue was purified by column chromatography (0-45% ethyl acetate / petroleum ether) to obtain the title compound 67-4 (600 mg, light yellow solid, yield 3.4%). LC-MS (ESI): m / z [MH] - :199.1.

[0674] Preparation of compound 67-5

[0675] Under nitrogen, compound 67-4 (600 mg, 2.98 mmol), DCM / MeOH (10:1, 11 mL), and DIEA (1.2 g, 8.95 mmol) were added to a reaction flask. After warming to 0°C, trimethylsilylated diazomethane (1.02 g, 8.95 mmol) was slowly added and stirred at room temperature for 16 hours. Aqueous solution (10 mL) was added. The mixture was extracted three times with dichloromethane (15 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by column chromatography (0-35% ethyl acetate / petroleum ether) to afford the title compound 67-5 (350 mg, anhydrous oil, 54% yield). 1 H NMR (400MHz, CDCl3) δ7.48–7.37(m,2H),7.01(d,J=13.0Hz,1H),6.49(d,J=10.8Hz,1H),3.94(s,3H).

[0676] Preparation of compound 67-7

[0677] Under nitrogen, compound 67-5 (350 mg, 1.63 mmol) and a solution of 2-butanone (10 mL) were added to a reaction flask, along with compound 67-6 (474 ​​mg, 1.63 mmol), potassium iodide (54 mg, 0.325 mmol), and potassium carbonate (450 mg, 3.26 mmol). The mixture was stirred at 90°C for 16 hours. LCMS confirmed the reaction was complete. Aqueous solution (10 mL) was added, and the mixture was extracted three times with ethyl acetate (15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried by rotary evaporation. The residue was concentrated and purified by column chromatography (0-40% ethyl acetate / petroleum ether) to afford the title compound 67-7 (140 mg, light yellow solid, 20% yield). LC-MS (ESI): m / z [MH] - :424.2.

[0678] Preparation of compound 67

[0679] Compound 67-7 (110 mg, 0.259 mmol), ethanol (10 mL), and sodium hydroxide (4 mL, 2 M) were added to a reaction flask. The mixture was heated to 70°C and stirred for 3 hours. LCMS confirmed the reaction was complete, and ice water (10 mL) was added to quench the reaction. The mixture was extracted three times with ethyl acetate (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by preparative separation (preparative method: mobile phase: A: 10 mmol formic acid in water; B: acetonitrile; column: Pursuit XRs C18, 21.2×250 mm, 10 μm; column temperature: 25°C; gradient: 69%-79% acetonitrile in 9.4-10.0 min; flow rate: 20 mL / min) to afford the title compound 67 (42.28 mg, 41% yield). LCMS (ESI): m / z [M+H] + :412.1, 1 H NMR (400MHz, DMSO-d6) δ11.38 (s, 1H), 7.59 (d, J = 7.9Hz, 2H), 7.29–7.05 (m, 10H), 2.28 (s, 3H). 19 F NMR(376MHz,DMSO-d6)δ-60.01(s,3F).

[0680] Preparation of compound ErSO 1

[0681] Preparation of compound E-1

[0682] Compound 7-3 (43.0 g, 88.4 mmol) and phenol (37.4 g, 397.8 mmol) were dissolved in DCM (300 mL). The reaction system was cooled to 0°C using an ice-water bath. Trifluoromethanesulfonic acid (66.3 g, 442.0 mmol) was added and stirred for 1 hour. The reaction solution was adjusted to a basic pH with saturated aqueous sodium bicarbonate solution, extracted twice with DCM (300 mL), and dried over anhydrous sodium sulfate. The organic phase was concentrated and the residue was purified on a silica gel column (EA / PE = 0-50%) to obtain the title compound E-1 (28.6 g). LC-MS (ESI): [M+H] + =454.1.

[0683] Preparation of compound ErSO

[0684] Compound E-1 was subjected to chiral separation (chromatographic column model: The title compound ErSO (single enantiomer) and E-2 (single enantiomer) were obtained using a 250×25 mm column (10 μm); mobile phase: A: Supercritical CO2, B: MeOH (+0.1% 7.0 mol / l Ammonia in MeOH); elution gradient: 15% B; flow rate: 70 mL / min; column temperature: 35°C; column pressure: 100 bar; detection wavelength: 214 nm; cycle: 2.6 min.

[0685] Compound ErSO: Chiral analysis method (chromatographic column model: 25*4.6mm, 3μm; mobile phase: A: CO2, B: MeOH (0.05% DEA); elution gradient: 5%-40% B; flow rate: 1.5mL / min; column temperature: 35°C; column pressure: 1500psi; detection wavelength: 214nm; RT = 2.061min). LC-MS (ESI): m / z [M+H] + :454.2. 1 H NMR (400MHz, DMSO-d6) δ11.28(s,1H),9.55(s,1H),7.56(dd,J=7.9,2.3Hz,2H),7.35(d,J=8 .8Hz,2H),7.25(d,J=8.8Hz,2H),7.22(m,1H),6.97(d,J=8.7Hz,2H),6.74(d,J=8.7Hz,2H). 19 F NMR(376MHz, DMSO-d6)δ-56.78(s,3F),-60.03(s,3F).

