WO2024175108A1 - Bicyclic compound, and preparation method therefor and use thereof - Google Patents

Abstract

Disclosed in the present invention are a compound as shown in formula (I), an optical isomer, tautomer or pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the compound, which pharmaceutical composition can be used for treating ER-positive or ERα-positive related diseases.

Description

Bicyclic compounds and preparation methods and uses thereof

This application claims the following priority:

CN202310162492.3, application date February 23, 2023;

CN202410176445.9, application date February 7, 2024;

CN202410195592.0, application date February 21, 2024.

Technical Field

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

The latest global cancer burden data for 2020 released by the World Health Organization's International Agency for Research on Cancer (IARC) show that breast cancer has surpassed lung cancer for the first time to become the most common cancer, with more than 2.26 million new cases reported in 2020 alone, accounting for 11.7% of total cancer incidence; more than 680,000 deaths from breast cancer worldwide that year, making it the fifth leading cause of cancer death. In China, there were approximately 420,000 new cases of breast cancer in 2020, making it the leading cancer among Chinese women, and nearly 120,000 deaths from breast cancer, making it the fourth leading cause of cancer death among women.

Breast cancer is a phenomenon in which breast epithelial cells undergo uncontrolled proliferation under the influence of a variety of carcinogenic factors; the most common type is the estrogen receptor α (ERα) positive type, which accounts for about 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.

Summary of the invention

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,

in,

Ring A is selected from heterocyclyl and heteroaryl;

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

X ₁ , X ₂ and X ₃ are independently selected from C(R ₃ ) and N;

X ₄ is selected from O and a single bond;

X ₅ is selected from CH(R ₅ ), S(═O) ₂ , C(═NR ₅ ) and C(═O);

X ₆ is selected from CH(R ₅ ) and N(R ₅ );

Y ₁ is selected from N(R ₄ ), CH(R ₄ ) and O;

Y ₂ is selected from O, S and N(R ₆ );

_R1 is independently selected from H, halogen, OH, CN, _NH2 , _C1-6 alkyl, _{C3-6 cycloalkyl, C3-6 cycloheteroalkyl} , _C1-6 alkyl-O-, _C1-6 alkyl-S-, _C1-6 alkyl-C(=O)-, _C1-6 alkyl-C(=O)O-, _C1-6 alkyl-OC(=O)-, _C1-6 alkyl- _NH- , -N( _C1-6 alkyl) ₂ , _C1-6 alkyl _- NH- _C1-6 alkyl-, _C1-6 alkyl-C(=O)NH-, _C3-6 cycloalkyl-C(=O)NH-, _C3-6 cycloheteroalkyl-C(=O)NH-, _C1-6 alkyl-NH-C(=O)-, _C3-6 cycloalkyl-NH-C(=O)-, C1-6 C _1-6 alkyl-S(＝O) ₂ -, C _1-6 alkyl-S(＝O) ₂ NH- 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) ₂ NH- or C _1-6 alkyl-NHS(＝O) ₂ - is optionally substituted by 1, 2 or 3 R;

R ₂ is independently selected from H, halogen, OH, CN, NH ₂ , C _1-6 alkyl, C _3-6 cycloalkyl, wherein the C _1-6 alkyl, C _3-6 cycloalkyl is optionally substituted by 1, 2 or 3 R;

_R3 is selected from H, halogen, CN, OH, _NH2 , -C(=O)OH, _C1-6 alkyl, _C3-6 cycloalkyl, _C3-6 cycloheteroalkyl, _C1-6 alkyl-O-, _C1-6 alkyl-S-, C1-6 alkyl-C(=O)-, _C1-6 alkyl-C(=O _{)O-, C1-6 alkyl-OC(=O)-, C1-6 alkyl-C(=O)NH-, C1-6 alkyl - NH} -C(=O)-, _C1-6 alkyl-S(=O) _2- , _C1-6 alkyl-S(=O) _2NH- and _C1-6 alkyl-NHS(=O) _2- , wherein the _C1-6 alkyl, _C3-6 cycloalkyl, _C3-6 cycloheteroalkyl, _C1-6 alkyl-O-, _C1-6 alkyl-S-, C1-6 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) ₂ NH- or C _1-6 alkyl-NHS(═O) ₂ - is optionally substituted by 1, 2 or 3 R;

R ₄ is selected from H, halogen, OH, CN, NH ₂ , C _1-6 alkyl, C _3-6 cycloalkyl, wherein the C _1-6 alkyl, C _3-6 cycloalkyl is optionally substituted by 1, 2 or 3 R;

R ₅ is selected from H, halogen, OH, CN, NH ₂ , C _1-6 alkyl, C _3-6 cycloalkyl and C _1-6 alkoxy, wherein the C _1-6 alkyl, C _3-6 cycloalkyl or C _1-6 alkoxy is optionally substituted by 1, 2 or 3 R;

R ₆ is independently selected from H, halogen, OH, CN, NH ₂ , C _1-6 alkyl, C _3-6 cycloalkyl, and the C _1-6 alkyl is optionally substituted by 1, 2 or 3 R;

R is independently selected from H, F, Cl, Br, I, OH, NH ₂ , 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, wherein 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 by 1 _, 2 or 3 R';

R' is selected from F, Cl, Br, I, OH, _NH2 , CN, CH ₃ , CH ₂ F, CHF ₂ and CF ₃ ;

n is 0, 1, 2, 3 or 4;

m is 0, 1, 2 or 3.

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

In some embodiments of the present invention, the above R ₄ is selected from H, OH, C _1-3 alkyl, the C _1-3 alkyl is optionally substituted by 1, 2 or 3 R, and other variables are as defined in the present invention.

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

In some embodiments of the present invention, the above R ₂ is independently selected from H, halogen, OH, CN, NH ₂ , C _1-3 alkyl, the C _1-3 alkyl is optionally substituted by 1, 2 or 3 R, and other variables are as defined in the present invention.

In some embodiments of the present invention, the above R ₂ is independently selected from H, F, Cl, Br, I, OH, CN, NH ₂ , methyl, CHF ₂ , CH ₂ OH, CH ₂ CH ₂ OH, and other variables are as defined in the present invention.

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

In some embodiments of the present invention, the above-mentioned ring B is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, furanyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thienopyridinyl, _C3-7 cycloalkyl and _C3-6 cycloheteroalkyl, and other variables are as defined in the present invention.

In some embodiments of the present invention, the above _R1 is independently selected from H, halogen, OH, CN, _C1-3 alkyl, _C1-3 alkyl-O-, _C1-3 alkyl _{-S-, C1-3 alkyl-C(＝O)-, C1-3 alkyl-OC(＝O)-, C1-3 alkyl - C(＝O)O-, C1-3 alkyl-NH-, -N(C1-3 alkyl)2, C1-3 alkyl-NH-C1-3 alkyl- , C1-3 alkyl - C (} ＝O)NH-, _C3-6 cycloalkyl-C(＝O)NH-, _C3-6 cycloheteroalkyl-C(＝O)NH-, _C1-3 alkyl-NH-C(＝O)-, _C1-3 alkyl-S(＝O) _2- , _C1-3 alkyl-S(＝O) _2NH- and C1-3 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) ₂ NH- 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.

In some embodiments of the present invention, the above R ₁ is independently selected from H, F, Cl, Br, I, OH, CN, Me, Other variables are as defined in the present invention.

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

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

In some embodiments of the present invention, _R3 is selected from H, halogen, OH, CN, -C(=O)OH, _C1-3 alkyl, _C3-6 cycloheteroalkyl, _C1-3 alkyl-O-, _C1-3 alkyl-C(=O)-, _C1-3 alkyl _- C(=O)O-, _C1-3 alkyl-OC(=O)-, _C1-3 alkyl-C(=O)NH-, _C1-3 alkyl-NH _- C(=O)-, _C1-3 alkyl-S(=O) _2- , _C1-3 alkyl-S(=O _{) 2NH- and C1-3 alkyl} -NHS(=O) _{2- .} 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) ₂ NH- or C _1-3 alkyl-NHS(═O) ₂ - is optionally substituted with 1, 2 or 3 R, and other variables are as defined herein.

In some embodiments of the present invention, the above R ₃ is selected from H, F, Cl, Br, -C(=O)OH, -CH ₃ , -OCH ₃ , -OCF ₃ , -CF ₃ , Other variables are as defined in the present invention.

In some embodiments of the present invention, the above R ₅ is selected from H and OH, and other variables are as defined in the present invention.

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

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

Ring A, Ring B, X ₁ , X ₂ , X ₃ , X ₄ , X ₅ , X ₆ , R ₁ , R ₂ , R ₄ , n and m are as defined above.

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

Ring B, X ₁ , X ₂ , X ₃ , X ₄ , X ₅ , X ₆ , R ₁ and n are as defined above.

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

Ring A, Ring B, X ₁ , X ₂ , X ₃ , X ₄ , X ₅ , X ₆ , Y ₁ , Y ₂ , R ₁ , R ₂ , n and m are as defined above.

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

Ring A, Ring B, X ₁ , X ₂ , X ₃ , X ₄ , X ₅ , X ₆ , R ₁ , R ₂ , R ₄ , n and m are as defined above.

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

Ring B, X ₁ , X ₂ , X ₃ , X ₄ , X ₅ , X ₆ , R ₁ and n are as defined above.

In another aspect of the present invention, the present invention also provides the following compounds, their optical isomers, tautomers or their pharmacologically acceptable A salt selected from:

In yet 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 are selected from:

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.

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

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 breast cancer, ovarian cancer, and endometrial cancer.

In yet 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 uterine cancer and cervical cancer.

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.

In another aspect of the present invention, the present invention also provides the aforementioned compound or its pharmaceutically acceptable salt or the aforementioned pharmaceutical composition for preparing a method for treating ERα Application of drugs in positive related diseases.

In yet 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 a drug for treating ER-positive related diseases.

Definition and Description

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

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

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

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

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

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

The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more atoms constituting the compound. For example, compounds may be labeled with radioactive isotopes, such as tritium ( ^3H ), iodine-125 ( ^125I ) or C-14 ( ^14C ). For another example, deuterated drugs may be formed by replacing hydrogen with heavy hydrogen. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, and extending the biological half-life of drugs. All isotopic composition changes of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention. "Optional" or "optionally" means that the event or situation described subsequently may but does not necessarily occur, and the description includes situations in which the event or situation occurs and situations in which the event or situation does not occur.

The term "substituted by..." means that any one or more H on a specific atom is replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the specific atom is normal and the substituted compound is stable. The term "optionally substituted by..." means that it may be substituted or not substituted, and unless otherwise specified, the type and number of the substituent can be any on the basis of chemical practicability.

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

A hyphen ("-") that is not between two letters or symbols indicates the point of attachment of a substituent. For example, _C1-6 alkylcarbonyl- refers to a _C1-6 alkyl group that is attached to the rest of the molecule via a carbonyl group. However, when the point of attachment of a substituent is obvious to one skilled in the art, for example, a halogen substituent, the "-" may be omitted.

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 L ₁ represents a single bond, it means that the structure is actually

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

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

When the listed linking group does not indicate its linking direction, its linking direction is arbitrary, for example, The connecting group L is at this time You can connect phenyl and cyclopentyl groups 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.

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

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-dimethylpentyl, 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 (-CH ₂ -), 1,1-ethylene (- CH(CH ₃ )-), 1,2-ethylene (-CH ₂ CH ₂ -), 1,1-propylene (-CH(CH ₂ CH ₃ )-), 1,2-propylene (-CH ₂ CH(CH ₃ )-), 1,3-propylene (-CH ₂ CH ₂ CH ₂ -), 1,4-butylene (-CH ₂ CH ₂ CH ₂ CH ₂ -), 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 independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, OH, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio and oxo.

The term "heteroalkyl" by itself or in combination with another term refers to a stable straight or branched 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) ₂ N(H)- and _-S (=O)N(H)-. In some embodiments, the heteroalkyl is C _1-6 heteroalkyl; in other embodiments, the heteroalkyl is C _1-3 heteroalkyl. The heteroatom or heteroatom group may be placed at any interior position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule, but the term "alkoxy" is a customary expression to refer to those alkyl groups 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 -CH ₃ , and up to two heteroatoms may be consecutive, for example -CH ₂ -NH-OCH ₃ .

Unless otherwise specified, the term "C _1-6 alkoxy" refers to those alkyl groups containing 1 to 6 carbon atoms connected to the rest of the molecule through an oxygen atom. The C _1-6 alkoxy includes C _1-4 , C _1-3 , C _1-2 , C _2-6 , C _2-4 , C ₆ , C ₅ , C ₄ and C ₃ alkoxy, etc. Examples of C _1-6 alkoxy 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, isopentyl and neopentyl), hexyl and the like.

Unless otherwise specified, the term "C _1-3 alkoxy" refers to those alkyl groups containing 1 to 3 carbon atoms connected to the rest of the molecule through an oxygen atom. The C _1-3 alkoxy includes C _1-3 , C _1-2 , C _2-3 , C ₁ , C ₂ and C ₃ alkoxy, etc. Examples of C _1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), etc.

Unless otherwise specified, the term "C _1-6 alkylamino" refers to those alkyl groups containing 1 to 6 carbon atoms that are attached to the rest of the molecule through an amino group. The C _1-6 alkylamino group includes C _1-4 , C _1-3 , C _{1-2, C 2-6 ,} C _2-4 , C ₆ , C ₅ , C ₄ , C ₃ and C ₂ alkylamino groups, etc. Examples of C _1-6 alkylamino groups include, but are not limited to, -NHCH ₃ , -N(CH ₃ ) ₂ , -NHCH ₂ CH ₃ , -N(CH ₃ )CH ₂ CH ₃ , -N(CH ₂ CH ₃ )(CH ₂ CH ₃ ), -NHCH ₂ CH ₂ CH ₃ , -NHCH ₂ (CH ₃ ) ₂ , -NHCH ₂ CH ₂ CH ₂ CH ₃ , and the like.

Unless otherwise specified, the term "C _1-3 alkylamino" refers to those alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule through an amino group. The C _1-3 alkylamino group includes C _1-3 , C _1-2 , C _2-3 , C ₁ , C ₂ and C ₃ alkylamino groups, etc. Examples of C _1-3 alkylamino groups include, but are not limited to, -NHCH ₃ , -N(CH ₃ ) ₂ , -NHCH ₂ CH ₃ , -N(CH ₃ )CH ₂ CH ₃ , -NHCH ₂ CH ₂ CH ₃ , -NHCH ₂ (CH ₃ ) ₂ , etc.

Unless otherwise specified, the term "C _1-6 alkylthio" refers to those alkyl groups containing 1 to 6 carbon atoms which are attached to the rest of the molecule via a sulfur atom. The C _1-6 alkylthio group includes C _1-4 , C _1-3 , C _1-2 , C _2-6 , C _2-4 , C ₆ , C ₅ , C ₄ , C ₃ and C ₂ alkylthio groups. Examples of C _1-6 alkylthio groups include, but are not limited to, -SCH ₃ , -SCH ₂ CH ₃ , -SCH ₂ CH ₂ CH ₃ , -SCH ₂ (CH ₃ ) ₂ and the like.

Unless otherwise specified, the term "C _1-3 alkylthio" refers to those alkyl groups containing 1 to 3 carbon atoms connected to the rest of the molecule through a sulfur atom. The C _1-3 alkylthio group includes C _1-3 , C _1-2 , C _2-3 , C ₁ , C ₂ and C ₃ alkylthio groups, etc. Examples of C _1-3 alkylthio groups include, but are not limited to, -SCH ₃ , -SCH ₂ CH ₃ , -SCH ₂ CH ₂ CH ₃ , -SCH ₂ (CH ₃ ) ₂ , etc.

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 cycloalkyls of spiro rings, condensed rings, and bridged rings.

Unless otherwise specified, the term "spirocycloalkyl" refers to a polycyclic group in which a carbon atom (called a spiro atom) is 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, more preferably 7 to 10. According to the number of shared spiro atoms between rings, the spirocycloalkyl is divided into a single spirocycloalkyl, a double spirocycloalkyl or a multi-spirocycloalkyl, preferably a single spirocycloalkyl and a double spirocycloalkyl. 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 spirocycloalkyl. Non-limiting examples of spirocycloalkyl include: wait.

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 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 a bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic alkyl. Non-limiting examples of fused cycloalkyls include: wait.

Unless otherwise specified, the term "bridged cycloalkyl" refers to a 5 to 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 to 14 members, and more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include: wait.

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

The cycloalkyl group may be optionally substituted or unsubstituted, and 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, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio and oxo.

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 are heteroatoms selected from nitrogen, oxygen or S(O) _m (wherein m is an integer from 0 to 2), but excluding the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms (which can be specific points or an interval consisting of two random 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. The limiting examples of monocyclic heterocyclic radical include azetidinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl etc., preferably tetrahydropyranyl, piperidinyl, pyrrolidinyl. Polycyclic heterocyclic radical includes the heterocyclic radical of spirocycle, condensed ring and bridged ring.

Unless otherwise specified, the term "spiro heterocyclic group" refers to a polycyclic heterocyclic group with 5 to 20 members, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _m (wherein m is an integer from 0 to 2), and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a completely conjugated π electron system. Preferably, it is 6 to 14 members, and more preferably 7 to 11 members. According to the number of spiro atoms shared between rings, spiro heterocyclic groups are divided into monospiro heterocyclic groups, bispiro heterocyclic groups or polyspiro heterocyclic groups, preferably monospiro heterocyclic groups and bispiro heterocyclic groups. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiro heterocyclic group. Non-limiting examples of spiro heterocyclic groups include: wait.

Unless otherwise specified, the term "fused heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 20 members, 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, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _m (wherein m is an integer from 0 to 2), and the remaining ring atoms are 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 a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include: wait.

Unless otherwise specified, the term "bridged heterocyclic group" refers to a 5-14-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 none of the rings has a completely conjugated π electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _m (wherein m is an integer from 0 to 2), and the remaining ring atoms are 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 a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, preferably a bicyclic, tricyclic or tetracyclic group, and more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged heterocyclic groups include: wait.

The heterocyclic ring includes the above-mentioned heterocyclic groups (such as monocyclic, fused ring, spirocyclic and bridged heterocyclic groups) fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, and its non-limiting examples include: wait.

The heterocyclic group may be optionally substituted or unsubstituted, and 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, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio and oxo.

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

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, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio and heterocycloalkylthio.

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 to 10 members, containing 1 to 3 heteroatoms; more preferably 5 or 6 members, containing 1 to 3 heteroatoms; non-limiting examples include pyrazolyl, imidazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazinyl, etc. 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.

The heteroaryl group may be optionally substituted or unsubstituted, and 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, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio and heterocycloalkylthio.

Unless otherwise specified, the term "alkylthio" refers to-S-(alkyl) and-S-(unsubstituted cycloalkyl), wherein the definition of alkyl or cycloalkyl is as described 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, substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, OH, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio and heterocycloalkylthio.

Unless otherwise specified, the term "cycloalkyloxy" means an -O-cycloalkyl group wherein cycloalkyl is as defined above.

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

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

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

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

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

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

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

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.

Unless otherwise specified, the term "C _1-6 alkyl" is used to represent a straight or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C _1-6 alkyl includes 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). Examples of C _1-5 alkyl 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, etc.

Unless otherwise specified, the term "C _1-3 alkyl" is used to represent a straight or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C _1-3 alkyl group includes C _1-2 and C _2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). Examples of C _1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), etc.

Unless otherwise specified, " _C2-6 alkenyl" is used to represent a straight 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. The _C2-6 alkenyl group includes _C2-4 , _C2-3 , _C4 , _C3 and _C2 alkenyl, etc.; it may be monovalent, divalent or polyvalent. Examples of _C2-6 alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, etc.

Unless otherwise specified, "C _2-3 alkenyl" is used to refer to a straight or branched hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon double bond, and the carbon-carbon double bond can be located at any position of the group. The C _2-3 alkenyl includes C ₃ and C ₂ alkenyl; the C _2-3 alkenyl can be monovalent, divalent or polyvalent. Examples of C _2-3 alkenyl include, but are not limited to, ethenyl, propenyl, etc.

Unless otherwise specified, "C _4-8 cycloalkyl" refers to a saturated monovalent monocyclic or bicyclic hydrocarbon group having 4-8 ring carbon atoms, such as 4-7 ring carbon atoms, such as 4-6 ring carbon atoms, such as 4-5 ring carbon atoms. For example, "C _4-8 cycloalkyl" means a cycloalkyl group having 4-8 ring carbon atoms. Similarly, "C _4-7 cycloalkyl" means a cycloalkyl group having 4-7 ring carbon atoms; "C _4-6 cycloalkyl" means a cycloalkyl group having 4-6 ring carbon atoms; "C _4-5 cycloalkyl" means 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.

Unless otherwise specified, "C _4-6 cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 4 to 6 carbon atoms, which is a monocyclic and bicyclic system, and the C _4-6 cycloalkyl includes C _4-5 , C _5-6 , C ₄ , C ₅ and C ₆ cycloalkyl, etc.; it can be monovalent, divalent or polyvalent. Examples of C _4-6 cycloalkyl include, but are not limited to, cyclobutyl, cyclopentyl, cyclohexyl, etc.

