WO2021098885A1

WO2021098885A1 - α-FLUOROCHALCONE DERIVATIVES AND APPLICATION THEREOF

Info

Publication number: WO2021098885A1
Application number: PCT/CN2020/130958
Authority: WO
Inventors: 楼金芳; 冯恩光; 沈锡明
Original assignee: 杭州百诚医药科技股份有限公司
Priority date: 2019-11-21
Filing date: 2020-11-23
Publication date: 2021-05-27
Also published as: CN112824380A

Abstract

Provided are α-fluorochalcone derivatives and an application thereof, the derivatives comprising a pharmaceutically acceptable salt thereof. Also provided is an application for the derivatives and the pharmaceutically acceptable salt thereof in the preparation of drugs for the treatment of PPAR receptor-related diseases. The provided derivatives are absorbed well in the body and have the characteristics of high bioavailability and a strong pharmacodynamic effect, and therefore have huge clinical application value.

Description

α-Fluorochalcone derivatives and their applications

Technical field

The invention belongs to the technical field of pharmaceutical preparations, and relates to an α-fluorochalcone derivative and an application thereof. Specifically, the derivatives relate to pharmaceutically acceptable salts and prodrugs, which are peroxisome proliferator-activated receptor (PPAR) agonists, and are useful for treating diseases related to abnormal expression of PPAR, and have clinical applications. The prospects are huge.

Background technique

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in developed countries or regions. It refers to the accumulation of excessive fat in the liver in the form of triglycerides (steatosis>5% of liver cell tissue) ). In addition to excessive fat, NAFLD patients are accompanied by liver cell damage and inflammation (steatohepatitis), the latter being nonalcoholic steatohepatitis (NASH). The simple steatosis in NAFLD has no correlation with short-term morbidity or mortality, but once it progresses to NASH, it significantly increases the risk of liver cirrhosis, liver failure, and hepatocellular carcinoma (HCC). Cirrhosis caused by NASH is a reason for the increasing number of liver transplants. In NASH patients, the morbidity and mortality caused by liver disease have greatly increased, and it is closely related to the increase in cardiovascular disease morbidity and mortality. The diagnosis of asymptomatic middle-aged male patients showed that 46% of patients had non-alcoholic fatty liver disease (NAFLD, 12.2% were NASH. NAFLD patients were mostly men, elderly, hypertensive and diabetic patients. 60%～76 % Of diabetics suffer from NAFLD, and 22% suffer from NASH. The number of children with NAFLD is also increasing year by year. Among obese children, 38% to 53% suffer from NAFLD. In China, the incidence of non-alcoholic fatty liver has increased to the highest One.

At present, only obeticholic acid (Obeticholic Acid) has been approved by the FDA to treat the disease. Chinese clinical commonly used drugs such as polyene phosphatidylcholine, hydrobacterin, ursodeoxycholic acid, and glycyrrhizic acid.

Peroxisome proliferator-activated receptor (PPAR) is a member of the nuclear hormone receptor superfamily. It is a ligand-activated transcription factor that regulates gene expression. There are three main subtypes: α, γ, and δ( Or β), α subtypes are mainly expressed in brown adipose tissue, liver, heart and skeletal muscles, and play a major role in the metabolism of bile acid, lipids and sugar; β subtypes have no obvious expression specificity and may have anti-inflammatory properties. Inflammation; γ subtype has a certain effect on insulin resistance. PPAR is associated with a variety of disease states, including dyslipidemia, hyperlipidemia, hypercholesterolemia, atherosclerosis, atherogenesis, hypertriglyceridemia, heart failure, myocardial infarction, vascular disease, Cardiovascular disease, hypertension, obesity, inflammation, arthritis, cancer, Alzheimer's disease, skin disease, respiratory disease, eye disease, IBD (stress bowel disease), ulcerative colitis and Crowe Gracious. From the perspective of the various conditional mechanisms of PPAR beneficial to liver function, PPAR agonists are one of the most effective potential drugs for the treatment of fatty liver.

Elafibranor (GFT-505) is a peroxisome proliferator activated α and δ receptor (PPARα/δ) agonist developed by the French company Genfit. It is currently in the treatment of non-alcoholic steatohepatitis (NASH) clinical phase III Research, and the second phase of clinical trials for the treatment of primary cholangitis (PBC). Elafibranor has no progress in clinical research for the treatment of type 2 diabetes (T2DM), dyslipidemia and liver fibrosis. Elafibranor acts on two subtypes of PPAR (α, δ), and preferentially acts on the PPARα family. The drug simultaneously targets multiple risk factors of microvessels and large blood vessels, such as high-density and low-density lipoprotein cholesterol, triglycerides, and inflammation, and has been shown to have effects on insulin resistance, diabetes, and atherosclerosis in preclinical studies. positive effects.

The following compounds are reported in the literature for the treatment of NASH.

There are also some researchers at home and abroad who have carried out early research on small molecule compounds of PPAR agonists. For example, CN 108658908A discloses a compound with a bicyclic ring structure, such as CN 1930122A discloses a 1,3-diphenylpropane-2 -En-1-one derivative compounds, which show good biological activity to all or part of the three subtypes of PPAR. For example, WO2017143038 discloses a deuterated chalcone derivative.

Summary of the invention

The present invention aims to provide an α-fluorochalcone derivative with a completely new structure, which has the activity of activating PPAR.

In order to solve the above technical problems, the present invention adopts the following technical solutions:

An α-fluorochalcone derivative is a compound represented by formula I or a pharmaceutically acceptable salt thereof:

Wherein: R ₁ and R ₂ are independently selected from H, halogen, CF ₃ , -CN, C _1-6 alkoxy, CF ₃ O, CHF ₂ O, C _1-6 alkylthio, CF ₃ S, CHF ₂ S, C _1-6 alkyl, C _1-6 alkyl sulfoxide group-, CF ₃ SO, C _1-6 alkyl sulfone group or CF ₃ SO ₂ , or selected from the group optionally by 1, 2 or Three R-substituted: C _1-6 alkyl, C _1-6 alkyl-S(=O)-, C _1-6 alkyl-S(=O) ₂ -, C _1-6 alkyl-( =0) ₂ -, C _1-6 alkoxy or C _1-6 alkylthio;

R ₃ and R ₄ are each independently selected from H, halogen, C _1-4 alkyl, C _1-4 alkoxy, including but not limited to Cl, Br, I, CH ₃ , Et, CH ₃ O;

R ₅ and R ₆ are each independently selected from H, C _1-6 alkyl, C _1-6 heteroalkyl, phenyl, 5-6 membered heteroaryl, R ₅ , R ₆ may also form a ring as C _{3 -6} cycloalkyl or 3-6 membered heterocycloalkyl; wherein R ₅ and R ₆ include but are not limited to methyl, ethyl, isopropyl, phenyl, pyrazolyl or pyridyl; R ₅ , R ₆ The ring is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

R _{7 is} selected from H or C _1-6 alkyl;

n is selected from 0, 1, 2, 3, 4, 5 or 6;

R is selected from H, F, Cl, Br, I, OH, CN, NH ₂ , COOH, C(=O)NH ₂ , Me, Et, CF ₃ , CHF ₂ , CH ₂ F, NHCH ₃ or N(CH ₃ ) ₂ .

In the preferred compound of formula I, R ₁ and R _{2 are} selected from H, halogen, CF ₃ , -CN, C _1-6 alkoxy, CF ₃ O, CHF ₂ O, C _1-6 alkylthio, CF ₃ S, CHF ₂ S, C _1-6 alkyl, C _1-6 alkyl sulfoxide group-, CF ₃ SO, C _1-6 alkyl sulfone group or CF ₃ SO ₂ ; wherein R ₁ , R _{2 are} preferably from Cl, Me, Et, CH ₃ O, EtO, n-Pr-O, i-PrO, CH ₃ S, EtS, n-PrS, i-PrO, CH ₃ SO, CH ₃ SO ₂ , CF ₃ O, CHF ₂ O, CF ₃ S, CHF ₂ S, CF ₃ SO or CF ₃ SO ₂ .

In the preferred compounds of formula I, R ₃ and R ₄ are each independently selected from H, halogen, C _1-4 alkyl or C _1-4 alkoxy, or each independently selected from the group optionally selected by 1, 2 or 3 One R-substituted C _1-4 alkyl group, C _1-4 alkoxy group.

In the preferred compound of formula I, R ₅ and R ₆ are each independently selected from H, C _1-6 alkyl, C _1-6 heteroalkyl, phenyl or 5-6 membered heteroaryl, R ₅ , R ₆ It can also form a C _3-6 cycloalkyl group or a 3-6 membered heterocycloalkyl group, R ₅ and R ₆ include but are not limited to methyl, ethyl, isopropyl, phenyl, pyrazolyl or pyridyl ; Or R ₅ , R ₆ form a ring to be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

Among the preferred compounds of formula I,

Selected from:

Among the preferred compounds of formula I,

Selected from:

An α-fluorochalcone derivative is a compound represented by formula II or a pharmaceutically acceptable salt thereof:

Wherein, when R _{1 is} selected from H or -XR, where X is selected from S, S(O), S(O) ₂ or O, and R is selected from Me, Et, CF ₃ , CHF ₂ , CH ₂ F, NHCH ₃ Or N(CH ₃ ) ₂ ; then R _{2 is} selected from H, halogen, C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkyl or halogenated C _1-6 alkoxy ;or

When R _{2 is} selected from H or -XR, wherein X is selected from S, S(O), S(O) ₂ or O, and R is selected from Me, Et, CF ₃ , CHF ₂ , CH ₂ F, NHCH ₃ or N (CH ₃ ) ₂ ; then R _{1 is} selected from H, halogen, C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkyl or halogenated C _1-6 alkoxy;

R ₃ and R ₄ are each independently selected from H, halogen, C _1-4 alkyl or C _1-6 alkoxy;

R ₅ and R ₆ are each independently selected from H, C _1-6 alkyl, phenyl or 5-6 membered heteroaryl, or R ₅ , R ₆ may also form a ring of C _3-6 cycloalkyl or 3 ～6-membered heterocycloalkyl;

R _{7 is} selected from H or C _1-6 alkyl;

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

The heteroaryl group and heterocycloalkyl group contain at least one heteroatom, and the heteroatom is selected from one or more of N, O, and S.

Preferably, it is a compound represented by formula IIa or a pharmaceutically acceptable salt thereof:

Wherein, R is selected from Me, Et, CF ₃ , CHF ₂ , CH ₂ F, NHCH ₃ or N(CH ₃ ) ₂ ;

R _{2 is} selected from H, halogen or C _1-6 alkyl;

R ₃ and R ₄ are each independently selected from H, halogen or C _1-4 alkyl;

R _{7 is} selected from H or C _1-6 alkyl;

Preferably, it is a compound represented by formula IIb or a pharmaceutically acceptable salt thereof:

R _{2 is} selected from H, halogen or C _1-6 alkyl;

R _{7 is} selected from H or C _1-6 alkyl;

Preferably, it is a compound represented by formula IIc or a pharmaceutically acceptable salt thereof:

R _{2 is} selected from H, halogen or C _1-6 alkyl;

R _{7 is} selected from H or C _1-6 alkyl;

Preferably, it is a compound represented by formula IId or a pharmaceutically acceptable salt thereof:

Wherein, R _{1 is} selected from H or -XR, X is selected from S, S(O), S(O) ₂ or O, and R is selected from Me, Et, CF ₃ , CHF ₂ , CH ₂ F, NHCH ₃ or N (CH ₃ ) ₂ ;

R _{2 is} selected from H, halogen or C _1-6 alkyl;

R _{7 is} selected from H or C _1-6 alkyl;

An α-fluorochalcone derivative, a compound numbered P001-P098 or a pharmaceutically acceptable salt thereof:

The present invention also provides a pharmaceutical composition comprising the aforementioned compound or a pharmaceutically acceptable salt thereof as an active ingredient, and one or more pharmaceutically acceptable carriers.

The present invention also provides a use of the aforementioned pharmaceutical composition in the preparation of a medicament for treating PPAR receptor-related diseases.

Preferably, PPAR receptor related diseases are: non-alcoholic steatohepatitis, liver fibrosis, insulin resistance, primary biliary cholangitis, dyslipidemia, hyperlipidemia, hypercholesterolemia, atherosclerosis , Hypertriglyceridemia, cardiovascular disease, obesity, kidney disease or degenerative brain disease.

More preferably, the kidney disease is selected from chronic kidney disease and renal failure, and the brain degenerative disease is selected from Alzheimer's disease.

Compared with the prior art, the beneficial effects of the present invention are as follows:

The present invention is modified on the basis of GFT-505 structure, developed a series of fluorochalcone derivatives, and carried out related biological experiments. The experimental results found that: in the in vitro model, α-fluorine substituted chalcone derivatives had a stronger inhibitory effect on liver fibrosis than the positive drug GFT-505; in the in vivo model, α-fluorine substituted chalcone derivatives The bioavailability of it also has a good performance.

Definition and explanation of related terms

Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A specific term or phrase without a special definition should not be considered as uncertain or unclear, but should be understood in its ordinary meaning. When a trade name appears in this article, it is meant to refer to its corresponding commodity or its active ingredient.

The term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues, but not Many toxicity, irritation, allergic reactions or other problems or complications are commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" refers to a salt of the compound of the present invention, which is prepared from a compound with specific substituents discovered in the present invention and a relatively non-toxic base. When the compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include but are not limited to sodium, potassium, calcium, magnesium, ammonium or organic ammonia.

In addition to salt forms, the compounds provided by the present invention also exist in prodrug forms. The prodrugs of the compounds described herein easily undergo chemical changes under physiological conditions to transform into the compounds of the invention. In addition, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in the in vivo environment.

Certain compounds of the present invention may exist in unsolvated or solvated forms, including hydrated forms. Generally speaking, the solvated form is equivalent to the unsolvated form, and both are included in the scope of the present invention.

The term "pharmaceutically acceptable carrier" refers to any preparation or carrier medium representative carrier that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects to the host or patient. , Vegetables and minerals, cream base, lotion base, ointment base, excipients, etc. These bases include suspending agents, tackifiers, penetration enhancers and the like. Their formulations are well known to those skilled in the field of cosmetics or topical medicine. For other information about the carrier, you can refer to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), and the content of this document is incorporated herein by reference.

The term "excipient" generally refers to the carrier, diluent and/or medium required to formulate an effective pharmaceutical composition.

For drugs or pharmacologically active agents, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect. For the oral dosage form of the present invention, the "effective amount" of one active substance in the composition refers to the amount required to achieve the desired effect when combined with another active substance in the composition. The determination of the effective amount varies from person to person, and depends on the age and general conditions of the recipient, as well as the specific active substance. The appropriate effective amount in a case can be determined by those skilled in the art according to routine experiments.

The terms "active ingredient", "therapeutic agent", "active substance" or "active agent" refer to a chemical entity that can effectively treat the target disorder, disease or condition.

The terms "optional", "optionally" or "preferably" refer to the event or condition described later that may but not necessarily occur, and the description includes the situation in which the event or condition occurs and the event or condition. The situation does not happen.

The term "substituted" means that any one or more hydrogen atoms on a specific atom are replaced by substituents, and may include deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the substituted compound is stable of. When the substituent is a keto group (ie =O), it means that two hydrogen atoms are substituted, and the ketone substitution will not occur on the aromatic group. The term "optionally substituted" means that it can be substituted or unsubstituted. Unless otherwise specified, the type and number of substituents can be arbitrary on the basis that they can be chemically realized.

When any variable (such as R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group can optionally be substituted with up to two Rs, and R in each case is independently selected. In addition, combinations of substituents and/or variants thereof are only permitted if such combinations result in stable compounds.

When the number of a linking group is 0, such as -(CRR) ₀ -, it means that the linking group is a single bond.

The term "alkyl" refers to a linear or branched saturated hydrocarbon group composed of carbon atoms and hydrogen atoms, such as C1-C6 alkyl, including but not limited to methyl, ethyl, propyl (including n-propyl and Isopropyl), butyl (containing n-butyl, isobutyl, sec-butyl or tert-butyl), pentyl (containing n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methyl Hexyl.

The term "cycloalkyl" refers to a monocyclic or bicyclic alkyl group composed of carbon atoms and hydrogen atoms, such as C3-C8 cycloalkyl, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclo Heptyl and cyclooctyl, etc.

The term "alkoxy" refers to a straight or branched chain alkyl group connected by an oxygen atom, such as a C1-C6 alkoxy group, including but not limited to methoxy, ethoxy, n-propoxy (containing n-propoxy Group and isopropoxy), butoxy (containing n-butoxy, isobutoxy, sec-butoxy or tert-butoxy), pentoxy (containing n-pentoxy, isopentoxy, new Pentyloxy), n-hexyloxy, 2-methylhexyloxy and the like.

The term "amino" refers to -NH ₂ .

The term "cycloalkyl" refers to a saturated monocyclic, bicyclic or polycyclic alkyl group composed of carbon atoms and hydrogen atoms, and which can be connected to the rest of the molecule through a single bond via any suitable carbon atom; In the case of a ring, it can be a parallel ring connection, a bridge ring connection or a spiral ring connection. In a certain scheme, typical monocyclic cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

The term "heterocycloalkyl" refers to a saturated cyclic group with heteroatoms, containing one or more heteroatoms independently selected from N, O, S, and the rest are stable 3-10 membered saturated carbons. Groups of heterocyclic ring systems. Unless otherwise specified in the specification, the heterocycloalkyl group may be a monocyclic, bicyclic or polycyclic ring system; when it is a polycyclic ring, it may be a fused ring connection, a bridged ring connection or a spiro ring connection . In a certain scheme, a typical 4-6 membered monocyclic heterocycloalkyl group containing one or more heteroatoms independently selected from N, O, and S includes but is not limited to

Wait. In a certain scheme, a typical 7-10 membered bicyclic heterocycloalkyl group containing one or more heteroatoms independently selected from N, O, and S includes but not limited to

Wait.

The term "aryl" refers to a full-carbon aromatic group with a fully conjugated π-electron system, which can be a single ring or a condensed ring, usually having 6-14 carbon atoms, preferably 6-12 carbon atoms, most It preferably has 6 carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl.

The term "heteroaryl" refers to an aromatic group containing heteroatoms, which can be a single ring or a condensed ring, preferably containing 1-4 5-12 membered heteroaryl groups independently selected from N, O, and S, including but Not limited to pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, Triazolyl, indolyl, etc. In a certain scheme, typical 5-6 membered monocyclic heteroaryl groups containing one or more heteroatoms independently selected from N, O, and S include but are not limited to

Wait.

The terms "halogenated C ₁ -C ₆ alkyl" and "halogenated C ₁ -C ₆ alkoxy" refer to one or more (especially 1 to 3) hydrogen atoms replaced by halogen atoms, especially fluorine Or chlorine atom.

The pharmaceutical composition of the present invention can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, Inhalants, gels, microspheres and aerosols, etc.

The pharmaceutical composition of the present invention can be manufactured by methods well known in the art, such as conventional mixing method, dissolution method, granulation method, sugar-coated pill method, grinding method, emulsification method, freeze-drying method and the like.

The administration route of the compound of the present invention or its pharmaceutically acceptable salt or its pharmaceutical composition includes but not limited to oral, rectal, transmucosal, enteral administration, or topical, transdermal, inhalation, parenteral , Sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration. The preferred route of administration is oral administration.

For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with a pharmaceutically acceptable carrier well known in the art. These carriers enable the compound of the present invention to be formulated into tablets, pills, lozenges, sugar coatings, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients. For example, for a pharmaceutical composition for oral administration, a tablet can be obtained by combining the active ingredient with one or more solid carriers, granulating the resulting mixture if necessary, and adding a small amount of excipients if necessary Processed into mixtures or granules to form tablets or tablet cores. The tablet core can be combined with a coating material suitable for enteric dissolution, and processed into a coating preparation form that is more conducive to absorption by organisms (such as humans).

Detailed ways

The following are specific embodiments of the present invention to further describe the technical solutions of the present invention, but the protection scope of the present invention is not limited to these embodiments. Any changes or equivalent substitutions that do not deviate from the concept of the present invention are included in the protection scope of the present invention.

Example 1: Compound P001

Step 1: Compound P001-b

At room temperature, the compound P001-a (4.00g, 24.06mmol, 1.00eq.), N-bromosuccinimide (NBS) (4.37g, 24.54mmol, 1.02eq.) and p-toluenesulfonic acid one The hydrate (4.58g, 24.06mmol, 1.00eq.) was dissolved in 12.00mL of anhydrous acetonitrile, and heated to 50°C at room temperature to react for 24 hours. The reaction solution was concentrated under reduced pressure, mixed with 40 mL of saturated sodium bicarbonate solution, extracted with dichloromethane (30 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried with anhydrous sodium sulfate, filtered, Concentrate under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography column (petroleum ether: ethyl acetate=95:5) to obtain compound P001-b. Yield: 60%.

MS m/s(ESI): 268.9[M+23].

Step 2: Compound P001-c

At room temperature, the compound P001-b (3.40g, 13.87mmol, 1.00eq.), tetrabutylammonium fluoride (TBAF) (5.70mL, 20.81mmol, 1.50eq.) and potassium fluoride (1.21g, 20.81mmol , 1.50eq.) was dissolved in anhydrous acetonitrile (12.00mL), heated to 80°C under the protection of nitrogen, and reacted for 24 hours. The reaction solution was concentrated under reduced pressure, mixed with 20 mL of water, extracted with ethyl acetate (30 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product . The crude product was purified by silica gel chromatography column (petroleum ether: ethyl acetate=95:5) to obtain compound P001-c. Yield: 34%.

MS m/s(ESI): 207.2[M+23].

Step 3: Compound P001-d

At room temperature, compound P001-c (2.19g, 11.89mmol, 1.00eq.) and 3,4-dimethyl-4-hydroxybenzaldehyde (1.79g, 11.89mmol, 1.00eq.) were dissolved in anhydrous methanol ( 55.00mL, 25.11eqv.), piperidine (3.30mL, 3.00eqv.) was added, and heated to room temperature under nitrogen to react for 96 hours. The reaction solution was concentrated under reduced pressure, mixed with 20 mL of water, extracted with ethyl acetate (20 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product . The crude product was purified by silica gel chromatography column (petroleum ether: dichloromethane=3:1) to obtain compound P001-d. Yield: 43%;

MS (ESI): 315.1 (M-1). ¹ H-NMR(400MHz; (CDCl ₃ )δ _H =7.83(d,J=8.2Hz,2H,ArH), 7.38(s,2H,ArH), 7.30(d,J=8.2Hz,2H,ArH) , 6.77 (d, J=37.2 Hz, 1H, CF=CH), 2.54 (s, 3H, SCH ₃ ), 2.28 (s, 6H, ArCH ₃ ).

Step 4: Compound P001-e

At room temperature, compound P001-d (0.50g, 1.58mmol, 1.00eq.) and tert-butyl α-bromoisobutyrate (3.00mL, 15.80mmol, 10.00eq.) were dissolved in anhydrous acetonitrile (15.00mL, 30.00eqv.), potassium carbonate (2.20g, 10.00eq.) was added, and the mixture was heated to 70°C for 96 hours under the protection of nitrogen. The reaction solution was concentrated under reduced pressure, diluted with 40 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by silica gel chromatography column (petroleum ether: dichloromethane=1:1) to obtain compound P001-e. Yield: 65%.

MS (ESI): 459.2 [M+1]. ¹ H-NMR(400MHz; (CDCl ₃ )δ _H =7.84(d,J=8.2Hz,2H,ArH),7.35(s,2H,ArH),7.29(d,J=8.2Hz,2H,ArH) ,6.76(d,J=37.0Hz,1H,CF=CH),2.54(s,3H,SCH ₃ ),2.26(s,6H,ArCH ₃ ),1.52(s,9H,OC(CH ₃ ) ₃ CO ), 1.46(s, 6H, C(CH ₃ ) ₂ ).