[0686] Compound E-2: Chiral analysis method (chromatographic column model: 25*4.6mm, 3μm; mobile phase: A: CO2, B: MeOH (0.05% DEA); elution gradient: 5%-40% B; flow rate: 1.5mL / min; column temperature: 35°C; column pressure: 1500psi; detection wavelength: 214nm; RT = 2.717min). LC-MS (ESI): m / z [M+H] + :454.2. 1 H NMR (400MHz, DMSO-d6) δ11.28(s,1H),9.55(s,1H),7.56(dd,J=7.9,2.3Hz,2H),7.35(d,J=8 .8Hz,2H),7.25(d,J=8.8Hz,2H),7.22(m,1H),6.97(d,J=8.7Hz,2H),6.74(d,J=8.7Hz,2H). 19F NMR(376MHz, DMSO-d6)δ-56.78(s,3F),-60.03(s,3F).

[0687] Preparation of compound SERA2 (other code names ErSO-TFPy, TEQ103) 2

[0688] Preparation of compound S-2

[0689] Compound S-1 (8.01 g, 27.90 mmol) and anhydrous THF (15 mL) were added to a reaction flask. The reaction system was cooled to -65°C, and n-BuLi (2.5 M in THF, 14.0 mL, 34.88 mmol) was slowly added dropwise. The system was stirred for 30 minutes, and then a solution of compound 1-1 (3.0 g, 13.95 mmol) in anhydrous THF (35.0 mL) was slowly added dropwise. The mixture was stirred at -65°C for 1 hour. The reaction system was warmed to 0°C and quenched with saturated aqueous ammonium chloride (50 mL). Water (100 mL) was then added, and the mixture was extracted three times with ethyl acetate (100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (0-25% ethyl acetate / petroleum ether) to afford the title compound S-2 (4.2 g, 54% yield). LC-MS (ESI): m / z [MH] - :422.1.

[0690] Preparation of compound S-3

[0691] Compound S-2 (3.0 g, 7.08 mmol), DCM (30 mL), and pyridine (1.1 g, 14.16 mmol) were added to a reaction flask and stirred thoroughly. Sulfonyl chloride (1.7 g, 14.16 mmol) was then slowly added dropwise at 0°C. The temperature was slowly raised to room temperature and stirred for one hour. TLC confirmed the reaction was complete. Water (60 mL) was added and the mixture was extracted three times with DCM (60 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a crude product of compound S-3 (2.8 g), which was used directly in the next step without further purification.

[0692] Preparation of compound S-5

[0693] Under nitrogen protection, compound S-3 (2.8 g, 6.34 mmol), compound S-4 (1.02 g, 5.71 mmol), cesium carbonate (4.13 g, 12.68 mmol) and DMF (30 mL) were added to a reaction flask and stirred at room temperature for 16 hours. The reaction was completed by LCMS. Water (60 mL) was added and extracted three times with ethyl acetate (60 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried. The concentrated residue was purified by C18 column (5-70% 0.05% NH3H2O / H2O) to obtain compound S-5 (489.55 mg, yield 17%). LC-MS (ESI): m / z [MH] - :433.3. 1 H NMR (400MHz, DMSO-d6) δ11.34(s,1H),9.66(s,1H),7.66(d,J=7.5Hz,1H),7.58(d,J=7.9Hz,1H),7.26(d,J =8.7Hz,2H),7.22(t,J=7.7Hz,1H),6.79(d,J=8.8Hz,2H),3.31(q,J=13.2Hz,2H),3.12(q,J=13.0Hz,2H). 19 F NMR(376MHz,DMSO-d6)δ-59.93(s,3F),-117.43(s,4F).

[0694] Preparation of compounds SERA2 and S-6

[0695] Compound S-5 was subjected to SFC preparative chiral separation (preparative separation method, instrument model: MGⅡpreparative SFC (SFC-14); chromatographic column model: ChiralPak AD, 250×30mm ID, 5μm; mobile phase: A is CO2, B is ethanol (0.1% ammonia water); elution gradient: B20%; flow rate: 150mL / min; column pressure: 100bar; column temperature: 38°C; detection wavelength: 220nm; cycle: ~7min) to obtain the title compounds SERA2 (218mg) and S-6 (222mg).