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 can be optionally oxidized (i.e., NO and S(O) _p , p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spirocyclic, cyclic and bridged rings. In addition, with respect to the "3-10 membered heterocycloalkyl", heteroatoms can occupy the position where 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, tetrahydrothienyl (including tetrahydrothien-2-yl and tetrahydrothien-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl, dioxepane The present invention also uses the term "5-9 membered bicycloalkyl" to represent a bicyclic ring having 5-9 ring atoms, such as bicyclo[1.1.1]pentane, 2,5-diazabicyclo[2.2.1]heptane, etc.

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 may be optionally oxidized (i.e., NO and S(O) _p , p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spirocyclic, cyclic and bridged rings. In addition, with respect to the "3-6 membered heterocyclyl", heteroatoms may occupy the position where the heterocycloalkyl is connected to the rest of the molecule. The 3-6 membered heterocycloalkyl includes 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyl, etc. 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.

"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 or does not occur. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and 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.

"Substituted" means that one or more H, preferably up to 5, more preferably 1 to 3 H in the 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 possible or impossible substitutions without undue effort (by experiment or theory). For example, an amino group or OH with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g. olefinic) bond.

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 may 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.

The term "stereoisomer" as used herein refers to compounds that have identical chemical constitution but differ in the arrangement of the atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers, and the like.

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

The term "diastereomer" as used herein refers to stereoisomers having 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 by high resolution analytical methods such as electrophoresis and chromatography such as HPLC.

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 represent the absolute configuration of the molecule about its chiral center. The prefixes d and l or (+) and (-) are used to represent the sign of the compound rotating plane polarized light, where (-) or l represent that the compound is left-handed. Compounds with the 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 generally 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.

The racemic mixture can be used as such or resolved into 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, they can be separated by mixing with chiral The individual isomers are chemically separated from the mixture by forming diastereomeric salts with a chiral acid (e.g., a single enantiomer of 10-camphorsulfonic acid, camphoric acid, α-bromocamphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, etc.), fractionally crystallizing the salt, and then freeing one or both of the resolved bases, optionally repeating this process, thereby obtaining one or two isomers that are 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 racemate can be covalently linked to a chiral compound (auxiliary) to obtain diastereomers.

The compounds disclosed in the present invention may have one or more chiral centers, each of which independently has an R configuration or an S configuration. The chiral centers of some compounds disclosed in the present invention are marked as *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, or a single configuration diastereoisomer monomer, or a diastereoisomer mixture with a single configuration of the chiral center (for example: other chiral center configurations have not been resolved). When the absolute configuration (R configuration, or S configuration) of the chiral center of the compounds disclosed in the present invention has not been identified, such compounds can be confirmed according to the corresponding retention time (RT or Rt) under the corresponding chromatographic column conditions (for example, chromatographic column model, chromatographic column filling material, chromatographic column size, mobile phase, etc.).

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 synthetic 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.

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.

Abbreviations:

CD ₃ OD or MeOD represents deuterated methanol; DMSO-d6 represents deuterated dimethyl sulfoxide; Chloroform-d or CDCl ₃ represents deuterated chloroform; AcOH represents acetic acid; N ₂ represents nitrogen; Ar represents argon; BBr ₃ represents boron tribromide; BH ₃ represents borane; (Boc) ₂ O represents di-tert-butyl dicarbonate; Et ₃ SiH represents triethylsilane; HATU represents 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; HOBt represents 1-hydroxybenzotriazole; K ₂ CO ₃ represents potassium carbonate; KOAc represents potassium acetate; MeONa represents sodium methoxide; LDA represents lithium diisopropylamide; i-PrMgCl represents isopropyl magnesium chloride; LiHMDS represents lithium bis(trimethylsilyl)amide; LiOH represents lithium hydroxide; m-CPBA represents m-chloroperbenzoic acid; Na ₂ CO ₃ represents sodium carbonate; NaBH ₄ represents sodium borohydride; NaCl represents sodium chloride; NaHCO ₃ represents sodium bicarbonate; NaOH represents sodium hydroxide; Na ₂ SO ₄ represents sodium sulfate; NBS represents N-bromosuccinimide; KI represents potassium iodide; n-BuLi represents n-butyllithium; NH ₄ Cl represents ammonium chloride; NMP represents N-methyl-2-pyrrolidone; Cs ₂ CO ₃ 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 CH ₃ CN represents acetonitrile; MeOH or methanol represents methanol; EtOH or ethanol represents ethanol; DEA represents diethylamine; DIPEA or DIEA represents N,N-diisopropylethylamine; DMAP represents 4-dimethylaminopyridine; DMF represents N,N-dimethylformamide; NH ₃ H ₂ O represents aqueous ammonia; DMSO represents dimethyl sulfoxide; EA or EtOAc represents ethyl acetate; Et ₂ O represents diethyl ether; PE represents petroleum ether; THF represents tetrahydrofuran; Toluene or tol. represents toluene; SOCl ₂ represents dichlorothionyl; TFA represents trifluoroacetic acid; TfOH represents trifluoromethanesulfonic acid; TMSI represents trimethylsilyl iodide; TMSCl represents trimethylsilyl chloride; FA represents formic acid; H ₂ O represents water; HCl represents hydrogen chloride gas; HCl aq. represents hydrochloric acid aqueous solution; ℃ represents degrees Celsius; rt represents room temperature; h represents hour; min represents minute; kg or KG represents kilogram; g represents gram; mg represents milligram; μg represents microgram; L represents liter; mL represents milliliter; mmol represents millimole; M represents mole; cm represents centimeter; mm represents millimeter; μm represents micrometer; nm represents nanometer; mL/min represents milliliter per minute; ¹ H NMR represents hydrogen nuclear magnetic spectrum; ¹⁹ F NMR represents fluorine nuclear magnetic spectrum; br.s represents broad singlet; s represents singlet; d represents doublet; t represents triplet; m represents multiplet; J represents coupling constant; Hz represents hertz; MHz represents megahertz; bar represents the pressure unit bar; psi represents the pressure unit pound per square inch; N ₂ stands for nitrogen; HPLC stands for high performance liquid chromatography; ID stands for =Inner diameter; Rt or RT represents retention time; LCMS or LC-MS represents liquid chromatography-mass spectrometry; m/z represents mass-to-charge ratio; ESI represents electrospray ionization; _CO2 represents carbon dioxide; TLC represents thin-layer chromatography; UV represents ultraviolet; ATCC represents American type culture collection; PK represents pharmacokinetic; NADPH represents nicotinamide adenine dinucleotide phosphate; CYP represents cytochrome P450; PBS (pH 7.4) represents phosphate buffered saline (PBS) at pH 7.4; FaSSIF represents fasting simulated intestinal fluid; FeSSIF represents fed simulated intestinal fluid; PPB represents plasma protein binding ratio; and GSH Trapping represents glutathione trapping assay.

DETAILED DESCRIPTION

The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only intended to illustrate the present invention and are not intended to limit the scope of the present invention. In the following examples, the experimental methods without specifying specific conditions are usually based on the normal 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 weight parts. Unless otherwise stated, the ratio of liquid is volume ratio.

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

Example 1: Preparation of Compound 1

Preparation of compound 1-2

Compound 4-bromo-2-methoxypyridine (1.75 g, 9.30 mmol) was added to anhydrous Et ₂ O (10.0 mL) solvent, and the reaction system was cooled to -65°C. At this temperature, n-BuLi (2.5 M tetrahydrofuran solution, 3.72 mL, 9.3 mmol) solution was slowly added dropwise to the reaction system, and the temperature was maintained and stirred for 30 minutes. Anhydrous tetrahydrofuran (3.0 mL) solution containing compound 1-1 (1 g, 4.65 mmol) was slowly added dropwise to the reaction system, and the temperature was maintained at -65°C and stirred for one hour. TLC detection showed that the reaction was complete. After the reaction system was heated to 0°C, saturated aqueous ammonium chloride solution (5.0 mL) was added to quench the reaction, followed by addition of water (20.0 mL). The reaction system was extracted three times with ethyl acetate (20 mL), and 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 1-2 (400 mg, yield 26.7%). LC-MS (ESI): m/z[M+H] ⁺ : 325.2. ¹ H NMR (400MHz, DMSO-d6) δ 11.06 (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).

Preparation of Compound 1-3

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) solvent, 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, 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 (preparation 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 at 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).

Preparation of Compound 1-4

m-CPBA (276.6 mg, 1.60 mmol) was added to a solution of CHCl ₃ (5.0 mL) containing compound 1-3 (500 mg, 1.06 mmol), and the reaction temperature was raised to 60°C and stirred for 1 hour. After the reaction was completed, a cold saturated aqueous sodium sulfite solution (10.0 mL) was added to quench the reaction, and 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, yield 46.3%). LC-MS (ESI): m/z[M+H] ⁺ :485.0.

Preparation of compound 1

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 completed, the reaction solution was dried by spin drying, MeOH (6.0 mL) and K ₂ CO ₃ (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),7.3 3(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).

Example 2: Preparation of Compound 2

Preparation of compound 2-2

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 solution. After the addition was completed, the reaction was stirred for half an hour at this temperature. Compound 1-1 (1 g, 4.65 mmol) was dissolved in tetrahydrofuran (3.0 mL), and slowly added dropwise to the reaction solution at -65°C. After the addition was completed, the reaction was stirred for one hour. The reaction was monitored by LCMS. Saturated ammonium chloride solution (5.0 mL) was added at low temperature to quench the reaction, 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 give the title compound 2-2 (550 mg, yield 29.5%). LC-MS (ESI): m/z[M+H] ⁺ :401.1.

Preparation of compound 2

Compound 2-2 (500 mg, 1.25 mmol) and trifluoromethoxybenzene (264.3 mg, 1.63 mmol) were dissolved in DCM (10.0 mL), and TfOH (938.2 mg, 6.25 mmol) was slowly added under nitrogen protection and ice-water bath to control the temperature. 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 (preparation 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 at 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＝8.9Hz,2H),7.23(t,J＝7.8Hz,1H),6.90(s,1H),6.37(d,J＝9.7Hz, 1H). ¹⁹ F NMR (376MHz, DMSO-d6) δ -56.78 (s, 3F), -60.01 (s, 3F).

Example 3: Preparation of Compounds 3A and 3B

Preparation of compound 3

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 protection. The reaction temperature was raised to 60°C, and the reaction was completed after one hour of reaction. Water (10 mL) was added, and 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 (preparation method: mobile phase: A: 0.1% TFA/H ₂ O; B: ACN; chromatographic 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 obtain the title compound 3 (29.14 mg, yield 30.1%). 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).

Preparation of compounds 3A and 3B

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 is CO ₂ , B is 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).

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: CO ₂ B: 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).

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: CO ₂ 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).

Example 4: Preparation of Compound 4

Preparation of compound 4-2

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

Preparation of compound 4

TfOH (4.62 g, 30.76 mmol) was added to a mixed solution of toluene (1.42 g, 15.38 mmol) and DCE (5.0 mL) containing compound 4-2 (500 mg, 1.54 mmol), and the reaction system was heated to 70 ° C and stirred for 2 h. The reaction was monitored by LCMS to be complete. The pH of the reaction solution was adjusted to weak alkalinity with saturated sodium bicarbonate aqueous solution, and the reaction system was extracted three times with DCM (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 aqueous solution; B: acetonitrile; chromatographic 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 obtain the title compound 4 (148.36 mg, yield 26%). 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). ¹⁹ F NMR(376MHz,DMSO-d6)δ-60.00(s,3F).

Example 5: Preparation of Compound 5

Preparation of compound 5

Compound 3 (260 mg, 0.572 mmol) was added to a single-mouth bottle, and a mixed solvent of acetonitrile-water (1:1, 5.0 mL) was added to the reaction bottle, followed by sodium hydroxide (92 mg, 2.29 mmol). The reaction system was cooled to 0°C, bromodifluoromethyl diethylphosphonate (230 mg, 0.858 mmol) was added thereto, and the reaction was continued for 3 hours. After the reaction was completed, water (10 mL) was added to the reaction system, 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 preparative separation (preparative column: Pursuit XRs C18 21.2×250 mm×10 μm; flow rate: 20 mL/min mobile phase: A-0.1% TFA aqueous solution, B-acetonitrile; gradient: 79-79% acetonitrile content, retention time 6.5-8.9 min) to obtain the title compound 5 (34.47 mg, yield 11.9%). 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).

Example 6: Preparation of Compound 6

Preparation of compound 6-2

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

Preparation of compound 6-3

Compound 6-2 (2.5 g, 7.57 mmol) and compound trifluoromethoxybenzene (1.6 g, 9.84 mmol) were dissolved in DCM (20 mL), and TfOH (5.7 g, 37.85 mmol) was slowly added dropwise in an ice-water bath under _N2 protection, and stirred for 30 min in an ice-water bath. The reaction was monitored by LC-MS to complete. The reaction solution was spin-dried and quenched with saturated sodium bicarbonate aqueous solution (30 mL), and 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 obtain the title compound 6-3 (900 mg, yield 25%). LC-MS (ESI): m/z[M+CH ₃ CN+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).

Preparation of compound 6

Compound 6-3 (400 mg, 0.82 mmol) was dissolved in 1,4-dioxane (1.5 mL), and then NaOH (300 mg, 7.5 mmol) in H ₂ O (1.5 mL) was added, and the mixture was heated to 100°C and stirred for 3 h. The reaction was monitored by LC-MS to complete. The reaction solution was adjusted to pH=1 with concentrated hydrochloric acid, filtered, and the filter cake was rinsed with water and then sent for preparative purification (preparative method: mobile phase: A: 0.1% TFA aqueous solution; B: acetonitrile; chromatographic 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, yield 34%). LC-MS (ESI): m/z[M+CH ₃ CN+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),7.3 0-7.25(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).

Example 7: Preparation of Compounds 7A and 7B

Preparation of compound 7-2

Compound 7-1 (4.00 g, 18.02 mmol) was dissolved in anhydrous DMF (50 mL), and Cs ₂ CO ₃ (8.81 g, 27.03 mmol) and BnBr (3.70 g, 21.63 mmol) were added to the reaction system in sequence, and the reaction was stirred at room temperature for 3 h. Water (30 mL) was directly 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 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.

Preparation of compound 7-3

At -78°C, n-BuLi (2.5M tetrahydrofuran solution, 64 mL, 160 mmol) was slowly added dropwise to an argon-protected 4-trifluoromethoxybromobenzene (42.4 g, 176.8 mmol) anhydrous tetrahydrofuran (200 mL) solution (note that the temperature inside the reaction system was controlled to be below -60°C). After the addition was completed, the mixture was stirred for one hour. Then, a tetrahydrofuran (100 mL) solution containing 1-1 (19.0 g, 88.4 mmol) was added dropwise to the reaction system, and the mixture was stirred for one hour. The reaction solution was poured into a saturated aqueous ammonium chloride solution (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[MH ₂ O+H] ⁺ =360.0.

Preparation of compound 7-4

Compound 7-3 (3.0 g, 8.0 mmol) was added to a single-mouth bottle, and acetic acid (20 mL), concentrated hydrochloric acid (2 mL) and stannous chloride dihydrate (4.5 g, 20.0 mmol) were added in sequence. 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 sodium bicarbonate aqueous solution, filtered with a thin layer of diatomaceous earth, and the filter cake was rinsed with a solution of EA/tetrahydrofuran = 5/1. The filtrate was extracted three times with ethyl acetate (100 mL), and the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and the concentrated residue was purified by chromatography column (EtOAc/PE = 0-20%) to obtain the title compound 7-4 (2.2 g, yield 75.9%). LCMS (ESI): m/z [MH] ^- = 359.9.

Preparation of compound 7-5

Add compound 7-4 (500 mg, 1.38 mmol) to a single-mouth bottle, and then add solvent 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). Heat the reaction system to 90 °C. The reaction mixture was 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 by 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.

Preparation of compound 7

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 then the reaction solution was heated to 65 ° C and stirred for 1 hour. The reaction system was cooled to room temperature, the pH was adjusted to alkaline with sodium bicarbonate aqueous solution, extracted three times with DCM (20 mL), and the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated, and purified by 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).

Preparation of compounds 7A and 7B

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 CO ₂ , B is ethanol (0.1% NH ₃ H ₂ O); 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).

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: CO ₂ 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).

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: CO ₂ 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).

Example 8: Preparation of Compounds 8A and 8B

Preparation of compound 8-1

Compound 1-2 (900 mg, 2.78 mmol) was dissolved in DCM (10 mL) solution. The air in the reaction system was replaced with nitrogen. SOBr ₂ (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. After the addition, stirring was continued for 2 hours in an ice-water bath. The reaction solution was concentrated to obtain the title compound 8-1 (1.03 g, crude product, yield 96.3%). LC-MS (ESI): m/z[MH] ^- = 384.9.

Preparation of compound 8-2

Compound 8-1 (900 mg, 2.33 mmol) and 4,4-difluoropiperidine (564 mg, 4.66 mmol) were added to DMF (10 mL) solvent, followed by cesium carbonate (2.27 g, 6.98 mmol), the reaction system was replaced with nitrogen protection, and reacted at room temperature for 2 hours. Water (40 mL) was added, extracted three times with ethyl acetate (50 mL), the organic phase was washed three times with saturated sodium chloride aqueous solution (10 mL), 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 8-2 (450 mg, 40.1%). LC-MS (ESI): m/z [MH] ^- = 426.1.

Preparation of compound 8

Compound 8-2 (400 mg, 0.94 mmol) was dissolved in DMF (5.0 mL), 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 (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. 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),7.23(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).

Preparation of compounds 8A and 8B

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 is CO ₂ , B is ethanol (0.1% NH ₃ H ₂ O); 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).

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: CO ₂ 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),7.23(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).

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: CO ₂ 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),7.23(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).

Example 9: Preparation of Compound 9

Preparation of compound 9-1

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 for protection. At room temperature, TfOH (3.20 g, 21.60 mmol) was slowly added dropwise and heated to 65 ° C and stirred for one hour. The reaction system was quenched with saturated sodium bicarbonate aqueous solution (5.0 mL), water (10 mL) was added, and dichloromethane (15 mL) was extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, and the organic phase was spin-dried. The residue was purified by 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.

Preparation of compound 9

Compound 9-1 (300 mg, 0.75 mmol) was dissolved in can (8.0 mL), TMSI (450.1 mg, 2.25 mmol) was added to the reaction solution, heated to 60°C and stirred for one hour. Water (6.0 mL) was added to the reaction system, and ethyl acetate (10 mL) was used for extraction three times. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by preparative separation (preparative method: mobile phase: A: 0.05% NH ₄ OH/H ₂ O; B: acetonitrile; chromatographic column: Xbridge 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, DM SO-d6)δ-60.07(s,3F),-114.29(s,1F).

Preparation of compounds 9A and 9B

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 is CO ₂ , B is Ethanol (0.1% NH ₃ H ₂ O); 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).

Compound 9A: 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: CO ₂ 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(37 6MHz, DMSO)δ-60.07(s,3F),-114.29(s,1F).

Compound 9B: 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: CO ₂ 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).

Example 10: Preparation of Compound 10

Preparation of compound 10-1

Compound 1-2 (800 mg, 2.5 mmol) was dissolved in DCE (20 mL), 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 sodium bicarbonate aqueous solution (20 mL) was added to the reaction system to quench the reaction, water (40 mL) was added, and DCM (50 mL) was extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrate was purified by chromatography (0-25% EA/PE) to obtain the title compound 10-1 (700 mg, 72.0%). LC-MS (ESI): m/z [MH] ^- = 397.0.

Preparation of compound 10

Compound 10-1 (200 mg, 0.5 mmol) was dissolved in CH ₃ CN (5.0 mL), and then TMSI (301.5 mg, 1.5 mmol) was added to the reaction solution, heated to 60°C, and stirred for 2 h. Water (15 mL) was added to the reaction system to quench the reaction, and ethyl acetate (10 mL) was used for extraction three times. The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrate was purified by reverse phase column (ACN/0.1% ammonia water = 5-95%) to obtain 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).

Example 11: Preparation of Compound 11

Preparation of compound 11-2

Compound 11-1 (3.81 g, 13.95 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL), then cooled to -78 °C, and n-BuLi (2.5 M tetrahydrofuran solution, 12.6 mL, 31.5 mmol) was slowly added dropwise to the reaction solution, and stirred at -78 °C for 30 minutes; a tetrahydrofuran (10 mL) solution containing compound 1-1 (1.5 g, 6.98 mmol) was added dropwise to the reaction system, stirred at -78 °C for 30 minutes, and then gradually warmed to room temperature and reacted for 12 hours. The reaction system was quenched with saturated aqueous ammonium chloride solution (8.0 mL), water (40 mL) was added, and ethyl acetate (40 mL) was extracted three times, the organic phases were combined, dried over anhydrous sodium sulfate, and the concentrate was purified by 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.

Preparation of compound 11

Compound 11-2 (300 mg, 0.73 mmol) was dissolved in DCE (8.0 mL), toluene (676 mg, 7.33 mmol) was added to the solvent, TfOH (1.10 g, 7.33 mmol) was added at room temperature, nitrogen was replaced, and the mixture was stirred at 70°C for 1 h. The reaction system was quenched with saturated sodium bicarbonate aqueous solution (5 mL), water (10 mL) was added, and DCM (10 mL) was extracted 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: 0.05% NH ₄ OH/H ₂ O; B: acetonitrile; chromatographic column: Xbridge 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).