Step 5: Compound P001

At room temperature, compound P001-e (0.23 g, 0.51 mmol, 1.00 eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00 mL), and reacted at room temperature for 1.5 hours. The reaction solution was diluted by adding 4 mL of dichloromethane, and then added with 15 mL of saturated sodium bicarbonate solution to wash until weakly alkaline, then washed with saturated ammonium chloride solution to become weakly acidic, and extracted with dichloromethane (10 mL×3). Combine the organic phases with water It was washed once, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound P001. Yield: 78%.

MS (ESI): 401.7 [M-1]. ¹ H-NMR(400MHz; (CDCl ₃ )δ _H =7.85(d,J=7.2Hz,2H,ArH), 7.38(s,2H,ArH), 7.30(d,J=7.2Hz,2H,ArH) , 6.77 (d, J=36.8 Hz, 1H, CF=CH), 2.54 (s, 3H, SCH ₃ ), 2.28 (s, 6H, ArCH ₃ ), 1.55 (s, 6H, CH ₃ ).

Example 2: Compound P002

At room temperature, dissolve compound P001-d (100mg, 0.32mmol, 1.00eq.) and isopropyl 2-bromoisobutyrate (510μL, 3.16mmol, 10.00eq.) in 6.00mL of anhydrous acetonitrile, then add carbonic acid Potassium (437mg, 10.00eq.), heated to 70°C under the protection of nitrogen, reacted for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether: dichloromethane=1:10) to obtain compound P002. Yield: 81%.

MS (ESI): 445 (M+1). ¹ H-NMR(400MHz; (CDCl ₃ )δ _H =7.79(d,J=8.2Hz,2H,ArH),7.46(s,2H,ArH),7.41(d,J=8.2Hz,2H,ArH) , 6.84 (d, J = 38.4 Hz, 1H, CF = CH), 4.99 (m, 1H, OCH), 2.56 (s, 3H, SCH ₃ ), 2.17 (s, 6H, ArCH ₃ ), 1.39 (s, 6H, CH ₃ ), 1.26 (d, 6H, CH ₃ ).

Example 3: Compound P003

Step 1: Compound P003-a

At room temperature, compound P001-d (1.58mmol, 1.00eq.) and tert-butyl 2-bromopropionate (15.80mmol, 10.00eq.) were dissolved in anhydrous acetonitrile (15.00mL, 30.00eqv.), and then added Potassium carbonate (2.20g, 10.00eq.) was heated to 70°C at room temperature and reacted for 96 hours. The reaction solution was concentrated under reduced pressure, diluted with 40 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified with a silica gel column (petroleum ether: dichloromethane = 1:10) to obtain compound P003-a. Yield: 87.9%.

MS(ESI): 445.2 [M+1].

Step 2: Compound P003

At room temperature, compound P003-a (0.51 mmol, 1.00 eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00 mL.), and reacted at room temperature for 1.5 hours. The reaction solution was diluted by adding 4 mL of dichloromethane, and then added with 15 mL of saturated sodium bicarbonate solution to wash until weakly alkaline, then washed with saturated ammonium chloride solution to become weakly acidic, and extracted with dichloromethane (10 mL×3). Combine the organic phases with water Washed once, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound P003. Yield: 98.6%.

MS(ESI): 387.7[M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3 Hz, 2H, ArH), 7.40 (s, 2H, ArH), 7.30 (d, J = 8.3 Hz, 2H, ArH), 6.77 (d,J=36.8Hz,1H,CF=CH), 4.65(q,1H,OCH), 2.55(s,3H,SCH ₃ ), 2.32(s,6H,ArCH ₃ ), 1.56(d,3H, CH ₃ ).

Compound P003-1

Referring to the synthesis method of compound P003, S-2-bromopropionate tert-butyl ester was used instead of 2-bromopropionate tert-butyl ester to obtain the chiral target compound P003-1.

MS(ESI): 389.7[M+1]

Compound P003-2

Referring to the synthesis method of compound P003, R-2-bromopropionate tert-butyl ester was used instead of 2-bromopropionate tert-butyl ester to obtain the chiral target compound P003-2.

MS (ESI): 389.7 [M+1].

Example 4: Compound P004

Step 1: Compound P004-a

At room temperature, dissolve compound P001-d (100mg, 0.32mmol, 1.00eq.) and ethyl-1-bromobutane formate (510μL, 3.16mmol, 10.00eq.) in 6.00mL of anhydrous ethyl acetate, Then potassium carbonate (437mg, 10.00eq.) was added and heated to 70°C for 4 days under the protection of nitrogen. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether:dichloromethane=1:10) to obtain compound P004-a. Yield: 21%.

MS(ESI): 443.2[M+1].

Step 2: Compound P004

At room temperature, compound P004-a (0.05 mmol, 1.00 eq.) was dissolved in 1.00 mL of 10% sodium hydroxide solution and 1.00 mL of tetrahydrofuran, and reacted at room temperature for 3 hours. The reaction solution was added with 30 mL saturated ammonium chloride solution, extracted with dichloromethane (10 mL×3), combined the organic phases, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound P004. Yield: 95.0%.

MS (ESI): 413.7 [M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3 Hz, 2H, ArH), 7.40 (s, 2H, ArH), 7.30 (d, J = 8.3 Hz, 2H, ArH), 6.77 (d, J = 36.8Hz, 1H, CF = CH), 2.55 (s, 3H, SCH ₃ ), 2.52-2.62 (m, 4H, CH ₂ ), 2.32 (s, 6H, ArCH ₃ ), 1.56 (m ,2H,CH ₂ ).

Example 5: Compound P005

At room temperature, dissolve compound P001-d (100mg, 0.32mmol, 1.00eq.) and isobutyl 5-chloro-2,2-dimethylvalerate (214μL, 0.95mmol, 3.00eq.) in anhydrous acetonitrile To 6.00 mL, potassium iodide (5 mg, 0.10 eq.) and potassium carbonate (437 mg, 10.00 eq.) were added, and the reaction was heated to 70° C. for 48 hours under the protection of nitrogen. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether:dichloromethane=1:10) to obtain compound P005. Yield: 81.2%.

MS (ESI): 501.7 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3, 2H, ArH), 7.40 (s, 2H, ArH), 7.30 (d, J = 8.3 Hz, 2H, ArH), 6.77 ( d, J = 36.8 Hz, 1H, CF = CH), 4.65 (t, 2H, OCH ₂ ), 4.29 (d, 2H, OCH ₂ ), 2.55 (s, 3H, SCH ₃ ), 2.32 (s, 6H, ArCH ₃ ), 1.92 (m, 1H, CH), 1.85 (m, 4H, CH ₂ ), 1.32 (s, 6H, CH ₃ ), 1.02 (d, 6H, CH ₃ ).

Example 6: Compound P006

Step 1: Compound P006-a

At room temperature, dissolve compound P001-d (100mg, 0.32mmol, 1.00eq.) and tert-butyl 2-bromobutyrate (706mg, 3.16mmol, 10.00eq.) in 6.00mL of anhydrous acetonitrile, and then add potassium carbonate (437mg, 3.16mmol, 10.00eq.), heated to 70°C for 48 hours under the protection of nitrogen. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether: dichloromethane=1:10) to obtain compound P006-a. Yield: 80.2%.

MS (ESI): 459.5 [M+1].

Step 2: Compound P006

At room temperature, compound P006-a (0.23 mmol, 1.00 eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00 mL), and reacted at room temperature for 1.5 hours. The reaction solution was diluted by adding 4 mL of dichloromethane, and then added with 15 mL of saturated sodium bicarbonate solution to wash until weakly alkaline, then washed with saturated ammonium chloride solution to become weakly acidic, and extracted with dichloromethane (10 mL×3). Combine the organic phases with water Washed once, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound P006. Yield: 97.2%.

MS(ESI): 401.3[M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3 Hz, 2H, ArH), 7.40 (s, 2H, ArH), 7.30 (d, J = 8.3 Hz, 2H, ArH), 6.77 (d,J=36.8Hz,1H,CF=CH), 4.65 (t, 1H, OCH), 2.55 (s, 3H, SCH ₃ ), 2.32 (s, 6H, ArCH ₃ ), 1.83 (m, 2H, CH ₂ ), 1.56 (t, 3H, CH ₃ ).

Compound P006-1

Refer to the synthesis method of compound P006, and replace tert-butyl 2-bromobutyrate with R-2-bromobutyrate to obtain the chiral target compound P006-1.

MS(ESI): 401.3[M-1]

Compound P006-2

Referring to the synthesis method of compound P006, S-2-bromobutyrate tert-butyl ester was used instead of 2-bromobutyrate tert-butyl ester to obtain the chiral target compound P006-1.

MS(ESI): 401.3[M-1].

Example 7: Compound P007

Step 1: Compound P007-a

At room temperature, compound P001-d (100mg, 0.32mmol, 1.00eq.) and ethyl 2-bromoisovalerate (661mg, 3.16mmol, 10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, and then carbonic acid was added Potassium (437 mg, 3.16 mmol, 10.00 eq.), heated to 70° C. under the protection of nitrogen, reacted for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether:dichloromethane=1:10) to obtain compound P007-a. Yield: 89.2%.

MS(ESI): 445.5 [M+1].

Step 2: Compound P007

At room temperature, compound P007-a (0.25 mmol, 1.00 eq.) was dissolved in 1.00 mL of 10% sodium hydroxide solution and 1.00 mL of tetrahydrofuran, and reacted at room temperature for 3 hours. The reaction solution was added with 30 mL saturated ammonium chloride solution, extracted with dichloromethane (10 mL×3), combined the organic phases, washed with water once, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound P007. Yield: 95.3%.

MS(ESI): 415.7[M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3 Hz, 2H, ArH), 7.40 (s, 2H, ArH), 7.30 (d, J = 7.5 Hz, 2H, ArH), 6.77 (d,J=36.8Hz,1H,CF=CH), 4.63(d,1H,OCH), 2.55(s,3H,SCH ₃ ), 2.32(s,6H,ArCH ₃ ), 1.65(m,1H, CH), 1.10 (d, 6H, CH ₃ ).

Example 8: Compound P008

Step 1: Compound P008-a

At room temperature, the compound P001-d (100mg, 0.32mmol, 1.00eq.) and ethyl 3-chloro-2,2-dimethylpropionate (157mg, 0.95mmol, 3.00eq.) were dissolved in anhydrous acetonitrile 6.00 Add potassium iodide (5mg, 0.10eq.) and potassium carbonate (437mg, 3.16mmol, 10.00eq.) to the mL, and heat to 70°C for 48 hours under the protection of nitrogen. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether: dichloromethane=1:10) to obtain compound P008-a. Yield: 88%.

MS(ESI): 445.3 [M+1].

Step 2: Compound P008

At room temperature, compound P008-a (0.26 mmol, 1.00 eq.) was dissolved in 1.00 mL of 10% sodium hydroxide solution and 1.00 mL of tetrahydrofuran, and reacted at room temperature for 3 hours. The reaction solution was added with 30 mL saturated ammonium chloride solution, extracted with dichloromethane (10 mL×3), combined the organic phases, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P008. Yield: 89.0%.

MS(ESI): 415.7[M-1]. ¹ H-NMR(400MHz; (CDCl ₃ )δ _H =7.85(d,J=7.2Hz,2H,ArH), 7.38(s,2H,ArH), 7.30(d,J=7.2Hz,2H,ArH) ,6.77(d,J=36.8Hz,1H,CF=CH), 4.45(s,2H,OCH ₂ ), 2.54(s,3H,SCH ₃ ), 2.28(s,6H,ArCH ₃ ), 1.55(s ,6H,CH ₃ ).

Example 9: Compound P009

Step 1: Compound P009-a

At room temperature, compound P001-d (100mg, 0.32mmol, 1.00eq.) and ethyl 3-chloropropionate (130mg, 0.95mmol, 3.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, then potassium iodide (5mg , 0.032mmol, 0.10eq.) and potassium carbonate (437mg, 10.00eq.), heated to 70°C under the protection of nitrogen and reacted for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether:dichloromethane=1:10) to obtain compound P009-a. Yield: 89.1%.

MS(ESI): 417.7[M+1].

Step 2: Compound P009

At room temperature, compound P009-a (0.26 mmol, 1.00 eq.) was dissolved in 1.00 mL of 10% sodium hydroxide solution and 1.00 mL of tetrahydrofuran, and reacted at room temperature for 3 hours. The reaction solution was added with 30 mL saturated ammonium chloride solution, extracted with dichloromethane (10 mL×3), combined the organic phases, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P009. Yield: 81.2%.

MS(ESI): 387.3[M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3, 2H, ArH), 7.40 (s, 2H, ArH), 7.30 (d, J = 8.3 Hz, 2H, ArH), 6.77 ( d, J = 36.8 Hz, 1H, CF = CH), 4.65 (t, 2H, OCH ₂ ), 4.45 (q, 2H, COCH ₂ ), 2.55 (s, 3H, SCH ₃ ), 2.32 (s, 6H, ArCH ₃ ).

Example 10: Compound P010

Step 1: Compound P010-a

At room temperature, the compound P001-d (100mg, 0.32mmol, 1.00eq.) and methyl 1-bromocyclopentanecarboxylate (655mg, 3.16mmol, 10.00eq.) were dissolved in anhydrous acetonitrile 6.00m (437mg, 3.16 mmol, 10.00eq.), heated to 70°C for 4 days under the protection of nitrogen. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether: dichloromethane=1:10) to obtain compound P010-a. Yield: 14%.

MS(ESI): 441.4 [M+1].

Step 2: Compound P010

At room temperature, compound P010-a (0.02 mmol, 1.00 eq.) was dissolved in 1.00 mL of 10% sodium hydroxide solution and 1.00 mL of tetrahydrofuran, and reacted at room temperature for 3 hours. The reaction solution was added with 30 mL saturated ammonium chloride solution, extracted with dichloromethane (10 mL×3), combined the organic phases, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P010. Yield: 93.5%.

MS (ESI): 427.2 [M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3 Hz, 2H, ArH), 7.40 (s, 2H, ArH), 7.30 (d, J = 8.3 Hz, 2H, ArH), 6.77 (d, J=36.8 Hz, 1H, CF=CH), 2.55 (s, 3H, SCH ₃ ), 2.32 (s, 6H, ArCH ₃ ), 1.96-1.56 (m, 8H, CH ₂ ).

Example 11: Compound P011

Step 1: Compound P011-a

At room temperature, compound P001-d (100mg, 0.32mmol, 1.00eq.) and methyl 1-bromocyclopropanecarboxylate (566mg, 3.16mmol, 10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, and potassium carbonate was added (437mg, 3.16mmol, 10.00eq.), heated to 70°C under the protection of nitrogen and reacted for 4 days. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether: dichloromethane=1:10) to obtain compound P011-a. Yield: 15%.

MS(ESI): 415.3 [M+1].

Step 2: Compound P011

At room temperature, compound P011-a (0.03 mmol, 1.00 eq.) was dissolved in 1.00 mL of 10% sodium hydroxide solution and 1.00 mL of tetrahydrofuran, and reacted at room temperature for 3 hours. The reaction solution was added with 30 mL saturated ammonium chloride solution, extracted with dichloromethane (10 mL×3), combined the organic phases, washed with water once, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P011. Yield: 90.5%.

MS (ESI): 399.2 [M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3 Hz, 2H, ArH), 7.39 (s, 2H, ArH), 7.30 (d, J = 8.3 Hz, 2H, ArH), 6.77 (d, J=36.8 Hz, 1H, CF=CH), 2.55 (s, 3H, SCH ₃ ), 2.32 (s, 6H, ArCH ₃ ), 1.54 (m, 4H, CH ₂ ).

Example 12: Compound P012

Step 1: Compound P012-a

At room temperature, compound P001-d (100mg, 0.32mmol, 1.00eq.) and tert-butyl bromoacetate (617mg, 3.16mmol, 10.00eq.) were dissolved in anhydrous acetonitrile (15.00mL, 30.00eqv.), and then added Potassium carbonate (2.20g, 10.00eq.), heated to 70°C under the protection of nitrogen, reacted for 96 hours. The reaction solution was concentrated under reduced pressure, diluted with 40 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by silica gel chromatography column (petroleum ether: dichloromethane=1:10) to obtain compound P012-a. Yield: 93.9%.

MS(ESI): 431.2 [M+1].

Step 2: Compound P012

At room temperature, compound P012-a (0.28 mmol, 1.00 eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00 mL.), and reacted at room temperature for 1.5 hours. The reaction solution was diluted by adding 4 mL of dichloromethane, and then added with 15 mL of saturated sodium bicarbonate solution to wash until weakly alkaline, then washed with saturated ammonium chloride solution to become weakly acidic, and extracted with dichloromethane (10 mL×3). Combine the organic phases with water Washed once, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P012. Yield: 95.6%.

MS(ESI): 373.4[M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3 Hz, 2H, ArH), 7.40 (s, 2H, ArH), 7.30 (d, J = 8.3 Hz, 2H, ArH), 6.77 (d, J=36.8 Hz, 1H, CF=CH), 4.89 (s, 2H, OCH ₂ CO), 2.55 (s, 3H, SCH ₃ ), 2.32 (s, 6H, ArCH ₃ ).

Example 13: Compound P013

Step 1: Compound P013-b

At room temperature, the compound P013-a (5.00g, 22.71mmol, 1.00eq.), N-bromosuccinimide (NBS) (4.12g, 23.16mmol, 1.02eq.) and p-toluenesulfonic acid one The hydrate (4.32g, 22.71mmol, 1.00eq.) was dissolved in anhydrous acetonitrile (12.00mL, 3.00eqv.) and reacted at 50°C for 24 hours. The reaction solution was concentrated under reduced pressure, mixed with 40 mL of saturated sodium bicarbonate solution, extracted with dichloromethane (30 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried with anhydrous sodium sulfate, filtered, Concentrate under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography column (petroleum ether: ethyl acetate=95:5) to obtain compound P013-b. Yield: 70%; MS m/s(ESI): 322.9[M+23].

Step 2: Compound P013-c

At room temperature, the compound P013-b (3.50g, 11.70mmol, 1.00eq.), tetrabutylammonium fluoride (TBAF) (5.00mL, 17.55mmol, 1.50eq.) and potassium fluoride (1.05g, 17.55mmol , 1.50eq.) was dissolved in anhydrous acetonitrile (12.00mL, 3.53eqv.) and reacted at 80°C for 24 hours. The reaction solution was concentrated under reduced pressure, mixed with 20 mL of water, extracted with ethyl acetate (30 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product . The crude product was purified with a silica gel column (petroleum ether: ethyl acetate=95:5) to obtain compound P013-c. Yield: 30%; MS m/s(ESI): 261.2[M+23].

The third step: compound P013-d

At room temperature, the compound P013-c (2.00g, 8.40mmol, 1.00eq.) and 3,5-dimethyl-4-hydroxybenzaldehyde (1.79g, 8.40mmol, 1.00eq.) in anhydrous methanol (55.00 mL, 27.50eqv.) piperidine 2.30mL, 3.00eqv.), heated to room temperature under the protection of nitrogen for 96 hours. The reaction solution was concentrated under reduced pressure, mixed with 20 mL of water, extracted with ethyl acetate (20 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product . The crude product was purified by silica gel chromatography column (petroleum ether: dichloromethane=3:1) to obtain compound P013-d. Yield: 48%.

MS (ESI): 369.1 (M-1).

Step 4: Compound P013-e

At room temperature, the compound P013-d (500mg, 1.35mmol, 1.00eq.) and tert-butyl 2-bromoisobutyrate (2.60mL, 13.50mmol, 10.00eq.) were dissolved in anhydrous acetonitrile (15.00mL, 30.00 eqv.), potassium carbonate (1.87g, 10.00eqv.) was added, and the mixture was heated to 70°C for 96 hours under the protection of nitrogen. The reaction solution was concentrated under reduced pressure, diluted with 40 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by silica gel chromatography column (petroleum ether:dichloromethane=1:1) to obtain compound P013-e. Yield: 67%.

MS(ESI): 513.2 [M+1].

Step 5: Compound P013

At room temperature, compound P013-e (300 mg, 0.59 mmol, 1.00 eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00 mL), and reacted at room temperature for 1.5 hours. The reaction solution was diluted by adding 4 mL of dichloromethane, and then added with 15 mL of saturated sodium bicarbonate solution to wash until weakly alkaline, then washed with saturated ammonium chloride solution to become weakly acidic, and extracted with dichloromethane (10 mL×3). Combine the organic phases with water Washed once, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound P013. Yield: 77%.

MS(ESI): 455.7[M-1]. ¹ H-NMR (400MHz; (CDCl ₃ )δ _H 7.85 (d, J = 7.2Hz, 2H, ArH), 7.38 (s, 2H, ArH), 7.30 (d, J = 7.2Hz, 2H, ArH), 6.77 (d, J=36.8 Hz, 1H, CF=CH), 2.28 (s, 6H, ArCH ₃ ), 1.55 (s, 6H, CH ₃ ).

Example 14: Compound P014

Step 1: Compound P014-b

At room temperature, the compound P014-a (4.00g, 19.78mmol, 1.00eq.), N-bromosuccinimide (NBS) (3.59g, 20.18mmol, 1.02eq.) and p-toluenesulfonic acid one The hydrate (3.84g, 19.78mmol, 1.00eq.) was dissolved in anhydrous acetonitrile (12.00mL, 3.00eqv.) and reacted at 50°C for 24 hours. The reaction solution was concentrated under reduced pressure, mixed with 40 mL of saturated sodium bicarbonate solution, extracted with dichloromethane (30 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried with anhydrous sodium sulfate, filtered, Concentrate under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography column (petroleum ether: ethyl acetate=95:5) to obtain compound P014-b. Yield: 58%; MS m/s(ESI): 304.9[M+23].

Step 2: Compound P014-c

At room temperature, compound P014-b (3.00g, 10.67mmol, 1.00eq.), tetrabutylammonium fluoride (TBAF) (4.40mL, 16.01mmol, 1.50eq.) and potassium fluoride (930mg, 16.01mmol, 1.50eq.) was dissolved in anhydrous acetonitrile (12.00mL) and reacted at 80°C for 24 hours. The reaction solution was concentrated under reduced pressure, mixed with 20 mL of water, extracted with ethyl acetate (30 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product . The crude product was purified by silica gel chromatography column (petroleum ether: ethyl acetate=95:5) to obtain compound P014-c. Yield: 34%; MS m/s(ESI): 243.2[M+23].

The third step: compound P014-d

At room temperature, compound P014-c (700mg, 3.18mmol, 1.00eq.) and 3,5-dimethyl-4-hydroxybenzaldehyde (478mg, 3.18mmol, 1.00eq.) in anhydrous methanol (10.00mL) Medium piperidine (873μL, 3.00eqv.), heated to room temperature under the protection of nitrogen, and reacted for 96 hours. The reaction solution was concentrated under reduced pressure, mixed with 20 mL of water, extracted with ethyl acetate (20 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product . The crude product was purified by a silica gel chromatography column (petroleum ether: dichloromethane=3:1) to obtain compound P014-d. Yield: 43%.

MS(ESI): 351[M-1].

Step 4: Compound P014

At room temperature, dissolve compound P014-d (100mg, 0.27mmol, 1.00eq.) and isopropyl 2-bromoisobutyrate (504μL, 2.70mmol, 10.00eq.) in 6.00mL of anhydrous acetonitrile, then add carbonic acid Potassium (373mg, 2.70mmol, 10.00eq.), heated to 70°C under the protection of nitrogen, reacted for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether: dichloromethane=1:10) to obtain compound P014. Yield: 81%.

MS(ESI): 481[M+1]. ¹ H-NMR(400MHz; (CDCl ₃ )δ _H =7.79(d,J=8.2Hz,2H,ArH),7.46(s,2H,ArH),7.41(d,J=8.2Hz,2H,ArH) ,7.20(t,J=38.3Hz,1H,CHF ₂ ), 6.84(d,J=38.4Hz,1H,CF=CH), 4.99(m,1H,OCH), 2.17(s,6H,ArCH ₃ ) , 1.39 (s, 6H, CH ₃ ), 1.26 (d, 6H, CH ₃ ).