[0696] Compound SERA2: Chiral analysis method (Instrument model: Waters UPC2 analytical SFC (SFC-H); Column model: ChiralPak AD, 50×4.6 mm ID, 3 μm; Mobile phase: A: CO2, B: Ethanol (0.05% DEA); Elution gradient: B 5-40%; Flow rate: 3 mL / min; Column temperature: 35°C; Column pressure: 100 bar; Detection wavelength: 220 nm; RT = 1.973 min). LC-MS (ESI): m / z [MH] - :433.4. 1 H NMR (400MHz, DMSO-d6) δ11.34(s,1H),9.65(s,1H),7.66(d,J=7.5Hz,1H),7.58(d,J=8.1Hz,1H),7.26(d,J =8.7Hz, 2H), 7.22 (t, J = 7.7Hz, 1H), 6.79 (d, J = 8.7Hz, 2H), 3.30 (q, J = 13.1Hz, 2H), 3.12 (q, J = 12.9Hz, 2H). 19 F NMR(376MHz, DMSO-d6)δ-59.93(s,3F),-117.44(s,4F).

[0697] Compound S-6: Chiral analysis method (instrument model: Waters UPC2 analytical SFC (SFC-H); chromatographic column model: ChiralPak AD, 50×4.6 mm ID, 3 μm; mobile phase: A: CO2 B: ethanol (0.05% DEA); elution gradient: B 5-40%; flow rate: 3 mL / min; column temperature: 35°C; column pressure: 100 bar; detection wavelength: 220 nm; RT = 2.350 min). LC-MS (ESI): m / z [MH] - :433.3. 1 H NMR (400MHz, DMSO-d6) δ11.34(s,1H),9.66(s,1H),7.66(d,J=7.5Hz,1H),7.58(d,J=8.0Hz,1H),7.26(d,J =8.7Hz,2H),7.22(t,J=7.7Hz,1H),6.79(d,J=8.7Hz,2H),3.31(q,J=13.0Hz,2H),3.12(q,J=12.8Hz,2H). 19 F NMR(376MHz, DMSO-d6)δ-59.92(s,3F),-117.43(s,4F).

[0698] References:

[0699] 1:Sci.Transl.Med.2021,13,eabf1383.

[0700] 2: J. Med. Chem. 2022, 65, 3894-3912.

[0701] Test Example 1: MCF-7 cell activity test

[0702] 1. Breast cancer cell line MCF-7 was purchased from ATCC. The cell culture medium was DMEM + 10% FBS. The cells were cultured in a 37°C, 100% relative humidity, 5% CO2 incubator.

[0703] 2. On the first day, harvest cells in the logarithmic growth phase, count them, and resuspend them in phenol red-free DMEM medium containing 10% FBS. Adjust the cell concentration to the appropriate level (determined based on the results of a cell density optimization experiment). Inoculate a 96-well plate and add 100 μL of the cell suspension to a cell count of 6,000 cells per well. Incubate the cells in a 37°C, 5% CO2 incubator for 24 hours.

[0704] 3. On the next day, different concentrations of compounds were added and the cells were incubated in a 37°C, 5% CO2 incubator for 24 hours.

[0705] 4. After the incubation period, add 10 μL of CCK-8 detection reagent to each well and incubate in a 37°C incubator for 2-4 hours.

[0706] 5. After gentle shaking, measure the absorbance at a wavelength of 450 nM on a SpectraMax M5 Reader. Use the absorbance at 650 nM as a reference (i.e., 450 nM absorbance - 650 nM absorbance) to calculate the inhibition rate.

[0707] 6. Calculate the inhibition rate of the drug on each cell growth according to the following formula: Cell growth inhibition rate % = [(Ac-As) / (Ac-Ab)] × 100%

[0708] As: OA of sample (cells + CCK-8 + test compound)

[0709] Ac: OA of normal growth cell control (cells + CCK-8 + DMSO)

[0710] Ab: blank control OA (culture medium + CCK-8 + DMSO)

[0711] IC was calculated using the software Graphpad Prism 6 using the formula XY-analysis / Nonlinear regression (curve fit) / Dose response-Inhibition / log (inhibitor) vs. response-Variable slope (four parameters). 50 Curve fitting and calculation of IC 50 value.

[0712] Table 1: Cytotoxicity test results of some compounds in MCF-7 cells

[0713] Conclusion: The compounds of the present invention have excellent cytotoxic activity in the MCF-7 cell cytotoxicity test.

[0714] Test Example 2: Mouse Pharmacokinetic Test

[0715] Dosing: Prepare dosing solutions on the day of administration. Weigh 2.0 mg of compound and dissolve in 5% DMSO + 10% Tween-20 + 85% PBS to obtain a 1.0 mg / mL intravenous solution. Weigh 2.0 mg of compound and dissolve in 5% DMSO + 10% Tween-20 + 85% PBS to obtain a 0.5 mg / mL oral solution.