Example 12: Preparation of Compounds 12A and 12B

Preparation of compound 12-1

Compound 7-2 (2.9 g, 9.29 mmol) was dissolved in anhydrous tetrahydrofuran (40 mL), the reaction system was replaced with nitrogen protection, 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, and a solution of compound 1-1 (0.80 g, 3.72 mmol) in anhydrous tetrahydrofuran (5 mL) was added dropwise to the reaction solution and stirred at -10°C for 2 hours. The reaction system was quenched with saturated aqueous ammonium chloride solution (10 mL), water (40 mL) was added, and ethyl acetate (40 mL) was extracted three times, the organic phases were combined, dried over anhydrous sodium sulfate, and the organic phase was spin-dried. The residue was purified by reverse chromatographic column (5%-95% H ₂ O (0.05% NH ₄ OH)/ACN) to obtain the title compound 12-1 (350 mg). LC-MS (ESI): m/z[M+H] ⁺ =402.0.

Preparation of compound 12

The compound (0.35 g, 1.63 mmol) and toluene (1.49 g, 16.30 mmol) were dissolved in anhydrous DCE (3.0 mL), and the atmosphere was replaced with nitrogen. TfOH (2.45 g, 16.30 mmol) was added to the reaction solution at room temperature, and the mixture was heated to 70 degrees and stirred for 1 hour. The reaction system was quenched with saturated sodium bicarbonate aqueous solution (5 mL), water (10 mL) was added, and dichloromethane (15 mL) was extracted 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/H ₂ O; B: acetonitrile; chromatographic 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 obtain the title compound 12 (6.48 mg, 1.03% yield). LCMS (ESI): m/z[M+1] ⁺ =386.2. ¹ H NMR (400 MHz, 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).

Preparation of compounds 12A and 12B

Compound 12 (1.0 g) was subjected to SFC chiral preparative separation (preparative separation method, instrument model: MGⅡpreparative SFC (SFC-14); chromatographic column model: ChiralPak AD, 250×30 mm ID, 10 μm; mobile phase: A is CO ₂ , B is ethanol (0.1% NH ₃ H ₂ O); 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).

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 CO ₂ , 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).

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 CO ₂ , 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).

Example 13: Preparation of Compound 13

Preparation of compound 13-1

Compound 12-1 (2 g, 4.99 mmol) and fluorobenzene (959 mg, 9.98 mmol) were dissolved in DCE (20 mL) solution. 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 NH ₄ Cl aqueous solution (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.

Preparation of compound 13

Compound 13-1 (380 mg, 0.79 mmol) and fluorobenzene (0.3 mL) were dissolved in DCE (4 mL), TfOH (2 mL) was slowly added dropwise, and the reaction system was heated to 80°C for 1 hour. The reaction solution was quenched with saturated NH ₄ Cl aqueous solution (3 mL), 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 (chromatographic column: Pursuit XRs C18, 19.5×250 mm, 10 μm; mobile phase A: 0.1% TFA/H ₂ O, 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 (400 MHz, 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).

Example 14: Preparation of Compound 14

Preparation of compound 14-1

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

Preparation of compound 14-2

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

Preparation of compound 14-3

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

Preparation of compound 14

Compound 14-3 (300 mg, 0.54 mmol) was dissolved in DCE (2 mL), TfOH (1 mL) was added dropwise to the reaction solution at room temperature, and stirred at 70°C for 1 h. Saturated sodium bicarbonate aqueous solution (5 mL) was added to the reaction solution, water (5 mL) was added, and DCM (20 mL) was extracted 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; chromatographic column: SunFire Sunfire C18, 250×19mm×10μm; column temperature: 25°C; gradient: 49%-59%; retention time: 8.2-9.4min; flow rate: 20mL/min)) to obtain the title compound 14 (105.98 mg, 41.8% yield). LCMS (ESI): m/z[M+H] ⁺ =470.2. ¹ H 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).

Example 15: Preparation of Compound 15

Preparation of compound 15-1

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 solution 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 solution was reacted at 70 ° C for 3 hours. The reaction solution was filtered using diatomaceous earth, the filtrate was added with water (30 mL), and extracted with ethyl acetate (40 mL) three times, the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and 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.

Preparation of compound 15-3

Compound 15-1 (300 mg, 0.973 mmol) was added to a round-bottom flask, and solvent 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) were added thereto in sequence. After nitrogen was replaced in the reaction system, the mixture was reacted at 90°C for 16 hours. Water (20 mL) was added to the reaction solution, and ethyl acetate (20 mL) was extracted twice. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and the concentrate was purified by normal phase column chromatography (ethyl acetate/petroleum ether = 0-100%) to obtain the title compound 15-3 (46 mg, yield 11.1%). LC-MS (ESI): m/z [MH] ^- = 425.0.

Preparation of compound 15

Compound 15-3 (46 mg, 0.107 mmol) was added to a single-mouth bottle, and DMF (3 mL), anhydrous p-toluenesulfonic acid (93 mg, 0.539 mmol) and lithium chloride (23 mg, 0.539 mmol) were added to the reaction bottle in sequence. The reaction solution was reacted at 120°C for 3 hours. Water (10 mL) was added to the reaction system, and ethyl acetate (10 mL) was extracted three times, and the organic phase was washed with saturated brine (30 mL). Drying with anhydrous sodium sulfate, the concentrate was purified by preparative separation (preparation method: mobile phase: A: 10 mmol formic acid solution; B: acetonitrile; chromatographic column: Pursuit XRs C18 250×19.5 mm×10 μm; column temperature: 25°C; gradient: 40%-45% acetonitrile at 8.0-9.2 min; flow rate: 20 mL/min)) to obtain the title compound 15 (11 mg, yield 22.2%). 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),6.3 5(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). ¹⁹ F NMR (376MHz, DMSO-d6) δ -60.13 (s), -89.69 (d, J = 232.7 Hz, 1F), -100.90 (d, J = 232.7, 1F).

Example 16: Preparation of Compound 16

Preparation of compound 16-2

4-Bromo-2-methoxypyridine (1.5 g, 8.19 mmol) was added to anhydrous tetrahydrofuran (20 mL) solvent, the reaction solution was cooled to -60 °C and n-butyl lithium (2.5 M tetrahydrofuran solution, 3.93 mL, 9.83 mmol) was slowly added dropwise, and the reaction system was stirred for 30 minutes; a tetrahydrofuran solution (5 mL) containing compound 16-1 (600 mg, 3.28 mmol) was slowly added dropwise to the reaction system, and the reaction was continued for 2 hours. Saturated aqueous ammonium chloride solution (10 mL), water (30 mL), and ethyl acetate (60 mL) were added to the reaction solution for extraction three times, and the organic phase was washed with saturated aqueous sodium chloride solution (60 mL). After the organic phase was concentrated, it was 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] ⁺ .

Preparation of compound 16-3

Compound 16-2 (400 mg, 1.37 mmol) was added to a round-bottom flask, and dichloromethane (5 mL), pyridine (217 mg, 2.74 mmol) and dichlorothionyl (326 mg, 2.74 mmol) were added thereto in sequence. The reaction solution was stirred for 2 hours; then tetrahydrofuran (15 mL), acetic acid (2 mL), zinc powder (447 mg, 6.84 mmol) were added, and the reaction solution was reacted at 70°C for 3 hours. The reaction solution was filtered with diatomaceous earth, 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), dried over anhydrous sodium sulfate, and the concentrate was purified by normal phase column chromatography (petroleum ether/ethyl acetate = 0-100%) to obtain the title compound 16-3 (230 mg, yield 60.83%). LC-MS (ESI): m/z 275.0 [MH] ^- .

Preparation of compound 16-5

Compound 16-3 (230 mg, 0.832 mmol) was added to a round-bottom flask, and solvent 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) were added thereto in sequence, and the reaction solution was reacted at 80°C for 5 hours. Then water (30 mL) was added to the reaction system, and ethyl acetate (30 mL) was extracted twice, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and 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] ^- .

Preparation of compound 16

Compound 16-5 (20 mg, 0.053 mmol) was added to a single-mouth bottle, and DMF (3 mL), anhydrous p-toluenesulfonic acid (50 mg, 0.290 mmol) and lithium chloride (13 mg, 0.295 mmol) were added to the reaction bottle in sequence, and the reaction solution was reacted at 120°C for 3 hours. Water (10 mL) was added to the reaction system, and ethyl acetate (10 mL) was extracted three times, and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and the concentrate was purified by preparative separation (preparation method: mobile phase: A: 10 mmol formic acid solution; B: acetonitrile; chromatographic column: Pursuit XRs C18 250×19.5 mm×10 μm; column temperature: 25°C; gradient: 46%-56% acetonitrile at 8.0-9.2 min; flow rate: 20 mL/min) to obtain the title compound 16 (11.17 mg, yield 58.04%). 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).

Example 17: Preparation of Compound 17

Preparation of compound 17-2

Dissolve compound 17-1 (4.9 g, 20.46 mmol) in tetrahydrofuran (20 mL) solution. Replace nitrogen three times, cool to about 0°C in an ice bath, slowly drop i-PrMgCl (1.3 M tetrahydrofuran solution, 15.74 mL, 20.46 mmol), stir at about 0°C for 0.5 hours; A tetrahydrofuran (15 mL) solution containing compound 1-1 (2 g, 9.3 mmol) was slowly added dropwise to the reaction solution, and the reaction system was gradually heated to room temperature and stirred for 1 hour. The reaction solution was quenched with a saturated NH ₄ Cl aqueous solution (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 obtain the title compound 17-2 (1.5 g, 49% yield). LC-MS (ESI): m/z[MH] ^- =326.9.

Preparation of compound 17-3

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 replaced 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 NaHCO ₃ aqueous solution (5 mL), water (5 mL) was added, and dichloromethane (10 mL) was extracted three times. 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.

Preparation of compound 17

Compound 17-3 (300 mg, 0.75 mmol) and thiourea (228.36 mg, 3 mmol) were dissolved in n-butanol (3 mL), and 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, 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).

Example 18: Preparation of Compound 18

Preparation of compound 18

Compound 18-1 (180 mg, 0.45 mmol) was dissolved in n-butanol (10 mL), and thiourea (136 mg, 1.79 mmol) was added. After the addition, nitrogen was replaced, and the temperature was raised to 120°C for reaction for 12 h. The reaction system was naturally cooled to room temperature, and water (20 mL) was added, and ethyl acetate (20 mL) was used for extraction three times. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrate was purified by preparative purification (preparative method: mobile phase: A: 0.1% TFA/H ₂ O; B: acetonitrile; chromatographic column: Atlantis TM T3 Prep OBD TM, 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, yield 3.9%). LC-MS (ESI): m/z[2M+H] ⁺ =799.5. ¹ H 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).

Example 19: Preparation of Compound 19

Preparation of compound 19-1

Compound 12 (250 mg, 0.649 mmol) was added to a single-mouth bottle, acetonitrile (5 mL) and tribromophosphine oxide (223 mg, 0.778 mmol) were added to the reaction bottle, and the reaction system was reacted at 80°C for 2 hours. The reaction system was cooled with an ice-water bath, quenched with a saturated sodium bicarbonate aqueous solution (15 mL), extracted three times with dichloromethane (20 mL), washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate, and 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).

Preparation of compound 19

Compound 19-1 (136 mg, 0.303 mmol), ammonia (30%, 212 mg, 6.07 mmol), and dioxane (5 mL) were added to a sealed pot in sequence, and nitrogen was blown in for 5 seconds before the sealed pot was closed. The reaction system was reacted at 120°C for 16 hours. Water (10 mL) was added to the reaction solution, and ethyl acetate (20 mL) was extracted twice. The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and 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).

Example 20: Preparation of Compound 20

Preparation of compound 20

Compound 19-1 (50 mg, 0.112 mmol) was added to a single-mouth bottle, and n-butanol (10 mL) and thiourea (11 mg, 0.134 mmol) were added to the reaction bottle respectively. The reaction system was reacted at 120°C for 3 hours. Water (15 mL) was added to the reaction solution, and ethyl acetate (20 mL) was used for extraction twice. The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and the concentrate was purified by preparative separation (preparative column: SunFire C1819×250 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] ⁺ . ¹ H 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).

Example 21: Preparation of Compound 21

Preparation of compound 21-1

Compound 12-1 (500 mg, 1.25 mmol) was added to a single-mouth bottle, and DCM (10 mL) and pyridine (197 mg, 2.49 mmol) were added in sequence. The reaction system was cooled to 0 ° C, and dichlorothionyl (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 dried, and DMF (5 mL), sodium bicarbonate (524 mg, 6.23 mmol) and 4,4-difluoropiperidine (300 mg, 2.49 mmol) were added thereto in sequence. The reaction solution was reacted at room temperature for 30 minutes. Water (20 mL) was added to the reaction system, and ethyl acetate (20 mL) was extracted three times. The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and 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] ^- .

Preparation of compound 21

Compound 21-1 (130 mg, 0.257 mmol) was added to a single-mouth bottle, and dichloroethane (5 mL) and TfOH (193 mg, 1.29 mmol) were added. The reaction solution was reacted at 60°C for 1 hour. The reaction system was quenched with saturated sodium bicarbonate aqueous solution (5 mL) under an ice-water bath, extracted three times with dichloromethane (20 mL), and the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and the concentrate was purified by HPLC preparation separation (preparative column: Pursuit XRs C18, 19.5×250×10 μm; flow rate: 20 mL/min mobile phase: A-0.1% TFA aqueous solution, 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＝7.5Hz,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).

Example 22: Preparation of Compound 22

Preparation of compound 22-2

Compound 22-1 (1.3 g, 4.46 mmol) was added to a single-mouth bottle, and solvent 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) were added in sequence. After the reaction system was replaced with nitrogen, the temperature was raised to 80 ° C and the reaction was carried out for 16 hours. After the reaction was completed, water (40 mL) was added to quench, ethyl acetate (40 mL) was extracted three times, and saturated brine (40 mL) was added to wash the organic phase, dried over anhydrous sodium sulfate, and the concentrate was purified by normal phase column chromatography (petroleum ether/ethyl acetate = 0-100%) to obtain the title compound 22-2 (140 mg, yield 7.7%). LC-MS (ESI): m/z 401.9 [MH] ^- .

Preparation of compound 22

Compound 22-2 (140 mg, 0.347 mmol) was added to a single-mouth bottle, tetrahydrofuran (5 mL) and sodium hydroxide aqueous solution (4.0 M, 0.35 mL, 1.39 mmol) were added to the reaction bottle, and the reaction system was reacted at 70°C for 16 hours. The reaction solution was quenched with saturated ammonium chloride aqueous solution (20 mL), extracted twice with ethyl acetate (20 mL), washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate, and the concentrate was purified by preparative separation (preparative column: Agilent C18 19×250 mm×10 μm; flow rate: 20 mL/min mobile phase: A is 0.1% TFA aqueous solution, B is 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).

Example 23: Preparation of Compound 23

Preparation of compound 23-1

Under nitrogen protection, i-PrMgCl (1.3M tetrahydrofuran solution, 26 mL, 33.8 mmol) was added dropwise to a tetrahydrofuran (30 mL) solution of 5-bromo-2-methoxypyrimidine (5.27 g, 27.89 mmol) at -78°C and stirred for 30 min, and then a tetrahydrofuran (20 mL) solution of compound 1-1 (3.0 g, 13.95 mmol) was added dropwise thereto, and the reaction system was stirred at room temperature for 16 hours. The reaction solution was quenched by adding saturated aqueous ammonium chloride solution (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 obtain the title compound 23-1 (700 mg, yield 16%). LC-MS (ESI): m/z[M+H] ⁺ = 326.1.

Preparation of compound 23-2

Compound 23-1 (700 mg, 2.15 mmol) was dissolved in a mixed solution of toluene (1.98 g, 21.54 mmol) and DCE (5 mL), and then TfOH (3.23 g, 21.54 mmol) was slowly added thereto, and the reaction solution was stirred at room temperature for 2 h. The reaction solution was adjusted to a weakly alkaline pH with a saturated sodium bicarbonate aqueous solution, extracted twice with DCM (20 mL), and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and the concentrate was purified by a C18 column (ACN: 0.1% NH ₃ .H ₂ O aqueous solution = 5%-50%) to obtain the title compound 23-2 (300 mg, yield 35%). LC-MS (ESI): m/z[M+H] ⁺ = 400.1.

Preparation of compound 23

Compound 23-2 (100 mg, 0.25 mmol), TMSCl (82 mg, 0.75 mmol) and KI (125 mg, 0.75 mmol) were dissolved in ACN (2 mL) solvent, and the reaction solution was heated to 60 ° C and stirred for 1 h. Water (10 mL) was added to the reaction solution, and ethyl acetate (20 mL) was used for extraction twice. The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and the concentrate was purified by preparative purification (preparative method: mobile phase: A: 0.1% NH ₄ HCO ₃ aqueous solution; B: acetonitrile; chromatographic 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).

Example 24: Preparation of Compound 24

Preparation of compound 24-2

Under _N2 protection, n-BuLi (2.5M tetrahydrofuran solution, 1.67mL, 4.18mmol) was added dropwise to tetrahydrofuran (3mL) containing 24-1 (506mg, 1.86mmol) at -78°C and stirred for 30min; a solution of 1-1 (200mg, 0.97mmol) in tetrahydrofuran (2mL) was added dropwise to the reaction system and stirred at -78°C for 2h. The reaction solution was quenched by adding saturated aqueous ammonium chloride solution (15mL), extracted three times with ethyl acetate (20mL), washed with saturated brine (10mL) and dried over anhydrous sodium sulfate, and the concentrate was purified by column chromatography (EA:PE=0-20%) to obtain the title compound 24-2 (100mg, yield 26%). LC-MS (ESI): m/z[MH] ^- =408.1.

Preparation of compound 24

Compound 24-2 (100 mg, 0.24 mmol) was dissolved in a mixed solvent of toluene (225 mg, 2.44 mmol) and DCM (1 mL), TfOH (367 mg, 2.44 mmol) was added dropwise thereto, and the reaction solution was stirred at room temperature for 2 h. The reaction solution was adjusted to a weakly alkaline pH with saturated sodium bicarbonate, extracted three times with ethyl acetate (20 mL), the organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and the concentrate was purified by preparative purification (preparation method: mobile phase: A: 0.1% NH ₄ HCO ₃ aqueous solution; B: acetonitrile; chromatographic 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, yield 18%). 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), 7.22–7.12 (m, 4H), 7.04 (d, J = 8.1Hz, 2H), 6.42 (d, J = 8.7Hz, 1H), 6.0 3(s,2H),2.27(s,3H). ¹⁹ F NMR (376MHz, DMSO-d6) δ-59.99 (s, 3F).

Example 25: Preparation of Compound 25

Preparation of compound 25-2

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, and the reaction solution was stirred for 1 hour. The reaction solution was concentrated to obtain compound 25-2 (500 mg, crude product). LC-MS (ESI): m/z [MH] ^- = 324.0.

Preparation of compound 25

Compound 25-2 (500 mg, 1.54 mmol) was dissolved in DMF (5 mL), and K ₂ CO ₃ (1.28 g, 9.24 mmol) and piperazine-2-one (308.37 mg, 3.08 mmol) were added respectively. The reaction solution was reacted at room temperature for 1 hour. The reaction was quenched with water (5 mL), 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, 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 (400 MHz, 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).

Example 26: Preparation of Compound 26

Preparation of compound 26-2

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

Preparation of compound 26-3

Compound 26-2 (1.71 g, 5.01 mmol) and toluene (4.62 g, 50.1 mmol) were dissolved in DCE (15 mL), nitrogen was replaced, TfOH (7.53 g, 50.1 mmol) was added, and the temperature was raised to 60°C for 12 h. The reaction solution was slowly poured into a saturated sodium bicarbonate ice water solution, extracted three times with DCM (50 mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and 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] ⁺ .

Preparation of compound 26-4

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 about 0°C. After addition, the reaction was continued for 20 min in an ice-water bath, and then the temperature was naturally raised to room temperature and the reaction was continued for 12 h. Water (15 mL) was added to the reaction solution, and DCM (20 mL) was extracted three times. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrate was purified by column chromatography (EA/PE=0-50%) to obtain the title compound 26-4 (110 mg, yield 39%). LC-MS (ESI): m/z=445.9[MH] ^- .

Preparation of compound 26

Compound 26-4 (110 mg, 0.25 mmol) was dissolved in 1,4-dioxane (1.5 mL), and then NH ₄ OH (1 mL) was added. After the addition, the reaction system was replaced with nitrogen, and the temperature was raised to 80°C for 1 h. Water (15 mL) was added to the reaction solution, and ethyl acetate (30 mL) was used for extraction three times. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The concentrate was purified by preparative method (preparative method: mobile phase: A: 0.05% NH ₃ H ₂ O/H ₂ O; B: acetonitrile; chromatographic 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, yield 1.5%). LC-MS (ESI): m/z=385.2[M+H] ⁺ . ¹ H NMR (400MHz, MeOD) δ8.06 (s, 2H), 7.56-7.54 (d, J = 8.0 Hz, 1H), 7.50-7.48 (d, J = 7.5 Hz, 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).