Example 15: Compound P015

Step 1: Compound P015-a

At room temperature, the compound P013-d (100mg, 0.27mmol, 1.00eq.) and tert-butyl 2-bromopropionate (2.70mmol, 10.00eq.) were dissolved in anhydrous acetonitrile (15.00mL, 30.00eqv.), and then Potassium carbonate (373mg, 2.70mmol, 10.00eq.) was added and heated to 70°C for 96 hours under the protection of nitrogen. The reaction solution was concentrated under reduced pressure, diluted with 40 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by silica gel chromatography column (petroleum ether:dichloromethane=1:10) to obtain compound P015-a. Yield: 92.6%.

MS (ESI): 499.3 [M+1].

Step 2: Compound P015

At room temperature, compound P015-a (0.22 mmol, 1.00 eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00 mL.), and reacted at room temperature for 1.5 hours. The reaction solution was diluted by adding 4 mL of dichloromethane, and then added with 15 mL of saturated sodium bicarbonate solution to wash until weakly alkaline, then washed with saturated ammonium chloride solution to become weakly acidic, and extracted with dichloromethane (10 mL×3). Combine the organic phases with water Washed once, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P015. Yield: 90.6%.

MS(ESI): 441.4[M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3 Hz, 2H, ArH), 7.40 (s, 2H, ArH), 7.30 (d, J = 8.3 Hz, 2H, ArH), 6.77 (d,J=36.8Hz,1H,CF=CH), 4.65(q,J=6.6Hz,1H,OCH), 2.32(s,6H,ArCH ₃ ), 1.56(d,J=6.6Hz,3H, CH ₃ ).

Example 16: Compound P016

Step 1: Compound P016-a

At room temperature, compound P014-d (95mg, 0.27mmol, 1.00eq.) and ethyl-1-bromocyclobutanecarboxylate (438μL, 2.70mmol, 10.00eq.) were dissolved in anhydrous acetonitrile (6.00mL) , Then add potassium carbonate (373mg, 2.70mmol, 10.00eq.), and heat to 70°C for 4 days under the protection of nitrogen. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether:dichloromethane=1:10) to obtain compound P016-a. Yield: 26.0%.

MS (ESI): 479.2 [M+1].

Step 2: Compound P016

At room temperature, compound P016-a (0.05 mmol, 1.00 eq.) was dissolved in 1.00 mL of 10% sodium hydroxide solution and 1.00 mL of tetrahydrofuran, and reacted at room temperature for 3 hours. The reaction solution was added with 30 mL saturated ammonium chloride solution, extracted with dichloromethane (10 mL×3), combined the organic phases, washed with water once, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P016. Yield: 83.6%.

MS (ESI): 449.7 [M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3 Hz, 2H, ArH), 7.40 (s, 2H, ArH), 7.30 (d, J = 8.3 Hz, 2H, ArH), 7.25 (t,J=37.2Hz,1H,CHF ₂ ), 6.77(d,J=36.8Hz,1H,CF=CH), 2.85-2.75(m,2H,CH ₂ ),2.52-2.62(m,2H, CH ₂ ), 2.32 (s, 6H, ArCH ₃ ).

Example 17: Compound P017

At room temperature, the compound P013-d (100mg, 0.27mmol, 1.00eq.) and 5-chloro-2,2-dimethylvalerate isobutyl ester (214μL, 0.81mmol, 3.00eq.) were dissolved in anhydrous acetonitrile To 6.00 mL, potassium iodide (5 mg, 0.032 mmol, 0.10 eq.) and potassium carbonate (373 mg, 2.70 mmol, 10.00 eq.) were added, and the reaction was heated to 70° C. for 48 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether: dichloromethane=1:10) to obtain compound P017. Yield: 88.3%.

MS (ESI): 555.7 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3 Hz, 2H, ArH), 7.40 (s, 2H, ArH), 7.30 (d, J = 8.3 Hz, 2H, ArH), 6.77 (d,J=36.8Hz,1H,CF=CH), 4.65(t,2H,OCH ₂ ), 4.29(d,2H,OCH ₂ ), 2.32(s,6H,ArCH ₃ ),1.92(m,1H , CH), 1.85 (m, 4H, CH ₂ ), 1.32 (s, 6H, CH ₃ ), 1.02 (d, 6H, CH ₃ ).

Example 18: Compound P018

Step 1: Compound P018-a

At room temperature, dissolve compound P014-d (95mg, 0.27mmol, 1.00eq.) and tert-butyl 2-bromobutyrate (527mg, 2.70mmol, 10.00eq.) in 6.00mL of anhydrous acetonitrile, and then add potassium carbonate (373mg, 2.70mmol, 10.00eq.), heated to 70°C for 48 hours under the protection of nitrogen. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether: dichloromethane=1:10) to obtain compound P018-a. Yield: 80.1%.

MS(ESI): 495.5 [M+1].

Step 2: Compound P018

At room temperature, compound P018-a (0.19 mmol, 1.00 eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00 mL), and reacted at room temperature for 1.5 hours. The reaction solution was diluted by adding 4 mL of dichloromethane, and then added with 15 mL of saturated sodium bicarbonate solution to wash until weakly alkaline, then washed with saturated ammonium chloride solution to become weakly acidic, and extracted with dichloromethane (10 mL×3). Combine the organic phases with water Washed once, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P018. Yield: 92.2%.

MS (ESI): 437.3 [M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3 Hz, 2H, ArH), 7.40 (s, 2H, ArH), 7.30 (d, J = 8.3 Hz, 2H, ArH), 7.21 (t,J=37.2Hz,1H,CHF ₂ ), 6.77(d,J=36.8Hz,1H,CF=CH), 4.65(t,1H,OCH), 2.32(s,6H,ArCH ₃ ),1.83 (m, 2H, CH ₂ ), 1.56 (t, 3H, CH ₃ ).

Example 19: Compound P019

Step 1: Compound P019-a

At room temperature, compound P013-d (100mg, 0.27mmol, 1.00eq.) and ethyl 2-bromoisovalerate (565mg, 2.70mmol, 10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, and then carbonic acid was added Potassium (373mg, 2.70mmol, 10.00eq.), heated to 70°C under the protection of nitrogen, reacted for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether: dichloromethane=1:10) to obtain compound P019-a. Yield: 56.2%.

MS (ESI): 499.5 [M+1].

Step 2: Compound P019

At room temperature, compound P019-a (0.13 mmol, 1.00 eq.) was dissolved in 1.00 mL of 10% sodium hydroxide solution and 1.00 mL of tetrahydrofuran, and reacted at room temperature for 3 hours. The reaction solution was added with 30 mL saturated ammonium chloride solution, extracted with dichloromethane (10 mL×3), combined the organic phases, washed with water once, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P019. Yield: 95.0%.

MS (ESI): 469.7 [M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3 Hz, 2H, ArH), 7.40 (s, 2H, ArH), 7.30 (d, J = 8.3 Hz, 2H, ArH), 6.77 (d,J=36.8Hz,1H,CF=CH),4.63(d,1H,OCH),2.32(s,6H,ArCH ₃ ),1.65(m,1H,CH),1.10(d,6H,CH ₃ ).

Example 20: Compound P020

Step 1: Compound P020-a

At room temperature, the compound P014-d (100mg, 0.27mmol, 1.00eq.) and ethyl 3-chloro-2,2-dimethylpropionate (134mg, 0.81mmol, 3.00eq.) were dissolved in anhydrous acetonitrile 6.00 Add potassium iodide (5mg, 0.10eq.) and potassium carbonate (373mg, 2.70mmol, 10.00eq.) to the mL, and heat to 70°C for 48 hours under the protection of nitrogen. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether: dichloromethane=1:10) to obtain compound P020-a. Yield: 84%.

MS (ESI): 481.3 [M+1].

Step 2: Compound P020

At room temperature, compound P020-a (0.20 mmol, 1.00 eq.) was dissolved in 1.00 mL of 10% sodium hydroxide solution and 1.00 mL of tetrahydrofuran, and reacted at room temperature for 3 hours. The reaction solution was added with 30 mL saturated ammonium chloride solution, extracted with dichloromethane (10 mL×3), combined the organic phases, washed with water once, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P020. Yield: 80.0%.

MS (ESI): 451.7 [M-1]. ¹ H-NMR (400MHz; (CDCl ₃ )δ _H = 7.85 (d, J = 7.2 Hz, 2H, ArH), 7.38 (s, 2H, ArH), 7.30 (d, J = 7.2 Hz, 2H, ArH) , 7.21 (t, J = 37.5 Hz, 1H, CHF ₂ ), 6.77 (d, J = 36.8 Hz, 1H, CF = CH), 4.45 (s, 2H, OCH ₂ ), 2.28 (s, 6H, ArCH ₃ ), 1.55(s, 6H, CH ₃ ).

Example 21: Compound P021

Step 1: Compound P021-a

At room temperature, the compound P013-d (100mg, 0.27mmol, 1.00eq.) and ethyl 3-chloropropionate (111mg, 0.81mmol, 3.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, then potassium iodide (5mg , 0.032mmol, 0.10eq.) and potassium carbonate (373mg, 2.70mmol, 10.00eq.), heated to 70°C for 48 hours under the protection of nitrogen. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether: dichloromethane=1:10) to obtain compound P021-a. Yield: 93.1%.

MS (ESI): 471.7 [M+1].

Step 2: Compound P021

At room temperature, compound P021-a (0.21 mmol, 1.00 eq.) was dissolved in 1.00 mL of 10% sodium hydroxide solution and 1.00 mL of tetrahydrofuran, and reacted at room temperature for 3 hours. The reaction solution was added with 30 mL saturated ammonium chloride solution, extracted with dichloromethane (10 mL×3), combined the organic phases, washed with water once, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P021. Yield: 52.2%.

MS(ESI): 441.3[M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3 Hz, 2H, ArH), 7.40 (s, 2H, ArH), 7.30 (d, J = 8.3 Hz, 2H, ArH), 6.77 (d, J=36.8 Hz, 1H, CF=CH), 4.65 (t, 2H, OCH ₂ ), 4.45 (q, 2H, COCH ₂ ), 2.32 (s, 6H, ArCH ₃ ).

Example 22: Compound P022

Step 1: Compound P022-a

At room temperature, compound P013-d (100mg, 0.27mmol, 1.00eq.) and methyl 1-bromocyclopentanecarboxylate (560mg, 2.70mmol, 10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, and then added Potassium carbonate (373mg, 2.70mmol, 10.00eq.), heated to 70°C under nitrogen protection, and reacted for 4 days. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether: dichloromethane=1:10) to obtain compound P022-a. Yield: 10%.

MS(ESI): 497.4 [M+1].

Step 2: Compound P022

At room temperature, compound P022-a (0.01 mmol, 1.00 eq.) was dissolved in 1.00 mL of 10% sodium hydroxide solution and 1.00 mL of tetrahydrofuran, and reacted at room temperature for 3 hours. The reaction solution was added with 30 mL saturated ammonium chloride solution, extracted with dichloromethane (10 mL×3), combined the organic phases, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P022. Yield: 69.5%.

MS(ESI): 481.2[M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3 Hz, 2H, ArH), 7.40 (s, 2H, ArH), 7.30 (d, J = 8.3 Hz, 2H, ArH), 6.77 (d, J=36.8 Hz, 1H, CF=CH), 2.32 (s, 6H, ArCH ₃ ), 1.96-1.56 (m, 8H, CH ₂ ).

Example 23: Compound P023

Step 1: Compound P023-a

At room temperature, compound P014-e (95mg, 0.27mmol, 1.00eq.) and methyl 1-bromocyclopropanecarboxylate (483mg, 2.70mmol, 10.00eq.) were dissolved in 6.00mL of anhydrous acetonitrile, and then potassium carbonate was added (373mg, 2.70mmol, 10.00eq.), heated to 70°C for 4 days under the protection of nitrogen. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether:dichloromethane=1:10) to obtain compound P023-a. Yield: 25%.

MS(ESI): 451.3 [M+1].

Step 2: Compound P023

At room temperature, compound P023-a (0.04 mmol, 1.00 eq.) was dissolved in 1.00 mL of 10% sodium hydroxide solution and 1.00 mL of tetrahydrofuran, and reacted at room temperature for 3 hours. The reaction solution was added with 30 mL saturated ammonium chloride solution, extracted with dichloromethane (10 mL×3), combined the organic phases, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P023. Yield: 91.5%.

MS (ESI): 435.2 [M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3 Hz, 2H, ArH), 7.39 (s, 2H, ArH), 7.30 (d, J = 8.3 Hz, 2H, ArH), 7.20 (t, J=38.3 Hz, 1H, CHF ₂ ), 6.77 (d, J=36.8 Hz, 1H, CF=CH), 2.32 (s, 6H, ArCH ₃ ), 1.54 (m, 4H, CH ₂ ).

Example 24: Compound P024

Step 1: Compound P024-a

At room temperature, compound P013-d (100mg, 0.27mmol, 1.00eq.) and tert-butyl bromoacetate (527mg, 2.70mmol, 10.00eq.) were dissolved in anhydrous acetonitrile (15.00mL, 30.00eqv.), and then added Potassium carbonate (373mg, 2.70mmol, 10.00eq.), heated to 70°C under nitrogen protection, and reacted for 96 hours. The reaction solution was concentrated under reduced pressure, diluted with 40 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified with a silica gel column (petroleum ether: dichloromethane = 1:10) to obtain compound P024-a. Yield: 93.8%.

MS(ESI): 485.2 [M+1].

Step 2: Compound P024

At room temperature, compound P024-a (0.23 mmol, 1.00 eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00 mL), and reacted at room temperature for 1.5 hours. The reaction solution was diluted by adding 4 mL of dichloromethane, and then added with 15 mL of saturated sodium bicarbonate solution to wash until weakly alkaline, then washed with saturated ammonium chloride solution to become weakly acidic, and extracted with dichloromethane (10 mL×3). Combine the organic phases with water Washed once, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P024. Yield: 95.6%.

MS (ESI): 427.3 [M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3 Hz, 2H, ArH), 7.40 (s, 2H, ArH), 7.30 (d, J = 8.3 Hz, 2H, ArH), 6.77 (d, J=36.8 Hz, 1H, CF=CH), 4.89 (s, 2H, OCH ₂ CO), 2.32 (s, 6H, ArCH ₃ ).

Example 25: Compound P025

Step 1: Compound P025-b

At room temperature, the compound P025-a (5.00g, 25.25mmol, 1.00eq.), N-bromosuccinimide (NBS) (4.587g, 25.57mmol, 1.02eq.) and p-toluenesulfonic acid one The hydrate (4.80g, 25.25mmol, 1.00eq.) was dissolved in anhydrous acetonitrile (15.00mL, 3.00eqv.) and reacted at 50°C for 24 hours. The reaction solution was concentrated under reduced pressure, mixed with 40 mL of saturated sodium bicarbonate solution, extracted with dichloromethane (30 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried with anhydrous sodium sulfate, filtered, Concentrate under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography column (petroleum ether: ethyl acetate=95:5) to obtain compound P025-b. Yield: 60%; MS m/s(ESI): 300.9[M+23].

Step 2: Compound P025-c

At room temperature, compound P025-b (3.50g, 12.63mmol, 1.00eq.), tetrabutylammonium fluoride (TBAF) (5.20mL, 18.94mmol, 1.50eq.) and potassium fluoride (1.10g, 18.94mmol , 1.50eq.) was dissolved in anhydrous acetonitrile (18.00mL, 5.14eqv.) and reacted at 80°C for 24 hours. The reaction solution was concentrated under reduced pressure, mixed with 20 mL of water, extracted with ethyl acetate (30 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product . The crude product was purified with a silica gel column (petroleum ether: ethyl acetate=95:5) to obtain compound P025-c. Yield: 42%; MS m/s(ESI): 239.2[M+23].

The third step: Compound P025-d

At room temperature, the compound P025-c (1.10g, 5.09mmol, 1.00eq.) and 3,5-dimethyl-4-hydroxybenzaldehyde (764mg, 5.09mmol, 1.00eq.) in anhydrous methanol (27.50mL , 25.00eqv.) in piperidine (1.40mL, 3.00eqv.), heated to room temperature under the protection of nitrogen to react for 96 hours. The reaction solution was concentrated under reduced pressure, mixed with 20 mL of water, extracted with ethyl acetate (20 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product . The crude product was purified by silica gel chromatography column (petroleum ether: dichloromethane=3:1) to obtain compound P025-d. Yield: 53%.

MS (ESI): 347.1 (M-1).

The fourth step: compound P025-g

At room temperature, compound P025-d (0.50g, 1.44mmol, 1.00eq.) and tert-butyl 2-bromoisobutyrate (2.70mL, 14.35mmol, 10.00eq.) were dissolved in anhydrous acetonitrile (15.00mL, 30.00eqv.), then potassium carbonate (2.20g, 10.00eqv.) was added, and the mixture was heated to 70°C for 96 hours under the protection of nitrogen. The reaction solution was concentrated under reduced pressure, diluted with 40 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by silica gel chromatography column (petroleum ether:dichloromethane=1:1) to obtain compound P025-e. Yield: 67%.

MS(ESI): 491.2 [M+1].

Step 5: Compound P025

At room temperature, compound P025-e (0.25 g, 0.58 mmol, 1.00 eq.) was dissolved in a 25% trifluoroacetic acid in dichloromethane solution (4.00 mL.), and reacted at room temperature for 1.5 hours. The reaction solution was diluted by adding 4 mL of dichloromethane, then added with 15 mL of saturated sodium bicarbonate solution to wash until weakly alkaline, then washed with saturated ammonium chloride solution to make it weakly acidic, extracted with dichloromethane (10 mL×3), combined the organic phases, and water Washed once, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 25. Yield: 80%.

MS (ESI): 433.4 [M-1]. ¹ H-NMR(400MHz; (CDCl ₃ )δ _H =8.54(d,J=7.2Hz,2H,ArH), 7.38(s,2H,ArH), 7.30(d,J=7.2Hz,2H,ArH) , 6.77 (d, J=36.8 Hz, 1H, CF=CH), 3.32 (s, 3H, SO ₂ CH ₃ ), 2.28 (s, 6H, ArCH ₃ ), 1.55 (s, 6H, CH ₃ ).

Example 26: Compound P026

At room temperature, dissolve compound P025-d (100mg, 0.29mmol, 1.00eq.) and isopropyl 2-bromoisobutyrate (463μL, 2.87mmol, 10.00eq.) in 6.00mL of anhydrous acetonitrile, then add carbonic acid Potassium (397mg, 2.87mmol, 10.00eq.), heated to 70°C under the protection of nitrogen, reacted for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether: dichloromethane=1:10) to obtain compound P026. Yield: 85%.

MS (ESI): 477 (M+1). ¹ H-NMR(400MHz; (CDCl ₃ )δ _H =8.56(d,J=8.2Hz,2H,ArH),7.46(s,2H,ArH),7.41(d,J=8.2Hz,2H,ArH) , 6.84 (d, J = 38.4 Hz, 1H, CF = CH), 4.99 (m, 1H, OCH), 3.32 (s, 3H, SO ₂ CH ₃ ), 2.17 (s, 6H, ArCH ₃ ), 1.39 ( s, 6H, CH ₃ ), 1.26 (d, 6H, CH ₃ ).

Example 27: Compound P027

Step 1: Compound P027-a

At room temperature, compound P025-d (100mg, 0.29mmol, 1.00eq.) and tert-butyl 2-bromopropionate (477mg, 2.87mmol, 10.00eq.) were dissolved in anhydrous acetonitrile (15.00mL, 30.00eqv.) , Then add potassium carbonate (397mg, 2.87mmol, 10.00eq.), heat to 70°C under nitrogen protection and react for 96 hours. The reaction solution was concentrated under reduced pressure, diluted with 40 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by silica gel chromatography column (petroleum ether: dichloromethane=1:10) to obtain compound P027-a. Yield: 82.9%.

MS (ESI): 477.2 [M+1].

Step 2: Compound P027

At room temperature, compound P027-a (0.22 mmol, 1.00 eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00 mL), and reacted at room temperature for 1.5 hours. The reaction solution was diluted by adding 4 mL of dichloromethane, and then added with 15 mL of saturated sodium bicarbonate solution to wash until weakly alkaline, then washed with saturated ammonium chloride solution to become weakly acidic, and extracted with dichloromethane (10 mL×3). Combine the organic phases with water Washed once, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P027. Yield: 92.6%.

MS (ESI): 419.7 [M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 8.54 (d, J = 8.3 Hz, 2H, ArH), 7.40 (s, 2H, ArH), 7.30 (d, J = 8.3 Hz, 2H, ArH), 6.77 (d, J = 36.8Hz, 1H, CF = CH), 4.65 (q, 1H, OCH), 3.32 (s, 3H, SO ₂ CH ₃ ), 2.32 (s, 6H, ArCH ₃ ), 1.56 (d, 3H, CH ₃ ).

Example 28: Compound P028

The first step: Compound P028-a

At room temperature, compound P025-d (100mg, 0.29mmol, 1.00eq.) and ethyl-1-bromocyclobutanecarboxylate (465μL, 2.87mmol, 10.00eq.) were dissolved in 6.00mL of anhydrous acetonitrile, Then potassium carbonate (397mg, 2.87mmol, 10.00eq.) was added and heated to 70°C for 4 days under the protection of nitrogen. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether:dichloromethane=1:10) to obtain compound P028-a. Yield: 26%.

MS (ESI): 475.2 [M+1].

Step 2: Compound P028

At room temperature, compound P028-a (0.05 mmol, 1.00 eq.) was dissolved in 1.00 mL of 10% sodium hydroxide solution and 1.00 mL of tetrahydrofuran, and reacted at room temperature for 3 hours. The reaction solution was added with 30 mL saturated ammonium chloride solution, extracted with dichloromethane (10 mL×3), combined the organic phases, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P028. Yield: 92.0%.

MS(ESI): 445.7[M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 8.54 (d, J = 8.3 Hz, 2H, ArH), 7.40 (s, 2H, ArH), 7.30 (d, J = 8.3 Hz, 2H, ArH), 6.77 (d,J=36.8Hz,1H,CF=CH),3.32(s,3H,SO ₂ CH ₃ ),2,85-2.75(m,4H,CH ₂ ),2.52-2.62(m,2H,CH ₂ ), 2.32 (s, 6H, ArCH ₃ ).

Example 29: Compound P029

At room temperature, compound P025-d (100mg, 0.29mmol, 1.00eq.) and 5-chloro-2,2-dimethylvalerate isobutyl ester (195μL, 0.86mmol, 3.00eq.) were dissolved in anhydrous acetonitrile Add potassium iodide (5mg, 0.032mmol, 0.10eq.) and potassium carbonate (397mg, 2.87mmol, 10.00eq.) to 6.00mL, and heat to 70°C for 48 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether: dichloromethane=1:10) to obtain compound P029. Yield: 82.6%.

MS (ESI): 533.7 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 7.3, 2H, ArH), 7.40 (s, 2H, ArH), 7.30 (d, J = 8.3 Hz, 2H, ArH), 6.77 ( d, J = 36.8 Hz, 1H, CF = CH), 4.65 (t, 2H, OCH ₂ ), 4.29 (d, 2H, OCH ₂ ), 3.32 (s, 3H, SO ₂ CH ₃ ), 2.32 (s, 6H, ArCH ₃ ), 1.92 (m, 1H, CH), 1.85 (m, 4H, CH ₂ ), 1.32 (s, 6H, CH ₃ ), 1.02 (d, 6H, CH ₃ ).

Example 30: Compound P030

Step 1: Compound P030-a

At room temperature, dissolve compound P025-d (100mg, 0.29mmol, 1.00eq.) and tert-butyl 2-bromobutyrate (560mg, 2.87mmol, 10.00eq.) in 6.00mL of anhydrous acetonitrile, and then add potassium carbonate (397mg, 2.87mmol, 10.00eq.), heated to 70°C under the protection of nitrogen and reacted for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether: dichloromethane=1:10) to obtain compound P030-a. Yield: 84.2%.

MS (ESI): 491.5 [M+1].