[0716] Take healthy male Six ICR mice, weighing 25-30 g, were divided into two groups (intravenous and oral groups), with three mice in each group, and administered a single dose. After three days of adaptive feeding, the mice were fasted overnight (10-12 hours) before the experiment. They were allowed to drink water freely during the experiment and resumed eating 4 hours after administration. Timing began after intravenous and oral administration, and blood was collected from the jugular vein at the planned time points (IV&PO 0.25, 0.5, 1, 2, 4, 6, 8, 10, 24, 48 hours). 40 μL of whole blood was collected at each point and placed in a 1.5 mL EP tube containing sodium heparin. The collected whole blood was placed on a vortexer and shaken twice to mix, placed on wet ice, and centrifuged at 8000 rpm for 5 minutes at 4°C within 1 hour. The supernatant plasma was taken and stored in a -80°C refrigerator until processed and analyzed.

[0717] Table 2: Pharmacokinetics in mice

[0718] Conclusion: Compared with the prior art, the compound of the present invention has significantly superior pharmacokinetic results in mice after intravenous injection and oral administration.

[0719] Test Example 3: Rat Pharmacokinetic Test

[0720] Dosing: Prepare dosing solutions on the day of administration. Weigh 6.0 mg of compound and dissolve in 5% DMSO + 10% Tween-20 + 85% PBS to obtain a 1.0 mg / mL intravenous solution. Weigh 18.0 mg of compound and dissolve in 35% DMSO + 10% Tween-20 + 85% PBS to obtain a 1.5 mg / mL oral solution.

[0721] Six healthy male SD rats weighing 220-300g were taken and divided into two groups (intravenous and oral groups), three rats in each group, and administered a single dose. After 3 days of adaptive feeding, the rats were fasted overnight (10-12h) the night before the experiment. They were allowed to drink water freely during the experiment and resumed eating 4h after administration. Timing began after intravenous and oral administration, and blood was collected through the jugular vein at the planned time points (IV&PO 0.25, 0.5, 1, 2, 4, 6, 8, 10, 24, 48h). 150μL of whole blood was collected at each point into an EP tube containing sodium heparin. The collected whole blood was placed on a vortex instrument and shaken twice to mix, placed on wet ice, centrifuged at 8000rpm for 5min at 4℃ within 1h, and the supernatant plasma was stored in a -80℃ refrigerator until processed and analyzed.

[0722] Table 3: Pharmacokinetics in rats

[0723] Conclusion: Compared with the prior art, the compound of the present invention has significantly superior pharmacokinetic results in rats after intravenous injection and oral administration.

[0724] Test Example 4: Manual patch clamp hERG test

[0725] 1. Experimental Design

[0726] The test sample was first dissolved in the solvent DMSO, and then diluted with extracellular solution (ECS) at a ratio of 0.3% (v / v) to prepare working solutions of the test sample of different concentrations.

[0727] 1.1 Preparing cells for the experiment

[0728] HEK293-hERG cells in the exponential growth phase were collected and resuspended in ECS for later use.

[0729] 1.2 Manual patch clamp test

[0730] The resuspended cells were seeded in a recording chamber, and single cells were randomly selected for recording.

[0731] The hERG channels are opened by holding the voltage at -80 mV and depolarizing to +60 mV for 850 ms. The voltage is then set to -50 mV and held for 1275 ms to generate a rebound current, also known as tail current. The peak value of the tail current is measured and used for analysis.

[0732] Start with the medium and monitor the tail current peak until it stabilizes for more than 3 bars. Then, perfuse the test article / positive control working solution until the current peak reaches a stable state. After stabilization, continue perfusing the next concentration of the test article. Continue testing until all concentrations have been tested.

[0733] The positive control, cisapride, was tested at a concentration of 0.1 μM, which inhibited hERG currents by more than 50%.

[0734] 1.3 Patch-clamp data acceptance criteria

[0735] Sealing standard:

[0736] A good whole-cell recording should meet the following conditions: path resistance (Rs) less than 10 MΩ; membrane resistance (Rm) greater than 500 MΩ and cell capacitance (Cm) less than 100 pF.

[0737] Current size:

[0738] The peak current amplitude is between 400pA and 5000pA.

[0739] Leakage current:

[0740] The absolute value of the leakage current should be less than 200pA.

[0741] 2. Data

[0742] The current response is calculated using the following formula:

[0743] (1-peak tail current recorded after perfusion of test article / positive control / peak tail current (onset current) recorded after perfusion of vehicle control) × 100%.

[0744] For each concentration, all the cell inhibition percentages were recorded and averaged, and the IC 50 The values ​​were obtained from the concentration-effect curves by the Hill fitting method.

[0745] In the formula, y = average inhibition rate of all cells;

[0746] Vmax=100%;

[0747] x = nominal concentration;

[0748] n = Hill coefficient;

[0749] k = concentration of the test substance at 50% inhibition.