Example 27: Preparation of Compound 27

Preparation of compound 27-2

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

Preparation of compound 27-3

At -78°C, n-BuLi (2.5M tetrahydrofuran solution, 3.4mL, 8.37mmol) was added dropwise to a tetrahydrofuran (5mL) solution of _N2- protected compound 27-2 (1.03g, 3.72mmol), and the temperature was maintained and stirred for 30min; then a tetrahydrofuran (5mL) solution of compound 1-1 (400mg, 1.86mmol) was added dropwise thereto, and the temperature was maintained and stirred for 1h. The reaction solution was quenched by adding saturated aqueous ammonium chloride solution (10mL), extracted three times with EtOAc (30mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was spin-dried. The residue was purified by column chromatography (EA:PE=0-50%) to obtain the title compound 27-3 (40mg, yield 5%). LC-MS (ESI): m/z[M+H] ⁺ 413.1.

Preparation of compound 27

Compound 27-3 (40 mg, 0.10 mmol) and toluene (90 mg, 0.99 mmol) were dissolved in DCE (2 mL), TfOH (3.23 g, 21.54 mmol) was added, and the mixture was stirred at room temperature for 2 h. The pH of the reaction solution was adjusted to weak alkalinity with saturated sodium bicarbonate, extracted three times with DCM (30 mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was spin-dried. The residue was purified by preparative purification (preparative method: mobile phase: A: 0.1% NH ₃ H ₂ O aqueous solution; B: acetonitrile; chromatographic 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, yield 8%). LC-MS (ESI): m/z[M+H] ⁺ =387.2. ¹ H NMR (400MHz, CDCl ₃ ) 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),2.2 9 (s, 3H). ¹⁹ F NMR (376MHz, CDCl ₃ ) δ-60.37 (s, 3F).

Example 28: Preparation of Compound 28

Preparation of Compound 28-2/28-3

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

Preparation of compound 28-4

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 solution was adjusted to a weakly alkaline pH with saturated sodium bicarbonate, extracted three times with DCM (30 mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was spin-dried. The residue was purified by preparative purification (preparative method: mobile phase: A: 0.1% NH ₃ H ₂ O aqueous solution; B: acetonitrile; chromatographic 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, yield 34%). 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).

Preparation of Compound 28

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 solution was adjusted with saturated sodium bicarbonate. The pH value was changed to weak alkaline, and DCM (30 mL) was used for extraction three times. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was spin-dried. The residue was purified by preparative method (preparative method: mobile phase: A: 0.1% NH ₃ H ₂ O aqueous solution; B: acetonitrile; chromatographic 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, yield 10%). 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).

Example 29: Preparation of Compound 29

Preparation of compound 29-2

Compound 22-1 (600 mg, 2.06 mmol) was added to a single-mouth bottle, and solvent 2-butanone (10 mL), compound 29-1 (434 mg, 2.47 mmol), potassium carbonate (570 mg, 4.12 mmol), potassium iodide (68 mg, 0.411 mmol) were added. After nitrogen was replaced, the mixture was stirred at 80°C for 16 hours. The reaction solution was quenched by adding water (20 mL). 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 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).

Preparation of compound 29

Compound 29-2 (40 mg, 0.103 mmol) was added to a single-mouth bottle, methanol (10 mL) and palladium carbon (10 mg) were added thereto, and the mixture was reacted at 60°C for 16 hours after replacing the hydrogen. The reaction solution was filtered using diatomaceous earth, 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).

Example 30: Preparation of Compound 30

Preparation of compound 30

CrO3 (497 mg, 4.98 mmol) was added to a solution of AcOH (4 mL) containing compound 12 (400 mg, 0.99 mmol). The system was then heated to 110°C and stirred for 16 hours. The reaction was complete after LCMS detection. The system was cooled to 0°C and quenched with saturated sodium bicarbonate aqueous solution (20.0 mL). The product 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. The residue was purified by preparative separation (preparative method: mobile phase: A: 0.05% _NH4OH / _H2O ; B: ACN; chromatographic 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 obtain the title compound 30 (31 mg, yield 7%). 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).

Example 31: Preparation of Compound 31

Preparation of compound 31-2

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), potassium iodide (194 mg, 1.17 mmol) were added in sequence. The system was warmed 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 subjected to column chromatography (0-15% ethyl acetate/petroleum ether) to obtain 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).

Preparation of compound 31

At room temperature, compound 31-2 (1.3 g, 3.50 mmol) was dissolved in DCM (25 mL) solvent, 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 to the system in batches at 0°C under nitrogen protection, and the temperature was slowly raised to room temperature and stirred for 16 hours. LCMS detected that the reaction was complete. The reaction solution was slowly poured into a cold 10% NaOH aqueous solution (30 mL) to quench the reaction, 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 water/H2O; B: ACN; chromatographic 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 give 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).

Example 32: Preparation of Compound 32-1/32-2

Preparation of Compound 32-1 and Compound 32-2

Compound 31 (400 mg, 1.02 mmol) was dissolved in methanol (60 mL) at room temperature. Pd/C (400 mg, 10%) was added under nitrogen protection, and the gas was replaced by hydrogen three times. The mixture was stirred at room temperature for 16 hours. The reaction was complete by LCMS detection, the reaction solution was filtered, the filtrate was dried, and the residue was purified by preparative separation (preparative method: mobile phase: A: 0.05% NH ₄ OH/H ₂ O; B: ACN; chromatographic column: Xbridge Xbridge C18, 19×250 mm, 10 μm; column temperature: 25°C; gradient: 42% to 42%; acetonitrile in 7.7-9 min, compound 32-1 (56 mg, yield: 15%); acetonitrile in 9-10.3 min; compound 32-2 (56 mg, yield: 15%) was obtained at a flow rate of 20 mL/min).

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).

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) .

Example 33: Preparation of Compound 33

Preparation of compound 33-1

Under nitrogen protection, 2,6-difluoro-4-iodopyridine (7.84 g, 32.54 mmol) was added to anhydrous THF (25.0 mL) solvent, and after stirring for 5 minutes, n-BuLi (2.5 M in THF, 16.5 mL, 40.67 mmol) solution was slowly added dropwise to the reaction system at -65°C, and the temperature was maintained and stirred for 30 minutes. Subsequently, anhydrous THF (10 mL) solution containing compound 1-1 (3.5 g, 16.27 mmol) was slowly added dropwise to the reaction system, and the temperature was maintained at -65°C and stirred for one hour. LCMS detection showed that the reaction was complete. The reaction system was added with saturated aqueous ammonium chloride solution (25 mL) to quench the reaction, followed by addition of water (25 mL), and 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 (0-25% ethyl acetate/petroleum ether) to give the title compound 33-1 (2.0 g, orange-yellow solid, yield 37%). LC-MS (ESI): m/z [MH] ^- : 329.0.

Preparation of compound 33-2

Under nitrogen protection, compound 33-2 (2.0 g, 6.06 mmol) and toluene (5.58 g, 60.60 mmol) were dissolved in DCE (20.0 mL) solvent, cooled to 0°C and TfOH (9.10 g, 60.60 mmol) was slowly added dropwise and stirred for 2 hours. LCMS detected that the reaction was complete. The reaction solution was slowly poured into saturated aqueous sodium bicarbonate solution (100 mL) to quench the reaction, and 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 give the title compound 33-2 (722 mg, white solid, yield 29%). 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). ¹⁹ F NMR(376MHz,DMSO-d6)δ-60.00(s,3F),-68.65(s,2F).

Preparation of compound 33

A 20% aqueous NaOH solution (1 mL) was added to a solution of compound 33-2 (100 mg, 0.25 mmol) in Dioxane (1.0 mL), and then the temperature was raised to 110°C and stirred for 16 hours. The reaction was complete when detected by LCMS. The system was cooled to room temperature and pH was adjusted to 1 with concentrated hydrochloric acid (2 mL). After stirring at room temperature for 30 minutes, the crude compound 33 was obtained by filtration. The crude product was purified by preparative separation (preparation method: mobile phase: A: 0.05% NH ₄ OH/H ₂ O; B: ACN; chromatographic column: Xbridge 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 obtain the title compound 33 (23 mg, yield 24%). 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).

Example 34: Preparation of Compound 34

Preparation of compound 34-2

Compound 34-1 (2.0 g, 6.87 mmol), compound 22-1 (1.4 g, 7.558 mol), KI (228 mg, 1.37 mmol), K ₂ CO ₃ (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 detected that the reaction was complete. The system was cooled to room temperature, water (40 mL) was added, and ethyl acetate (40 mL) was extracted three times, dried over anhydrous sodium sulfate, and the concentrated residue was purified by normal phase column chromatography (0-30% ethyl acetate/petroleum ether) to obtain the title compound 34-2 (2 g, light yellow oil, yield 65%). LC-MS (ESI): m/z[MH] ^- : 441.8.

Preparation of compound 34-3

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 protection. The gas was replaced with hydrogen three times and stirred at room temperature for 2 hours. LCMS detected that the reaction was complete. Filter, concentrate the filtrate, and the residue was purified by normal phase column chromatography (0-40% ethyl acetate/petroleum ether) to obtain the title compound 34-3 (1.5 g, white oil, yield 80%). LC-MS (ESI): m/z [MH] ^- : 411.8.

Preparation of compound 34-4

Compound 34-3 (1.3 g, 3.13 mmol) and H ₂ SO ₄ (2M, 6.4 mL, 12.87 mmol) were added to a reaction flask, cooled to 0°C, and NaNO ₂ (238 mg, 3.45 mmol) was added in batches. After stirring for 30 minutes, 1M H ₂ SO ₄ 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 after LCMS detection. The reaction was cooled to room temperature, saturated ammonium chloride (30 mL) was added to quench, the reaction system was extracted twice with ethyl acetate (30 mL), dried over anhydrous sodium sulfate, and the concentrated residue was purified by reverse phase column chromatography (NH ₃ .H ₂ O:ACN=5-95%) to obtain the title compound 34-4 (115 mg, yellow oil, yield 9%). LC-MS(ESI): [M+H] ⁺ :415.2. ¹ H 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), 7.1 5–7.09(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).

Preparation of compound 34

Under nitrogen protection, compound 34-4 (64 mg, 0.16 mmol) was dissolved in anhydrous dichloroethane (2 mL), and BBr ₃ (0.64 mL, 1 M in DCM, 0.64 mmol) was slowly added dropwise at 0°C. The system was heated to 50°C and stirred for 1 hour. LCMS detected that the reaction was complete. The system was quenched by adding NaHCO ₃ aqueous solution (10 mL), 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 (preparative method: mobile phase: A: 0.1% FA/H2O; B: ACN; chromatographic column: Agilent C18, 19*250mm, 10μm; column temperature: 25°C; gradient: 55% to 55%; acetonitrile in 5.5-6.5min; flow rate: 20mL/min) to obtain 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).

Example 35: Preparation of Compound 35

Preparation of compound 35-2

Compound 22-1 (400.0 mg, 1.37 mmol) was dissolved in 2-butanone (6 mL) solvent, and 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 in sequence under stirring at room temperature, and then the temperature was raised to 90°C and stirred for 16 hours. LCMS detected that the reaction was complete. After the reaction system was cooled 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% NH ₃ H ₂ O/H ₂ O; B: ACN; chromatographic 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 give 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).

Preparation of compound 35

Compound 35-2 (50 mg, 0.12 mmol) was dissolved in DMF (2.0 mL) at room temperature, and then LiCl (25.43 mg, 0.60 mmol) and TsOH (103.32 mg, 0.60 mmol) were added in sequence. The system was heated to 120°C and stirred for one hour. LCMS detected that the reaction was complete. After cooling to room temperature, the product was filtered and the filtrate was concentrated to dryness. The residue was then purified by preparative separation (preparation method: mobile phase: A: 0.1% TFA/H2O; B: ACN; chromatographic column: Atlantis TM T3 Prep OBD TM, 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 give the title compound 35 (11 mg, yield 23%). 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).

Example 36: Preparation of Compound 36

Preparation of compound 36-2

Under nitrogen protection, compound 36-1 (5.78 g, 27.90 mmol) was dissolved in anhydrous THF (50.0 mL) solvent, cooled to -65 ° C, and n-BuLi (2.5 M in THF, 13.95 mL, 34.88 mmol) solution 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 detected that the reaction was complete. Saturated aqueous ammonium chloride solution (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 subjected to column chromatography (0-15% ethyl acetate/petroleum ether) to obtain the title compound 36-2 (3 g, yellow solid, yield 52%). LC-MS(ESI):m/z[MH] ^- :342.0.

Preparation of compound 36-3

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 then 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 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.

Preparation of compound 36-4

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 to a solution of 2-butanone (10.0 mL) containing compound 36-3 (500 mg, 1.53 mmol). The system was heated to 90 ° C and stirred for 16 hours. After the reaction was detected by LCMS, the system was cooled to 0 ° C and then slowly added with ice water (10 mL) to quench the reaction, and 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 (0-25% 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.

Preparation of compound 36

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 under stirring at room temperature. The temperature was raised to 65° C. and stirred for one hour. LCMS detected that the reaction was complete. After the reaction system was cooled to 0°C, a saturated sodium bicarbonate solution (6 mL) was added to quench the reaction, followed by the addition of water (4 mL), extraction with dichloromethane (10 mL) three times, 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; chromatographic column: Atlantis TM T3 Prep OBD TM, 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, yield 51%). 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＝2.1Hz,1H), ^{7.74– 19} F NMR(376MHz, DMSO-d6)δ-56.78(s,3F),-59.94(s,3F).

Example 37: Preparation of Compound 37

Preparation of compound 37-1

Under nitrogen protection, magnesium chips (1.2g, 46.48mmol) and 2 iodine particles were added to anhydrous tetrahydrofuran (10mL) solvent. 3,4-difluorobromobenzene (4.5g, 23.24mmol) was dissolved in anhydrous tetrahydrofuran (20mL) to prepare solution A. Solution A (2mL) was first slowly added to the reaction system, heated to 50°C and stirred vigorously. After the brown color disappeared, the remaining solution A (18mL) was slowly added and the reaction temperature was kept at 50°C. After the addition was completed, the reaction solution was naturally cooled to room temperature to obtain tetrahydrofuran solution B of 3,4-difluorophenylmagnesium bromide. Under nitrogen protection, compound 1-1 (2.0g, 9.30mmol) and anhydrous tetrahydrofuran (20mL) were added to the reaction bottle. At 0°C, solution B (20mL) was slowly added to the reaction system. After the addition was completed, stirring was continued for 1 hour. LCMS detected that the reaction was complete. Water (50 mL) was added to quench the reaction, and ethyl acetate (60 mL) was used to extract twice, and the organic phases were combined. The residue was dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (0-50% ethyl acetate/petroleum ether) to obtain the title compound 37-1 (2.5 g, yellow oil, yield 81%). LC-MS (ESI): m/z [MH] ^- : 328.0.

Preparation of compound 37-2

Under nitrogen protection, 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 the reaction bottle. The system was heated to 120 ° C and stirred for 2 hours. LCMS detected that the reaction was complete. 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, yield 84%). LC-MS (ESI): m/z [MH] ^- : 311.9.

Preparation of compound 37-3

Under nitrogen protection, compound 37-2 (2.0 g, 6.39 mmol) was dissolved in 2-butanone (50 mL) solvent, and 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) 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, water (60 mL) was added, and it 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 obtain the title compound. Compound 37-3 (700 mg, yellow solid, yield 22%). LC-MS (ESI): m/z [MH] ^- : 496.0.

Preparation of compound 37

Under nitrogen protection, compound 37-3 (200 mg, 0.402 mmol) was dissolved in DCE (10 mL) solvent, and then TfOH (603 mg, 4.02 mmol) was added. The system was heated to 60 ° C and stirred for 2 hours. After the reaction was completed by LCMS, the temperature was lowered to 0 ° C, and saturated sodium bicarbonate (20 mL) was slowly added to quench the reaction, and 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 (preparation method: mobile phase: A: 10 mmol formic acid solution; B: acetonitrile; chromatographic column: XBridge C18 250*19mm*10μm; column temperature: 25 ° C; gradient: 40%-48% acetonitrile in 7.32-7.86min; flow rate: 20mL/min) to obtain the title compound 37 (70 mg, yield 44%). 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),7.2 8–7.19(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).

Example 38: Preparation of Compound 38

Preparation of compound 38-1

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), potassium iodide (170 mg, 1.03 mmol) were added to the reaction bottle, heated to 90°C and stirred for 2 hours. LCMS detected that the reaction was complete, the reaction system was cooled to room temperature, water (50 mL) was added, and extracted twice with ethyl acetate (80 mL), the organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by reverse phase column (10-75% ACN/0.1FA% in H ₂ O) to obtain the title compound 38-1 (240 mg, white solid, yield 11%). LC-MS (ESI): m/z [MH] ^- : 401.9.

Preparation of compound 38

Compound 38-1 (216 mg, 0.53 mmol) was dissolved in 1,4-dioxane (0.5 mL) solvent, and then ammonia methanol solution (1 mL, 7 mol/L in MeOH, 7.00 mmol) was added, and the temperature was raised to 110°C and stirred for 20 hours under a sealed tube. The reaction was detected by LCMS, and the reaction system was directly concentrated. The residue was purified by preparative separation (preparation method: mobile phase: A: 0.1% TFA/H2O; B: ACN; chromatographic column: Pursuit XRs10 C18 19*250mm*10μm, 10μm; column temperature: 25°C; gradient: 51%～51%; acetonitrile in 8.5-9.5min; flow rate: 20mL/min) to obtain the title compound 38 (76.64 mg, yield 33%). 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).

Example 39: Preparation of Compound 39

Preparation of compound 39-2

Under nitrogen protection, compound 39-1 (1.48 g, 6.23 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL), then warmed to -65 ° C, and n-BuLi (2.74 mL, 2.5 M in THF, 6.85 mmol) solution was slowly added dropwise to the reaction system. After stirring for 30 minutes, a solution of anhydrous tetrahydrofuran (10 mL) containing compound 1-1 (670 mg, 3.115 mmol) was slowly added dropwise to the reaction system. After stirring for one hour, LCMS detected that the reaction was complete. Saturated aqueous ammonium chloride solution (25 mL) was added to quench the reaction, followed by water (20 mL), 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 subjected to column chromatography (0-25% ethyl acetate/petroleum ether) to obtain the title compound 39-2 (750 mg, yellow oil, yield 64%). LC-MS(ESI):m/z:[MH] ^- :372.8.

Preparation of compound 39-3

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. The reaction was complete by LCMS. The reaction system was cooled to room temperature, and a saturated aqueous solution of NaHCO ₃ (10 mL) was added to quench the reaction. The reaction system was extracted three times with dichloromethane (20 mL), and 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 obtain the title compound 39-3 (200 mg, yellow oil, yield 55.6%). LC-MS (ESI): m/z[MH] ^- : 446.9.

Preparation of compound 39

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. The reaction was complete when detected by LCMS. The reaction system was cooled to room temperature, and a saturated sodium chloride aqueous 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 NH ₄ HCO ₃ /H ₂ O; B: ACN; chromatographic 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, yield 50%). 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).

Example 40: Preparation of Compound 40

Preparation of compound 40-3

Under nitrogen protection, 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). Stir at 50 ° C for 16 hours. After the reaction system was cooled to room temperature, 2N hydrochloric acid aqueous solution (10 mL) was added and stirred for 10 minutes. The system was filtered, 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 and stirred for 3 hours. After the reaction solution was cooled to room temperature, it was slowly poured into ice water (200 mL). Filter, rinse the filter cake with water (80 mL), and 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.

Preparation of compound 40-4

Dissolve p-bromotrifluoromethoxybenzene (2.4 g, 9.99 mmol) in anhydrous tetrahydrofuran (10 mL) solvent. At -65 ° C, n-BuLi (2.5 M in THF, 4.79 mL, 11.99 mmol) solution was slowly added dropwise to the reaction system. 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 completed by LCMS. Saturated aqueous ammonium chloride solution (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 subjected to column chromatography (0-25% ethyl acetate/petroleum ether) to obtain the title compound 40-4 (800 mg, yellow solid, yield 59%). LC-MS (ESI): m/z[MH] ^- :336.0.

Preparation of compound 40-5

Under nitrogen protection, compound 40-4 (800 mg, 2.37 mmol), acetic acid (5 mL), hydrochloric acid (0.5 mL), stannous chloride dihydrate (1.3 g, 5.93 mmol) were added to the reaction flask. The temperature was raised to 120 ° C and stirred for 2 hours. LCMS detected that the reaction was complete. Cooled to room temperature, saturated sodium bicarbonate (20 mL) was added to quench the reaction, and ethyl acetate (30 mL) was used for extraction 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 40-5 (600 mg, yellow solid, yield 78%). LC-MS (ESI): m/z [MH] ^- : 320.0.

Preparation of Compound 40-6

Under nitrogen protection, 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 the reaction flask. The temperature was raised to 90 ° C and stirred for 16 hours. LCMS detected that the reaction was complete, and water (20 mL) was added after cooling to room temperature. 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.

Preparation of Compound 40

Compound 40-6 (200 mg, 0.395 mmol) was dissolved in DCE (5 mL) solvent, and then TfOH (592 mg, 3.95 mmol) was slowly added dropwise. The temperature was raised to 60 ° C and stirred for 3 hours. LCMS detected that the reaction was complete. After the system was cooled to room temperature, ice water (10 mL) was added to quench, and dichloromethane (15 mL) was extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by preparative separation (preparation method: mobile phase: A: 10 mmol formic acid solution; B: acetonitrile; chromatographic 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, yield 36%). LCMS (ESI): m/z[M+H] ⁺ :416.2. ¹ H 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),6.9 2(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).