Step 2: Compound P030

At room temperature, compound P030-a (0.22 mmol, 1.00 eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00 mL), and reacted at room temperature for 1.5 hours. The reaction solution was diluted by adding 4 mL of dichloromethane, and then added with 15 mL of saturated sodium bicarbonate solution to wash until weakly alkaline, then washed with saturated ammonium chloride solution to become weakly acidic, and extracted with dichloromethane (10 mL×3). Combine the organic phases with water Washed once, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P030. Yield: 97.2%.

MS (ESI): 433.3 [M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 8.54 (d, J = 8.3 Hz, 2H, ArH), 7.40 (s, 2H, ArH), 7.30 (d, J = 8.3 Hz, 2H, ArH), 6.77 (d, J = 36.8Hz, 1H, CF = CH), 4.65 (t, 1H, OCH), 3.34 (s, 3H, SO ₂ CH ₃ ), 2.32 (s, 6H, ArCH ₃ ), 1.83 (m, 2H, CH ₂ ), 1.56 (d, 3H, CH ₃ ).

Example 31: Compound P031

Step 1: Compound P031-a

At room temperature, compound P025-d (100mg, 0.29mmol, 1.00eq.) and ethyl 2-bromoisovalerate (601mg, 2.87mmol, 10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, and then carbonic acid was added Potassium (397mg, 2.87mmol, 10.00eq.), heated to 70°C under the protection of nitrogen, reacted for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether:dichloromethane=1:10) to obtain compound P031-a. Yield: 79.2%.

MS(ESI): 477.5[M+1].

Step 2: Compound P031

At room temperature, compound P031-a (0.20 mmol, 1.00 eq.) was dissolved in 1.00 mL of 10% sodium hydroxide solution and 1.00 mL of tetrahydrofuran, and reacted at room temperature for 3 hours. The reaction solution was added with 30 mL saturated ammonium chloride solution, extracted with dichloromethane (10 mL×3), combined the organic phases, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P031. Yield: 91.3%.

MS(ESI): 447.7[M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 8.54 (d, J = 8.3 Hz, 2H, ArH), 7.40 (s, 2H, ArH), 7.30 (d, J = 8.3 Hz, 2H, ArH), 6.77 (d, J = 36.8Hz, 1H, CF = CH), 4.63 (d, 1H, OCH), 3.34 (s, 3H, SO ₂ CH ₃ ), 2.32 (s, 6H, ArCH ₃ ), 1.65 (m, 1H, CH), 1.10 (d, 6H, CH ₃ ).

Example 32: Compound P032

Step 1: Compound P032-a

At room temperature, the compound P025-d (100mg, 0.29mmol, 1.00eq.) and ethyl 3-chloro-2,2-dimethylpropionate (142mg, 0.86mmol, 3.00eq.) were dissolved in anhydrous acetonitrile 6.00 Add potassium iodide (5mg, 0.10eq.) and potassium carbonate (397mg, 2.87mmol, 10.00eq.) to the mL, and heat to 70°C for 48 hours under the protection of nitrogen. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether:dichloromethane=1:10) to obtain compound P032-a. Yield: 82%.

MS (ESI): 477.3 [M+1].

Step 2: Compound P032

At room temperature, compound P032-a (0.21 mmol, 1.00 eq.) was dissolved in 1.00 mL of 10% sodium hydroxide solution and 1.00 mL of tetrahydrofuran, and reacted at room temperature for 3 hours. The reaction solution was added with 30 mL saturated ammonium chloride solution, extracted with dichloromethane (10 mL×3), combined the organic phases, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P032. Yield: 81.0%.

MS(ESI): 447.7[M-1]. ¹ H-NMR(400MHz; (CDCl ₃ )δ _H =8.54(d,J=7.2Hz,2H,ArH), 7.38(s,2H,ArH), 7.30(d,J=7.2Hz,2H,ArH) ,6.77(d,J=36.8Hz,1H,CF=CH), 4.45(s, 2H, OCH ₂ ), 3.34(s, 3H, SO ₂ CH ₃ ), 2.28(s, 6H, ArCH ₃ ), 1.55 (s, 6H, CH ₃ ).

Example 33: Compound P033

Step 1: Compound P033-a

At room temperature, compound P025-d (100mg, 0.29mmol, 1.00eq.) and ethyl 3-chloropropionate (118mg, 0.86mmol, 3.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, then potassium iodide (5mg , 0.032mmol, 0.10eq.) and potassium carbonate (397mg, 2.87mmol, 10.00eq.), heated to 70°C for 48 hours under the protection of nitrogen. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether: dichloromethane=1:10) to obtain compound P033-a. Yield: 90.1%.

MS (ESI): 449.7 [M+1].

Step 2: Compound P033

At room temperature, compound P033-a (0.25 mmol, 1.00 eq.) was dissolved in 1.00 mL of 10% sodium hydroxide solution and 1.00 mL of tetrahydrofuran, and reacted at room temperature for 3 hours. The reaction solution was added with 30 mL saturated ammonium chloride solution, extracted with dichloromethane (10 mL×3), combined the organic phases, washed with water once, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P033. Yield: 81.2%.

MS (ESI): 419.3 [M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 8.54 (d, J = 7.3, 2H, ArH), 7.40 (s, 2H, ArH), 7.30 (d, J = 8.3 Hz, 2H, ArH), 6.77 ( d, J = 36.8Hz, 1H, CF = CH), 4.65 (t, 2H, OCH ₂ ), 4.45 (t, 2H, COCH ₂ ), 3.34 (s, 3H, SO ₂ CH ₃ ), 2.32 (s, 6H, ArCH ₃ ).

Example 34: Compound P034

The first step: compound P034-a

At room temperature, compound P025-d (100mg, 0.29mmol, 1.00eq.) and methyl 1-bromocyclopentanecarboxylate (600mg, 2.87mmol, 10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, and then added Potassium carbonate (397mg, 2.87mmol, 10.00eq.), heated to 70°C under nitrogen protection, and reacted for 4 days. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether:dichloromethane=1:10) to obtain compound P034-a. Yield: 17%.

MS(ESI): 475.4[M+1]

Step 2: Compound P034

At room temperature, compound P034-a (0.02 mmol, 1.00 eq.) was dissolved in 1.00 mL of 10% sodium hydroxide solution and 1.00 mL of tetrahydrofuran, and reacted at room temperature for 3 hours. The reaction solution was added with 30 mL saturated ammonium chloride solution, extracted with dichloromethane (10 mL×3), combined the organic phases, washed with water once, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P034. Yield: 90.5%.

MS (ESI): 459.2 [M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 8.54 (d, J = 8.3 Hz, 2H, ArH), 7.40 (s, 2H, ArH), 7.30 (d, J = 8.3 Hz, 2H, ArH), 6.77 (d, J=36.8 Hz, 1H, CF=CH), 3.34 (s, 3H, SO ₂ CH ₃ ), 2.32 (s, 6H, ArCH ₃ ), 1.96-1.56 (m, 8H, CH ₂ ).

Example 35: Compound P035

Step 1: Compound P035-a

At room temperature, compound P025-d (100mg, 0.29mmol, 1.00eq.) and methyl 1-bromocyclohexanecarboxylate (636mg, 2.87mmol, 10.00eq.) were dissolved in 6.00mL of anhydrous acetonitrile, and then added Potassium carbonate (397mg, 2.87mmol, 10.00eq.), heated to 70°C under nitrogen protection, and reacted for 4 days. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether:dichloromethane=1:10) to obtain compound P035-a. Yield: 16%.

MS (ESI): 489.3 [M+1].

Step 2: Compound P035

At room temperature, compound P035-a (0.02 mmol, 1.00 eq.) was dissolved in 1.00 mL of 10% sodium hydroxide solution and 1.00 mL of tetrahydrofuran, and reacted at room temperature for 3 hours. The reaction solution was added with 30 mL saturated ammonium chloride solution, extracted with dichloromethane (10 mL×3), combined the organic phases, washed with water once, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P035. Yield: 95.5%.

MS(ESI): 473.2[M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 8.54 (d, J = 8.3 Hz, 2H, ArH), 7.39 (s, 2H, ArH), 7.30 (d, J = 8.3 Hz, 2H, ArH), 6.77 (d, J=36.8 Hz, 1H, CF=CH), 3.34 (s, 3H, SO ₂ CH ₃ ), 2.32 (s, 6H, ArCH ₃ ), 1.94-1.50 (m, 10H, CH ₂ ).

Example 36: Compound P036

Step 1: Compound P036-a

At room temperature, compound P025-d (100mg, 0.29mmol, 1.00eq.) and tert-butyl bromoacetate (560mg, 2.87mmol, 10.00eq.) were dissolved in anhydrous acetonitrile (15.00mL, 30.00eqv.), and then added Potassium carbonate (397 mg, 2.87 mmol, 10.00 eq.) was heated to 70° C. under the protection of nitrogen and reacted for 96 hours. The reaction solution was concentrated under reduced pressure, diluted with 40 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by silica gel chromatography column (petroleum ether: dichloromethane=1:10) to obtain compound P036-a. Yield: 50.9%.

MS(ESI): 463.2 [M+1].

Step 2: Compound P036

At room temperature, compound P036-a (0.12 mmol, 1.00 eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00 mL, 17.24 eqv.), and reacted at room temperature for 1.5 hours. The reaction solution was diluted by adding 4 mL of dichloromethane, and then added with 15 mL of saturated sodium bicarbonate solution to wash until weakly alkaline, then washed with saturated ammonium chloride solution to become weakly acidic, and extracted with dichloromethane (10 mL×3). Combine the organic phases with water Washed once, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P036. Yield: 91.6%.

MS(ESI): 405.4[M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 8.54 (d, J = 8.3 Hz, 2H, ArH), 7.40 (s, 2H, ArH), 7.30 (d, J = 8.3 Hz, 2H, ArH), 6.77 (d, J=36.8 Hz, 1H, CF=CH), 4.89 (s, 2H, OCH ₂ CO), 3.34 (s, 3H, SO ₂ CH ₃ ), 2.32 (s, 6H, ArCH ₃ ).

Example 37: Compound P037

Step 1: Compound P037-b

At room temperature, the compound P037-a (5.00g, 33.29mmol, 1.00eq.), N-bromosuccinimide (NBS) (6.04g, 33.96mmol, 1.02eq.) and p-toluenesulfonic acid one The hydrate (6.33g, 33.29mmol, 1.00eq.) was dissolved in anhydrous acetonitrile (15.00mL, 3.00eqv.) and reacted at 50°C for 24 hours. The reaction solution was concentrated under reduced pressure, mixed with 40 mL of saturated sodium bicarbonate solution, extracted with dichloromethane (30 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried with anhydrous sodium sulfate, filtered, Concentrate under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography column (petroleum ether: ethyl acetate=95:5) to obtain compound P037-b. Yield: 66%; MS m/s(ESI): 252.4[M+23].

Step 2: Compound P037-c

At room temperature, the compound P037-b (3.50g, 15.28mmol, 1.00eq.), tetrabutylammonium fluoride (TBAF) (6.30mL, 22.92mmol, 1.50eq.) and potassium fluoride (1.33g, 22.92mmol , 1.50eq.) was dissolved in anhydrous acetonitrile (18.00mL, 5.14eqv.) and reacted at 80°C for 24 hours. The reaction solution was concentrated under reduced pressure, mixed with 20 mL of water, extracted with ethyl acetate (30 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product . The crude product was purified by silica gel chromatography column (petroleum ether: ethyl acetate=95:5) to obtain compound P037-c. Yield: 32%; MS m/s(ESI): 191.2[M+23].

Step 3: Compound P037-d

At room temperature, compound P037-c (1.50g, 8.92mmol, 1.00eq.) and 3,5-dimethyl-4-hydroxybenzaldehyde (1.34g, 8.92mmol, 1.00eq.) in anhydrous methanol (30.00 mL, 20.00eqv.) piperidine (1.40mL, 3.00eqv.), heated to room temperature under the protection of nitrogen, and reacted for 96 hours. The reaction solution was concentrated under reduced pressure, mixed with 20 mL of water, extracted with ethyl acetate (20 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product . The crude product was purified by silica gel chromatography column (petroleum ether: dichloromethane=3:1) to obtain compound P037-d. Yield: 43%.

MS (ESI): 299.1 (M-1).

Step 4: Compound P037-e

At room temperature, compound P037-d (500mg, 1.66mmol, 1.00eq.) and tert-butyl 2-bromoisobutyrate (2.70mL, 16.65mmol, 10.00eq.) were dissolved in anhydrous acetonitrile (15.00mL, 30.00 eqv.), then potassium carbonate (2.30g, 10.00eq.) was added, and the mixture was heated to 70°C for 96 hours under the protection of nitrogen. The reaction solution was concentrated under reduced pressure, diluted with 40 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified with a silica gel column (petroleum ether:dichloromethane=1:1) to obtain compound P037-e. Yield: 60%.

MS(ESI): 443.2[M+1].

Step 5: Compound P037

At room temperature, compound P037-e (250 mg, 0.56 mmol, 1.00 eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00 mL.) and reacted at room temperature for 1.5 hours. The reaction solution was diluted by adding 4 mL of dichloromethane, and then added with 15 mL of saturated sodium bicarbonate solution to wash until weakly alkaline, then washed with saturated ammonium chloride solution to become weakly acidic, and extracted with dichloromethane (10 mL×3). Combine the organic phases with water Washed once, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound P037. Yield: 90%.

MS(ESI): 385.4[M-1]. ¹ H-NMR(400MHz; (CDCl ₃ )δ _H =7.85(d,J=7.2Hz,2H,ArH), 7.38(s,2H,ArH), 7.30(d,J=7.2Hz,2H,ArH) , 6.77 (d, J=36.8 Hz, 1H, CF=CH), 3.70 (s, 3H, OCH ₃ ), 2.28 (s, 6H, ArCH ₃ ), 1.55 (s, 6H, CH ₃ ).

Example 38: Compound P038

At room temperature, dissolve compound P037-d (100mg, 0.33mmol, 1.00eq.) and isopropyl 2-bromoisobutyrate (537μL, 3.33mmol, 10.00eq.) in 6.00mL of anhydrous acetonitrile, then add carbonic acid Potassium (460mg, 10.00eq.), heated to 70°C under the protection of nitrogen, reacted for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether:dichloromethane=1:10) to obtain compound P038. Yield: 83%.

MS (ESI): 429 (M+1). ¹ H-NMR(400MHz; (CDCl ₃ )δ _H =7.79(d,J=8.2Hz,2H,ArH),7.46(s,2H,ArH),7.41 (d,J=8.2Hz,2H,ArH) , 6.84 (d, J = 38.4 Hz, 1H, CF = CH), 4.99 (m, 1H, OCH), 3.70 (s, 3H, OCH ₃ ), 2.17 (s, 6H, ArCH ₃ ), 1.39 (s, 6H, CH ₃ ), 1.26 (d, 6H, CH ₃ ).

Example 39: Compound P039

Step 1: Compound P039-a

At room temperature, compound P037-d (100mg, 0.33mmol, 1.00eq.) and tert-butyl 2-bromopropionate (553mg, 3.33mmol, 10.00eq.) were dissolved in anhydrous acetonitrile (15.00mL, 30.00eqv.) , Then add potassium carbonate (460mg, 10.00eq.), and heat to 70°C under the protection of nitrogen to react for 96 hours. The reaction solution was concentrated under reduced pressure, diluted with 40 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by silica gel chromatography column (petroleum ether:dichloromethane=1:10) to obtain compound P039-a. Yield: 80.9%.

MS (ESI): 429.2 [M+1].

Step 2: Compound P039

At room temperature, compound P039-a (0.24 mmol, 1.00 eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00 mL.), and reacted at room temperature for 1.5 hours. The reaction solution was diluted by adding 4 mL of dichloromethane, and then added with 15 mL of saturated sodium bicarbonate solution to wash until weakly alkaline, then washed with saturated ammonium chloride solution to become weakly acidic, and extracted with dichloromethane (10 mL×3). Combine the organic phases with water Washed once, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P039. Yield: 94.6%.

MS (ESI): 371.7 [M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3 Hz, 2H, ArH), 7.40 (s, 2H, ArH), 7.30 (d, J = 8.3 Hz, 2H, ArH), 6.77 (d,J=36.8Hz,1H,CF=CH), 4.65(q,1H,OCH), 3.70(s,3H,OCH ₃ ), 2.32(s,6H,ArCH ₃ ), 1.56(d,3H, CH ₃ ).

Example 40: Compound P040

The first step: compound P040-a

At room temperature, compound P037-d (100mg, 0.33mmol, 1.00eq.) and ethyl-1-bromocyclobutanecarboxylate (539μL, 3.33mmol, 10.00eq.) were dissolved in 6.00mL of anhydrous acetonitrile, Then potassium carbonate (460mg, 10.00eq.) was added, and it was heated to 70°C for 4 days under the protection of nitrogen. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether: dichloromethane=1:10) to obtain compound P040-a. Yield: 22%.

MS(ESI): 427.2 [M+1].

Step 2: Compound P040

At room temperature, compound P040-a (0.05 mmol, 1.00 eq.) was dissolved in 1.00 mL of 10% sodium hydroxide solution and 1.00 mL of tetrahydrofuran, and reacted at room temperature for 3 hours. The reaction solution was added with 30 mL saturated ammonium chloride solution, extracted with dichloromethane (10 mL×3), combined the organic phases, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P040. Yield: 95.0%.

MS(ESI): 397.7[M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3 Hz, 2H, ArH), 7.40 (s, 2H, ArH), 7.30 (d, J = 8.3 Hz, 2H, ArH), 6.77 (d,J=36.8Hz,1H,CF=CH),3.70(s,3H,OCH ₃ ),2,85-2.75(m,2H,CH ₂ ),2.52-2.62(m,2H,CH ₂ ) , 2.32 (s, 6H, ArCH ₃ ).

Example 41: Compound P041

At room temperature, compound P037-d (100mg, 0.33mmol, 1.00eq.) and 5-chloro-2,2-dimethylvalerate isobutyl ester (225μL, 1.00mmol, 3.00eq.) were dissolved in anhydrous acetonitrile Add potassium iodide (5mg, 0.032mmol, 0.10eq.) and potassium carbonate (460mg, 10.00eq.) to 6.00mL, and heat to 70°C for 48 hours under the protection of nitrogen. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether: dichloromethane=1:10) to obtain compound P041. Yield: 81.6%.

MS (ESI): 485.6 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 7.3, 2H, ArH), 7.40 (s, 2H, ArH), 7.30 (d, J = 8.3 Hz, 2H, ArH), 6.77 ( d, J = 36.8 Hz, 1H, CF = CH), 4.65 (t, 2H, OCH ₂ ), 4.29 (d, 2H, OCH ₂ ), 3.70 (s, 3H, OCH ₃ ), 2.32 (s, 6H, ArCH ₃ ), 1.92 (m, 1H, CH), 1.85 (m, 4H, CH ₂ ), 1.32 (s, 6H, CH ₃ ), 1.02 (d, 6H, CH ₃ ).

Example 42: Compound P042

Step 1: Compound P042-a

At room temperature, dissolve compound P037-d (100mg, 0.33mmol, 1.00eq.) and tert-butyl 2-bromobutyrate (650mg, 3.33mmol, 10.00eq.) in 6.00mL of anhydrous acetonitrile, and then add potassium carbonate (460mg, 10.00eq.), heated to 70°C under the protection of nitrogen, and reacted for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether:dichloromethane=1:10) to obtain compound P042-a. Yield: 87.2%.

MS (ESI): 443.5 [M+1].

Step 2: Compound P042

At room temperature, compound P042-a (0.26 mmol, 1.00 eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00 mL), and reacted at room temperature for 1.5 hours. The reaction solution was diluted by adding 4 mL of dichloromethane, and then added with 15 mL of saturated sodium bicarbonate solution to wash until weakly alkaline, then washed with saturated ammonium chloride solution to become weakly acidic, and extracted with dichloromethane (10 mL×3). Combine the organic phases with water Washed once, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P042. Yield: 93.2%.

MS(ESI): 385.3[M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3 Hz, 2H, ArH), 7.40 (s, 2H, ArH), 7.30 (d, J = 8.3 Hz, 2H, ArH), 6.77 (d, J = 36.8Hz, 1H, CF = CH), 4.65 (t, 1H, OCH), 3.70 (s, 3H, OCH ₃ ), 2.32 (s, 6H, ArCH ₃ ), 1.83 (m, 2H, CH ₂ ), 1.56 (d, 3H, CH ₃ ).

Example 43: Compound P043

Step 1: Compound P043-a

At room temperature, compound P037-d (100mg, 0.33mmol, 1.00eq.) and ethyl 2-bromoisovalerate (696mg, 3.33mmol, 10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, and then carbonic acid was added Potassium (460mg, 10.00eq.), heated to 70°C under the protection of nitrogen, reacted for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether: dichloromethane=1:10) to obtain compound P043-a. Yield: 75.2%.

MS (ESI): 429.5 [M+1].

Step 2: Compound P043

At room temperature, compound P043-a (0.22 mmol, 1.00 eq.) was dissolved in 1.00 mL of 10% sodium hydroxide solution and 1.00 mL of tetrahydrofuran, and reacted at room temperature for 3 hours. The reaction solution was added with 30 mL saturated ammonium chloride solution, extracted with dichloromethane (10 mL×3), combined the organic phases, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P043. Yield: 90.3%.

MS (ESI): 399.7 [M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3 Hz, 2H, ArH), 7.40 (s, 2H, ArH), 7.30 (d, J = 8.3 Hz, 2H, ArH), 6.77 (d,J=36.8Hz,1H,CF=CH), 4.63(d,1H,OCH), 3.70(s,3H,OCH ₃ ), 2.32(s,6H,ArCH ₃ ), 1.65(m,1H, CH), 1.10 (d, 6H, CH ₃ ).

Example 44: Compound P044

The first step: Compound P044-a

At room temperature, the compound P037-d (100mg, 0.33mmol, 1.00eq.) and ethyl 3-chloro-2,2-dimethylpropionate (165mg, 1.00mmol, 3.00eq.) were dissolved in anhydrous acetonitrile 6.00 Add potassium iodide (5mg, 0.10eq.) and potassium carbonate (460mg, 10.00eq.) to the mL, and heat to 70°C for 48 hours under the protection of nitrogen. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether: dichloromethane=1:10) to obtain compound P044-a. Yield: 87%.

MS (ESI): 429.3 [M+1].

Step 2: Compound P044

At room temperature, compound P044-a (0.26 mmol, 1.00 eq.) was dissolved in 1.00 mL of 10% sodium hydroxide solution and 1.00 mL of tetrahydrofuran, and reacted at room temperature for 3 hours. The reaction solution was added with 30 mL saturated ammonium chloride solution, extracted with dichloromethane (10 mL×3), combined the organic phases, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P044. Yield: 88.0%.

MS (ESI): 399.7 [M-1]. ¹ H-NMR (400MHz; (CDCl ₃ )δ _H = 7.85 (d, J = 7.2 Hz, 2H, ArH), 7.38 (s, 2H, ArH), 7.30 (d, J = 7.2 Hz, 2H, ArH) , 6.77 (d, J=36.8 Hz, 1H, CF=CH), 4.45 (s, 2H, OCH ₂ ), 2.28 (s, 6H, ArCH ₃ ), 1.55 (s, 6H, CH ₃ ).

Example 45: Compound P045

Step 1: Compound P045-a

At room temperature, compound P037-d (100mg, 0.33mmol, 1.00eq.) and ethyl 3-chloropropionate (137mg, 1.00mmol, 3.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, then potassium iodide (5mg , 0.032mmol, 0.10eq.) and potassium carbonate (460mg, 10.00eq.), heated to 70°C under the protection of nitrogen and reacted for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether:dichloromethane=1:10) to obtain compound P045-a. Yield: 91.5%.

MS (ESI): 401.7 [M+1].

Step 2: Compound P045

At room temperature, compound P045-a (0.27 mmol, 1.00 eq.) was dissolved in 1.00 mL of 10% sodium hydroxide solution and 1.00 mL of tetrahydrofuran, and reacted at room temperature for 3 hours. The reaction solution was added with 30 mL saturated ammonium chloride solution, extracted with dichloromethane (10 mL×3), combined the organic phases, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound P045. Yield: 83.2%.