[0750] 3. Some hERG test results

[0751] 7A:IC 50 >10μM.

[0752] Test Example 5: CYP inhibition test

[0753] An in vitro assay system was used to evaluate the effects of compounds on the activities of seven cytochrome P450 (CYP) isoenzymes (CYP1A2, CYP2C9, CYP2D6, and CYP3A) in human liver microsomes. Specific probe substrates for the CYP450 isoenzymes were incubated with human liver microsomes and various concentrations of the compound (0, 0.0300, 0.100, 0.300, 1.00, 3.00, and 10.0 μM). The reaction was initiated by the addition of the coenzyme NADPH. After the reaction, the samples were processed and the metabolites produced by the probe substrates were detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS). Based on the resulting dose-response curves, the IC values ​​of the test compounds for the specific probe substrate reactions catalyzed by each CYP isoenzyme were calculated. 50 value.

[0754] Some test results

[0755] Compound 7A showed IC1 in the CYP 1A2 / 2C9 / 2D6 / 3A4 (testosterone) / 3A4 (midazolam) inhibition assay. 50 >10μM.

[0756] Conclusion: The compounds of the present invention have weak CYP inhibitory effects in CYP 1A2 / 2C9 / 2D6 / 3A4 (testosterone) / 3A4 (midazolam) subtypes.

[0757] Test Example 6: CYP3A4 time-dependent inhibition (TDI) test

[0758] A series of compound concentrations were added to the mixed human liver microsomes (HLM) incubation system and pre-incubated for 30 minutes with or without reduced nicotinamide adenine dinucleotide phosphate (NADPH). After pre-incubation, the probe substrate solution and the mixed solution of NADPH and substrate were added to the corresponding sample wells. After incubation for a certain period of time, the reaction was terminated and the enzyme activity of the incubation system was measured. The IC under the two conditions was calculated. 50 Value, compare IC 50 Fold shift, assessing the time-dependent inhibitory effect of the study drug.

[0759] Some test results

[0760] Compound 7A did not inhibit CYP 3A4 isoforms in a time-dependent manner.

[0761] Test Example 7: Solubility Test

[0762] Add 15 μL of a 10 mM stock solution of test compound or control compound to the assay well, followed by 485 μL of PBS (pH 7.4) / FaSSIF / FeSSIF solution. Stir using a molded PTFE / Silicone plate and a stir bar at 1100 rpm at 25°C for 2 hours. Filter the sample, aspirate 5 μL of the filtrate, add 5 μL of DMSO, and then add 490 μL of an acetonitrile / water (1:1, v:v) solution containing an internal standard. Aspirate the appropriate amount of the solution for quantitative analysis of compound concentration by LC-MS / MS.

[0763] Some test results

[0764] Conclusion: Compared with the prior art, the compound of the present invention has better PBS (pH 7.4) solubility.

[0765] Test Example 8: Caco-2 cell monolayer permeability test

[0766] After 14 to 21 days of culture, a bidirectional drug transport test was performed on a Caco-2 cell monolayer model. After 2 hours of incubation, the concentrations at the receiving and donating ends were detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS). The apparent permeability coefficient (Papp) and efflux ratio (ER) were calculated to investigate the permeability of the drug and provide a reference for the evaluation of intestinal drug absorption.

[0767] Some test results

[0768] Conclusion: Compared with the prior art, the compound of the present invention has significantly superior permeability results in the in vitro Caco-2 permeability test.

[0769] Test Example 9: PPB plasma protein binding rate test

[0770] Plasma samples with a compound concentration of 1 μM were prepared from plasma obtained from CD-1 mice, Sprague-Dawley rats, beagles, cynomolgus monkeys, and humans. The samples were dialyzed against phosphate buffer at 37°C for 4 hours in a 96-well equilibrium dialysis apparatus. Warfarin was used as a control compound. The concentrations of the analytes in plasma and dialysis buffer were determined by LC-MS / MS, and the free rate f was calculated. u value.

[0771] Some test results

[0772] Conclusion: The compounds of the present invention showed higher free drug concentrations in various plasma protein binding tests.

[0773] Test Example 10: Glutathione Trapping (GSH Trapping) Test

[0774] Compound (10 μM) was added to human liver microsome solution (1 mg / mL), and then NADPH and GSH powder were added to the system. The mixture was pre-incubated at 37°C for 1 hour. The samples were post-processed and the GSH binding products were analyzed by LC-UV-MS / MS.

[0775] Some test results

[0776] Compound 7A: negative.

[0777] Test Example 11: MCF-7 human breast cancer orthotopic transplantation model test in nude mice

[0778] 1.1 Experimental animals and cell culture

[0779] For the experimental animals, female BALB / c nude mice (SPF grade, 6–8 weeks old, weighing 18–23 g, 42 mice) were purchased from Shanghai Bikeway Biotechnology Co., Ltd. and housed in a standard SPF animal facility. The mice were housed individually, maintained a natural circadian rhythm, and had free access to food. The room temperature was 23°C ± 2°C, and the relative humidity was 40%–60%.