Example 41: Preparation of Compound 41

Preparation of compound 41-3

Under nitrogen protection, 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). Stir 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, 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 stirred at 80 ° C for 3 hours. After cooling to room temperature, the reaction solution was slowly poured into ice water (200 mL). Suction filtration, 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, yield 43%). LC-MS(ESI):m/z[MH] ^- :194.0.

Preparation of compound 41-4

Dissolve p-bromotrifluoromethoxybenzene (4.62 g, 19.17 mmol) in anhydrous tetrahydrofuran (20 mL) solvent. At -65 ° C, n-BuLi (2.5 M in THF, 9.20 mL, 23.01 mmol) solution was slowly added dropwise to the reaction system. 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 detected that the reaction was complete. Saturated aqueous ammonium chloride solution (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 concentrated residue was subjected to column chromatography (0-25% ethyl acetate/petroleum ether) to obtain the title compound 41-4 (1.1 g, yellow solid, yield 40%). LC-MS(ESI):m/z[MH] ^- :355.9.

Preparation of compound 41-5

Under nitrogen protection, 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 the reaction flask. The temperature was raised to 120°C and stirred for 2 hours. The reaction was complete when LCMS was performed. The mixture was cooled to room temperature, saturated sodium bicarbonate (30 mL) was added to quench the reaction, and the mixture was extracted three times with ethyl acetate (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the residue was concentrated. The residue was purified by column chromatography (0-25% ethyl acetate/petroleum ether) to obtain the title compound 41-5 (760 mg, yellow solid, yield 72.3%). LC-MS (ESI): m/z [MH] ^- : 339.9.

Preparation of compound 41-6

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 the reaction flask. The temperature was raised to 90 ° C and stirred for 16 hours. LCMS detected that the reaction was complete, and an aqueous solution (20 mL) was added. 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.

Preparation of compound 41

Compound 41-6 (180 mg, 0.342 mmol) was dissolved in DCE (5 mL) solvent, and then TfOH (513 mg, 3.42 mmol) was slowly added dropwise. The temperature was raised to 60 ° C and stirred for 3 hours. LCMS detected that the reaction was complete. After cooling to room temperature, ice water (10 mL) was added to the system to quench the reaction, and dichloromethane (15 mL) was extracted three times. The organic phases were combined and dried over anhydrous sodium sulfate. The concentrated residue was purified by preparative separation (preparation method: mobile phase: A: 10 mmol formic acid solution; B: acetonitrile; chromatographic 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, yield 42%). 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).

Preparation of Compounds 41A and 41B

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 is CO ₂ , B is ethanol (0.1% NH ₃ H ₂ O); 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).

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: CO ₂ , 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.

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: CO ₂ , 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.

Example 42: Preparation of Compound 42

Preparation of compound 42-1

Under nitrogen protection, 2-fluoro-4-bromo-toluene (3.9 g, 20.46 mmol) was added to anhydrous THF (40 mL) solvent, and n-BuLi (2.5 M in THF, 8.2 mL, 20.46 mmol) solution was slowly added dropwise to the reaction system at -65 °C. After stirring for 30 minutes, the solution containing the compound was added. A solution of 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 detection showed that the reaction was complete. Saturated aqueous ammonium chloride solution (50 mL) was added to the reaction system to quench the reaction, followed by water (50 mL), and extracted three times with ethyl acetate (100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was subjected to column chromatography (0-25% ethyl acetate/petroleum ether) to obtain the title compound 42-1 (1.6 g, yellow solid, yield 34%). LC-MS (ESI): m/z[MH] ^- :324.0.

Preparation of compound 42-2

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 the reaction flask. The temperature was raised to 120 ° C and stirred for 1 hour. The reaction was detected by LCMS. After the system was cooled to room temperature, it was adjusted to alkaline with saturated sodium bicarbonate aqueous solution, extracted three times with ethyl acetate (40 mL), the organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was subjected to column chromatography (0-20% ethyl acetate/petroleum ether) to obtain the title compound 42-2 (900 mg, yellow oil, yield 72.8%). LC-MS (ESI): m/z [MH] ^- : 307.7.

Preparation of compound 42-3

Compound 42-2 (300 mg, 0.971 mmol), compound 7-2 (303 mg, 0.971 mmol), KI (32 mg, 0.914 mmol), K ₂ CO ₃ (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. The reaction was completed by LCMS detection, the temperature was lowered to room temperature, water (5 mL) was added and 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.

Preparation of compound 42

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 temperature was raised to 120 ° C and stirred for 1 hour. The reaction was detected by LCMS. After cooling to room temperature, saturated NaHCO ₃ aqueous solution (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 (preparation method: mobile phase: A: 0.1% FA/H2O; B: ACN; chromatographic 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, yield 41%). LC-MS(ESI): m/z[M+H] ⁺ :404.2. ¹ H 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).

Example 43: Preparation of Compound 43

Preparation of compound 43-2

Under nitrogen protection, compound 43-1 (6.28 g, 27.90 mmol) was added to anhydrous THF (50 mL) solvent. After the reaction system was cooled 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 anhydrous THF (20 mL) containing compound 1-1 (3.00 g, 13.95 mmol) was slowly added dropwise to the reaction system. After stirring for 1 hour, the reaction was detected by LCMS. Saturated aqueous ammonium chloride solution (10 mL) was added to the reaction system to quench the reaction, followed by addition of water (30 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 subjected to column chromatography (0-20% ethyl acetate/petroleum ether) to obtain the title compound 43-2 (2.0 g, yellow solid, yield 30%). LC-MS(ESI):m/z[MH] ^- :359.9.

Preparation of compound 43-3

At room temperature, compound 43-2 (1.80 g, 4.98 mmol), tetrahydrofuran (20 mL), pyridine (0.79 g, 9.96 mmol) were added to the 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 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.

Preparation of compound 43-4

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

Preparation of compound 43-5

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 2-butanone (5 mL) containing compound 43-4 (510 mg, 1.48 mmol) was slowly added dropwise to the reaction system. After stirring for 16 hours, the reaction was detected by LCMS. After the reaction system was cooled to 0 ° C, water (10 mL) was added to quench, and ethyl acetate (20 mL) was extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was subjected to 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.

Preparation of compound 43

Under nitrogen protection, compound 43-5 (90 mg, 0.17 mmol) was dissolved in DCE (2.0 mL), and then 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, and the reaction was complete when detected by LCMS. After the system was cooled to 0°C, a saturated sodium bicarbonate solution (3 mL) was slowly added to quench the reaction, and then water (5 mL) was added, 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% NH ₄ OH/H ₂ O; B: ACN; chromatographic 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).

Example 44: Preparation of Compound 44

Preparation of compound 44-1

Compound 12-1 (700 mg, 1.74 mmol) and pyridine (275 mg, 3.48 mmol) were dissolved in DCM (15 mL). At 0 ° C, thionyl chloride (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 that the reaction was complete. Saturated sodium bicarbonate aqueous solution (20 mL) was added to the reaction system to quench, followed by water (20 mL), and extracted three times with ethyl acetate (40 mL), the organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was subjected to column chromatography (0-30% ethyl acetate/petroleum ether) to obtain the title compound 44-1 (530 mg, yellow solid, yield 56%). LC-MS (ESI): m/z[MH] ^- :417.9.

Preparation of compound 44-2

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

Preparation of compound 44-3

Compound 44-2 (300 mg, 0.78 mmol), bromocyclohexane (152 mg, 0.93 mmol), KI (26 mg, 0.16 mmol), K ₂ CO ₃ (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. The reaction was completed by LCMS detection. The reaction solution was cooled to room temperature, water (10 mL) was added, and ethyl acetate (10 mL) was extracted three times, dried over anhydrous sodium sulfate, and the organic phases were combined. The concentrated residue was subjected to column chromatography (0-30% ethyl acetate/petroleum ether) to obtain the title compound 44-3 (27 mg, yellow oil, yield 7%). LC-MS (ESI): m/z[MH] ^- : 466.0.

Preparation of compound 44

Compound 44-3 (27 mg, 0.058 mmol) was dissolved in dichloroethane (0.5 mL), and trifluoromethanesulfonic acid (0.2 mL) was slowly added, heated to 65°C and stirred for 1 hour. LCMS detected that the reaction was complete, the reaction solution was cooled to room temperature, and sodium bicarbonate aqueous solution (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 (preparation method: mobile phase: A: 0.05% NH3H2O/H2O, B: ACN; chromatographic column: XBridge XBridge C18, 19*250mm, 10μm: 25°C; gradient: 35%-40%; retention time: 5.98-8.57min of 16min; flow rate: 20mL/min) to obtain the title compound 44 (7 mg, yield 32%). 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,1H),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).

Example 45: Preparation of Compound 45

Preparation of compound 45-2

Compound 45-1 (11 g, 87.96 mmol), hydroxylamine hydrochloride (15.27 g, 219.75 mmol) and H ₂ O (60 mL) were added to a reaction flask, and concentrated hydrochloric acid (4 mL) was 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 H ₂ O (10 mL) was added to the reaction system. After stirring for one hour, the reaction was completed by LCMS. The system was cooled to room temperature, filtered, the filtrate was discarded, water (70 mL) was added to the filter cake, and 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.

Preparation of compound 45-3

Compound 45-2 (17.4 g, 88.75 mmol) and concentrated sulfuric acid (80 mL) were added to the reaction flask and stirred at 80 ° C for one hour. LCMS detected that the reaction was complete. After cooling to room temperature, saturated sodium bicarbonate aqueous solution (160 mL) was slowly added dropwise to quench the reaction, followed by water (160 mL). 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 subjected to column chromatography (0-40% ethyl acetate/petroleum ether) to obtain the title compound 45-3 (1.57 g, yellow solid, yield 10%). LC-MS (ESI): m/z [MH] ^- : 178.1.

Preparation of compound 45-4

Under nitrogen protection, p-bromotrifluoromethoxybenzene (4.04 g, 16.75 mmol) was added to anhydrous THF (8 mL) solvent. After cooling to -65 ° C, n-BuLi (2.5 M in THF, 6.7 mL, 16.75 mmol) solution was slowly added dropwise to the reaction system and stirred for 30 minutes. Subsequently, a solution of compound 45-3 (1.2 g, 6.70 mmol) in anhydrous THF (4 mL) was slowly added dropwise to the reaction system. After stirring for one hour, the reaction was detected to be complete by LCMS. Saturated aqueous ammonium chloride solution (12 mL) was added to the reaction system to quench the reaction, followed by addition of water (12 mL), 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 subjected to column chromatography (0-40% ethyl acetate/petroleum ether) to obtain the title compound 45-4 (1.7 g, yellow oil, yield 68%). LC-MS(ESI):m/z[MH] ^- :340.0.

Preparation of compound 45-5

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 the reaction flask. The temperature was raised to 120 ° C and stirred for 1 hour. LCMS detected that the reaction was complete, the reaction system was cooled to room temperature, and saturated sodium bicarbonate aqueous solution was adjusted to alkalinity and then extracted three times with ethyl acetate (40 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was subjected to column chromatography (0-30% ethyl acetate/petroleum ether) to obtain the title compound 45-5 (590 mg, light yellow solid, yield 36%). LC-MS (ESI): m/z [MH] ^- : 324.0.

Preparation of compound 45-6

Compound 45-5 (300 mg, 0.92 mmol), compound 7-2 (318 mg, 1.02 mmol), 2-Butanone (5 mL) and K ₂ CO ₃ (382 mg, 2.77 mmol) were added to a reaction flask. The mixture was heated to 90°C and stirred for 16 hours. LCMS detected that the reaction was complete, and the reaction solution was cooled to room temperature, extracted with water (5 mL) and ethyl acetate (5 mL) three times, 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.

Preparation of compound 45

Compound 45-6 (360 mg, 0.71 mmol), dichloroethane (4 mL) and trifluoromethanesulfonic acid (2 mL) were added to the reaction bottle and stirred at 65°C for 1 hour. The reaction was detected by LCMS. The reaction solution was cooled to room temperature, and then a saturated sodium bicarbonate aqueous solution (10 mL) was slowly added to quench the reaction. The reaction system was extracted three times with dichloromethane (10 mL), and the organic phase was combined and dried over anhydrous sodium sulfate. The concentrated residue was purified by preparative separation (preparation method: mobile phase: A: 0.05% NH3H2O/H2O, B: ACN; chromatographic column: XBridge XBridge C18, 19*250mm, 10μm: 25°C; gradient: 41% to 47%; retention time: 9.25-11.25min of 16min; flow rate: 20mL/min) to obtain the title compound 45 (136 mg, yield 45%). 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),7.34(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).

Example 46: Preparation of Compound 46

Preparation of compound 46-2

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 the reaction flask, followed by slow dropwise addition of concentrated hydrochloric acid (3 mL). After heating to 120 °C, an aqueous solution (20 mL) of chloral hydrate (4.61 g, 27.88 mmol) was added dropwise to the reaction flask and stirred for 2 hours. The reaction was completed by LCMS detection. The system was cooled to room temperature, and ice water (30 mL) was added, followed by THF (20 mL) to dissolve the oil, and 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 a 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.

Preparation of compound 46-3

Compound 46-2 (6.40 g, 31.98 mmol) and concentrated sulfuric acid (50 mL) were added to the reaction flask. The system was heated to 80°C and stirred for two hours. The reaction was complete when LCMS detected that the reaction was complete. After the system was cooled to room temperature, ice water (50 mL) was poured in to quench the reaction. Ethyl acetate (50 mL) was added. Extract three times, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate the residue to obtain the title compound 46-3 (3.9 g, brown solid, yield 43%) by column chromatography (0-30% ethyl acetate/petroleum ether). LC-MS (ESI): m/z [MH] ^- : 182.1.

Preparation of compound 46-4

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

Preparation of compound 46-5

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) solvent, and then 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 detected by LCMS. After the reaction system was cooled to 0 ° C, a saturated sodium bicarbonate solution (10 mL) was slowly added to quench, and water (10 mL) was added. 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.

Preparation of compound 46-6

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 the reaction bottle. The system was heated to 90 ° C and stirred for 16 hours. LCMS detected that the reaction was complete. After the reaction system was cooled to 0 ° C, water (10 mL) was added to quench, 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 subjected to 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.

Preparation of Compound 46

Compound 46-6 (260 mg, 0.51 mmol), DCE (3 mL) and TfOH (1.5 mL, ρ = 1.7 mol / L) were added to the reaction bottle. The system was heated to 65 ° C and stirred for 1 hour. LCMS detected that the reaction was complete, and the reaction system was cooled to 0 ° C and then slowly added with saturated sodium bicarbonate solution (5 mL) to quench the reaction, followed by water (6 mL) and extracted three times with dichloromethane (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was subjected to 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),6.4 6(t,J＝2.0Hz,1H). ^19F NMR(376MHz,DMSO-d6)δ-56.78(s,3F),-137.02(d,1F),-154.97(d,1F).

Example 47: Preparation of Compound 47

Preparation of compound 47-2

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 the reaction flask, followed by slow dropwise addition of concentrated hydrochloric acid (4 mL). The reaction system was heated to 120 ° C, and an aqueous solution (20 mL) of chloral hydrate (8.2 g, 49.57 mmol) was added dropwise to the reaction flask and stirred for 2 hours. The reaction was completed by LCMS detection. The system was cooled to room temperature, and ice water (50 mL) was added, followed by THF (20 mL) to dissolve the oil, and 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 a crude product 47-2 (13.0 g, brown solid) which was directly used in the next step. LC-MS (ESI): m/z[M+H] ⁺ :209.2.

Preparation of compound 47-3

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

Preparation of compound 47-4

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

Preparation of compound 47-5

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) solvent, and then 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 completed 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, and water (10 mL) and acetic acid were added. The mixture was extracted with ethyl ester (30 mL) for 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 target compound 47-5 (610 mg, white solid, yield 27%). LC-MS (ESI): m/z [MH] ^- : 336.0.

Preparation of compound 47-6

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 the reaction bottle. The system was heated to 90 ° C and stirred for 8 hours. LCMS detected that the reaction was complete. After the 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 subjected to 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.

Preparation of compound 47

Compound 47-6 (170 mg, 0.33 mmol), DCE (2 mL) and TfOH (1.0 mL, ρ = 1.7 mol / L) were added to the reaction bottle, the system was heated to 65 ° C and stirred for 1 hour. LCMS detected that the reaction was complete, the system was cooled to 0 ° C and slowly added with saturated sodium bicarbonate solution (5 mL) to quench, then water (6 mL) was added, and extracted with dichloromethane (10 mL) three times, the organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by preparative separation (preparation method: mobile phase: A: 0.05% NH ₄ OH / H ₂ O; B: ACN; chromatographic column: XBridge XBridge C18, 19 × 250 mm, 10 μm; column temperature: 25 ° C; gradient: 42% ~ 42%; acetonitrile in 9.0-10.1min; flow rate: 20mL / min) to obtain the title compound 47 (9 mg, yield 6%). 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).

Example 48: Preparation of Compound 48

Preparation of compound 48-3

Under nitrogen protection, 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 the 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. Filter by suction, wash the filter cake with water (100 mL), add sulfuric acid (100 mL) after the filter cake is dried, heat to 80 ° C and stir for 3 hours. LCMS detection reaction is complete. After the system is cooled to room temperature, slowly pour into ice water (200 mL). Filter by suction, wash the filter cake with water (80 mL), and dry the filter cake to obtain the title compound 48-3 (1.5 g, yellow solid, yield 10%). LC-MS(ESI):m/z[MH] ^- :190.0.

Preparation of compound 48-4

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

Preparation of compound 48-5

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) solvent, and then concentrated hydrochloric acid (1 mL) was slowly added to the reaction system. The temperature was raised to 120 ° C and stirred for 2 hours. The reaction was completed by LCMS. After the reaction 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 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.

Preparation of Compound 48-6

Compound 48-5 (270 mg, 0.80 mmol), compound 7-2 (275 mg, 0.88 mmol), 2-butanone (10 mL), potassium carbonate (221 mg, 1.60 mmol) were added to the reaction bottle. 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, water (10 mL) was added to quench, 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 subjected to 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.

Preparation of Compound 48

Compound 48-6 (180 mg, 0.35 mmol), DCE (5 mL) and TfOH (518 mg, 3.45 mmol) were added to the reaction bottle. The system was heated to 60 ° C and stirred for 3 hours. LCMS detected that the reaction was complete, the reaction system was cooled to 0 ° C and then slowly added with saturated sodium bicarbonate solution (5 mL) to quench, water (6 mL) was added, and dichloromethane (10 mL) was extracted three times, the organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by preparative separation (preparation method: mobile phase: A: 10 mmol ammonia solution; B: acetonitrile; chromatographic 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, yield 10%). 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),6.4 6(d,J＝2.1Hz,1H),3.69(s,3H),2.26(s,3H). ¹⁹ F NMR(376MHz,DMSO-d6)δ-56.76(s,3F).

Example 49: Preparation of Compound 49

Preparation of Compound 49-1

Compound 44-2 (540 mg, 1.40 mmol), bromocycloheptane (298 mg, 1.68 mmol), KI (46 mg, 0.28 mmol), K ₂ CO ₃ (580 mg, 4.20 mmol) and 2-Butanone (6 mL) were added to the reaction flask. The mixture was stirred at 90° C. for 16 hours. LCMS detection After the reaction was completed, the reaction solution was cooled to room temperature, water (10 mL) was added, and ethyl acetate (10 mL) was used for extraction three times, and the mixture was dried over anhydrous sodium sulfate. The organic phases were combined, concentrated, and purified by column chromatography (0-30% ethyl acetate/petroleum ether) to obtain the title compound 49-1 (270 mg, yellow oil, yield 40.2%). LC-MS (ESI): m/z [MH] ^- : 480.2.

Preparation of compound 49

Compound 49-1 (150 mg, 0.31 mmol) was dissolved in dichloroethane (3 mL), and trifluoromethanesulfonic acid (1.2 mL) was slowly added, and the temperature was raised to 65°C and stirred for 1 hour. The reaction was detected by LCMS, and the reaction solution was cooled to room temperature. A sodium bicarbonate aqueous solution (5 mL) was slowly added to quench the reaction. The reaction system was extracted three times with dichloromethane (10 mL), and the organic phases were combined and dried over anhydrous sodium sulfate. The concentrated residue was purified by preparative separation (preparation method: mobile phase: A: 0.05% NH3H2O/H2O, B: ACN; chromatographic column: XBridge XBridge C18, 19*250mm, 10μm: 25°C; gradient: 47% to 52%; retention time: 7.92-8.67min of 16min; flow rate: 20mL/min) to obtain the title compound 49 (13 mg, yield 11%). 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),2.7 1–2.62(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).

Example 50: Preparation of Compound 50

Preparation of compound 50-2

Under nitrogen protection, compound 50-1 (23 g, 132.19 mmol) and 1-(trifluoromethyl)-1,2-benzidoyl-3(1H)-one (12.5 g, 39.66 mmol) were added to anhydrous DCE (100 mL) solvent. The system was heated to 90°C and stirred for 16 hours. The reaction was detected by LCMS. The temperature was lowered to 0°C and stirred for 1 hour. Solids precipitated and were filtered. The filtrate was concentrated and then purified by column chromatography (0-15% ethyl acetate/petroleum ether) to obtain the title compound 50-2 (3.0 g, colorless oil, yield 9%). ¹ H NMR (400 MHz, DMSO-d6) δ8.55 (d, J＝2.6 Hz, 1H), 8.28 (dd, J＝8.7, 2.6 Hz, 1H), 7.33 (d, J＝8.7 Hz, 1H).