MS(ESI): 371.3[M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 7.3, 2H, ArH), 7.40 (s, 2H, ArH), 7.30 (d, J = 8.3 Hz, 2H, ArH), 6.77 ( d, J = 36.8Hz, 1H, CF = CH), 4.65 (t, 2H, OCH ₂ ), 4.45 (t, 2H, COCH ₂ ), 3.70 (s, 3H, OCH ₃ ), 2.32 (s, 6H, ArCH ₃ ).

Example 46: Compound P046

Step 1: Compound P046-a

At room temperature, compound P037-d (100mg, 0.33mmol, 1.00eq.) and methyl 1-bromocyclopentanecarboxylate (690mg, 3.33mmol, 10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, and then added Potassium carbonate (460mg, 10.00eq.), heated to 70°C under the protection of nitrogen, reacted for 4 days. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether:dichloromethane=1:10) to obtain compound P046-a. Yield: 19%.

MS (ESI): 427.4 [M+1].

Step 2: Compound P046

At room temperature, compound P046-a (0.04 mmol, 1.00 eq.) was dissolved in 1.00 mL of 10% sodium hydroxide solution and 1.00 mL of tetrahydrofuran, and reacted at room temperature for 3 hours. The reaction solution was added with 30 mL saturated ammonium chloride solution, extracted with dichloromethane (10 mL×3), combined the organic phases, washed with water once, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P046. Yield: 90.0%.

MS(ESI): 411.2[M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3 Hz, 2H, ArH), 7.40 (s, 2H, ArH), 7.30 (d, J = 8.3 Hz, 2H, ArH), 6.77 (d, J=36.8 Hz, 1H, CF=CH), 3.70 (s, 3H, OCH ₃ ), 2.32 (s, 6H, ArCH ₃ ), 1.96-1.56 (m, 8H, CH ₂ ).

Example 47: Compound P047

Step 1: Compound P047-a

At room temperature, compound P037-d (100mg, 0.33mmol, 1.00eq.) and methyl 1-bromocyclohexanecarboxylate (737mg, 3.33mmol, 10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, and then added Potassium carbonate (460mg, 10.00eq.), heated to 70°C under the protection of nitrogen, reacted for 4 days. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether: dichloromethane=1:10) to obtain compound P047-a. Yield: 17%.

MS (ESI): 441.3 [M+1].

Step 2: Compound P047

At room temperature, compound P047-a (0.03 mmol, 1.00 eq.) was dissolved in 1.00 mL of 10% sodium hydroxide solution and 1.00 mL of tetrahydrofuran, and reacted at room temperature for 3 hours. The reaction solution was added with 30 mL saturated ammonium chloride solution, extracted with dichloromethane (10 mL×3), combined the organic phases, washed with water once, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P047. Yield: 90.5%.

MS(ESI): 425.2[M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3 Hz, 2H, ArH), 7.39 (s, 2H, ArH), 7.30 (d, J = 8.3 Hz, 2H, ArH), 6.77 (d, J=36.8 Hz, 1H, CF=CH), 3.70 (s, 3H, OCH ₃ ), 2.32 (s, 6H, ArCH ₃ ), 1.94-1.50 (m, 10H, CH ₂ ).

Example 48: Compound P048

Step 1: Compound P048-a

At room temperature, compound P037-d (100mg, 0.33mmol, 1.00eq.) and tert-butyl bromoacetate (650mg, 3.33mmol, 10.00eq.) were dissolved in anhydrous acetonitrile (15.00mL, 30.00eqv.), and then added Potassium carbonate (460mg, 10.00eq.), heated to 70°C under the protection of nitrogen, reacted for 96 hours. The reaction solution was concentrated under reduced pressure, diluted with 40 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by silica gel chromatography column (petroleum ether:dichloromethane=1:10) to obtain compound POP48-a. Yield: 84.9%.

MS (ESI): 415.2 [M+1].

Step 2: Compound P048

At room temperature, compound P048-a (0.25 mmol, 1.00 eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00 mL), and reacted at room temperature for 1.5 hours. The reaction solution was diluted by adding 4 mL of dichloromethane, and then added with 15 mL of saturated sodium bicarbonate solution to wash until weakly alkaline, then washed with saturated ammonium chloride solution to become weakly acidic, and extracted with dichloromethane (10 mL×3). Combine the organic phases with water Washed once, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P048. Yield: 90.6%.

MS(ESI): 357.4[M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3 Hz, 2H, ArH), 7.40 (s, 2H, ArH), 7.30 (d, J = 8.3 Hz, 2H, ArH), 6.77 (d, J=36.8 Hz, 1H, CF=CH), 4.89 (s, 2H, OCH ₂ CO), 3.70 (s, 3H, OCH ₃ ), 2.32 (s, 6H, ArCH ₃ ).

Example 49: Compound P049

The first step: Compound P049-b

At room temperature, compound P049-a (5.00g, 41.61mmol, 1.00eq.), N-bromosuccinimide (NBS) (7.56g, 42.45mmol, 1.02eq.) and p-toluenesulfonic acid one The hydrate (7.92g, 41.61mmol, 1.00eq.) was dissolved in anhydrous acetonitrile (15.00mL, 3.00eqv.) and reacted at 50°C for 24 hours. The reaction solution was concentrated under reduced pressure, mixed with 40 mL of saturated sodium bicarbonate solution, extracted with dichloromethane (30 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried with anhydrous sodium sulfate, filtered, Concentrate under reduced pressure to obtain a crude product. The crude product was purified with a silica gel column (petroleum ether: ethyl acetate=95:5) to obtain compound P049-b. Yield: 62%; MS m/s(ESI): 222.4[M+23].

Step 2: Compound P049-c

At room temperature, compound P049-b (3.00g, 15.08mmol, 1.00eq.), tetrabutylammonium fluoride (TBAF) (6.20mL, 22.61mmol, 1.50eq.) and potassium fluoride (1.31g, 22.61mmol , 1.50eq.) was dissolved in anhydrous acetonitrile (18.00mL, 6.00eqv.) and reacted at 80°C for 24 hours. The reaction solution was concentrated under reduced pressure, mixed with 20 mL of water, extracted with ethyl acetate (30 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product . The crude product was purified with a silica gel column (petroleum ether: ethyl acetate=95:5) to obtain compound P049-c. Yield: 30%; MS m/s(ESI): 161.2[M+23].

The third step: compound P049-d

At room temperature, the compound P049-c (1.00g, 7.24mmol, 1.00eq.) and 3,5-dimethyl-4-hydroxybenzaldehyde (1.09g, 7.24mmol, 1.00eq.) in anhydrous methanol (20.00 mL, 20.00eqv.) piperidine (2.00mL, 3.00eqv.), heated to room temperature under the protection of nitrogen, and reacted for 96 hours. The reaction solution was concentrated under reduced pressure, mixed with 20 mL of water, extracted with ethyl acetate (20 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product . The crude product was purified by silica gel chromatography column (petroleum ether: dichloromethane=3:1) to obtain compound P049-d. Yield: 40%.

MS (ESI): 269.1 (M-1).

Step 4: Compound P049-e

At room temperature, compound P049-d (500mg, 1.85mmol, 1.00eq.) and tert-butyl 2-bromoisobutyrate (3.50mL, 18.50mmol, 10.00eq.) were dissolved in anhydrous acetonitrile (15.00mL, 30.00 eqv.), then add potassium carbonate (2.56g, 10.00eq.), and heat to 70°C for 96 hours under the protection of nitrogen. The reaction solution was concentrated under reduced pressure, diluted with 40 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by silica gel chromatography column (petroleum ether: dichloromethane=1:1) to obtain compound P049-e. Yield: 60%.

MS(ESI): 413.2 [M+1].

Step 5: Compound P049

At room temperature, compound P049-e (250 mg, 0.61 mmol, 1.00 eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00 mL), and reacted at room temperature for 1.5 hours. The reaction solution was diluted by adding 4 mL of dichloromethane, and then added with 15 mL of saturated sodium bicarbonate solution to wash until weakly alkaline, then washed with saturated ammonium chloride solution to become weakly acidic, and extracted with dichloromethane (10 mL×3). Combine the organic phases with water Washed once, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P049. Yield: 92%.

MS(ESI): 355.4[M-1]. ¹ H-NMR (400MHz; (CDCl ₃ )δ _H = 7.85 (d, J = 7.2 Hz, 2H, ArH), 7.38 (s, 2H, ArH), 7.30 (m, 3H, ArH), 6.77 (d, J=36.8 Hz, 1H, CF=CH), 2.28 (s, 6H, ArCH ₃ ), 1.55 (s, 6H, CH ₃ ).

Example 50: Compound P050

At room temperature, compound P049-d (100mg, 0.37mmol, 1.00eq.) and isopropyl 2-bromoisobutyrate (734mg, 3.70mmol, 10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, and then carbonic acid was added Potassium (511mg, 10.00eq.), heated to 70°C under the protection of nitrogen, reacted for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether: dichloromethane=1:10) to obtain compound P050. Yield: 80%.

MS (ESI): 399.4 (M+1). ¹ H-NMR(400MHz; (CDCl ₃ )δ _H =7.79(d,J=8.2Hz,2H,ArH),7.46(s,2H,ArH),7.40(m,3H,ArH),6.84(d, J = 38.4Hz, 1H, CF = CH), 4.99 (q, 1H, OCH), 2.17 (s, 6H, ArCH ₃ ), 1.39 (s, 6H, CH ₃ ), 1.26 (d, 6H, CH ₃ ) .

Example 51: Compound P051

Step 1: Compound P051-a

At room temperature, compound P049-d (100mg, 0.37mmol, 1.00eq.) and tert-butyl 2-bromopropionate (774mg, 3.70mmol, 10.00eq.) were dissolved in anhydrous acetonitrile (15.00mL, 30.00eqv.) , Then add potassium carbonate (511mg, 10.00eq.), heat to 70°C under nitrogen protection and react for 96 hours. The reaction solution was concentrated under reduced pressure, diluted with 40 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by silica gel chromatography column (petroleum ether: dichloromethane=1:10) to obtain compound P051-a. Yield: 81.9%.

MS (ESI): 399.2 [M+1].

Step 2: Compound P051

At room temperature, compound P051-a (0.27 mmol, 1.00 eq.) was dissolved in a 25% trifluoroacetic acid solution in dichloromethane (4.00 mL), and reacted at room temperature for 1.5 hours. The reaction solution was diluted by adding 4 mL of dichloromethane, and then added with 15 mL of saturated sodium bicarbonate solution to wash until weakly alkaline, then washed with saturated ammonium chloride solution to become weakly acidic, and extracted with dichloromethane (10 mL×3). Combine the organic phases with water Washed once, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P051. Yield: 97.6%.

MS (ESI): 341.7 [M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3 Hz, 2H, ArH), 7.40 (s, 2H, ArH), 7.30 (m, 3H, ArH), 6.77 (d, J = 36.8 Hz, 1H, CF=CH), 4.65 (q, 1H, OCH), 2.32 (s, 6H, ArCH ₃ ), 1.56 (d, 3H, CH ₃ ).

Example 52: Compound P052

The first step: compound P052-a

At room temperature, compound P049-d (100mg, 0.37mmol, 1.00eq.) and ethyl-1-bromocyclobutanecarboxylate (767mg, 3.70mmol, 10.00eq.) were dissolved in 6.00mL of anhydrous acetonitrile, Then potassium carbonate (511mg, 10.00eq.) was added and heated to 70°C for 4 days under the protection of nitrogen. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether:dichloromethane=1:10) to obtain compound P052-a. Yield: 20%.

MS(ESI): 397.2 [M+1].

Step 2: Compound P052

At room temperature, compound P052-a (0.05 mmol, 1.00 eq.) was dissolved in 1.00 mL of 10% sodium hydroxide solution and 1.00 mL of tetrahydrofuran, and reacted at room temperature for 3 hours. The reaction solution was added with 30 mL saturated ammonium chloride solution, extracted with dichloromethane (10 mL×3), combined the organic phases, washed with water once, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P052. Yield: 94.0%.

MS(ESI): 367.7[M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3 Hz, 2H, ArH), 7.40 (s, 2H, ArH), 7.30 (m, 3H, ArH), 6.77 (d, J = 36.8Hz, 1H, CF = CH), 2,85-2.75 (m, 4H, CH ₂ ), 2.52-2.62 (m, 2H, CH ₂ ), 2.32 (s, 6H, ArCH ₃ ), 2.10-1.93 ( m, 2H, CH ₂ ), 1.56 (d, 3H, CH ₃ ).

Example 53: Compound P053

At room temperature, the compound P049-d (100mg, 0.37mmol, 1.00eq.) and 5-chloro-2,2-dimethylvalerate isobutyl ester (817mg, 1.00mmol, 3.00eq.) were dissolved in anhydrous acetonitrile Add potassium iodide (5mg, 0.032mmol, 0.10eq.) and potassium carbonate (511mg, 10.00eq.) to 6.00mL, and heat to 70°C for 48 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether: dichloromethane=1:10) to obtain compound P053. Yield: 86.6%.

MS(ESI): 455.5 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ) δH = 7.84 (d, J = 7.3, 2H, ArH), 7.40 (s, 2H, ArH), 7.30 (m, 3H, ArH), 6.77 (d, J = 36.8 Hz ,1H,CF=CH),4.65(t,2H,OCH ₂ ), 4.29(d,2H,OCH ₂ ), 2.32(s,6H,ArCH ₃ ),1.92(m,1H,CH),1.85(m , 4H, CH ₂ ), 1.32 (s, 6H, CH ₃ ), 1.02 (d, 6H, CH ₃ ).

Example 54: Compound P054

Step 1: Compound P054-a

At room temperature, dissolve compound P049-d (100mg, 0.37mmol, 1.00eq.) and tert-butyl 2-bromobutyrate (722mg, 3.70mmol, 10.00eq.) in 6.00mL of anhydrous acetonitrile, and then add potassium carbonate (511mg, 10.00eq.), heated to 70°C for 48 hours under the protection of nitrogen. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether:dichloromethane=1:10) to obtain compound P054-a. Yield: 84.2%.

MS (ESI): 413.5 [M+1].

Step 2: Compound P054

At room temperature, compound P054-a (0.28 mmol, 1.00 eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00 mL), and reacted at room temperature for 1.5 hours. The reaction solution was diluted by adding 4 mL of dichloromethane, and then added with 15 mL of saturated sodium bicarbonate solution to wash until weakly alkaline, then washed with saturated ammonium chloride solution to become weakly acidic, and extracted with dichloromethane (10 mL×3). Combine the organic phases with water Washed once, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P054. Yield: 86.2%.

MS(ESI): 355.3[M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3 Hz, 2H, ArH), 7.40 (s, 2H, ArH), 7.30 (m, 3H, ArH), 6.77 (d, J = 36.8 Hz, 1H, CF=CH), 4.65 (t, 1H, OCH), 2.32 (s, 6H, ArCH ₃ ), 1.83 (m, 2H, CH ₂ ), 1.56 (d, 3H, CH ₃ ).

Example 55: Compound P055

Step 1: Compound P055-a

At room temperature, compound P049-d (100mg, 0.37mmol, 1.00eq.) and ethyl 2-bromoisovalerate (774mg, 3.70mmol, 10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, and then carbonic acid was added Potassium (511mg, 10.00eq.), heated to 70°C under the protection of nitrogen, reacted for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether: dichloromethane=1:10) to obtain compound P055-a. Yield: 70.0%.

MS (ESI): 399.5 [M+1].

Step 2: Compound P055

At room temperature, compound P055-a (0.23 mmol, 1.00 eq.) was dissolved in 1.00 mL of 10% sodium hydroxide solution and 1.00 mL of tetrahydrofuran, and reacted at room temperature for 3 hours. The reaction solution was added with 30 mL saturated ammonium chloride solution, extracted with dichloromethane (10 mL×3), combined the organic phases, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P055. Yield: 80.8%.

MS (ESI): 369.7 [M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3 Hz, 2H, ArH), 7.40 (s, 2H, ArH), 7.30 (m, 3H, ArH), 6.77 (d, J = 36.8 Hz, 1H, CF=CH), 4.63 (d, 1H, OCH), 2.32 (s, 6H, ArCH ₃ ), 1.65 (m, 1H, CH), 1.10 (d, 6H, CH ₃ ).

Example 56: Compound P056

Step 1: Compound P056-a

At room temperature, the compound P049-d (100mg, 0.37mmol, 1.00eq.) and ethyl 3-chloro-2,2-dimethylpropionate (183mg, 1.11mmol, 3.00eq.) were dissolved in anhydrous acetonitrile 6.00 Add potassium iodide (5mg, 0.10eq.) and potassium carbonate (511mg, 10.00eq.) to the mL, and heat to 70°C for 48 hours under the protection of nitrogen. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether:dichloromethane=1:10) to obtain compound P056-a. Yield: 89%.

MS (ESI): 399.3 [M+1].

Step 2: Compound P056

At room temperature, compound P056-a (0.31 mmol, 1.00 eq.) was dissolved in 1.00 mL of 10% sodium hydroxide solution and 1.00 mL of tetrahydrofuran, and reacted at room temperature for 3 hours. The reaction solution was added with 30 mL saturated ammonium chloride solution, extracted with dichloromethane (10 mL×3), combined the organic phases, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound P056. Yield: 86%.

MS (ESI): 369.7 [M-1]. ¹ H-NMR (400MHz; (CDCl ₃ )δ _H = 7.85 (d, J = 7.2 Hz, 2H, ArH), 7.38 (s, 2H, ArH), 7.30 (m, 3H, ArH), 6.77 (d, J=36.8 Hz, 1H, CF=CH), 4.45 (s, 2H, OCH ₂ ), 2.28 (s, 6H, ArCH ₃ ), 1.55 (s, 6H, CH ₃ ).

Example 57: Compound P057

Step 1: Compound P057-a

At room temperature, compound P049-d (100mg, 0.37mmol, 1.00eq.) and ethyl 3-chloropropionate (152mg, 1.11mmol, 3.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, then potassium iodide (5mg , 0.032mmol, 0.10eq.) and potassium carbonate (511mg, 10.00eq.), heated to 70°C for 48 hours under the protection of nitrogen. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether:dichloromethane=1:10) to obtain compound P057-a. Yield: 90.5%.

MS (ESI): 471.7 [M+1].

Step 2: Compound P057

At room temperature, compound P057-a (0.31 mmol, 1.00 eq.) was dissolved in 1.00 mL of 10% sodium hydroxide solution and 1.00 mL of tetrahydrofuran, and reacted at room temperature for 3 hours. The reaction solution was added with 30 mL saturated ammonium chloride solution, extracted with dichloromethane (10 mL×3), combined the organic phases, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound P057. Yield: 83.0%.

MS(ESI): 341.3[M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 7.3, 2H, ArH), 7.40 (s, 2H, ArH), 7.30 (m, 3H, ArH), 6.77 (d, J = 36.8 Hz, 1H, CF=CH), 4.65 (t, 2H, OCH ₂ ), 4.45 (t, 2H, COCH ₂ ), 2.32 (s, 6H, ArCH ₃ ).

Example 58: Compound P058

Step 1: Compound P058-a

At room temperature, compound P049-d (100mg, 0.37mmol, 1.00eq.) and methyl 1-bromocyclopentanecarboxylate (766mg, 3.70mmol, 10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, and then added Potassium carbonate (511mg, 10.00eq.), heated to 70°C under the protection of nitrogen, reacted for 4 days. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether:dichloromethane=1:10) to obtain compound P058-a. Yield: 20%.

MS(ESI): 397.4 [M+1].

Step 2: Compound P058

At room temperature, compound P058-a (0.05 mmol, 1.00 eq.) was dissolved in 1.00 mL of 10% sodium hydroxide solution and 1.00 mL of tetrahydrofuran, and reacted at room temperature for 3 hours. The reaction solution was added with 30 mL saturated ammonium chloride solution, extracted with dichloromethane (10 mL×3), combined the organic phases, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P058. Yield: 86.0%.

MS(ESI): 381.2[M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3 Hz, 2H, ArH), 7.40 (s, 2H, ArH), 7.30 (m, 3H, ArH), 6.77 (d, J = 36.8 Hz, 1H, CF=CH), 2.32 (s, 6H, ArCH ₃ ), 1.96-1.56 (m, 8H, CH ₂ ).

Example 59: Compound P059

The first step: compound P059-a

At room temperature, compound P049-d (100mg, 0.37mmol, 1.00eq.) and methyl 1-bromocyclopropanecarboxylate (662mg, 3.70mmol, 10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, then potassium carbonate was added (511mg, 10.00eq.), heated to 70°C under the protection of nitrogen, and reacted for 4 days. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether:dichloromethane=1:10) to obtain compound P059-a. Yield: 35%.

MS (ESI): 369.3 [M+1].

Step 2: Compound P059

At room temperature, compound P059-a (0.11 mmol, 1.00 eq.) was dissolved in 1.00 mL of 10% sodium hydroxide solution and 1.00 mL of tetrahydrofuran, and reacted at room temperature for 3 hours. The reaction solution was added with 30 mL saturated ammonium chloride solution, extracted with dichloromethane (10 mL×3), combined the organic phases, washed with water once, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P059. Yield: 90.0%.

MS(ESI): 353.2[M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3 Hz, 2H, ArH), 7.39 (s, 2H, ArH), 7.30 (m, 3H, ArH), 6.77 (d, J = 36.8 Hz, 1H, CF=CH), 2.32 (s, 6H, ArCH ₃ ), 1.54 (m, 4H, CH ₂ ).

Example 60: Compound P060

Step 1: Compound P060-a

At room temperature, compound P049-d (100mg, 0.37mmol, 1.00eq.) and tert-butyl bromoacetate (722mg, 3.70mmol, 10.00eq.) were dissolved in anhydrous acetonitrile (15.00mL, 30.00eqv.), and then added Potassium carbonate (511mg, 10.00eq.), heated to 70°C under the protection of nitrogen, reacted for 96 hours. The reaction solution was concentrated under reduced pressure, diluted with 40 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by silica gel chromatography column (petroleum ether: dichloromethane=1:10) to obtain compound P060-a. Yield: 85.9%.

MS(ESI): 385.2 [M+1].

Step 2: Compound P060

At room temperature, compound P060-a (0.30 mmol, 1.00 eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00 mL), and reacted at room temperature for 1.5 hours. The reaction solution was diluted by adding 4 mL of dichloromethane, and then added with 15 mL of saturated sodium bicarbonate solution to wash until weakly alkaline, then washed with saturated ammonium chloride solution to become weakly acidic, and extracted with dichloromethane (10 mL×3). Combine the organic phases with water Washed once, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P060. Yield: 90.0%.

MS(ESI): 327.4[M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3 Hz, 2H, ArH), 7.40 (s, 2H, ArH), 7.30 (m, 3H, ArH), 6.77 (d, J = 36.8 Hz, 1H, CF=CH), 4.89 (s, 2H, OCH ₂ CO), 2.32 (s, 6H, ArCH ₃ ).

Example 61: Compound P061

Step 1: Compound P061-b

At room temperature, the compound P061-a (4.00g, 21.95mmol, 1.00eq.), N-bromosuccinimide (NBS) (4.00g, 22.39mmol, 1.02eq.) and p-toluenesulfonic acid one The hydrate (4.17g, 21.95mmol, 1.00eq.) was dissolved in anhydrous acetonitrile (12.00mL, 3.00eqv.) and reacted at 50°C for 24 hours. The reaction solution was concentrated under reduced pressure, mixed with 40 mL of saturated sodium bicarbonate solution, extracted with dichloromethane (30 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried with anhydrous sodium sulfate, filtered, Concentrate under reduced pressure to obtain a crude product. The crude product was purified with a silica gel column (petroleum ether: ethyl acetate=95:5) to obtain compound P061-b. Yield: 69%; MS m/s(ESI): 260.9[M-1].