[0780] Human breast cancer MCF-7 (ECACC-86012803) cells were cultured as monolayers in EMEM (EBSS) medium supplemented with 10% heat-inactivated fetal bovine serum, 2 mM glutamine, 1% non-essential amino acids (NEAA), and 1% penicillin / streptomycin / amphotericin B in a 37°C, 5% CO2 incubator. Cells were routinely digested and passaged twice weekly using trypsin-EDTA. When cells reached the exponential growth phase, they were harvested, counted, and plated.

[0781] 1.2 Construction of animal model, grouping and drug administration

[0782] Three days before tumor cell inoculation, estrogen tablets (0.36 mg / tablet) were subcutaneously inoculated on the left shoulder. 6 MCF-7 cells were mixed with Matrigel at a ratio of 1:1 and injected into the mammary fat pad of mice. 3The animals were randomly divided into groups according to the tumor volume using Excel randomization software. Each group consisted of 6 tumor-bearing mice and was treated for three weeks. Among them, the vehicle group (5% DMSO + 10% Tween-20 + 85% PBS, po, QD); Fulvestrant group (5 mg / mouse, sc, QW); ErSO group (40 mg / kg, po, QD); 7A group (0.15 mg / kg, po, QD); 7A group (0.5 mg / kg, po, QD); 7A group (0.25 mg / kg, po, BID), and 7A group (0.5 mg / kg, po, BID) were treated. The body weight of the animals was monitored twice a week to adjust the drug dosage. The tumor diameter was measured with a vernier caliper twice a week. The formula for calculating the tumor volume is: V = 0.5a × b 2 , a and b represent the major and minor diameters of the tumor, respectively. The antitumor efficacy of the test substances was evaluated using TGI (%) or relative tumor growth rate (T / C) (%). Data are presented as mean ± SEM. Statistical analysis was performed on day 21 after dosing for all treatment groups to assess intergroup differences. Comparisons among three or more groups were analyzed using one-way ANOVA. All data were analyzed using Graph Pad Prism 8.0. A p < 0.05 was considered significant.

[0783] Conclusion: Compared with existing technologies, the compounds of this invention achieved highly significant tumor inhibitory effects at significantly lower doses. In an orthotopic MCF-7 human breast cancer nude mouse model, no treatment groups showed significant weight loss, and no mice morbidity or mortality occurred during the experiment. Compared with the solvent control group, the ErSO (40 mg / kg, QD) and 7A (0.5 mg / kg, BID) treatment groups demonstrated highly significant tumor inhibition, with TGI values ​​of 142.76% and 141.71%, respectively.

[0784] The above describes exemplary embodiments of the present invention. It should be understood that the scope of protection of this application is not limited to the above exemplary embodiments. Any modifications, equivalent substitutions, improvements, etc. made by those skilled in the art within the spirit and principles of the present invention should be included in the scope of protection of this application.