Preparation of compound 50-3

Under nitrogen protection, compound 50-2 (3.0 g, 12.40 mmol) was added to anhydrous tetrahydrofuran (50 mL) solvent. At -65 ° C, n-BuLi (2.5M in THF, 6.20 mL, 15.50 mmol) solution was slowly added dropwise to the reaction system 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 detected that the reaction was complete. Saturated aqueous ammonium chloride solution (5 mL) was added to quench the reaction. Water (20 mL) was added and extracted with ethyl acetate (20 mL) three times. The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was subjected to column chromatography (0-50% ethyl acetate/petroleum ether) to obtain the title compound 50-3 (750 mg, Yellow solid, yield 32%). LC-MS (ESI): m/z [MH] ^- : 377.1.

Preparation of Compound 50-5

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

Preparation of Compound 50-6

Compound 50-5 (300 mg, 0.83 mmol), compound 7-2 (284 mg, 0.91 mmol), 2-butanone (10 mL), potassium carbonate (229 mg, 1.66 mmol) were added to the reaction flask. The system was heated to 90 ° C and stirred for 16 hours. LCMS detected that the reaction was complete. After the reaction system was cooled to room temperature, 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 subjected to 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.

Preparation of compound 50

Compound 50-6 (80 mg, 0.146 mmol), DCE (5 mL) and TfOH (110 mg, 0.730 mmol) were added to the reaction bottle, and the system was heated to 60 ° C and stirred for 2 hours. LCMS detected that the reaction was complete, and the reaction system was cooled to 0 ° C and then slowly added with saturated sodium bicarbonate solution (10 mL) to quench the reaction, followed by adding water (10 mL), and extracted three times with dichloromethane (10 mL), and the organic phases were combined and dried over anhydrous sodium sulfate. The concentrated residue was purified by preparative separation (preparation method: mobile phase: A: 10 mmol formic acid solution; B: acetonitrile; chromatographic column: ECLIPSE PLUS C18 40 g; gradient: 5%-60% acetonitrile; flow rate: 30 mL/min) to obtain the title compound 50 (21 mg, yield 32%). 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).

Example 51: Preparation of Compound 51

Preparation of compound 51-2

Compound 51-1 (11 g, 87.96 mmol), hydroxylamine hydrochloride (15.27 g, 219.75 mmol) and H ₂ O (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). At 120°C, a solution of chloral hydrate (11.63 g, 70.32 mmol) in H ₂ O (10 mL) was added to the reaction system. 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 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).

Preparation of compound 51-3

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. The reaction was complete by LCMS detection. The reaction solution was slowly added dropwise to a saturated sodium bicarbonate aqueous solution (160 mL) at 0°C to quench the reaction. Water (160 mL) was then added. 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 subjected to column chromatography (0-40% ethyl acetate/petroleum ether) to obtain the title compound 51-3 (4.8 g, yellow solid, yield 45%). LC-MS (ESI): m/z[MH] ^- : 178.1.

Preparation of compound 51-4

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

Preparation of compound 51-5

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 the reaction flask. The temperature was raised to 120 ° C and stirred for 1 hour. LCMS detected that the reaction was complete, the reaction system was cooled to room temperature, and saturated sodium bicarbonate aqueous solution was adjusted to alkalinity and then extracted three times with ethyl acetate (40 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was subjected to column chromatography (0-30% ethyl acetate/petroleum ether) to obtain the title compound 51-5 (1.78 g, light yellow solid, yield 93%). LC-MS (ESI): m/z [MH] ^- : 324.4.

Preparation of compound 51-6

Compound 51-5 (300 mg, 0.92 mmol), compound 7-2 (345 mg, 1.10 mmol), 2-Butanone (5 mL) and K ₂ CO ₃ (382 mg, 2.77 mmol) were added to a reaction flask. The temperature was raised to 90°C and stirred for 16 hours. LCMS detected that the reaction was complete, and the reaction solution was cooled to room temperature, and water (5 mL) was added and extracted with ethyl acetate (10 mL) three times. 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.

Preparation of compound 51

Compound 51-6 (200 mg, 0.39 mmol), dichloroethane (3 mL) and trifluoromethanesulfonic acid (1.5 mL) were added to the reaction bottle and stirred at 65°C for 1 hour. The reaction was detected by LCMS. The reaction solution was cooled to room temperature, and then a saturated sodium bicarbonate aqueous solution (10 mL) was slowly added to quench the reaction. The reaction system was extracted three times with dichloromethane (10 mL), and 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; chromatographic column: XBridge XBridge C18, 19*250mm, 10μm: 25°C; gradient: 41% to 46%; retention time: 7.81-10.38min of 16min; flow rate: 20mL/min) to obtain the title compound 51 (11 mg, yield 7%). 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).

Example 52: Preparation of Compound 52

Preparation of compound 52-1

Under nitrogen protection, 1,3-dibromobenzene (30.0 g, 127.83 mmol) was dissolved in anhydrous tetrahydrofuran (200 mL) solvent. After cooling to -65 °C, n-BuLi (2.5 M in THF, 51 mL, 127.83 mmol) solution 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, and the reaction was detected by LCMS after stirring for 2 hours. Saturated aqueous ammonium chloride solution (50 mL) was added to the system to quench, followed by water (200 mL), and extracted twice with ethyl acetate (300 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was subjected to column chromatography (0-40% ethyl acetate/petroleum ether) to obtain the title compound 52-1 (12 g, yellow solid, yield 63%). LC-MS(ESI): m/z[MH] ^- :370.9.

Preparation of compound 52-2

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 the reaction flask. The temperature was raised to 120 ° C and stirred for 3 hours. LCMS detected that the reaction was complete, the reaction system was cooled to room temperature, and saturated sodium bicarbonate aqueous solution was adjusted to alkalinity and then extracted three times with ethyl acetate (300 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was subjected to column chromatography (0-30% ethyl acetate/petroleum ether) to obtain the title compound 52-2 (8.7 g, yellow solid, yield 75%). LC-MS (ESI): m/z [MH] ^- : 353.9.

Preparation of compound 52-3

Compound 52-2 (2.7 g, 7.58 mmol), compound 7-2 (2.6 g, 8.34 mmol), 2-Butanone (50 mL) and K ₂ CO ₃ (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 detected that the reaction was complete, and the reaction solution was cooled to room temperature, and water (5 mL) was added and extracted with ethyl acetate (10 mL) three times. 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.

Preparation of compound 52-4

Compound 52-3 (200 mg, 0.370 mmol) was dissolved in toluene (10 mL) solvent, followed by 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 replace the carbon monoxide gas three times. The system was heated to 90 ° C and stirred for 16 hours. LCMS detected that the reaction was complete. After cooling to room temperature, water (20 mL) was added, and the pH was adjusted to acidic with 1M hydrochloric acid aqueous solution, and then extracted three times with ethyl acetate (30 mL). Drying over anhydrous sodium sulfate and concentrating the residue gave the title compound 52-4 (50 mg, yellow solid, yield 26%). LC-MS (ESI): m/z [MH] ^- : 504.4.

Preparation of compound 52-5

Under nitrogen protection, compound 52-4 (50 mg, 0.099 mmol) was dissolved in DMF (3 mL) solvent, followed by the addition of 2-methoxyethylamine (8.17 mg, 0.108 mmol) and HATU (56 mg, 0.148 mmol). After stirring at room temperature for 30 minutes, DIEA (18 mg, 0.148 mmol) was added to the reaction system. Stir at room temperature for 2 hours. LCMS detected that the reaction was complete. Water (20 mL) was added and extracted twice with ethyl acetate (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (0-45% 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.

Preparation of compound 52

Compound 52-5 (40 mg, 0.071 mmol), dichloroethane (5 mL) and trifluoromethanesulfonic acid (106.5 mg, 0.71 mmol) were added to the reaction flask. Stir at 50 °C for 2 hours. LCMS detected that the reaction was complete, and the reaction solution was cooled to room temperature, then slowly added with saturated sodium bicarbonate aqueous solution (10 mL) to quench, extracted with dichloromethane (10 mL) three times, combined with the organic phase, dried over anhydrous sodium sulfate, and concentrated The residue was purified by preparative separation (preparation method: mobile phase: A: 10 mmol formic acid solution; B: acetonitrile; chromatographic column: ECLIPSE PLUS C18 40 g; gradient: 5%-65% acetonitrile; flow rate: 30 mL/min)) to obtain the title compound 52 (14 mg, yield 43%). 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).

Example 53: Preparation of Compound 53

Preparation of compound 53-1

Under nitrogen protection, 5-bromo-2-trifluoromethylpyridine (7.5 g, 33.20 mmol) was dissolved in anhydrous THF (40 mL) solvent. After cooling to -15 °C, isopropylmagnesium chloride lithium chloride solution (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 detected that the reaction was complete. Water (60 mL) was added to the system to quench the reaction, and the mixture was extracted with ethyl acetate (120 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 give the title compound 53-1 (4.3 g, yellow solid, yield 71%). LC-MS (ESI): m/z [MH] ^- : 361.1

Preparation of compound 53-2

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

Preparation of compound 53-3

Under nitrogen protection, compound 53-5 (3 g, 7.88 mmol), palladium carbon (1.12 g, 10%) and anhydrous methanol (30 mL) were added to the reaction flask. The gas was replaced with hydrogen three times and stirred at room temperature for 16 hours. LCMS detected the end 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 obtain compound 53-3 (1.05 g, yellow solid, yield 38%) LC-MS (ESI): m/z[MH] ^- : 345.4.

Preparation of compound 53-4

Compound 53-3 (800 mg, 2.31 mmol), compound 7-2 (865.17 mg, 2.77 mmol), 2-Butanone (8 mL) and K ₂ CO ₃ (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 detected that the reaction was complete, and the reaction solution was cooled to room temperature, and water (5 mL) was added 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 53-4 (260 mg, yellow oil, yield 21%) LC-MS (ESI): m/z[MH] ^- : 529.2.

Preparation of compound 53

Compound 53-4 (130 mg, 0.25 mmol), dichloroethane (1.5 mL) and trifluoromethanesulfonic acid (0.5 mL) were added to a reaction bottle and stirred at 65° C. for 1 hour. After the reaction was completed, LCMS detected that the reaction solution was cooled to room temperature, and then saturated aqueous sodium bicarbonate solution (4 mL) was slowly added to quench, extracted three times with dichloromethane (4 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by preparative separation (preparation method: mobile phase: A: 0.1% FA/ _H2O ; B: acetonitrile; chromatographic column: Atlantis™ T3 Prep OBD™ 19*250mm, 10μm; gradient: 44%-50% retention time: 8.4-9.4min of 16min; flow rate: 20mL/min) to obtain 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).

Example 54: Preparation of Compound 54

Preparation of compound 54-2

Under nitrogen protection, the compound 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) solvent. At 0°C, DIAD (10.5 g, 52.02 mmol) was slowly added dropwise to the reaction system. Stir for 2 hours, and the reaction was completed by TLC detection. Then water (50 mL) was added, and ethyl acetate (50 mL) was extracted twice, the organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was subjected to column chromatography (0-15% methanol/dichloromethane) to obtain the title compound 54-2 (3.5 g, light yellow solid, yield 37%). LC-MS (ESI): m/z[M+H] ⁺ :270.2

Preparation of compound 54-3

Under nitrogen protection, compound 54-2 (3.5 g, 13.94 mmol) was dissolved in anhydrous THF (25 mL) solvent. 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 detected that the reaction was complete. Water (10 mL) was added to the system to quench, and ethyl acetate (10 mL) was extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (0-40% ethyl acetate/petroleum ether) to obtain the title compound 54-3 (1.1 g, yellow solid, yield 38%). LC-MS (ESI): m/z [MH] ^- : 405.1.

Preparation of compound 54-4

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 the reaction flask. The temperature was raised to 120 ° C and stirred for 2 hours. LCMS detected that the reaction was complete, the reaction system was cooled to room temperature, and the pH was adjusted to alkaline with saturated sodium bicarbonate aqueous solution and extracted three times with ethyl acetate (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was subjected to column chromatography (0-30% ethyl acetate/petroleum ether) to obtain the title compound 54-4 (400 mg, yellow solid, yield 37%). LC-MS (ESI): m/z[MH] ^- : 389.2.

Preparation of compound 54-5

Compound 54-4 (400 mg, 1.02 mmol), compound 7-2 (352 mg, 1.13 mmol), 2-Butanone (10 mL) and K ₂ CO ₃ (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 detected that the reaction was complete, and the reaction solution was cooled to room temperature, and water (10 mL) was added 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 54-5 (150 mg, yellow solid, yield 25%). LC-MS (ESI): m/z[MH] ^- : 573.3.

Preparation of compound 54

Compound 54-5 (150 mg, 0.261 mmol), dichloroethane (1.5 mL) and trifluoromethanesulfonic acid (391.5 mg, 2.61 mmol) were added to the reaction bottle, heated to 60 ° C and stirred for 1 hour. LCMS detected that the reaction was complete, the reaction solution was cooled to room temperature, and then slowly added saturated sodium bicarbonate aqueous solution (10 mL) to quench, and extracted with dichloromethane (10 mL) three times. The organic phases were combined and dried over anhydrous sodium sulfate. The concentrated residue was purified by preparative separation (preparation method: mobile phase: A: 10 mmol formic acid solution; B: acetonitrile; chromatographic 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. ¹ H NMR (400MHz, DMSO-d6) δ13.17(s,1H),8.28(s,1H),7.79(d,J＝7.6Hz,1H),7.72(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),1.7 5–1.48(m,3H). ^19F NMR(376MHz,DMSO-d6)δ-60.02(s,3F).

Example 55: Preparation of Compound 55

Preparation of compound 55-2

Under nitrogen protection, compound 55-1 (1.90 g, 8.86 mmol) was added to anhydrous tetrahydrofuran (20 mL) solvent. At -65 ° C, n-BuLi (2.5 M in THF, 3.54 mL, 8.86 mmol) solution was slowly added dropwise to the reaction system and stirred for 30 minutes. Subsequently, a solution of compound 1-1 (0.95 g, 4.43 mmol) in anhydrous THF (10 mL) was slowly added dropwise to the reaction system. After stirring for 2 hours, LCMS detected that the reaction was complete, and then saturated ammonium chloride aqueous solution (10 mL) was added to quench, water (20 mL) was added, and ethyl acetate (20 mL) was extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was subjected to column chromatography (0-50% ethyl acetate/petroleum ether) to obtain the title compound 55-2 (800 mg, light solid, yield 39%). LC-MS (ESI): m/z [MH] ^- : 349.1.

Preparation of compound 55-3

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 the reaction flask. The temperature was raised to 120 ° C and stirred for 1 hour. LCMS detected that the reaction was complete, the reaction system was cooled to room temperature, and the pH was adjusted to alkaline with saturated sodium bicarbonate aqueous solution, and then extracted three times with ethyl acetate (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was subjected to column chromatography (0-30% ethyl acetate/petroleum ether) to obtain the title compound 55-3 (500 mg, yellow solid, yield 60%). LC-MS (ESI): m/z[MH] ^- : 333.0.

Preparation of compound 55-4

Compound 55-4 (450 mg, 1.35 mmol), compound 7-2 (632.02 mg, 2.03 mmol), 2-Butanone (5 mL) and K ₂ CO ₃ (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 detected that the reaction was complete, and the reaction solution was cooled to room temperature, and water (5 mL) and ethyl acetate (10 mL) were added and extracted three times. 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, yield 7%). LC-MS (ESI): m/z[MH] ^- : 517.0.

Preparation of compound 55

Compound 55-4 (80.00 mg, 0.15 mmol), dichloroethane (3 mL) and trifluoromethanesulfonic acid (1 mL) were added to a reaction bottle and stirred at 65°C for 1 hour. The reaction was detected by LCMS. The reaction solution was cooled to room temperature, and then slowly added with saturated sodium bicarbonate aqueous solution (10 mL) to quench, extracted with dichloromethane (10 mL) three times, and the organic phase was combined and dried over anhydrous sodium sulfate. The concentrated residue was purified by preparative separation (preparative method: mobile phase: A: 0.1% FA/H ₂ O; B: ACN; chromatographic column: Atlantis TM T3 Prep OBD TM 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, yield 27%). LC-MS(ESI):m/z[M+H+ACN] ⁺ :470.2. ¹ H 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, 4.6 Hz, 1H), 7.42 (s, 1H), 7.36 (t, J = 7.9 Hz, 1H), 6.61–6.57 (m, 1H). ¹⁹ F NMR (376MHz, DMSO-d6) δ-60.02 (s, 3F).

Example 56: Preparation of Compound 56

Preparation of compound 56-1

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), Pd ₂ (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 detected that the reaction was complete. After cooling 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 by column chromatography (0-50% ethyl acetate/petroleum ether) to obtain the title compound 56-1 (2 g, yellow solid, yield 60%) LC-MS (ESI): m/z[MH] ^- : 639.2.

Preparation of compound 56-2

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

Preparation of compound 56-4

Under nitrogen protection, 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), stirred at room temperature for 20 minutes, and then DIEA (0.53 g, 4.09 mmol) was added. After stirring for 16 hours, the reaction was detected by LCMS. Water (15 mL) was added, and ethyl acetate (15 mL) was extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (0-100% ethyl acetate/petroleum ether) to obtain compound 56-4 (1.7 g, white solid, yield 85%) LC-MS (ESI): m/z [MH] ^- : 708.1.

Preparation of compound 56-5

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 TFA (6.7 mL) was added. The system was slowly warmed to room temperature and stirred for 1 hour. LCMS detected that the reaction was complete. Saturated sodium bicarbonate aqueous solution (20 mL) was added to quench the reaction, and DCM (20 mL) was extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give a crude compound 56-5 (1.3 g, milky white solid, yield 89%) LC-MS (ESI): m/z [MH] ^- : 608.0.

Preparation of compound 56-6

Compound 56-5 (1.3 g, 2.13 mmol), formaldehyde aqueous solution (0.4 g, 37%, 4.26 mmol) and acetic acid (1 mL) were added to methanol (15 mL) solvent, stirred at room temperature for 20 minutes, and then sodium cyanoborohydride (0.27 g, 4.26 mmol) was added. After stirring for 2 hours, the reaction was detected by LCMS. Saturated ammonium chloride aqueous solution (20 mL) was added to quench the reaction, and ethyl acetate (20 mL) was extracted three times, the organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was subjected to 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.

Preparation of Compound 56

Compound 56-6 (300 mg, 0.048 mmol), dichloroethane (4 mL) and trifluoromethanesulfonic acid (1.5 mL) were added to a reaction bottle and stirred at 65° C. for 1 hour. The reaction was detected by LCMS. The reaction solution was cooled to room temperature, and then saturated sodium bicarbonate aqueous solution (10 mL) was slowly added to quench, and extracted with dichloromethane (10 mL) three times. The organic phases were combined and dried over anhydrous sodium sulfate. The concentrated residue was purified by C18 reverse phase (5-60% acetonitrile/0.1% FA aqueous solution) to obtain compound 56 (23 mg, yield 9%) LC-MS (ESI): m/z[M+H] ⁺ : 534.3. ¹ H NMR (400MHz, DMSO-d ₆ ) 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).

Example 57: Preparation of Compound 57

Preparation of compound 57-2

At -65°C, n-BuLi (2.5M tetrahydrofuran solution, 64mL, 160mmol) was slowly added dropwise to an argon-protected 4-trifluoromethoxybromobenzene (3.36g, 13.94mmol) in anhydrous tetrahydrofuran (30mL) solution (note that the temperature inside the reaction system should be controlled below -60°C). After the addition was completed, the mixture was stirred for one hour. Then, a tetrahydrofuran (15mL) solution containing 57-1 (1.50g, 6.97mmol) was added dropwise to the reaction system, and the mixture was stirred for one hour. The reaction solution was poured into a saturated aqueous ammonium chloride solution (50mL), extracted twice with ethyl acetate (50mL), washed with saturated brine (50mL), dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 57-2 (2.80g, light yellow solid, yield 93%). LC-MS (ESI): m/z[MH] ^- :376.1.

Preparation of compound 57-3

Compound 57-2 (2.30 g, 6.10 mmol) was added to a single-mouth bottle, and acetic acid (25 mL), concentrated hydrochloric acid (2.5 mL) and stannous chloride dihydrate (3.44 g, 15.25 mmol) were added in sequence. 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 sodium bicarbonate aqueous solution, filtered with a thin layer of diatomaceous earth, and the filter cake was rinsed with a solution of EA/tetrahydrofuran = 5/1. The filtrate was extracted three times with ethyl acetate (30 mL), dried over anhydrous sodium sulfate, and the concentrated residue was purified by 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.

Preparation of compound 57-4

Compound 57-3 (1.10 g, 3.05 mmol) was added to a single-mouth bottle, followed by the addition of solvent 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 residue was concentrated. The residue was purified by 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.