Step 2: Compound P061-c

At room temperature, the compound P061-b (3.50g, 13.40mmol, 1.00eq.), tetrabutylammonium fluoride (TBAF) (5.60mL, 20.10mmol, 1.50eq.) and potassium fluoride (1.17g, 20.10mmol , 1.50eq.) was dissolved in anhydrous acetonitrile (14.00mL, 4.00eqv.) and reacted at 80°C for 24 hours. The reaction solution was concentrated under reduced pressure, mixed with 20 mL of water, extracted with ethyl acetate (30 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product . The crude product was purified with a silica gel column (petroleum ether: ethyl acetate=95:5) to obtain compound P061-c. Yield: 30%; MS m/s(ESI): 199.2[M-1].

The third step: compound P061-d

At room temperature, compound P061-c (2.00g, 9.99mmol, 1.00eq.) and 3,5-dimethyl-4-hydroxybenzaldehyde (1.50g, 9.99mmol, 1.00eq.) in anhydrous methanol (50.00 mL, 25.00eqv.) in piperidine (2.80mL, 3.00eqv.), heated to room temperature under the protection of nitrogen, and reacted for 96 hours. The reaction solution was concentrated under reduced pressure, mixed with 20 mL of water, extracted with ethyl acetate (20 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product . The crude product was purified by silica gel chromatography column (petroleum ether: dichloromethane=3:1) to obtain compound P061-d. Yield: 48%.

MS (ESI): 331.1 (M-1).

Step 4: Compound P061-e

At room temperature, compound P061-d (0.50g, 1.50mmol, 1.00eq.) and tert-butyl 2-bromoisobutyrate (3.00mL, 15.04mmol, 10.00eq.) were dissolved in anhydrous acetonitrile (15.00mL, 30.00eqv.), then potassium carbonate (2.08g, 10.00eqv.) was added, and the reaction was heated to 70°C for 96 hours under the protection of nitrogen. The reaction solution was concentrated under reduced pressure, diluted with 40 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by silica gel chromatography column (petroleum ether: dichloromethane=1:1) to obtain compound P061-e. Yield: 60%.

MS(ESI): 473.2[M-1].

Step 5: Compound P061

At room temperature, compound P061-e (200 mg, 0.42 mmol, 1.00 eq.) was dissolved in a 25% trifluoroacetic acid solution in dichloromethane (4.00 mL.), and reacted at room temperature for 1.5 hours. The reaction solution was diluted by adding 4 mL of dichloromethane, and then added with 15 mL of saturated sodium bicarbonate solution to wash until weakly alkaline, then washed with saturated ammonium chloride solution to become weakly acidic, and extracted with dichloromethane (10 mL×3). Combine the organic phases with water Washed once, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P061. Yield: 88%.

MS(ESI): 417.7[M-1]. ¹ H-NMR(400MHz; (CDCl ₃ )δ _H =7.85(d,J=7.2Hz,2H,ArH), 7.38(s,2H,ArH), 7.30(d,J=7.2Hz,2H,ArH) , 6.77 (d, J=36.8 Hz, 1H, CF=CH), 2.54 (s, 3H, SCH ₃ ), 2.28 (s, 6H, ArCH ₃ ), 1.55 (s, 6H, CH ₃ ).

Example 62: Compound P062

At room temperature, compound P061-d (100mg, 0.30mmol, 1.00eq.) and isopropyl 2-bromoisobutyrate (629mg, 3.01mmol, 10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, and then carbonic acid was added Potassium (416mg, 3.01mmol, 10.00eqv.), heated to 70°C under nitrogen protection, reacted for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether:dichloromethane=1:10) to obtain compound P062. Yield: 80%.

MS (ESI): 459 (M-1). ¹ H-NMR(400MHz; (CDCl ₃ )δ _H =7.79(d,J=8.2Hz,1H,ArH),7.46(s,2H,ArH),7.41(d,J=8.2Hz,1H,ArH) ,6.84(d,J=38.4Hz,1H,CF=CH),6.75(s,1H,ArH),4.99(m,1H,OCH),2.56(s,3H,SCH ₃ ), 2.17(s,6H) , ArCH ₃ ), 1.39 (s, 6H, OC (CH ₃ ) ₂ ), 1.26 (d, 6H, CH ₃ ).

Example 63: Compound P063

Step 1: Compound P063-a

At room temperature, compound P061-d (100mg, 0.30mmol, 1.00eq.) and tert-butyl 2-bromopropionate (630mg, 3.01mmol, 10.00eq.) were dissolved in anhydrous acetonitrile (15.00mL, 30.00eqv.) , Then added potassium carbonate (416mg, 10.00eqv.), heated to 70°C under the protection of nitrogen and reacted for 96 hours. The reaction solution was concentrated under reduced pressure, diluted with 40 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by silica gel chromatography column (petroleum ether: dichloromethane=1:10) to obtain compound P063-a. Yield: 80.5%.

MS (ESI): 459.2 [M-1].

Step 2: Compound P063

At room temperature, compound P063-a (0.22 mmol, 1.00 eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00 mL, 17.24 eqv.), and reacted at room temperature for 1.5 hours. The reaction solution was diluted by adding 4 mL of dichloromethane, and then added with 15 mL of saturated sodium bicarbonate solution to wash until weakly alkaline, then washed with saturated ammonium chloride solution to become weakly acidic, and extracted with dichloromethane (10 mL×3). Combine the organic phases with water Washed once, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P063. Yield: 92.6%.

MS (ESI): 403.7 [M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3 Hz, 1H, ArH), 7.40 (s, 2H, ArH), 7.30 (d, J = 8.3 Hz, 1H, ArH), 6.77 (d,J=36.8Hz,1H,CF=CH), 6.75 (s, 1H, ArH), 4.65 (q, 1H, OCH), 2.55 (s, 3H, SCH ₃ ), 2.32 (s, 6H, ArCH) ₃ ), 1.56 (d, 3H, CH ₃ ).

Example 64: Compound P064

Step 1: Compound P064-a

At room temperature, compound P061-d (100mg, 0.30mmol, 1.00eq.) and ethyl-1-bromocyclobutanecarboxylate (624mg, 3.01mmol, 10.00eq.) were dissolved in 6.00mL of anhydrous acetonitrile, Then potassium carbonate (416mg, 10.00eqv.) was added and heated to 70°C for 4 days under the protection of nitrogen. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether: dichloromethane=1:10) to obtain compound P064-a. Yield: 18%.

MS (ESI): 457.2 [M-1].

Step 2: Compound P064

At room temperature, compound P064-a (0.03 mmol, 1.00 eq.) was dissolved in 1.00 mL of 10% sodium hydroxide solution and 1.00 mL of tetrahydrofuran, and reacted at room temperature for 3 hours. The reaction solution was added with 30 mL saturated ammonium chloride solution, extracted with dichloromethane (10 mL×3), combined the organic phases, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P064. Yield: 95.0%.

MS (ESI): 429.7 [M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3 Hz, 1H, ArH), 7.40 (s, 2H, ArH), 7.30 (d, J = 8.3 Hz, 1H, ArH), 6.77 (d,J=36.8Hz,1H,CF=CH),6.75(s,1H,ArH),2.55(s,3H,SCH ₃ ),2,85-2.75(m,4H,CH ₂ ),2.52- 2.62 (m, 2H, CH ₂ ), 2.32 (s, 6H, ArCH ₃ ).

Example 65: Compound P065

Step 1: Compound P065

At room temperature, the compound P061-d (100mg, 0.30mmol, 1.00eq.) and 5-chloro-2,2-dimethylvalerate isobutyl ester (199mg, 0.90mmol, 3.00eq.) were dissolved in anhydrous acetonitrile Add potassium iodide (5mg, 0.032mmol, 0.10eq.) and potassium carbonate (416mg, 10.00eqv.) to 6.00mL, and heat to 70°C for 48 hours under the protection of nitrogen. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether:dichloromethane=1:10) to obtain compound P065. Yield: 93.2%.

MS(ESI): 515.3[M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3 Hz, 1H, ArH), 7.40 (s, 2H, ArH), 7.30 (d, J = 8.3 Hz, 1H, ArH), 6.77 (d,J=36.8Hz,1H,CF=CH), 6.75(s,1H,ArH), 4.65(t,2H,OCH ₂ ), 4.29(d,2H,OCH ₂ ), 2.55(s,3H, SCH ₃ ), 2.32(s, 6H, ArCH ₃ ), 1.92(m, 1H, CH), 1.85(m, 4H, CH ₂ ), 1.32(s, 6H, CH ₃ ), 1.02(d, 6H, CH ₃ ).

Example 66: Compound P066

Step 1: Compound P066-a

At room temperature, dissolve compound P061-d (100mg, 0.30mmol, 1.00eq.) and tert-butyl 2-bromobutyrate (588mg, 3.01mmol, 10.00eq.) in 6.00mL of anhydrous acetonitrile, and then add potassium carbonate (416mg, 10.00eq.), heated to 70°C under the protection of nitrogen, and reacted for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether:dichloromethane=1:10) to obtain compound P066-a. Yield: 88.2%.

MS(ESI): 473.5[M-1].

Step 2: Compound P066

At room temperature, compound P066-a (0.24 mmol, 1.00 eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00 mL), and reacted at room temperature for 1.5 hours. The reaction solution was diluted by adding 4 mL of dichloromethane, and then added with 15 mL of saturated sodium bicarbonate solution to wash until weakly alkaline, then washed with saturated ammonium chloride solution to become weakly acidic, and extracted with dichloromethane (10 mL×3). Combine the organic phases with water Washed once, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P066. Yield: 91.2%.

MS (ESI): 417.3 [M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3 Hz, 1H, ArH), 7.40 (s, 2H, ArH), 7.30 (d, J = 8.3 Hz, 1H, ArH), 6.77 (d,J=36.8Hz,1H,CF=CH), 6.75 (s, 1H, ArH), 4.65 (t, 1H, OCH), 2.55 (s, 3H, SCH ₃ ), 2.32 (s, 6H, ArCH) ₃ ), 1.83 (m, 2H, CH ₂ ), 1.56 (d, 3H, CH ₃ ).

Example 67: Compound P067

Step 1: Compound P067-a

At room temperature, compound P061-d (100mg, 0.30mmol, 1.00eq.) and ethyl 2-bromoisovalerate (630mg, 3.01mmol, 10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, and then carbonic acid was added Potassium (416mg, 10.00eq.), heated to 70°C under the protection of nitrogen, reacted for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether: dichloromethane=1:10) to obtain compound P067-a. Yield: 83.2%.

MS (ESI): 459.5 [M-1].

Step 2: Compound P067

At room temperature, compound P067-a (0.22 mmol, 1.00 eq.) was dissolved in 1.00 mL of 10% sodium hydroxide solution and 1.00 mL of tetrahydrofuran, and reacted at room temperature for 3 hours. The reaction solution was added with 30 mL saturated ammonium chloride solution, extracted with dichloromethane (10 mL×3), combined the organic phases, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P067. Yield: 92.3%.

MS (ESI): 431.7 [M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3 Hz, 1H, ArH), 7.40 (s, 2H, ArH), 7.30 (d, J = 8.3 Hz, 1H, ArH), 6.77 (d,J=36.8Hz,1H,CF=CH), 6.75(s,1H,ArH), 4.63(d,1H,OCH), 2.55(s,3H,SCH ₃ ), 2.32(s,6H,ArCH) ₃ ), 1.65 (m, 1H, CH), 1.10 (d, 6H, CH ₃ ).

Example 68: Compound P068

Step 1: Compound P068-a

At room temperature, the compound P061-d (100mg, 0.30mmol, 1.00eq.) and ethyl 3-chloro-2,2-dimethylpropionate (149mg, 0.90mmol, 3.00eq.) were dissolved in anhydrous acetonitrile 6.00 Add potassium iodide (5mg, 0.10eq.) and potassium carbonate (416mg, 10.00eq) to the mL, and heat to 70°C for 48 hours under the protection of nitrogen. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether: dichloromethane=1:10) to obtain compound P068-a. Yield: 84%.

MS (ESI): 459.3 [M-1].

Step 2: Compound P068

At room temperature, compound P068-a (0.23 mmol, 1.00 eq.) was dissolved in 1.00 mL of 10% sodium hydroxide solution and 1.00 mL of tetrahydrofuran, and reacted at room temperature for 3 hours. The reaction solution was added with 30 mL saturated ammonium chloride solution, extracted with dichloromethane (10 mL×3), combined the organic phases, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P068. Yield: 79.0%.

MS (ESI): 431.7 [M-1]. ¹ H-NMR(400MHz; (CDCl ₃ )δ _H =7.85(d,J=7.2Hz,1H,ArH), 7.38(s,2H,ArH), 7.30(d,J=7.2Hz,1H,ArH) ,6.77(d,J=36.8Hz,1H,CF=CH),6.75(s,1H,ArH),4.45(s,2H,OCH ₂ ),2.54(s,3H,SCH ₃ ), 2.28(s, 6H, ArCH ₃ ), 1.55 (s, 6H, CH ₃ ).

Example 69: Compound P069

Step 1: Compound P069-a

At room temperature, compound P061-d (100mg, 0.30mmol, 1.00eq.) and ethyl 3-chloropropionate (123mg, 0.90mmol, 3.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, then potassium iodide (5mg , 0.032mmol, 0.10eq.) and potassium carbonate (416mg, 10.00eqv.), heated to 70°C for 48 hours under the protection of nitrogen. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether:dichloromethane=1:10) to obtain compound P069-a. Yield: 81.6%.

MS (ESI): 431.7 [M-1].

Step 2: Compound P069

At room temperature, compound P069-a (0.22 mmol, 1.00 eq.) was dissolved in 1.00 mL of 10% sodium hydroxide solution and 1.00 mL of tetrahydrofuran, and reacted at room temperature for 3 hours. The reaction solution was added with 30 mL saturated ammonium chloride solution, extracted with dichloromethane (10 mL×3), combined the organic phases, washed with water once, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P069. Yield: 86.2%.

MS (ESI): 403.3 [M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3 Hz, 1H, ArH), 7.40 (s, 2H, ArH), 7.30 (d, J = 8.3 Hz, 1H, ArH), 6.77 (d,J=36.8Hz,1H,CF=CH), 6.75(s,1H,ArH), 4.65(t,2H,OCH ₂ ), 4.45(t,2H,COCH ₂ ), 2.55(s,3H, SCH ₃ ), 2.32 (s, 6H, ArCH ₃ ).

Example 70: Compound P070

Step 1: Compound P070-a

At room temperature, compound P061-d (100mg, 0.30mmol, 1.00eq.) and methyl 1-bromocyclopentanecarboxylate (624mg, 3.01mmol, 10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, and then added Potassium carbonate (416mg, 10.00eqv.), heated to 70°C under nitrogen protection, reacted for 4 days. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether: dichloromethane=1:10) to obtain compound P070-a. Yield: 29%.

MS(ESI): 457.4[M-1].

Step 2: Compound P070

At room temperature, compound P070-a (0.06 mmol, 1.00 eq.) was dissolved in 1.00 mL of 10% sodium hydroxide solution and 1.00 mL of tetrahydrofuran, and reacted at room temperature for 3 hours. The reaction solution was added with 30 mL saturated ammonium chloride solution, extracted with dichloromethane (10 mL×3), combined the organic phases, washed with water once, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P070. Yield: 90.5%.

MS(ESI): 443.2[M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3 Hz, 1H, ArH), 7.40 (s, 2H, ArH), 7.30 (d, J = 8.3 Hz, 1H, ArH), 6.77 (d,J=36.8Hz,1H,CF=CH), 6.75(s,1H,ArH), 2.55(s,3H,SCH ₃ ), 2.32(s,6H,ArCH ₃ ),1.96-1.56(m, 8H, CH ₂ ).

Example 71: Compound P071

Step 1: Compound P071-a

At room temperature, compound P061-d (100mg, 0.30mmol, 1.00eq.) and methyl 1-bromocyclohexanecarboxylate (666mg, 3.01mmol, 10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, and then added Potassium carbonate (416mg, 10.00eqv.), heated to 70°C under nitrogen protection, reacted for 4 days. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether: dichloromethane=1:10) to obtain compound P071-a. Yield: 19%.

MS(ESI): 471.3[M-1].

Step 2: Compound P071

At room temperature, compound P071-a (0.03 mmol, 1.00 eq.) was dissolved in 1.00 mL of 10% sodium hydroxide solution and 1.00 mL of tetrahydrofuran, and reacted at room temperature for 3 hours. The reaction solution was added with 30 mL saturated ammonium chloride solution, extracted with dichloromethane (10 mL×3), combined the organic phases, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P071. Yield: 90.0%.

MS (ESI): 457.2 [M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3 Hz, 1H, ArH), 7.39 (s, 2H, ArH), 7.30 (d, J = 8.3 Hz, 1H, ArH), 6.77 (d, J = 36.8 Hz, 1H, CF = CH), 6.75 (s, 1H, ArH), 2.55 (s, 3H, SCH ₃ ), 2.32 (s, 6H, ArCH ₃ ), 1.94-1.50 (m, 10H, CH ₂ ).

Example 72: Compound P072

Step 1: Compound P072-a

At room temperature, compound P061-d (100mg, 0.30mmol, 1.00eq.) and tert-butyl bromoacetate (588mg, 3.01mmol, 10.00eq.) were dissolved in anhydrous acetonitrile (15.00mL, 30.00eqv.), and then added Potassium carbonate (416mg, 10.00eqv.), heated to 70°C under the protection of nitrogen, reacted for 96 hours. The reaction solution was concentrated under reduced pressure, diluted with 40 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by silica gel chromatography column (petroleum ether: dichloromethane=1:10) to obtain compound P072-a. Yield: 90.9%.

MS (ESI): 445.2 [M-1].

Step 2: Compound P072

At room temperature, compound P072-a (0.27 mmol, 1.00 eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00 mL, 17.24 eqv.), and reacted at room temperature for 1.5 hours. The reaction solution was diluted by adding 4 mL of dichloromethane, and then added with 15 mL of saturated sodium bicarbonate solution to wash until weakly alkaline, then washed with saturated ammonium chloride solution to become weakly acidic, and extracted with dichloromethane (10 mL×3). Combine the organic phases with water Washed once, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P072. Yield: 90.6%.

MS (ESI): 389.4 [M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3 Hz, 1H, ArH), 7.40 (s, 2H, ArH), 7.30 (d, J = 8.3 Hz, 1H, ArH), 6.77 (d,J=36.8Hz,1H,CF=CH), 6.75 (s, 1H, ArH), 4.89 (s, 2H, OCH ₂ CO), 2.55 (s, 3H, SCH ₃ ), 2.32 (s, 6H ,ArCH ₃ ).

Example 73: Compound P073

Step 1: Compound P073-a

At room temperature, the compound P001-c (2.50g, 13.57mmol, 1.00eq.) and 3-methyl-4-hydroxybenzaldehyde (1.85g, 13.57mmol, 1.00eq.) in anhydrous methanol (55.00mL, 25.11 eqv.) piperidine (3.30 mL, 3.00 eqv.), heated to room temperature under nitrogen protection, and reacted for 96 hours. The reaction solution was concentrated under reduced pressure, mixed with 20 mL of water, extracted with ethyl acetate (20 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product . The crude product was purified by silica gel chromatography column (petroleum ether: dichloromethane=3:1) to obtain compound P073-a. Yield: 42%.

MS (ESI): 301.1 (M-1).

Step 2: Compound P073-b

At room temperature, compound P073-a (0.50g, 1.29mmol, 1.00eq.) and tert-butyl 2-bromoisobutyrate (2.40mL, 12.87mmol, 10.00eq.) were dissolved in anhydrous acetonitrile (15.00mL, 30.00eqv.), potassium carbonate (1.78g, 10.00eqv.) was added, and the reaction was heated to 70°C for 96 hours under the protection of nitrogen. The reaction solution was concentrated under reduced pressure, diluted with 40 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by silica gel chromatography column (petroleum ether:dichloromethane=1:1) to obtain compound P073-b. Yield: 60%.

MS(ESI): 445.2 [M+1].

Step 3: Compound P073

At room temperature, compound P073-a (100 mg, 0.22 mmol, 1.00 eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00 mL, 17.24 eqv.), and reacted at room temperature for 1.5 hours. The reaction solution was diluted by adding 4 mL of dichloromethane, and then added with 15 mL of saturated sodium bicarbonate solution to wash until weakly alkaline, then washed with saturated ammonium chloride solution to become weakly acidic, and extracted with dichloromethane (10 mL×3). Combine the organic phases with water Washed once, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P073. Yield: 80%.

MS(ESI): 387.7[M-1]. ¹ H-NMR(400MHz; (CDCl ₃ )δ _H =7.85(d,J=7.2Hz,2H,ArH),7.82(d,J=8.2Hz,1H,ArH),7.38(s,1H,ArH) ,7.30(d,J=7.2Hz,2H,ArH),6.77(d,J=36.8Hz,1H,CF=CH),6.58(d,J=8.2Hz,1H,ArH),2.54(s,3H , SCH ₃ ), 2.28 (s, 3H, ArCH ₃ ), 1.55 (s, 6H, CH ₃ ).

Example 74: Compound P074

At room temperature, compound P073-a (100mg, 0.33mmol, 1.00eq.) and isopropyl 2-bromoisobutyrate (534μL, 3.31mmol, 10.00eq.) were dissolved in 6.00mL of anhydrous acetonitrile, and then carbonic acid was added Potassium (457mg, 10.00eq.), heated to 70°C under the protection of nitrogen, reacted for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether: dichloromethane=1:10) to obtain compound P074. Yield: 80%.

MS (ESI): 431 (M+1). ¹ H-NMR(400MHz; (CDCl ₃ )δ _H =7.79(d,J=8.2Hz,2H,ArH),7.72(d,J=8.2Hz,1H,ArH),7.46(s,1H,ArH) ,7.41(d,J=8.2Hz,2H,ArH), 6.84(d,J=38.4Hz,1H,CF=CH), 6.58(d,J=8.2Hz,1H,ArH), 4.99(m,1H , OCH), 2.56 (s, 3H, SCH ₃ ), 2.17 (s, 3H, ArCH ₃ ), 1.39 (s, 6H, C(CH ₃ ) ₂ ), 1.26 (d, 6H, CH ₃ ).

Example 75: Compound P075

Step 1: Compound P075-a

At room temperature, compound P073-a (100mg, 0.33mmol, 1.00eq.) and tert-butyl 2-bromopropionate (550μL, 3.31mmol, 10.00eq.) were dissolved in anhydrous acetonitrile (3.00mL, 30.00eqv.) , Then add potassium carbonate (457mg, 10.00eq.), heat to 70°C under nitrogen protection and react for 96 hours. The reaction solution was concentrated under reduced pressure, diluted with 40 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by silica gel chromatography column (petroleum ether: dichloromethane=1:10) to obtain compound P075-a. Yield: 80.0%.

MS(ESI): 431.2 [M+1].

Step 2: Compound P075

At room temperature, compound P075-a (0.24 mmol, 1.00 eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00 mL), and reacted at room temperature for 1.5 hours. The reaction solution was diluted by adding 4 mL of dichloromethane, and then added with 15 mL of saturated sodium bicarbonate solution to wash until weakly alkaline, then washed with saturated ammonium chloride solution to become weakly acidic, and extracted with dichloromethane (10 mL×3). Combine the organic phases with water Washed once, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain POP75. Yield: 96.6%.

MS (ESI): 373.7 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3 Hz, 2H, ArH), 7.82 (d, J = 8.2 Hz, 1H, ArH), 7.40 (s, 1H, ArH), 7.30 (d,J=8.3Hz,2H,ArH), 6.77(d,J=36.8Hz,1H,CF=CH), 6.58(d,J=8.2Hz,1H,ArH), 4.65(q,1H,OCH ), 2.55 (s, 3H, SCH ₃ ), 2.32 (s, 3H, ArCH ₃ ), 1.56 (d, 3H, CH ₃ ).

Example 76: Compound P076

The first step: Compound P076-a

At room temperature, compound P073-a (100mg, 0.33mmol, 1.00eq.) and ethyl-1-bromocyclobutanecarboxylate (536μL, 3.31mmol, 10.00eq.) were dissolved in 6.00mL of anhydrous acetonitrile, Then potassium carbonate (457mg, 10.00eq.) was added, and it was heated to 70°C for 4 days under the protection of nitrogen. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether:dichloromethane=1:10) to obtain compound P076-a. Yield: 20%.