Claims

1. A compound represented by formula (I), its optical isomers, tautomers or pharmaceutically acceptable salts thereof, in, Ring A is selected from heterocyclyl and heteroaryl; Ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; X1, X2 and X3 are independently selected from C(R3) and N; X4 is selected from O and a single bond; X5 is selected from CH(R5), S(=O)2, C(=NR5) and C(=O); X6 is selected from CH(R5) and N(R5); Y1 is selected from N(R4), CH(R4) and O; Y2 is selected from O, S and N(R6); R1 is independently selected from H, halogen, OH, CN, NH2, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloheteroalkyl, C 1-6 Alkyl-O-, C 1- 6-alkyl-S-, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-C(=O)O-, C 1-6 Alkyl-OC(=O)-, C 1-6 Alkyl-NH-, -N(C 1-6 Alkyl)2, C 1- 6-Alkyl-NH-C 1-6 Alkyl-, C 1-6 Alkyl-C(=O)NH-, C 3-6 Cycloalkyl-C(=O)NH-, C 3-6 Cycloheteroalkyl-C(=O)NH-, C 1-6 Alkyl-NH-C(=O)-, C 3-6 Cycloalkyl-NH-C(=O)-, C 3-6 Cycloheteroalkyl-NH-C(=O)-, C 1-6 Alkyl-S(=O)2-, C 1-6 Alkyl-S(=O)2NH- and C 1-6 Alkyl-NHS(=O)2-, the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloheteroalkyl, C 1-6 Alkyl-O-, C 1-6 Alkyl-S-, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-C(=O)O-, C 1-6 Alkyl-OC(=O)-, C 1-6 Alkyl-NH-, -N(C 1-6 Alkyl)2, C 1-6 Alkyl-NH-C 1-6 Alkyl-, C 1-6 Alkyl-C(=O)NH-, C 3-6 Cycloalkyl-C(=O)NH-, C 3-6 Cycloheteroalkyl-C(=O)NH-, C 1-6 Alkyl-NH-C(=O)-, C 3- 6-cycloalkyl-NH-C(=O)-, C 3-6 Cycloheteroalkyl-NH-C(=O)-, C 1-6 Alkyl-S(=O)2-, C 1-6 Alkyl-S(=O)2NH- or C 1-6 Alkyl-NHS(═O)2- is optionally substituted with 1, 2 or 3 R; R2 is independently selected from H, halogen, OH, CN, NH2, C 1-6 Alkyl, C 3-6 Cycloalkyl, the C 1-6 Alkyl, C 3-6 Cycloalkyl is optionally substituted with 1, 2 or 3 R; R3 is selected from H, halogen, CN, OH, NH2, -C(=O)OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloheteroalkyl, C 1-6 Alkyl-O-, C 1-6 Alkyl-S-, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-C(=O)O-, C 1-6 Alkyl-OC(=O)-, C 1-6 Alkyl-C(=O)NH-, C 1-6 Alkyl-NH-C(=O)-, C 1-6 Alkyl-S(=O)2-, C 1-6 Alkyl-S(=O)2NH- and C 1-6 Alkyl-NHS(=O)2-, the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloheteroalkyl, C 1-6 Alkyl-O-, C 1-6 Alkyl-S-, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-C(=O)O-, C 1-6 Alkyl-OC(=O)-, C 1-6 Alkyl-C(=O)NH-, C 1-6 Alkyl-NH-C(=O)-, C 1-6 Alkyl-S(=O)2-, C 1-6 Alkyl-S(=O)2NH- or C 1-6 Alkyl-NHS(═O)2- is optionally substituted with 1, 2 or 3 R; R4 is selected from H, halogen, OH, CN, NH2, C 1-6 Alkyl, C 3-6 Cycloalkyl, the C 1-6 Alkyl, C 3-6 Cycloalkyl is optionally substituted with 1, 2 or 3 R; R5 is selected from H, halogen, OH, CN, NH2, C 1-6 Alkyl, C 3-6 Cycloalkyl and C 1-6 Alkoxy, the C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 The alkoxy group is optionally substituted with 1, 2 or 3 R; R6 are independently selected from H, halogen, OH, CN, NH2 and C 1-6 Alkyl, C 3-6 Cycloalkyl, the C 1-6 The alkyl group is optionally substituted with 1, 2 or 3 R; R is independently selected from H, F, Cl, Br, I, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1- 6-alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl and C 3-6 Cycloheteroalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl or C 3-6 Cycloheteroalkyl is optionally substituted with 1, 2 or 3 R'; R' is selected from F, Cl, Br, I, OH, NH2, CN, CH3, CH2F, CHF2 and CF3; n is 0, 1, 2, 3 or 4; m is 0, 1, 2 or 3.

2. The compound according to claim 1, its optical isomers, tautomers or pharmaceutically acceptable salts thereof, wherein: Structural unit Selected from 3. The compound according to claim 1, its optical isomers, tautomers or pharmaceutically acceptable salts thereof, wherein: R4 is selected from H, OH, C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R groups.

4. The compound according to claim 1, its optical isomers, tautomers or pharmaceutically acceptable salts thereof, wherein: Ring A is selected from 5. The compound according to any one of claims 1 or 4, its optical isomers, tautomers or pharmaceutically acceptable salts thereof, wherein: R2 is independently selected from H, halogen, OH, CN, NH2, C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R groups.

6. The compound according to claim 5, its optical isomers, tautomers or pharmaceutically acceptable salts thereof, wherein: R2 is independently selected from H, F, Cl, Br, I, OH, CN, NH2, methyl, CHF2, CH2OH, CH2CH2OH.

7. The compound according to any one of claims 4 or 6, its optical isomers, tautomers or pharmaceutically acceptable salts thereof, wherein: Structural unit Selected from 8. The compound according to claim 1, its optical isomers, tautomers or pharmaceutically acceptable salts thereof, wherein: Ring B is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, furanyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thienopyridinyl, C 3-7 Cycloalkyl and C 3-6 Cycloheteroalkyl.