Preparation of compound 57

Compound 57-4 (150 mg, 0.28 mmol) was dissolved in DCE (3 mL), TfOH (1.0 mL) was added at room temperature, and then the reaction solution was heated to 60 ° C and stirred for 1 hour. The reaction system was cooled to room temperature, the pH was adjusted to alkaline with sodium bicarbonate aqueous solution, extracted three times with DCM (20 mL), and the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated, and purified by reverse phase column (5-50% acetonitrile/0.1% formic acid aqueous solution) to obtain the title compound 57 (80 mg, yield 64%). LC-MS (ESI): m/z[M+H] ⁺ :456.1. ¹ H 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 (37 6MHz, DMSO-d6)δ-56.79(s,3F),-61.25(s,3F).

Example 58: Preparation of Compound 58

Preparation of compound 58-1

Compound 44-2 (1.4 g, 3.63 mmol), compound 7-2 (1.13 g, 3.63 mmol), 2-Butanone (15 mL) and K ₂ CO ₃ (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 detected that the reaction was complete, and the reaction solution was cooled to room temperature, and water (20 mL) was added and 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.

Preparation of Compound 58

Compound 58-1 (130 mg, 0.23 mmol) was dissolved in dichloroethane (1.5 mL), and trifluoromethanesulfonic acid (0.5 mL) was slowly added, heated to 60°C and stirred for 1 hour. LCMS detected that the reaction was complete, the reaction solution was cooled to room temperature, and sodium bicarbonate aqueous solution (5 mL) was slowly added to quench, and dichloromethane (10 mL) was extracted three times, 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/ _{H 2} O 5-95%) to obtain 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). ¹⁹ F NMR (376MHz, DMSO-d6) δ-59.99(s,3F).

Example 59: Preparation of Compound 59

Preparation of compound 59-1

Under argon protection, (4-bromophenyl)sulfur pentafluoride (3.5 g, 12.28 mmol) was dissolved in anhydrous ether (60.0 mL). After the system was cooled to -65 °C, tert-butyl lithium (1.3 M in pentane, 9.4 mL, 12.28 mmol) solution was slowly added dropwise to the system. 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, and the temperature was maintained at -65 °C and stirred for another hour. LCMS detected that the reaction was complete. Saturated aqueous ammonium chloride solution (100 mL) was added to quench the reaction, followed by water (25 mL), and the reaction system was extracted three times with ethyl acetate (30 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried, and the concentrated residue was purified by column chromatography (0-20% ethyl acetate/petroleum ether) to give the title compound 59-1 (1.3 g, light yellow oil, yield 55.6%). LC-MS (ESI): m/z [MH] ^- : 418.0.

Preparation of compound 59-2

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

Preparation of compound 59-3

Compound 59-2 (400 mg, 0.99 mmol), 2-butanone (10 mL), 2-benzyl-5-iodopyridazine-3-one (402 mg, 1.29 mmol) and potassium phosphate (630 mg, 2.97 mmol) were added to the reaction bottle, and then heated to 90 ° C and stirred for 16 hours. LCMS detected that the reaction was complete, cooled to room temperature, and an aqueous solution of ammonium chloride (30 mL) was added to quench the reaction, and then extracted twice with ethyl acetate (50 mL), and the organic phase was washed with saturated brine (30 mL). Drying over anhydrous sodium sulfate, filtering, spin drying, and concentrating the residue by column chromatography (0-20% ethyl acetate/petroleum ether) to obtain the title compound 59-3 (370 mg, light yellow solid, yield 63%). LC-MS (ESI): m/z [MH] ^- : 586.1.

Preparation of compound 59

Compound 59-3 (270 mg, 0.46 mmol), DCE (2.5 mL) and trifluoromethanesulfonic acid (0.5 mL) were added to the reaction bottle, and then heated to 65°C and stirred for 2 hours. LCMS detected that the reaction was complete, the reaction system was cooled to room temperature, and a cold saturated sodium bicarbonate solution (100 mL) was slowly added dropwise to quench, and 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 spin-dried. The concentrated residue was chromatographed on a reverse phase C18 column (5-50% ACN/0.1% FA) to obtain compound 59. (154.48mg, yield 67%) LC-MS (ESI): m/z[M+H] ⁺ :498.2. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 13.23 (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).

Example 60: Preparation of Compound 60

Preparation of compound 60-2

Under nitrogen protection, compound 60-1 (8.4 g, 37.18 mmol) was added to anhydrous THF (100 mL), and 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 and stirred at -20°C for one hour. The reaction was completed by LCMS. Saturated aqueous ammonium chloride solution (100 mL) was added to quench the reaction, and the mixture was extracted three times with EA (100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-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[M-H]-: 362.0.

Preparation of compound 60-3

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 bottle, cooled to 0 ° C, thionyl chloride (1.64 g, 13.76 mmol) was added dropwise, and the temperature was slowly raised to room temperature and stirred for one hour. The reaction was completed by LCMS detection. Water (60 mL) was added to the reaction system, and DCM (60 mL) was extracted three times. The organic phases were combined, washed with brine (180 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was concentrated to give a crude compound 60-3 (3 g, yellow oil) LC-MS (ESI): m/z[MH] ^- : 380.0.

Preparation of compound 60-4

Under nitrogen protection, palladium carbon (1.13 g), methanol (25 mL) and compound 60-3 (2.8 g, 7.34 mmol) were added to the reaction bottle, and then the gas was replaced with a hydrogen balloon 3 times, and the reaction was stirred for 16 hours. LCMS detected that the reaction was complete. Filter, spin dry, and concentrate the residue to obtain compound 60-4 (1.45 g, yellow solid, yield 56%) by column chromatography (0-25% ethyl acetate/petroleum ether) LC-MS (ESI): m/z [MH] ^- : 346.0.

Preparation of Compound 60-5

Compound 60-4 (300 mg, 0.86 mmol), 2-benzyl-5-iodopyridazin-3-one (295.26 mg, 12.75 mmol), K ₂ CO ₃ (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. The reaction was completed by LCMS. 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, the organic phases were combined, filtered, and dried by spin drying. The concentrated residue was 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.

Preparation of Compound 60

Compound 60-5 (70 mg, 0.13 mmol), DCE (2 mL) and trifluoromethanesulfonic acid (0.7 mL) were added to the reaction flask, and the temperature was raised to 60°C and stirred for one hour. The reaction was completed by LCMS. The reaction system was cooled to room temperature, saturated sodium bicarbonate aqueous solution (20 mL) was added, and DCM (20 mL) was extracted three times. The organic phases were combined, washed with saturated brine (8 mL), dried over anhydrous sodium sulfate, and filtered. The product was spin dried and concentrated, and the residue was purified by preparative separation (preparation method: mobile phase: A: 0.1% FA/H2O; B: ACN; chromatographic column: Atlantis TM T3 Prep OBD TM, C18, 19×250mm, 10μm; column temperature: 25°C; gradient: 50% to 55%; acetonitrile in 9.3-10.2min; flow rate: 20mL/min) to give the title compound 60 (15mg, yield 27%). LC-MS (ESI): m/z[M+H] ⁺ : 442.2. ¹ H NMR (400MHz, DMSO-d ₆ ) 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, 1 H). ¹⁹ F NMR(376MHz, DMSO-d ₆ )δ-59.96(s,3F),-68.95(s,3F).

Example 61: Preparation of Compounds 61, 61A and 61B

Preparation of compound 61-2

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 bottle and stirred at room temperature for 5 hours. LCMS detected that the reaction was complete, ice water (15 mL) was added to quench, and ethyl acetate (20 mL) was used for extraction three times. The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was subjected to column chromatography (0-25% ethyl acetate/petroleum ether) to obtain compound 61-2 (350 mg, yellow solid, yield 60%). LC-MS (ESI): m/z [MH] ^- : 525.2.

Preparation of Compound 61

Compound 61-2 (350 mg, 0.66 mmol), DCE (3 mL) and TfOH (1.7 M, 1.5 mL) were added to the reaction bottle and stirred at room temperature for one hour. After the reaction was completed by LCMS, the system was cooled to 0°C and saturated sodium bicarbonate solution (5 mL) was added to quench the reaction, and then water (15 mL) was added and extracted with dichloromethane (15 mL) three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The concentrated residue was purified by preparative separation (preparation method: mobile phase: A: 0.1% FA/H ₂ O; B: ACN; chromatographic 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, yield 70%). LC-MS(ESI): m/z[M+H] ⁺ :437.1. ¹ H NMR (400MHz, DMSO-d ₆ ) δ13.26 (s, 1H), δ 11.65 (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).

Preparation of Compounds 61A and 61B

Compound 61 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 is CO ₂ , B is 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).

Compound 61A: 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: CO ₂ 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=0.975 min). LCMS (ESI): m/z [M+H] ⁺ : 437.0.

Compound 61B: 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: CO ₂ 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.

Example 62: Preparation of Compound 62

Preparation of compound 62-1

Under nitrogen protection, compound 2,6-dichloro-4-iodopyridine (5.1 g, 18.59 mmol) and anhydrous THF (15 mL) were added to the reaction bottle. At -10 ° C, a solution of isopropylmagnesium chloride lithium chloride complex (1.3 M in THF, 18 mL, 23.24 mmol) was slowly added dropwise to the reaction system. 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 detected that the reaction was complete. Saturated aqueous ammonium chloride solution (25 mL) was added to quench the reaction, followed by water (25 mL), and ethyl acetate (50 mL) was extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The concentrated residue was subjected to column chromatography (0-25% ethyl acetate/petroleum ether) to obtain the title compound 62-1 (1.7 g, orange-yellow solid, yield 30.2%). LC-MS(ESI):m/z[MH] ^- :360.9.

Preparation of compound 62-2

At room temperature, compound 62-1 (1.7 g, 4.70 mmol), toluene (4.32 g, 46.96 mmol) and DCE (10.0 mL), TfOH (7.05 g, 46.96 mmol) were added to a reaction bottle and reacted at 60°C for 2 hours. LCMS detected that the reaction was complete, and the reaction solution was poured into a cold saturated sodium bicarbonate aqueous solution (20 mL) for quenching. The reaction system was extracted three times with DCM (20 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried. The concentrated residue was subjected to column chromatography (0-25% ethyl acetate/petroleum ether) to obtain the title compound 62-2 (440 mg, white solid, yield 35%). LC-MS (ESI): m/z[M+H] ⁺ :437.1. ¹ H NMR (400MHz, DMSO-d ₆ ) δ10.33 (s, 1H), 7.75 (d, J = 7.5Hz, 1H), 7.61 (d, J = 8.0Hz, 1H), 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-d ₆ ) δ-59.97 (s,3F).

Preparation of Compound 62

Compound 62-2 (100 mg, 0.25 mmol), tert-butyl alcohol (1.0 mL), KOH (64 mg, 1.15 mmol) were added to the reaction bottle, heated to 100°C and stirred for 16 hours. LCMS detected the end of the reaction, adjusted the pH to 5-6 with 3M hydrochloric acid, and dried by spin drying. The concentrated residue was purified by preparative separation (preparative method: mobile phase: A: 0.05% NH ₄ OH/H ₂ O; B: ACN; chromatographic column: Xbridge 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 obtain the title compound 62 (26 mg, yield 27%).

LC-MS(ESI):m/z[M+H+ACN] ⁺ :460.2. ¹ H NMR (400MHz, DMSO-d ₆ ) 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).

Example 63: Preparation of Compound 63

Preparation of compound 63-2

Under nitrogen protection, p-bromotrifluoromethoxybenzene (28.3 g, 117.35 mmol) was added to anhydrous THF (150 mL) solvent, and n-BuLi (2.5 M in THF, 46.6 mL, 117.35 mmol) solution 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 detected that the reaction was complete. Saturated aqueous ammonium chloride solution (200 mL) was added, and ethyl acetate (400 mL) was extracted three times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried, and the concentrated residue was purified by column chromatography (ethyl acetate/petroleum ether 0-60%) to obtain compound 63-2 (21.9 g, yellow oil, yield 71%) LC-MS (ESI): m/z[MH] ^- : 455.9.

Preparation of compound 63-3

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 the reaction bottle, heated to 120 ° C and stirred for 5 hours. LCMS detected that the reaction was complete. Cooled to room temperature, saturated sodium bicarbonate aqueous solution was added to adjust the pH to alkaline, extracted three times with ethyl acetate (200 mL), combined organic phases, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The concentrated residue was purified by column chromatography (ethyl acetate/petroleum ether 0-60%) to obtain compound 63-3 (10.2 g, white solid, yield 48.3%) LC-MS (ESI): m/z[MH] ^- : 439.9.

Preparation of compound 63-4

Compound 63-3 (5.1 g, 11.59 mmol), 2-benzyl-5-iodopyridazin-3-one (4.0 g, 12.75 mmol), K ₂ CO ₃ (4.8 g, 34.77 mmol) and 2-Butanone (60 mL) were added to a reaction bottle and stirred at 90°C for 16 hours. The reaction was completed by LCMS. The reaction system was cooled to room temperature, 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 by spin drying. The concentrated residue was 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.

Preparation of compound 63-5

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

Preparation of compound 63

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

Example 64: Preparation of Compound 64

Preparation of Compound 64-1

Under nitrogen protection, compound 1,4-dibromobenzene (13.71 g, 58.10 mmol) and anhydrous THF (50.0 mL) were added to the reaction bottle. At -65 ° C, n-BuLi (2.5 M in THF, 23.3 mL, 58.10 mmol) solution was slowly added dropwise to the reaction system. 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. Stir for 1 hour, and LCMS detection showed that the reaction was complete. Saturated aqueous ammonium chloride solution (10 mL) was added to quench the reaction, followed by water (50 mL), and ethyl acetate (50 mL) was extracted twice. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The concentrated residue was subjected to column chromatography (0-30% ethyl acetate/petroleum ether) to obtain the title compound 64-1 (8.1 g, yellow solid, yield 93%). LC-MS(ESI):m/z[MH] ^- :370.0.

Preparation of compound 64-2

Compound 64-1 (8.0 g, 21.50 mmol), acetic acid (10 mL), hydrochloric acid (10 mL), 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 detected that the reaction was complete, and cold sodium bicarbonate aqueous solution (200 mL) was slowly added to quench, and EA (200 mL) was extracted three times, the organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was subjected to normal phase (0-30% ethyl acetate/petroleum ether) to obtain the title compound 64-2 (5.1 g, yellow solid, yield 66%). LC-MS (ESI): m/z[MH] ^- : 354.0.

Preparation of compound 64-3

Compound 64-2 (5.0 g, 14.04 mmol), 2-butanone (50 mL), 2-benzyl-5-iodopyridazine-3-one (5.3 g, 16.85 mmol), potassium carbonate (3.88 g, 28.08 mmol) were added to the reaction flask. The temperature was raised to 90 ° C and stirred for 16 hours. LCMS detected that the reaction was complete and an aqueous solution (50 mL) was added. It 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 concentrated residue was purified by column chromatography (0-50% ethyl acetate/petroleum ether) to obtain the title compound 64-3 (4.5 g, yellow solid, yield 59%). LC-MS(ESI):m/z[MH] ^- :540.1.

Preparation of compound 64-4

Under nitrogen protection, compound 64-3 (4.0 g, 7.40 mmol), dioxane (50. mL), 1,1-bis(diphenylphosphino)diferronichloridopalladium (II) (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 the reaction bottle and stirred at 100°C for 16 hours. LCMS detected that the reaction was complete, and aqueous solution (50 mL) was added, and ethyl acetate (50 mL) was extracted three times, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-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 the reaction flask and stirred at room temperature for 16 hours, then extracted three times with ethyl acetate (50 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried, and 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.

Preparation of compound 64-5

Under nitrogen protection, compound (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 the reaction bottle and stirred at room temperature for 1 hour. LCMS detected that the reaction was complete, and aqueous solution (10 mL) was added, and ethyl acetate (10 mL) was extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The concentrated residue was purified by column chromatography (0-40% ethyl acetate/petroleum ether) to obtain the title compound 64-5 (224 mg, yellow solid, yield 50%). LC-MS (ESI): m/z [MH] ^- : 560.1.

Preparation of Compound 64

Compound 64-5 (224 mg, 0.399 mmol), DCE (3.0 mL), and trifluoromethanesulfonic acid (1.0 mL) were added to the reaction flask. Stir at 60°C for 2 hours. LCMS detected that the reaction was complete, and cold saturated sodium bicarbonate (10 mL) was added to quench the reaction. The reaction system was extracted three times with dichloromethane (10 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried. The concentrated residue was purified by preparative separation (preparation method: mobile phase: A: 10 mmol formic acid solution; B: acetonitrile; chromatographic column: ECLIPSE PLUS C18 40 g; gradient: 5%-50% acetonitrile; flow rate: 30 mL/min) to obtain the title compound 64 (66.39 mg, yield 39%). LCMS (ESI): m/z[M+H] ⁺ :472.2. ¹ H NMR (400MHz, DMSO-d ₆ ) 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-d ₆ ) δ -41.76 (s, 3F), -60.04 (s, 3F).

Example 65: Preparation of Compound 65

Preparation of Compound 65

Under nitrogen protection, 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 the reaction flask, followed by dropwise addition of LiHMDS (1.0 mol/L in THF, 1.5 mL, 1.48 mmol), and the temperature was raised to 85 ° C and stirred for 3 hours. LCMS detected that the reaction was complete. Cool to room temperature, add water (10 mL), extract three times with ethyl acetate (10 mL), combine the organic phases, dry over anhydrous sodium sulfate, filter, spin dry, and concentrate the residue to prepare (preparation method: mobile phase: A: 0.1% FA aqueous solution; B: acetonitrile; chromatographic column: Atlantis TM T3 Prep OBD TM, 19*250mm, 10μm; Column temperature: 25°C; gradient: 28%-28% retention time: 5.3-8.1 min of 16 min; flow rate: 20 mL/min) was purified to obtain compound 65 (79 mg, yield 38%). LC-MS (ESI): m/z [M+H] ⁺ : 554.3. ¹ H NMR (400MHz, Methanol-d ₄ ) δ7.88 (d, J = 2.0 Hz, 1H), 7.42–7.36 (m, 2H), 7.35–7.29 (m, 3H), 7.15 (d, J = 2.0 Hz, 1H), 6.68 (d, J = 2.1 Hz, 1H), 3.29–3.24 (m, 4H) ,2.92–2.85(m,4H),2.55(s,3H). ¹⁹ F NMR (376MHz, Methanol-d ₄ )δ-59.46(s,3F),-62.95(s,3F).

Example 66: Preparation of Compound 66

Preparation of compound 66-1

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 the reaction bottle and stirred at 60 ° C for one hour. The reaction was completed by LCMS. The reaction system was adjusted to alkaline with saturated sodium bicarbonate aqueous solution, extracted three times with ethyl acetate (30 mL), the organic phases were combined, washed with brine (60 mL), dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The concentrated residue was subjected to column chromatography (0-60% ethyl acetate/petroleum ether) to obtain compound 66-1 (400 mg, yield 32.4%), LC-MS (ESI): m/z [MH] ^- : 399.0.

Preparation of Compound 66

Compound 66-1 (400 mg, 0.001 mmol) was dissolved in ACN (5 mL) solvent, TMSI (800 mg, 0.004 mmol) was added at room temperature, and the reaction system was heated to 60°C and stirred for one hour. The reaction was detected by LCMS. The reaction system was cooled to room temperature, water (10 mL) was added, and extracted three times with ethyl acetate (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The concentrated residue was 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-d ₆ ) δ11.60(br.s,1H),11.31(s,1H),9.58(br.s,1H),7.58(dd,J＝7.7,3.6Hz,2H),7.31(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-d ₆ ) δ-60.05 (s, 3F).

Example 67: Preparation of Compound 67

Preparation of compound 67-2

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

Preparation of compound 67-3

Under nitrogen protection, compound 67-2 (11.0 g, 72.79 mmol), tetrahydrofuran (100 mL), methanol (100 mL), palladium carbon (2 g, 10%) were added to the reaction bottle, hydrogen was replaced by hydrogen balloon 3 times, and the reaction was stirred at room temperature for 5 hours. Filter and spin dry to obtain the crude title compound 67-3 (12.0 g, blue-brown solid). LC-MS (ESI): m/z [M+H] ⁺ : 138.2.

Preparation of compound 67-4

Compound 67-3 (12.0 g, 87.50 mmol) and hydrobromic acid (40% aqueous solution, 100 mL) were added to the 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 spin drying. 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.

Preparation of compound 67-5

Under nitrogen protection, 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 the reaction bottle, warmed to 0°C, and 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 organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The concentrated residue was purified by column chromatography (0-35% ethyl acetate/petroleum ether) to obtain the title compound 67-5 (350 mg, anhydrous oil, yield 54%). ¹ H NMR (400MHz, CDCl ₃ ) δ7.48–7.37 (m, 2H), 7.01 (d, J = 13.0 Hz, 1H), 6.49 (d, J = 10.8 Hz, 1H), 3.94 (s, 3H).

Preparation of compound 67-7

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

Preparation of compound 67

Compound 67-7 (110 mg, 0.259 mmol), ethanol (10 mL) and sodium hydroxide (4 mL, 2 M) were added to the reaction flask. The temperature was raised to 70 °C and stirred for 3 hours. LCMS detected that the reaction was complete, ice water (10 mL) was added to quench the reaction, ethyl acetate (10 mL) was extracted three times, 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 aqueous solution; B: acetonitrile; chromatographic 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 obtain the title compound 67 (42.28 mg, yield 41%). LCMS (ESI): m/z[M+H] ⁺ :412.1, ¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.38 (s, 1H), 7.59 (d, J＝7.9Hz, 2H), 7.29–7.05 (m, 10H), 2.28 (s, 3H). ¹⁹ F NMR (376MHz, DMSO-d ₆ ) δ-6 0.01(s,3F).