MS (ESI): 429.2 [M+1].

Step 2: Compound P076

At room temperature, compound P076-a (0.05 mmol, 1.00 eq.) was dissolved in 1.00 mL of 10% sodium hydroxide solution and 1.00 mL of tetrahydrofuran, and reacted at room temperature for 3 hours. The reaction solution was added with 30 mL saturated ammonium chloride solution, extracted with dichloromethane (10 mL×3), combined the organic phases, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P076. Yield: 92.0%.

MS (ESI): 399.7 [M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3 Hz, 2H, ArH), 7.82 (d, J = 8.2 Hz, 1H, ArH), 7.40 (s, 1H, ArH), 7.30 (d,J=8.3Hz,2H,ArH),6.77(d,J=36.8Hz,1H,CF=CH),6.58(d,J=8.2Hz,1H,ArH),2.55(s,3H,SCH ₃ ), 2,85-2.75 (m, 4H, CH ₂ ), 2.52-2.62 (m, 2H, CH ₂ ), 2.32 (s, 3H, ArCH ₃ ).

Example 77: Compound P077

At room temperature, compound P073-a (100mg, 0.33mmol, 1.00eq.) and 5-chloro-2,2-dimethylvalerate isobutyl ester (224μL, 0.99mmol, 3.00eq.) were dissolved in anhydrous acetonitrile Add potassium iodide (5mg, 0.032mmol, 0.10eq.) and potassium carbonate (457mg, 10.00eq.) to 6.00mL, and heat to 70°C for 48 hours under the protection of nitrogen. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether: dichloromethane=1:10) to obtain compound P077. Yield: 80.2%.

MS (ESI): 487.3 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 7.3, 2H, ArH), 7.82 (d, J = 8.2 Hz, 1H, ArH), 7.40 (s, 1H, ArH), 7.30 ( d, J = 8.3 Hz, 2H, ArH), 6.77 (d, J = 36.8 Hz, 1H, CF = CH), 6.58 (d, J = 8.2 Hz, 1H, ArH), 4.65 (t, 2H, OCH ₂ ), 4.29 (d, 2H, OCH ₂ ), 2.55 (s, 3H, SCH ₃ ), 2.32 (s, 3H, ArCH ₃ ), 1.92 (m, 1H, CH), 1.85 (m, 4H, CH ₂ ) , 1.32 (s, 6H, CH ₃ ), 1.02 (d, 6H, CH ₃ ).

Example 78: Compound P078

Step 1: Compound P078-a

At room temperature, compound P073-a (100mg, 0.33mmol, 1.00eq.) and tert-butyl 2-bromobutyrate (646mg, 3.31mmol, 10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, and potassium carbonate was added (457mg, 10.00eq.), heated to 70°C under the protection of nitrogen, and reacted for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether:dichloromethane=1:10) to obtain compound P078-a. Yield: 83.2%.

MS(ESI): 445.5 [M+1].

Step 2: Compound P078

At room temperature, compound P078-a (0.25 mmol, 1.00 eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00 mL), and reacted at room temperature for 1.5 hours. The reaction solution was diluted by adding 4 mL of dichloromethane, and then added with 15 mL of saturated sodium bicarbonate solution to wash until weakly alkaline, then washed with saturated ammonium chloride solution to become weakly acidic, and extracted with dichloromethane (10 mL×3). Combine the organic phases with water Washed once, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P078. Yield: 90.0%.

MS(ESI): 387.3[M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3 Hz, 2H, ArH), 7.82 (d, J = 8.2 Hz, 1H, ArH), 7.40 (s, 1H, ArH), 7.30 (d,J=8.3Hz,2H,ArH), 6.77(d,J=36.8Hz,1H,CF=CH), 6.58(d,J=8.2Hz,1H,ArH), 4.65(t,1H,OCH ), 2.55 (s, 3H, SCH ₃ ), 2.32 (s, 3H, ArCH ₃ ), 1.83 (m, 2H, CH ₂ ), 1.56 (d, 3H, CH ₃ ).

Example 79: Compound P079

The first step: compound P079-a

At room temperature, compound P073-a (100mg, 0.33mmol, 1.00eq.) and ethyl 2-bromoisovalerate (693mg, 3.31mmol, 10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, and then carbonic acid was added Potassium (457mg, 10.00eq.), heated to 70°C under the protection of nitrogen, reacted for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether:dichloromethane=1:10) to obtain compound P079-a. Yield: 89.0%.

MS (ESI): 431.5 [M+1].

Step 2: Compound P079

At room temperature, compound P079-a (0.27 mmol, 1.00 eq.) was dissolved in 1.00 mL of 10% sodium hydroxide solution and 1.00 mL of tetrahydrofuran, and reacted at room temperature for 3 hours. The reaction solution was added with 30 mL saturated ammonium chloride solution, extracted with dichloromethane (10 mL×3), combined the organic phases, washed with water once, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P079. Yield: 95.3%.

MS (ESI): 401.7 [M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3 Hz, 2H, ArH), 7.82 (d, J = 8.2 Hz, 1H, ArH), 7.40 (s, 1H, ArH), 7.30 (d,J=8.3Hz,2H,ArH), 6.77(d,J=36.8Hz,1H,CF=CH), 6.58(d,J=8.2Hz,1H,ArH), 4.63(d,1H,OCH ), 2.55 (s, 3H, SCH ₃ ), 2.32 (s, 3H, ArCH ₃ ), 1.65 (m, 1H, CH), 1.10 (d, 6H, CH ₃ ).

Example 80: Compound P080

Step 1: Compound P080-a

At room temperature, compound P073-a (100mg, 0.33mmol, 1.00eq.) and ethyl 3-chloro-2,2-dimethylpropionate (163mg, 0.99mmol, 3.00eq.) were dissolved in anhydrous acetonitrile 6.00 Add potassium iodide (5mg, 0.10eq.) and potassium carbonate (457mg, 10.00eq.) to the mL, and heat to 70°C for 48 hours under the protection of nitrogen. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether:dichloromethane=1:10) to obtain compound P080-a. Yield: 83%.

MS (ESI): 431.3 [M+1].

Step 2: Compound P080

At room temperature, compound P080-a (0.25 mmol, 1.00 eq.) was dissolved in 1.00 mL of 10% sodium hydroxide solution and 1.00 mL of tetrahydrofuran, and reacted at room temperature for 3 hours. Add 30 mL of saturated ammonium chloride solution to the reaction solution, extract with dichloromethane (10 mL×3), combine the organic phases, wash once with water, once with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain P080. Yield: 80.0%.

MS (ESI): 401.7 [M-1]. ¹ H-NMR(400MHz; (CDCl ₃ )δ _H =7.85(d,J=7.2Hz,2H,ArH),7.82(d,J=8.2Hz,1H,ArH),7.38(s,1H,ArH) ,7.30(d,J=7.2Hz,2H,ArH), 6.77(d,J=36.8Hz,1H,CF=CH), 6.58(d,J=8.2Hz,1H,ArH), 4.45(s,2H , OCH ₂ ), 2.54 (s, 3H, SCH ₃ ), 2.28 (s, 3H, ArCH ₃ ), 1.55 (s, 6H, CH ₃ ).

Example 81: Compound P081

Step 1: Compound P081-a

At room temperature, compound P073-a (100mg, 0.33mmol, 1.00eq.) and ethyl 3-chloropropionate (136mg, 0.99mmol, 3.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, then potassium iodide (5mg , 0.10eq.) and potassium carbonate (457mg, 10.00eq.), heated to 70°C under the protection of nitrogen and reacted for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether: dichloromethane=1:10) to obtain compound P081-a. Yield: 89.0%.

MS(ESI): 403.7 [M+1].

Step 2: Compound P081

At room temperature, compound P081-a (0.27 mmol, 1.00 eq.) was dissolved in 1.00 mL of 10% sodium hydroxide solution and 1.00 mL of tetrahydrofuran, and reacted at room temperature for 3 hours. The reaction solution was added with 30 mL saturated ammonium chloride solution, extracted with dichloromethane (10 mL×3), combined the organic phases, washed with water once, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P081. Yield: 88%.

MS(ESI): 373.3[M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3 Hz, 2H, ArH), 7.82 (d, J = 8.2 Hz, 1H, ArH), 7.40 (s, 1H, ArH), 7.30 (d,J=8.3Hz,2H,ArH), 6.77(d,J=36.8Hz,1H,CF=CH), 6.58(d,J=8.2Hz,1H,ArH), 4.65(t,2H,OCH ₂ ), 4.45 (t, 2H, COCH ₂ ), 2.55 (s, 3H, SCH ₃ ), 2.32 (s, 3H, ArCH ₃ ).

Example 82: Compound P082

Step 1: Compound P082-a

At room temperature, compound P073-a (100mg, 0.33mmol, 1.00eq.) and methyl 1-bromocyclopentanecarboxylate (686mg, 3.31mmol, 10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, and then added Potassium carbonate (457mg, 10.00eq.), heated to 70°C under the protection of nitrogen, reacted for 4 days. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether: dichloromethane=1:10) to obtain compound P082-a. Yield: 29%.

MS(ESI): 429.4 [M+1].

Step 2: Compound P082

At room temperature, compound P082-a (0.08 mmol, 1.00 eq.) was dissolved in 1.00 mL of 10% sodium hydroxide solution and 1.00 mL of tetrahydrofuran, and reacted at room temperature for 3 hours. The reaction solution was added with 30 mL saturated ammonium chloride solution, extracted with dichloromethane (10 mL×3), combined the organic phases, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P082. Yield: 90.5%.

MS(ESI): 413.2[M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3 Hz, 2H, ArH), 7.82 (d, J = 8.2 Hz, 1H, ArH), 7.40 (s, 1H, ArH), 7.30 (d,J=8.3Hz,2H,ArH),6.77(d,J=36.8Hz,1H,CF=CH),6.58(d,J=8.2Hz,1H,ArH),2.55(s,3H,SCH ₃ ), 2.32 (s, 3H, ArCH ₃ ), 1.96-1.56 (m, 8H, CH ₂ ).

Example 83: Compound P083

The first step: Compound P083-a

At room temperature, compound P073-a (100mg, 0.33mmol, 1.00eq.) and methyl 1-bromocyclohexanecarboxylate (732mg, 3.31mmol, 10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, and then added Potassium carbonate (457mg, 10.00eq.), heated to 70°C under the protection of nitrogen, reacted for 4 days. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether:dichloromethane=1:10) to obtain compound P083-a. Yield: 18%.

MS(ESI): 443.3 [M+1].

Step 2: Compound P083

At room temperature, compound P083-a (0.04 mmol, 1.00 eq.) was dissolved in 1.00 mL of 10% sodium hydroxide solution and 1.00 mL of tetrahydrofuran, and reacted at room temperature for 3 hours. The reaction solution was added with 30 mL saturated ammonium chloride solution, extracted with dichloromethane (10 mL×3), combined the organic phases, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P083. Yield: 80.9%.

MS (ESI): 427.2 [M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3 Hz, 2H, ArH), 7.82 (d, J = 8.2 Hz, 1H, ArH), 7.39 (s, 1H, ArH), 7.30 (d,J=8.3Hz,2H,ArH),6.77(d,J=36.8Hz,1H,CF=CH),6.58(d,J=8.2Hz,1H,ArH),2.55(s,3H,SCH ₃ ), 2.32 (s, 3H, ArCH ₃ ), 1.94-1.50 (m, 10H, CH ₂ ).

Example 84: Compound P084

Step 1: Compound P084-a

At room temperature, compound P073-a (100mg, 0.33mmol, 1.00eq.) and tert-butyl bromoacetate (648mg, 3.31mmol, 10.00eq.) were dissolved in anhydrous acetonitrile (15.00mL, 30.00eqv.), and then added Potassium carbonate (457mg, 10.00eq.), heated to 70°C under the protection of nitrogen, reacted for 96 hours. The reaction solution was concentrated under reduced pressure, diluted with 40 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by silica gel chromatography column (petroleum ether: dichloromethane=1:10) to obtain compound P084-a. Yield: 94%.

MS(ESI): 417.2 [M+1].

Step 2: Compound P084

At room temperature, compound P084-a (0.29 mmol, 1.00 eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00 mL), and reacted at room temperature for 1.5 hours. The reaction solution was diluted by adding 4 mL of dichloromethane, and then added with 15 mL of saturated sodium bicarbonate solution to wash until weakly alkaline, then washed with saturated ammonium chloride solution to become weakly acidic, and extracted with dichloromethane (10 mL×3). Combine the organic phases with water Washed once, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P084. Yield: 95.0%.

MS (ESI): 359.4 [M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3 Hz, 2H, ArH), 7.82 (d, J = 8.2 Hz, 1H, ArH), 7.40 (s, 1H, ArH), 7.30 (d,J=8.3Hz,2H,ArH), 6.77(d,J=36.8Hz,1H,CF=CH), 6.58(d,J=8.2Hz,1H,ArH), 4.89(s,2H,OCH ₂ CO), 2.55 (s, 3H, SCH ₃ ), 2.32 (s, 3H, ArCH ₃ ).

Example 85: Compound P085

Step 1: Compound P085-a

At room temperature, the compound P001-c (2.50g, 13.57mmol, 1.00eq.) and p-hydroxybenzaldehyde (1.66g, 13.57mmol, 1.00eq.) in anhydrous methanol (55.00mL, 25.11eqv.) piperidine (3.80mL, 3.00eqv.), heated to room temperature under the protection of nitrogen, and reacted for 96 hours. The reaction solution was concentrated under reduced pressure, mixed with 20 mL of water, extracted with ethyl acetate (20 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product . The crude product was purified by silica gel chromatography column (petroleum ether: dichloromethane=3:1) to obtain compound P085-a. Yield: 52%.

MS (ESI): 287.1 (M-1).

Step 2: Compound P085-b

At room temperature, compound P085-a (0.50g, 1.73mmol, 1.00eq.) and tert-butyl 2-bromoisobutyrate (3.30mL, 17.34mmol, 10.00eq.) were dissolved in anhydrous acetonitrile (15.00mL, 30.00eqv.), potassium carbonate (2.40g, 10.00eqv.) was added, and the reaction was heated to 70°C for 96 hours under the protection of nitrogen. The reaction solution was concentrated under reduced pressure, diluted with 40 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by silica gel chromatography column (petroleum ether:dichloromethane=1:1) to obtain compound P085-b. Yield: 65%.

MS(ESI): 431.2 [M+1].

The third step: compound P085

At room temperature, compound P085-b (100 mg, 0.23 mmol, 1.00 eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00 mL), and reacted at room temperature for 1.5 hours. The reaction solution was diluted by adding 4 mL of dichloromethane, and then added with 15 mL of saturated sodium bicarbonate solution to wash until weakly alkaline, then washed with saturated ammonium chloride solution to become weakly acidic, and extracted with dichloromethane (10 mL×3). Combine the organic phases with water Washed once, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P085. Yield: 90%.

MS (ESI): 373.7 [M-1]. ¹ H-NMR(400MHz; (CDCl ₃ )δ _H =7.85(d,J=7.2Hz,2H,ArH), 7.82(d,J=8.2Hz,2H,ArH),7.38(d,J=8.2Hz ,2H,ArH),7.30(d,J=7.2Hz,2H,ArH),6.77(d,J=36.8Hz,1H,CF=CH),2.54(s,3H,SCH ₃ ),1.55(s, 6H, CH ₃ ).

Example 86: Compound P086

At room temperature, compound P085-a (100mg, 0.35mmol, 1.00eq.) and isopropyl 2-bromoisobutyrate (560μL, 3.47mmol, 10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, and then carbonic acid was added Potassium (457mg, 10.00eq.), heated to 70°C under the protection of nitrogen, reacted for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether:dichloromethane=1:10) to obtain compound P086. Yield: 80%.

MS (ESI): 417 (M+1). ¹ H-NMR(400MHz; (CDCl ₃ )δ _H =7.79(d,J=8.2Hz,2H,ArH), 7.72(d,J=8.2Hz,2H,ArH),7.46(d,J=8.2Hz ,2H,ArH),7.41(d,J=8.2Hz,2H,ArH),6.84(d,J=38.4Hz,1H,CF=CH),4.99(m,1H,OCH),2.56(s,3H ,SCH ₃ ), 1.39(s, 6H, C(CH ₃ ) ₂ ), 1.26(d, 6H, CH ₃ ).

Example 87: Compound P087

Step 1: Compound P087-a

At room temperature, compound P085-a (100mg, 0.35mmol, 1.00eq.) and tert-butyl 2-bromopropionate (576μL, 3.47mmol, 10.00eq.) were dissolved in anhydrous acetonitrile (3.00mL, 30.00eqv.) , Then add potassium carbonate (480mg, 10.00eq.), and heat to 70°C under the protection of nitrogen to react for 96 hours. The reaction solution was concentrated under reduced pressure, diluted with 40 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by silica gel chromatography column (petroleum ether: dichloromethane=1:10) to obtain compound P087-a. Yield: 80.0%.

MS(ESI): 417.2 [M+1].

Step 2: Compound P087

At room temperature, compound P087-a (0.25 mmol, 1.00 eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00 mL), and reacted at room temperature for 1.5 hours. The reaction solution was diluted by adding 4 mL of dichloromethane, and then added with 15 mL of saturated sodium bicarbonate solution to wash until weakly alkaline, then washed with saturated ammonium chloride solution to become weakly acidic, and extracted with dichloromethane (10 mL×3). Combine the organic phases with water Washed once, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P087. Yield: 90.6%.

MS (ESI): 359.7 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3 Hz, 2H, ArH), 7.82 (d, J = 8.2 Hz, 2H, ArH), 7.40 (d, J = 8.2 Hz, 2H ,ArH),7.30(d,J=8.3Hz,2H,ArH),6.77(d,J=36.8Hz,1H,CF=CH),6.58(d,J=8.2Hz,1H,ArH),4.65( q, 1H, OCH), 2.55 (s, 3H, SCH ₃ ), 1.56 (d, 3H, CH ₃ ).

Example 88: Compound P088

Step 1: Compound P088-a

At room temperature, compound P085-a (100mg, 0.35mmol, 1.00eq.) and ethyl-1-bromocyclobutanecarboxylate (562μL, 3.47mmol, 10.00eq.) were dissolved in 6.00mL of anhydrous acetonitrile, Then potassium carbonate (480mg, 10.00eq.) was added, and the reaction was heated to 70°C for 4 days under the protection of nitrogen. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether:dichloromethane=1:10) to obtain compound P088-a. Yield: 30%.

MS (ESI): 415.2 [M+1].

Step 2: Compound P088

At room temperature, compound P088-a (0.09 mmol, 1.00 eq.) was dissolved in 1.00 mL of 10% sodium hydroxide solution and 1.00 mL of tetrahydrofuran, and reacted at room temperature for 3 hours. The reaction solution was added with 30 mL saturated ammonium chloride solution, extracted with dichloromethane (10 mL×3), combined the organic phases, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound P088. Yield: 95.0%.

MS(ESI): 385.7[M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3 Hz, 2H, ArH), 7.82 (d, J = 8.2 Hz, 2H, ArH), 7.40 (d, J = 8.2 Hz, 2H ,ArH),7.30(d,J=8.3Hz,2H,ArH),6.77(d,J=36.8Hz,1H,CF=CH),2.55(s,3H,SCH ₃ ),2,85-2.75( m, 4H, CH ₂ ), 2.52-2.62 (m, 2H, CH ₂ ).

Example 89: Compound P089

At room temperature, compound P085-a (100mg, 0.35mmol, 1.00eq.) and 5-chloro-2,2-dimethylvalerate isobutyl ester (235μL, 1.04mmol, 3.00eq.) were dissolved in anhydrous acetonitrile To 6.00 mL, potassium iodide (5 mg, 0.10 eq.) and potassium carbonate (480 mg, 10.00 eq.) were added, and the reaction was heated to 70° C. for 48 hours under the protection of nitrogen. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether: dichloromethane=1:10) to obtain compound P089. Yield: 82%.

MS(ESI): 473.3 [M+1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3 Hz, 2H, ArH), 7.82 (d, J = 8.2 Hz, 2H, ArH), 7.40 (d, 2H, J = 8.2 Hz ,ArH),7.30(d,J=8.3Hz,2H,ArH),6.77(d,J=36.8Hz,1H,CF=CH), 4.65(t,2H,OCH ₂ ), 4.29(d,2H, OCH ₂ ), 2.55 (s, 3H, SCH ₃ ), 1.92 (q, 1H, CH), 1.85 (m, 4H, CH ₂ ), 1.32 (s, 6H, CH ₃ ), 1.02 (d, 6H, CH ₃ ).

Example 90: Compound P090

Step 1: Compound P090-a

At room temperature, compound P085-a (100mg, 0.35mmol, 1.00eq.) and tert-butyl 2-bromobutyrate (677mg, 3.47mmol, 10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, then potassium carbonate was added (480mg, 10.00eq.), heated to 70°C under the protection of nitrogen, and reacted for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether:dichloromethane=1:10) to obtain compound P090-a. Yield: 83%.

MS (ESI): 431.5 [M+1].

Step 2: Compound P090

At room temperature, compound P090-a (0.27 mmol, 1.00 eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00 mL), and reacted at room temperature for 1.5 hours. The reaction solution was diluted by adding 4 mL of dichloromethane, and then added with 15 mL of saturated sodium bicarbonate solution to wash until weakly alkaline, then washed with saturated ammonium chloride solution to become weakly acidic, and extracted with dichloromethane (10 mL×3). Combine the organic phases with water Washed once, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P090. Yield: 90.0%.

MS(ESI): 373.3[M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3 Hz, 2H, ArH), 7.82 (d, J = 8.2 Hz, 2H, ArH), 7.40 (d, J = 8.2 Hz, 2H ,ArH),7.30(d,J=8.3Hz,2H,ArH),6.77(d,J=36.8Hz,1H,CF=CH),4.65(t,1H,OCH),2.55(s,3H,SCH ₃ ), 1.83 (m, 2H, CH ₂ ), 1.56 (d, 3H, CH ₃ ).

Example 91: Compound P091

Step 1: Compound P091-a

At room temperature, compound P085-a (100mg, 0.35mmol, 1.00eq.) and ethyl 2-bromoisovalerate (726mg, 3.47mmol, 10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, and then carbonic acid was added Potassium (480mg, 10.00eq.), heated to 70°C under the protection of nitrogen, reacted for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether: dichloromethane=1:10) to obtain compound P091-a. Yield: 85.0%.

MS(ESI): 417.5[M+1].

Step 2: Compound P091

At room temperature, compound P091-a (0.28 mmol, 1.00 eq.) was dissolved in 1.00 mL of 10% sodium hydroxide solution and 1.00 mL of tetrahydrofuran, and reacted at room temperature for 3 hours. The reaction solution was added with 30 mL saturated ammonium chloride solution, extracted with dichloromethane (10 mL×3), combined the organic phases, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P091. Yield: 90.0%.

MS(ESI): 387.7[M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3 Hz, 2H, ArH), 7.82 (d, J = 8.2 Hz, 2H, ArH), 7.40 (d, J = 8.2 Hz, 2H ,ArH),7.30(d,J=8.3Hz,2H,ArH),6.77(d,J=36.8Hz,1H,CF=CH),4.63(d,1H,OCH),2.55(s,3H,SCH ₃ ), 1.65 (m, 1H, CH), 1.10 (d, 6H, CH ₃ ).

Example 92: Compound P092

Step 1: Compound P092-a

At room temperature, compound P085-a (100mg, 0.35mmol, 1.00eq.) and ethyl 3-chloro-2,2-dimethylpropionate (172mg, 1.04mmol, 3.00eq.) were dissolved in anhydrous acetonitrile 6.00 Add potassium iodide (5mg, 0.10eq.) and potassium carbonate (480mg, 10.00eq.) to the mL, and heat to 70°C for 48 hours under the protection of nitrogen. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether:dichloromethane=1:10) to obtain compound P092-a. Yield: 86%.

MS (ESI): 417.3 [M+1].