9. The compound according to claim 1, its optical isomers, tautomers or pharmaceutically acceptable salts thereof, wherein: R1 is independently selected from H, halogen, OH, CN, C 1-3 Alkyl, C 1-3 Alkyl-O-, C 1-3 Alkyl-S-, C 1-3 Alkyl-C(=O)-, C 1-3 Alkyl-OC(=O)-, C 1-3 Alkyl-C(=O)O-, C 1-3 Alkyl-NH-, -N(C 1-3 Alkyl)2, C 1-3 Alkyl-NH-C 1-3 Alkyl-, C 1-3 Alkyl-C(=O)NH-, C 3-6 Cycloalkyl-C(=O)NH-, C 3-6 Cycloheteroalkyl-C(=O)NH-, C 1-3 Alkyl-NH-C(=O)-, C 1-3 Alkyl-S(=O)2-, C 1-3 Alkyl-S(=O)2NH- and C 1-3 Alkyl-NHS(=O)2-, the C 1-3 Alkyl, C 1-3 Alkyl-O-, C 1-3 Alkyl-S-, C 1-3 Alkyl-C(=O)-, C 1-3 Alkyl-OC(=O)-, C 1-3 Alkyl-C(=O)O-, C 1-3 Alkyl-NH-, -N(C 1-3 Alkyl)2, C 1-3 Alkyl-NH-C 1-3 Alkyl-, C 1-3 Alkyl-C(=O)NH-, C 3-6 Cycloalkyl-C(=O)NH-, C 3-6 Cycloheteroalkyl-C(=O)NH-, C 1-3 Alkyl-NH-C(=O)-, C 1-3 Alkyl-S(=O)2-, C 1-3 Alkyl-S(=O)2NH- or C 1-3 Alkyl-NHS(=O)2- is optionally substituted with 1, 2 or 3 R groups.

10. The compound according to claim 9, its optical isomers, tautomers or pharmaceutically acceptable salts thereof, wherein: R1 is independently selected from H, F, Cl, Br, I, OH, CN, Me, 11. The compound according to claim 8 or 10, its optical isomers, tautomers or pharmaceutically acceptable salts thereof, wherein: Structural unit Selected from 12. The compound according to claim 1, its optical isomers, tautomers or pharmaceutically acceptable salts thereof, wherein: Structural unit Selected from 13. The compound according to claim 1, its optical isomers, tautomers or pharmaceutically acceptable salts thereof, wherein: R3 is selected from H, halogen, OH, CN, -C(=O)OH, C 1-3 Alkyl, C 3-6 Cycloheteroalkyl, C 1-3 Alkyl-O-, C 1-3 Alkyl-C(=O)-, C 1-3 Alkyl-C(=O)O-, C 1-3 Alkyl-OC(=O)-, C 1-3 Alkyl-C(=O)NH-, C 1-3 Alkyl-NH-C(=O)-, C 1-3 Alkyl-S(=O)2-, C 1-3 Alkyl-S(=O)2NH- and C 1-3 Alkyl-NHS(=O)2-, the C 1-3 Alkyl, C 3-6 Cycloheteroalkyl, C 1-3 Alkyl-O-, C 1-3 Alkyl-C(=O)-, C 1-3 Alkyl-C(=O)O-, C 1-3 Alkyl-OC(=O)-, C 1-3 Alkyl-C(=O)NH-, C 1-3 Alkyl-NH-C(=O)-, C 1-3 Alkyl-S(=O)2-, C 1-3 Alkyl-S(=O)2NH- or C 1-3 Alkyl-NHS(=O)2- is optionally substituted with 1, 2 or 3 R groups.

14. The compound according to claim 13, its optical isomers, tautomers or pharmaceutically acceptable salts thereof, wherein: R3 is selected from H, F, Cl, Br, -C(=O)OH, -CH3, -OCH3, -OCF3, -CF3, 15. The compound according to claim 1, its optical isomers, tautomers or pharmaceutically acceptable salts thereof, wherein: R5 is selected from H, OH.

16. The compound according to claim 12, 14 or 15, its optical isomers, tautomers or pharmaceutically acceptable salts thereof, wherein: Structural unit Selected from 17. A compound, an optical isomer, a tautomer or a pharmaceutically acceptable salt thereof, selected from:

18. A compound, an optical isomer, a tautomer or a pharmaceutically acceptable salt thereof, selected from:

19. A pharmaceutical composition, wherein: The pharmaceutical composition comprises the compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof.

20. The pharmaceutical composition of claim 19, further comprising one or more pharmaceutically acceptable carriers, diluents or excipients.

21. Use of the compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 20 in the preparation of drugs for treating breast cancer, ovarian cancer, uterine cancer, endometrial cancer, and cervical cancer.

22. Use of the compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 20 in the preparation of drugs for treating myeloma, head and neck cancer, thyroid cancer, prostate cancer, testicular cancer, esophageal cancer, lung cancer, liver cancer, gastric cancer, kidney cancer, bile duct cancer, gallbladder cancer, pancreatic cancer, colorectal cancer, bladder cancer, bone cancer, skin cancer, brain tumors, neuroblastoma, lymphoma, and leukemia.

23. Use of the compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 20 in the preparation of a drug for treating ERα-positive related diseases.

24. Use of the compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 20 in the preparation of a drug for treating ER-positive related diseases.

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