Preparation of compound ^ErSO1

Preparation of compound E-1

Compound 7-3 (43.0 g, 88.4 mmol) and compound phenol (37.4 g, 397.8 mmol) were dissolved in DCM (300 mL). The reaction system was cooled to 0°C with an ice-water bath, and trifluoromethanesulfonic acid (66.3 g, 442.0 mmol) was added. The mixture was stirred for 1 hour. The pH of the reaction solution was adjusted to alkaline with a saturated sodium bicarbonate aqueous solution, extracted twice with DCM (300 mL), dried over anhydrous sodium sulfate, and the organic phase was concentrated and the residue was purified by 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.

Preparation of compound ErSO

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

Compound ErSO: Chiral analysis method (chromatographic column model: 25*4.6mm, 3μm; mobile phase: A: CO ₂ , 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).

Compound E-2: Chiral analysis method (chromatographic column model: 25*4.6mm, 3μm; mobile phase: A: CO ₂ , 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). ¹⁹ F NMR (376MHz, DMSO-d6) δ -56.78 (s, 3F), -60.03 (s, 3F).

Preparation of compound ^SERA2 (other code names ErSO-TFPy, TEQ103)

Preparation of compound S-2

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

Preparation of compound S-3

Compound S-2 (3.0 g, 7.08 mmol), DCM (30 mL), pyridine (1.1 g, 14.16 mmol) were added to the reaction bottle, stirred evenly, and then thionyl chloride (1.7 g, 14.16 mmol) was slowly added dropwise at 0°C, and the temperature was slowly raised to room temperature and stirred for one hour. The reaction was completed by TLC detection. Water (60 mL) and DCM (60 mL) were added to extract three times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a crude compound S-3 (2.8 g), which was used directly in the next step without purification.

Preparation of compound S-5

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 bottle and stirred at room temperature for 16 hours. The reaction was completed by LCMS. Water (60 mL) was added and extracted with ethyl acetate (60 mL) three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried. The concentrated residue was purified by C18 column (5-70% 0.05% NH ₃ H ₂ O/H ₂ O) to obtain compound S-5 (489.55 mg, yield 17%). LC-MS (ESI): m/z [MH] ^- : 433.3. ¹ H NMR (400MHz, DMSO-d ₆ ) 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-d ₆ ) δ -59.93 (s, 3F), -117.43 (s, 4F).

Preparation of compounds SERA2 and S-6

Compound S-5 was subjected to SFC chiral preparative separation (preparative separation method, instrument model: MGⅡpreparative SFC (SFC-14); chromatographic column model: ChiralPak AD, 250×30 mm ID, 5 μm; mobile phase: A is CO ₂ , B is ethanol (0.1% ammonia water); elution gradient: B20%; flow rate: 150 mL/min; column pressure: 100 bar; column temperature: 38°C; detection wavelength: 220 nm; cycle: ~7 min) to obtain the title compounds SERA2 (218 mg) and S-6 (222 mg).

Compound SERA2: 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: CO ₂ 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-d ₆ ) 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-d ₆ ) δ -59.93 (s, 3F), -117.44 (s, 4F).

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: CO ₂ 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-d ₆ ) 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-d ₆ ) δ - 59.92 (s, 3F), - 117.43 (s, 4F).

References:

1:Sci.Transl.Med.2021,13,eabf1383.

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

Test Example 1: MCF-7 cell activity test

1. The breast cancer cell line MCF-7 was purchased from ATCC, the cell culture medium was DMEM + 10% FBS, and the cells were cultured in an incubator at 37°C, 100% relative humidity, and 5% _CO2 .

2. On the first day, cells in logarithmic growth phase were collected, counted, and resuspended in phenol red-free DMEM medium containing 10% FBS. The cell concentration was adjusted to an appropriate concentration (determined according to the results of the cell density optimization test), inoculated into a 96-well plate, and 100 μL of cell suspension was added to make the cell number 6000/well. The cells were incubated in a 37°C, 5% _CO2 incubator for 24 hours.

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.

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

5. After gently shaking, measure the absorbance at a wavelength of 450 nM on the SpectraMax M5 Reader, and use the absorbance at 650 nM as a reference (i.e., 450 nM absorbance - 650 nM absorbance) to calculate the inhibition rate.

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

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

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

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

The _IC50 curve was fitted and the _IC50 value was calculated using the software Graphpad Prism 6 and the calculation formula XY-analysis/Nonlinear regression (curve fit)/Dose response-Inhibition/log (inhibitor) vs. response-Variable slope (four parameters).

Table 1: Test results of cytotoxicity of some compounds in MCF-7 cells

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

Test Example 2: Mouse Pharmacokinetic Test

Preparation: The dosing solution was prepared on the day of administration. Weigh 2.0 mg of the compound and dissolve it in 5% DMSO + 10% Tween-20 + 85% PBS to prepare a 1.0 mg/mL intravenous dosing solution; weigh 2.0 mg of the compound and dissolve it in 5% DMSO + 10% Tween-20 + 85% PBS to obtain a 0.5 mg/mL oral dosing solution.

Take healthy male Six ICR mice, weighing 25-30g, were divided into two groups (intravenous and oral groups), three mice in each group, and administered once. After 3 days of adaptive feeding, the mice were fasted overnight (10-12h) before the experiment, and were allowed to drink water freely during the experiment. They resumed eating 4h 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, 48h). 40μL of whole blood was collected at each point into a 1.5mL EP tube containing sodium heparin. The collected whole blood was placed on a vortexer 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.

Table 2: Pharmacokinetics in mice

Conclusion: Compared with the prior art, the compounds of the present invention have significantly superior pharmacokinetic results in intravenous injection and oral PK in mice.

Test Example 3: Rat Pharmacokinetic Test

Preparation: The dosing solution was prepared on the day of administration. Weigh 6.0 mg of the compound and dissolve it in 5% DMSO + 10% Tween-20 + 85% PBS to prepare a 1.0 mg/mL intravenous dosing solution; weigh 18.0 mg of the compound and dissolve it in 35% DMSO + 10% Tween-20 + 85% PBS to obtain a 1.5 mg/mL oral dosing solution.

Six healthy male SD rats weighing 220-300 g were divided into two groups (intravenous and oral groups), three rats in each group, and given a single dose. After 3 days of adaptive feeding, mice were fasted overnight (10-12h) before the experiment, and were allowed to drink water freely during the experiment. They resumed eating 4h after administration. The 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, 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 vortexer 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.

Table 3: Pharmacokinetics in rats

Conclusion: Compared with the prior art, the compounds of the present invention have significantly superior pharmacokinetic results in rat intravenous injection and oral PK.

Test Example 4: Manual patch clamp hERG test

1. Experimental Design

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 form working solutions of different concentrations of the test sample.

1.1 Preparation of cells for experiment

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

1.2 Manual patch clamp test

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

The clamping voltage was -80 mV, and the hERG channels were opened by depolarization to +60 mV for 850 ms. Then, the voltage was set to -50 mV for 1275 ms to generate a rebound current or tail current, the peak of which was measured and used for analysis.

Start with the solvent, monitor the tail current peak until more than 3 lines are stable, then perfuse the test sample/positive control working solution until the current peak reaches a stable state. After stabilization, continue to perfuse the next concentration of the test sample until all concentrations are tested.

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

1.3 Acceptance criteria for patch clamp data

Sealing standard:

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.

Current size:

The peak current amplitude is between 400pA and 5000pA.

Leakage Current:

The absolute value of leakage current should be less than 200pA.

2. Data

The current response is calculated using the following formula:

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

For each concentration, all cell inhibition percentages were recorded and averaged, and _IC50 values were derived from the concentration-effect curves using the Hill fitting method.

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

Vmax＝100％；

x = nominal concentration;

n = Hill coefficient;

k = test sample concentration at 50% inhibition.

3. Some hERG test results

7A: IC ₅₀ >10μM.

Test Example 5: CYP inhibition test

The in vitro test system was used to evaluate the effects of compounds on the activities of seven isozymes (CYP1A2, CYP2C9, CYP2D6 and CYP3A) of human liver microsomal cytochrome P450 (CYP). Specific probe substrates of CYP450 isozymes were incubated with human liver microsomes and different concentrations (0, 0.0300, 0.100, 0.300, 1.00, 3.00, 10.0 μM) of compounds, and the coenzyme NADPH was added to initiate the reaction. 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 dose-response curves finally obtained, the IC ₅₀ values of the test compounds on the reaction of specific probe substrates catalyzed by each CYP isozyme were calculated.

Some test results

Compound 7A has an IC ₅₀ >10 μM in the inhibition test of CYP 1A2/2C9/2D6/3A4 (testosterone)/3A4 (midazolam).

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

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

A series of concentrations of compounds were added to the mixed human liver microsomes (HLM) as the incubation system, and pre-incubated for 30 minutes with or without reduced nicotinamide adenine dinucleotide phosphate (NADPH). After pre-incubation, probe substrate solution and NADPH and substrate mixed solution were added to the corresponding sample wells, respectively. After incubation for a certain period of time, the reaction was terminated, the enzyme activity of the incubation system was determined, the _IC50 values in the two cases were calculated, the _IC50 shift multiples were compared, and the time-dependent inhibitory effect of the study drug was evaluated.

Some test results

Compound 7A showed no time-dependent inhibition of CYP 3A4 isoforms.

Test Example 7: Solubility Test

15 μL of the test compound or control compound 10 mM stock solution was added to the experimental test well, followed by 485 μL of PBS (pH 7.4)/FaSSIF/FeSSIF solution. Stir with molded PTFE/Silicone and a stirring bar at 25°C, 1100 rpm for 2 hours, then filter the sample, take 5 μL of the filtrate, add 5 μL of DMSO, and then add 490 μL of acetonitrile/water (1:1, v:v) solution containing the internal standard. Take an appropriate amount of solution for Compound concentrations were quantified by LC-MS/MS.

Some test results

Conclusion: Compared with the prior art, the compounds of the present invention have better PBS (pH 7.4) solubility.

Test Example 8: Caco-2 Cell Monolayer Permeability Test

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

Some test results

Conclusion: Compared with the prior art, the compounds of the present invention have significantly superior membrane permeability results in the in vitro Caco-2 membrane permeability test.

Test Example 9: PPB plasma protein binding rate test

Plasma samples with a compound concentration of 1 μM were prepared from plasma of CD-1 mice, Sprague-Dawley rats, beagles, cynomolgus monkeys and humans, respectively, and placed in a 96-well equilibrium dialysis device and dialyzed with phosphate buffer solution at 37°C for 4 hours. Warfarin was used as a control compound in this experiment. The concentration of the analyte in plasma and dialysis buffer was determined by LC-MS/MS, and the free rate f _u value was calculated.

Some test results

Conclusion: The compounds of the present invention show higher free drug concentrations in various plasma protein binding tests.

Test Example 10: Glutathione Trapping (GSH Trapping) Test

The compound (10 μM) was added to a human liver microsome solution (1 mg/mL), and then NADPH and GSH powder were added to the system and pre-incubated at 37°C for 1 hour. The sample was post-treated and the GSH binding product was analyzed by LC-UV-MS/MS.

Some test results

Compound 7A: negative.

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

1.1 Experimental animals and cell culture

Experimental Animals Female BALB/c nude mice (SPF grade, 6-8 weeks old, weight 18-23g, 42 mice) were ordered from Shanghai Bikaikoyi Biotechnology Co., Ltd. and kept in a standard SPF grade experimental animal room. Nude mice were kept in separate cages, with natural circadian rhythm changes and free diet. The room temperature was 23℃±2℃, and the relative humidity was 40%-60%.

Human breast cancer MCF-7 (ECACC-86012803) cells were cultured in monolayer in vitro. The culture conditions were 10% heat-inactivated fetal bovine serum, 2mM Glutamine, 1% Non-Essential Amino Acids (NEAA), 1% penicillin/streptomycin/amphotericin B in EMEM (EBSS) medium and cultured in a 37°C, 5% CO ₂ incubator. The cells were routinely digested and passaged with trypsin-EDTA twice a week. When the cells were in the exponential growth phase, the cells were harvested, counted, and inoculated.

1.2 Construction, grouping and drug administration of animal models

Three days before tumor cell inoculation, estrogen tablets (0.36 mg/tablet) were subcutaneously inoculated on the left shoulder. 0.2 mL (10×10 ⁶ ) of MCF-7 cells were mixed with matrix gel at a ratio of 1:1 and injected into the mammary fat pad of mice. When the average tumor volume reached 250 mm ³ , group administration began. The 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. 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), 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 calculation formula of tumor volume is: V = 0.5a × b ² , a and b represent the long diameter and short diameter of the tumor, respectively. The anti-tumor efficacy of the test substance was evaluated by TGI (%) or relative tumor proliferation rate T/C (%). Data are presented as Mean ± SEM, and all treatment groups were statistically analyzed based on the data on day 21 after group administration to evaluate the differences between groups. Comparisons between three or more groups were analyzed using one-way ANOVA, and all data were analyzed using Graph Pad Prism 8.0. p < 0.05 was considered to be significantly different.

Conclusion: Compared with the prior art, the compounds of the present invention achieved a very significant tumor inhibition effect at a significantly lower dosage. In the MCF-7 human breast cancer nude mouse orthotopic transplantation model test, all the drug administration groups did not show significant weight loss, and all mice did not get sick or die during the experiment. Compared with the solvent control group, the test ErSO (40 mg/kg, QD) and 7A (0.5 mg/kg, BID) treatment groups showed a very significant tumor inhibition effect, with TGI values of 142.76% and 141.71%, respectively.

The exemplary embodiments of the present invention are described above. It should be understood that the protection scope of the present 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 protection scope of the present application.

Claims (24)

The 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; X ₁ , X ₂ and X ₃ are independently selected from C(R ₃ ) and N; X ₄ is selected from O and a single bond; X ₅ is selected from CH(R ₅ ), S(═O) ₂ , C(═NR ₅ ) and C(═O); X ₆ is selected from CH(R ₅ ) and N(R ₅ ); Y ₁ is selected from N(R ₄ ), CH(R ₄ ) and O; Y ₂ is selected from O, S and N(R ₆ ); _R1 is independently selected from H, halogen, OH, CN, _NH2 , _C1-6 alkyl, _{C3-6 cycloalkyl, C3-6 cycloheteroalkyl} , _C1-6 alkyl-O-, _C1-6 alkyl-S-, _C1-6 alkyl-C(=O)-, _C1-6 alkyl-C(=O)O-, _C1-6 alkyl-OC(=O)-, _C1-6 alkyl- _NH- , -N( _C1-6 alkyl) ₂ , _C1-6 alkyl _- NH- _C1-6 alkyl-, _C1-6 alkyl-C(=O)NH-, _C3-6 cycloalkyl-C(=O)NH-, _C3-6 cycloheteroalkyl-C(=O)NH-, _C1-6 alkyl-NH-C(=O)-, _C3-6 cycloalkyl-NH-C(=O)-, C1-6 C _1-6 alkyl-S(＝O) ₂ -, C _1-6 alkyl-S(＝O) ₂ NH- 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) ₂ NH- or C _1-6 alkyl-NHS(＝O) ₂ - is optionally substituted by 1, 2 or 3 R; R ₂ is independently selected from H, halogen, OH, CN, NH ₂ , C _1-6 alkyl, C _3-6 cycloalkyl, wherein the C _1-6 alkyl, C _3-6 cycloalkyl is optionally substituted by 1, 2 or 3 R; _R3 is selected from H, halogen, CN, OH, _NH2 , -C(=O)OH, _C1-6 alkyl, _C3-6 cycloalkyl, _C3-6 cycloheteroalkyl, _C1-6 alkyl-O-, _C1-6 alkyl-S-, C1-6 alkyl-C(=O)-, _C1-6 alkyl-C(=O _{)O-, C1-6 alkyl-OC(=O)-, C1-6 alkyl-C(=O)NH-, C1-6 alkyl - NH} -C(=O)-, _C1-6 alkyl-S(=O) _2- , _C1-6 alkyl-S(=O) _2NH- and _C1-6 alkyl-NHS(=O) _2- , wherein the _C1-6 alkyl, _C3-6 cycloalkyl, _C3-6 cycloheteroalkyl, _C1-6 alkyl-O-, _C1-6 alkyl-S-, C1-6 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) ₂ NH- or C _1-6 alkyl-NHS(═O) ₂ - is optionally substituted by 1, 2 or 3 R; R ₄ is selected from H, halogen, OH, CN, NH ₂ , C _1-6 alkyl, C _3-6 cycloalkyl, wherein the C _1-6 alkyl, C _3-6 cycloalkyl is optionally substituted by 1, 2 or 3 R; R ₅ is selected from H, halogen, OH, CN, NH ₂ , C _1-6 alkyl, C _3-6 cycloalkyl and C _1-6 alkoxy, wherein the C _1-6 alkyl, C _3-6 cycloalkyl or C _1-6 alkoxy is optionally substituted by 1, 2 or 3 R; R ₆ is independently selected from H, halogen, OH, CN, NH ₂ , C _1-6 alkyl, C _3-6 cycloalkyl, and the C _1-6 alkyl is optionally substituted by 1, 2 or 3 R; R is independently selected from H, F, Cl, Br, I, OH, NH ₂ , 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, wherein 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 by 1 _, 2 or 3 R'; R' is selected from F, Cl, Br, I, OH, _NH2 , CN, CH ₃ , CH ₂ F, CHF ₂ and CF ₃ ; n is 0, 1, 2, 3 or 4; m is 0, 1, 2 or 3. The compound according to claim 1, its optical isomers, tautomers or pharmaceutically acceptable salts thereof, wherein the structural unit Selected from The compound according to claim 1, its optical isomers, tautomers or pharmaceutically acceptable salts thereof, wherein R ₄ is selected from H, OH, C _1-3 alkyl, and the C _1-3 alkyl is optionally substituted by 1, 2 or 3 R. The compound according to claim 1, its optical isomers, tautomers or pharmaceutically acceptable salts thereof, wherein ring A is selected from
The compound according to any one of claims 1 or 4, its optical isomers, tautomers or pharmaceutically acceptable salts thereof, wherein R ₂ is independently selected from H, halogen, OH, CN, NH ₂ , C _1-3 alkyl, and the C _1-3 alkyl is optionally substituted by 1, 2 or 3 R. The compound according to claim 5, its optical isomers, tautomers or pharmaceutically acceptable salts thereof, wherein R ₂ is independently selected from H, F, Cl, Br, I, OH, CN, NH ₂ , methyl, CHF ₂ , CH ₂ OH, CH ₂ CH ₂ OH. 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 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. The compound according to claim 1, its optical isomers, tautomers or pharmaceutically acceptable salts thereof, wherein R ₁ 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) ₂ NH- 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) ₂ NH- or C _1-3 alkyl-NHS(＝O) ₂ - is optionally substituted with 1, 2 or 3 R. The compound according to claim 9, its optical isomers, tautomers or pharmaceutically acceptable salts thereof, wherein R ₁ is independently selected from H, F, Cl, Br, I, OH, CN, Me, The compound according to claim 8 or 10, its optical isomers, tautomers or pharmaceutically acceptable salts thereof, wherein the structural unit Selected from The compound according to claim 1, its optical isomers, tautomers or pharmaceutically acceptable salts thereof, wherein the structural unit Selected from 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, _C1-3 alkyl, _C3-6 cycloheteroalkyl, _C1-3 alkyl-O-, _C1-3 alkyl-C(=O)-, _C1-3 alkyl-C(=O)O-, _C1-3 alkyl-OC(=O)-, _C1-3 alkyl-C(=O)NH-, _C1-3 alkyl-NH-C(=O)-, _C1-3 alkyl-S(=O) _2- , _C1-3 alkyl-S(=O) _2NH- and _C1-3 alkyl-NHS(=O) _2- ; the _C1-3 alkyl, _C3-6 cycloheteroalkyl, _C1-3 alkyl-O-, _C1-3 alkyl-C(=O)-, C1-3 alkyl- 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) ₂ NH— or C _1-3 alkyl-NHS(═O) ₂ — is optionally substituted by 1, 2 or 3 R. The compound according to claim 13, its optical isomers, tautomers or pharmaceutically acceptable salts thereof, wherein R ₃ is selected from H, F, Cl, Br, -C(=O)OH, -CH ₃ , -OCH ₃ , -OCF ₃ , -CF ₃ , The compound according to claim 1, its optical isomers, tautomers or pharmaceutically acceptable salts thereof, wherein R ₅ is selected from H and OH. The compound according to claim 12, 14 or 15, its optical isomers, tautomers or pharmaceutically acceptable salts thereof, wherein: Structural unit Selected from A compound, an optical isomer, a tautomer or a pharmaceutically acceptable salt thereof, which is selected from:



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




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. The pharmaceutical composition according to claim 19, further comprising one or more pharmaceutically acceptable carriers, diluents or excipients. 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 breast cancer, ovarian cancer, uterine cancer, endometrial cancer, or cervical cancer. 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. 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. 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.