Step 2: Compound P092

At room temperature, compound P092-a (0.28 mmol, 1.00 eq.) was dissolved in 1.00 mL of 10% sodium hydroxide solution and 1.00 mL of tetrahydrofuran, and reacted at room temperature for 3 hours. The reaction solution was added with 30 mL saturated ammonium chloride solution, extracted with dichloromethane (10 mL×3), combined the organic phases, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P092. Yield: 80.0%.

MS(ESI): 387.7[M-1]. ¹ H-NMR(400MHz; (CDCl ₃ )δ _H =7.85(d,J=7.2Hz,2H,ArH), 7.82(d,J=8.2Hz,2H,ArH),7.38(d,J=8.2Hz ,2H,ArH),7.30(d,J=7.2Hz,2H,ArH), 6.77(d,J=36.8Hz,1H,CF=CH),6.58(d,J=8.2Hz,1H,ArH), 4.45 (s, 2H, OCH ₂ ), 2.54 (s, 3H, SCH ₃ ), 1.55 (s, 6H, CH ₃ ).

Example 93: Compound P093

Step 1: Compound P093-a

At room temperature, compound P085-a (100mg, 0.35mmol, 1.00eq.) and ethyl 3-chloropropionate (143mg, 1.04mmol, 3.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, then potassium iodide (5mg , 0.10eq.) and potassium carbonate (480mg, 10.00eq.), heated to 70°C under the protection of nitrogen and reacted for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether: dichloromethane=1:10) to obtain compound P093-a. Yield: 80.0%.

MS (ESI): 389.7 [M+1].

Step 2: Compound P093

At room temperature, compound P093-a (0.27 mmol, 1.00 eq.) was dissolved in 1.00 mL of 10% sodium hydroxide solution and 1.00 mL of tetrahydrofuran, and reacted at room temperature for 3 hours. The reaction solution was added with 30 mL saturated ammonium chloride solution, extracted with dichloromethane (10 mL×3), combined the organic phases, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P093. Yield: 89%.

MS (ESI): 359.3 [M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 7.3, 2H, ArH), 7.82 (d, J = 8.2 Hz, 2H, ArH), 7.40 (s, J = 8.2 Hz, 2H, ArH), 7.30 (d, J = 8.3 Hz, 2H, ArH), 6.77 (d, J = 36.8 Hz, 1H, CF = CH), 6.58 (d, J = 8.2 Hz, 1H, ArH), 4.65 (t , 2H, OCH ₂ ), 4.45 (t, 2H, COCH ₂ ), 2.55 (s, 3H, SCH ₃ ).

Example 94: Compound P094

Step 1: Compound P094-a

At room temperature, compound P085-a (100mg, 0.35mmol, 1.00eq.) and methyl 1-bromocyclopentanecarboxylate (719mg, 3.47mmol, 10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, and then added Potassium carbonate (480mg, 10.00eq.), heated to 70°C under the protection of nitrogen, reacted for 4 days. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether:dichloromethane=1:10) to obtain compound P094-a. Yield: 30%.

MS (ESI): 415.4 [M+1].

Step 2: Compound P094

At room temperature, compound P094-a (0.09 mmol, 1.00 eq.) was dissolved in 1.00 mL of 10% sodium hydroxide solution and 1.00 mL of tetrahydrofuran, and reacted at room temperature for 3 hours. The reaction solution was added with 30 mL saturated ammonium chloride solution, extracted with dichloromethane (10 mL×3), combined the organic phases, washed with water once, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P094. Yield: 90.0%.

MS (ESI): 399.2 [M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3 Hz, 2H, ArH), 7.82 (d, J = 8.2 Hz, 2H, ArH), 7.40 (d, J = 8.2 Hz, 1H ,ArH),7.30(d,J=8.3Hz,2H,ArH),6.77(d,J=36.8Hz,1H,CF=CH),6.58(d,J=8.2Hz,1H,ArH),2.55( s, 3H, SCH ₃ ), 1.96-1.56 (m, 8H, CH ₂ ).

Example 95: Compound P095

Step 1: Compound P095-a

At room temperature, compound P085-a (100mg, 0.35mmol, 1.00eq.) and methyl 1-bromocyclohexanecarboxylate (768mg, 3.47mmol, 10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, and then added Potassium carbonate (480mg, 10.00eq.), heated to 70°C under the protection of nitrogen, reacted for 4 days. The reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by preparative chromatography plate (petroleum ether:dichloromethane=1:10) to obtain compound P095-a. Yield: 20%.

MS(ESI): 387.3 [M+1].

Step 2: Compound P095

At room temperature, compound P095-a (0.05 mmol, 1.00 eq.) was dissolved in 1.00 mL of 10% sodium hydroxide solution and 1.00 mL of tetrahydrofuran, and reacted at room temperature for 3 hours. The reaction solution was added with 30 mL saturated ammonium chloride solution, extracted with dichloromethane (10 mL×3), combined the organic phases, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P095. Yield: 80.0%.

MS(ESI): 371.2[M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3 Hz, 2H, ArH), 7.82 (d, J = 8.2 Hz, 2H, ArH), 7.39 (d, J = 8.2 Hz, 2H ,ArH),7.30(d,J=8.3Hz,2H,ArH),6.77(d,J=36.8Hz,1H,CF=CH),6.58(d,J=8.2Hz,1H,ArH),2.55( s, 3H, SCH ₃ ), 1.55 (m, 4H, CH ₂ ).

Example 96: Compound P096

Step 1: Compound P096-a

At room temperature, compound P085-a (100mg, 0.35mmol, 1.00eq.) and tert-butyl bromoacetate (677mg, 3.47mmol, 10.00eq.) were dissolved in anhydrous acetonitrile (15.00mL, 30.00eqv.), and then added Potassium carbonate (480mg, 10.00eq.), heated to 70°C under the protection of nitrogen, reacted for 96 hours. The reaction solution was concentrated under reduced pressure, diluted with 40 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by silica gel chromatography column (petroleum ether: dichloromethane=1:10) to obtain compound P096-a. Yield: 94%.

MS(ESI): 403.2 [M+1].

Step 2: Compound P096

At room temperature, compound P096-a (0.30 mmol, 1.00 eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00 mL), and reacted at room temperature for 1.5 hours. The reaction solution was diluted by adding 4 mL of dichloromethane, and then added with 15 mL of saturated sodium bicarbonate solution to wash until weakly alkaline, then washed with saturated ammonium chloride solution to become weakly acidic, and extracted with dichloromethane (10 mL×3). Combine the organic phases with water Washed once, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P096. Yield: 91.0%.

MS(ESI): 345.4[M-1]. ¹ H NMR (400MHz, CDCl ₃ ) δ _H = 7.84 (d, J = 8.3 Hz, 2H, ArH), 7.82 (d, J = 8.2 Hz, 2H, ArH), 7.40 (d, J = 8.2 Hz, 2H ,ArH),7.30(d,J=8.3Hz,2H,ArH),6.77(d,J=36.8Hz,1H,CF=CH),6.58(d,J=8.2Hz,1H,ArH), 4.89( s, 2H, OCH ₂ CO), 2.55 (s, 3H, SCH ₃ ).

Example 97: Compound P097

Step 1: Compound P097-a

At room temperature, the compound P001-c (2.00g, 10.86mmol, 1.00eq.) and 3,5-dichloro-4-hydroxybenzaldehyde (2.08g, 10.86mmol, 1.00eq.) in anhydrous methanol (50.00mL , 25.11eqv.) piperidine (3.00mL, 3.00eqv.), heated to room temperature under the protection of nitrogen, and reacted for 96 hours. The reaction solution was concentrated under reduced pressure, mixed with 20 mL of water, extracted with ethyl acetate (20 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product . The crude product was purified by silica gel chromatography column (petroleum ether: dichloromethane=3:1) to obtain compound P097-a. Yield: 38%.

MS (ESI): 356.1 (M-1).

Step 2: Compound P097-b

At room temperature, compound P097-a (0.50g, 1.40mmol, 1.00eq.) and tert-butyl 2-bromoisobutyrate (2.70mL, 14.00mmol, 10.00eq.) were dissolved in anhydrous acetonitrile (15.00mL, 30.00eqv.), then potassium carbonate (1.94g, 10.00eqv.) was added, and the mixture was heated to 70°C for 96 hours under the protection of nitrogen. The reaction solution was concentrated under reduced pressure, diluted with 40 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by silica gel chromatography column (petroleum ether:dichloromethane=1:1) to obtain compound P097-b. Yield: 60%.

MS (ESI): 500.2 [M+1].

The third step: compound P097

At room temperature, compound P097-b (200 mg, 0.40 mmol, 1.00 eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00 mL), and reacted at room temperature for 1.5 hours. The reaction solution was diluted by adding 4 mL of dichloromethane, and then added with 15 mL of saturated sodium bicarbonate solution to wash until weakly alkaline, then washed with saturated ammonium chloride solution to become weakly acidic, and extracted with dichloromethane (10 mL×3). Combine the organic phases with water Washed once, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P097. Yield: 79%.

MS(ESI): 442.7[M-1]. ¹ H-NMR (400MHz; (CDCl ₃ )δ _H = 8.10 (s, 2H, ArH), 7.85 (d, J = 7.2 Hz, 2H, ArH), 7.30 (d, J = 7.2 Hz, 2H, ArH) , 6.77 (d, J=36.8 Hz, 1H, CF=CH), 2.54 (s, 3H, SCH ₃ ), 1.55 (s, 6H, CH ₃ ).

Example 98: Compound P098

Step 1: Compound P098-a

At room temperature, the compound P001-c (2.00g, 10.86mmol, 1.00eq.) and 2-methyl-4-hydroxybenzaldehyde (1.48g, 10.86mmol, 1.00eq.) in anhydrous methanol (50.00mL, 25.11 eqv.) piperidine (3.00 mL, 3.00 eqv.), heated to room temperature under nitrogen protection, and reacted for 96 hours. The reaction solution was concentrated under reduced pressure, mixed with 20 mL of water, extracted with ethyl acetate (20 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product . The crude product was purified by silica gel chromatography column (petroleum ether: dichloromethane=3:1) to obtain compound P098-a. Yield: 37%.

MS (ESI): 301.1 (M-1).

Step 2: Compound P098-b

At room temperature, compound P098-a (0.50g, 1.65mmol, 1.00eq.) and tert-butyl 2-bromoisobutyrate (3.10mL, 16.54mmol, 10.00eq.) were dissolved in anhydrous acetonitrile (15.00mL, 30.00eqv.), then potassium carbonate (2.29g, 10.00eqv.) was added, and the reaction was heated to 70°C for 96 hours under the protection of nitrogen. The reaction solution was concentrated under reduced pressure, diluted with 40 mL of water and mixed, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with water until neutral, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was purified by silica gel chromatography column (petroleum ether: dichloromethane=1:1) to obtain compound P098-b. Yield: 60%.

MS(ESI): 445.2 [M+1].

The third step: compound P098

At room temperature, compound P098-b (200 mg, 0.45 mmol, 1.00 eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00 mL), and reacted at room temperature for 1.5 hours. The reaction solution was diluted by adding 4 mL of dichloromethane, and then added with 15 mL of saturated sodium bicarbonate solution to wash until weakly alkaline, then washed with saturated ammonium chloride solution to become weakly acidic, and extracted with dichloromethane (10 mL×3). Combine the organic phases with water Washed once, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P098. Yield: 75%.

MS(ESI): 387.7[M-1]. ¹ H-NMR(400MHz; (CDCl ₃ )δ _H =7.85(d,J=7.2Hz,2H,ArH), 7.58(d,J=8.2Hz,1H,ArH), 7.30(d,J=7.2Hz ,2H,ArH),6.85(d,J=8.2Hz,1H,ArH),6.82(s,1H,ArH),6.77(d,J=36.8Hz,1H,CF=CH),2.54(s,3H) , SCH ₃ ), 2.32 (s, 3H, ArCH ₃ ), 1.55 (s, 6H, CH ₃ ).

Example 99 The activity of the compound of the present invention on PPAR

Plasmid vectors containing PPARα(Kanamycin+), PPARδ(Kanamycin+), pPPRE3-TK_Luciferase(Kanamycin+) were introduced into DH5a competent cells, and the target plasmids were obtained by monoclonal and amplification culture. Use Plasmid Miniprep Kit to extract the target plasmid, and transfect the luciferase and PPAR expression vector into Hela cells. After 24 hours of transfection, the cells ^{were seeded into a 96-well plate at 5*10 5} /ml, and 12 hours later, the compound of the present invention and the positive compound were added. The initial concentration of the compound is 10000nM, and it is diluted to 10 concentration gradients by a ratio of 1:2. After 24 hours of incubation in the incubator, luciferase detection reagent was added, the luminous intensity was detected by a Tecan Spark microplate reader, and the EC ₅₀ value was calculated.

Table 1 The agonistic activity of the compounds of the present invention on PPARα and δ (EC ₅₀ value, nM)

化合物编号Compound number	PPARαPPARα	PPARδPPARδ
GFT-505GFT-505	++++++	++
P001P001	++++++++	++++
P002P002	++++++++	++++
P003P003	++++++++	++++++
P004P004	++++++	++++
P006P006	++++++	++++
P007P007	++++++	++++
P008P008	++++++	++++
P010P010	++++++	++
P013P013	++++++	++++
P015P015	++++++	++++
P018P018	++++++	++
P025P025	++++	++
P030P030	++++	++
P037P037	++++++	++++
P039P039	++++++	++++
P045P045	++++++	++
P049P049	++++	++
P051P051	++++++	++
P057P057	++++++	++
P061P061	++++++	++++
P063P063	++++++	++++
P073P073	++++++	++++
P085P085	++++++	++
P087P087	++++++++	++
P090P090	++++++	++++
P092P092	++++	++
P097P097	++++++	++
P098P098	++++++	++

[Note] ++++: means that EC ₅₀ value is less than 10nM

+++: represents that the EC ₅₀ value is greater than or equal to 10nM and less than 50nM;

++: represents that the EC ₅₀ value is greater than or equal to 50 nM and less than 100 nM;

+: represents that the EC ₅₀ value is greater than or equal to 100 nM and less than 500 nM.

_{The experimental results show that the EC 50} value of the agonistic effect of the compound of the present invention on PPARα and PPARδ is better than that of the positive control drug, indicating that the compound of the present invention has stronger activity.

Example 100 Animal bioavailability of the compound of the present invention

The rats were fasted with water for 12h. After administration, about 400μL of blood was taken from the orbit of each animal, EDTA-Na ₂ anticoagulant, and the time points for the intravenous administration group were: 2min, 10min, 30min, 1h, 2h, 4h after administration of the test substance , 6h, 8h, 24h and 30h; the collection time points of the intragastric administration group are: 5min, 10min, 30min, 1h, 2h, 3h, 4h, 6h, 8h, 24h and 30h after administration of the test substance. After collection, place it in an ice bath and centrifuge within 1 hour to separate plasma (centrifugation conditions: 6000 rpm, 8 min, 4°C). Vortex and mix at 2500 rpm for 1 min, take 100.0 μL of plasma sample into a 1.5 mL centrifuge tube, add 10.0 μL of internal standard working solution (1.000 μg/mL), vortex at 2500 rpm for 1 min, and then centrifuge at 17000×g at 4°C for 15 min. The supernatant was analyzed by UHPLC-MS/MS, and 2.0 μL was injected. The data was analyzed and processed with WinNonLin7.0 pharmacokinetic software.

The results of the in vivo pharmacokinetic study of compound P001 in SD rats (n=3) showed that after intravenous administration (dose 1.0mg/kg), the half-life T _1/2 of compound P001 in rats was 1.63±0.15h , C _max is 5115.19±269.84ng/mL. After compound P001 was administered intragastrically (dose 10.0mg/kg), the half-life T _1/2 in rats was 1.46±0.37h, _Cmax was 4603.24±1048.8ng/mL, and the absolute bioavailability was 40.88%.

The document CN108658908A reported that the Cmax of GFT-505 was 1138 ng/mL after intragastric administration of 20 mg/kg, indicating that the compound P001 of the present invention has a higher blood concentration and is more effective than GFT-505.

Example 101 The effect of the compound of the present invention on collagen I protein expression

Set up a blank control group, a TGFβ1 model group, a GFT-505 positive control group, and a compound group of the present invention. LX-2 (hepatic stellate cells) was spread on a 6-well plate with 5*10 ⁵ cells in each well. The original culture was discarded after 12 hours Base, respectively add 2% serum-containing medium, add GFT-505 and the compounds of the present invention P001, P002, P003, the final concentration is 10 μM, the blank control group is replaced with the same amount of medium. After 1 hour, the blank control group was replaced with the same amount of medium, and the other groups were added with TGFβ1, the final concentration was 1ng/ml. After 48 hours, the cells were digested with trypsin, and the expression of Collagen Ⅰ protein was detected by Western Blot. The relative expression levels of Collagen Ⅰ protein in each group are shown in Table 2.

Table 2 Relative expression level of Collagen Ⅰ protein in each group

组别Group	样品sample	蛋白相对表达水平Relative protein expression level
空白组对照组Blank control group	培养基Culture medium	0.180.18
模型组Model group	TGFβ1TGFβ1	0.710.71
阳性对照组Positive control group	GFT-505GFT-505	0.520.52
本发明实施例1Example 1 of the present invention	P001P001	0.380.38
本发明实施例2Example 2 of the present invention	P002P002	0.330.33
本发明实施例3Example 3 of the present invention	P003P003	00

The compounds P001, P002, and P003 of the present invention can effectively reduce the expression of Collagen I protein, and have obvious effects. Compared with the positive control drug GFT-505, the activity is stronger, and the compound P003 has the best effect.

Claims

An α-fluorochalcone derivative is a compound represented by formula I or a pharmaceutically acceptable salt thereof:

among them:

R 1 and R 2 are independently selected from H, halogen, CF 3 , -CN, C 1-6 alkoxy, CF 3 O, CHF 2 O, C 1-6 alkylthio, CF 3 S, CHF 2 S, C 1-6 alkyl, C 1-6 alkyl sulfoxide group-, CF 3 SO, C 1-6 alkyl sulfone group or CF 3 SO 2 , or selected from 1, 2 or 3 R substituted: C 1-6 alkyl, C 1-6 alkyl-S(=O)-, C 1-6 alkyl-S(=O) 2 -, C 1-6 alkyl-(=O ) 2 -, C 1-6 alkoxy or C 1-6 alkylthio;

R 3 and R 4 are each independently selected from H, halogen, C 1-4 alkyl, C 1-4 alkoxy, including but not limited to Cl, Br, I, CH 3 , Et, CH 3 O;

R 5 and R 6 are each independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, phenyl, 5-6 membered heteroaryl, R 5 , R 6 may also form a ring as C 3 -6 cycloalkyl or 3-6 membered heterocycloalkyl; wherein R 5 and R 6 include but are not limited to methyl, ethyl, isopropyl, phenyl, pyrazolyl or pyridyl; R 5 , R 6 The ring is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

R 7 is selected from H or C 1-6 alkyl;

n is selected from 0, 1, 2, 3, 4, 5 or 6;

R is selected from H, F, Cl, Br, I, OH, CN, NH 2 , COOH, C(=O)NH 2 , Me, Et, CF 3 , CHF 2 , CH 2 F, NHCH 3 or N(CH 3 ) 2 .
The α-fluorochalcone derivatives according to claim 1, wherein in the compound of formula I, R 1 and R 2 are selected from H, halogen, CF 3 , -CN, C 1- 6 alkoxy, CF 3 O, CHF 2 O , C 1-6 alkylthio, CF 3 S, CHF 2 S , C 1-6 alkyl, C 1-6 alkylsulfoxide group -, CF 3 SO , C 1-6 alkylsulfone group or CF 3 SO 2 ; wherein R 1 , R 2 are preferably selected from Cl, Me, Et, CH 3 O, EtO, n-Pr-O, i-PrO, CH 3 S, EtS , N-PrS, i-PrO, CH 3 SO, CH 3 SO 2 , CF 3 O, CHF 2 O, CF 3 S, CHF 2 S, CF 3 SO, or CF 3 SO 2 .
The α-fluorochalcone derivatives according to claim 1, wherein in the compound of formula I, R 3 and R 4 are independently selected from H, halogen, and C 1-4 alkyl Or C 1-4 alkoxy, or each independently selected from C 1-4 alkyl and C 1-4 alkoxy optionally substituted with 1, 2 or 3 R.
The α-fluorochalcone derivatives according to claim 1, wherein in the compound of formula I, R 5 and R 6 are independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, phenyl or 5-6 membered heteroaryl, R 5 , R 6 can also form a C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, R 5 , R 6 Including but not limited to methyl, ethyl, isopropyl, phenyl, pyrazolyl or pyridyl; or R 5 and R 6 form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
The α-fluorochalcone derivatives according to claim 1, wherein in the compound of formula I,

Selected from:
The α-fluorochalcone derivatives according to claim 1, wherein in the compound of formula I,

Selected from:
The α-fluorochalcone derivatives according to claim 1, which is a compound represented by formula II or a pharmaceutically acceptable salt thereof:

among them:

When R 1 is selected from H or -XR, wherein X is selected from S, S(O), S(O) 2 or O, and R is selected from Me, Et, CF 3 , CHF 2 , CH 2 F, NHCH 3 or N (CH 3 ) 2 ; then R 2 is selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl or halogenated C 1-6 alkoxy; or

When R 2 is selected from H or -XR, wherein X is selected from S, S(O), S(O) 2 or O, and R is selected from Me, Et, CF 3 , CHF 2 , CH 2 F, NHCH 3 or N (CH 3 ) 2 ; then R 1 is selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl or halogenated C 1-6 alkoxy;

R 3 and R 4 are each independently selected from H, halogen, C 1-4 alkyl or C 1-6 alkoxy;

R 5 and R 6 are each independently selected from H, C 1-6 alkyl, phenyl or 5-6 membered heteroaryl, or R 5 , R 6 may also form a ring of C 3-6 cycloalkyl or 3 ～6-membered heterocycloalkyl;

R 7 is selected from H or C 1-6 alkyl;

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

The heteroaryl group and heterocycloalkyl group contain at least one heteroatom, and the heteroatom is selected from one or more of N, O, and S.
The α-fluorochalcone derivative according to claim 7, which is a compound represented by formula IIa or a pharmaceutically acceptable salt thereof:

Wherein, R is selected from Me, Et, CF 3 , CHF 2 , CH 2 F, NHCH 3 or N(CH 3 ) 2 ;

R 2 is selected from H, halogen or C 1-6 alkyl;

R 3 and R 4 are each independently selected from H, halogen or C 1-4 alkyl;

R 5 and R 6 are each independently selected from H, C 1-6 alkyl, phenyl or 5-6 membered heteroaryl, or R 5 , R 6 may also form a ring of C 3-6 cycloalkyl or 3 ～6-membered heterocycloalkyl;

R 7 is selected from H or C 1-6 alkyl;

The heteroaryl group and heterocycloalkyl group contain at least one heteroatom, and the heteroatom is selected from one or more of N, O, and S.
The α-fluorochalcone derivative according to claim 7, which is a compound represented by formula IIb or a pharmaceutically acceptable salt thereof:

Wherein, R is selected from Me, Et, CF 3 , CHF 2 , CH 2 F, NHCH 3 or N(CH 3 ) 2 ;

R 2 is selected from H, halogen or C 1-6 alkyl;

R 3 and R 4 are each independently selected from H, halogen or C 1-4 alkyl;

R 5 and R 6 are each independently selected from H, C 1-6 alkyl, phenyl or 5-6 membered heteroaryl, or R 5 , R 6 may also form a ring of C 3-6 cycloalkyl or 3 ～6-membered heterocycloalkyl;

R 7 is selected from H or C 1-6 alkyl;

The heteroaryl group and heterocycloalkyl group contain at least one heteroatom, and the heteroatom is selected from one or more of N, O, and S.
The α-fluorochalcone derivative according to claim 7, which is a compound represented by formula IIc or a pharmaceutically acceptable salt thereof:

Wherein, R is selected from Me, Et, CF 3 , CHF 2 , CH 2 F, NHCH 3 or N(CH 3 ) 2 ;

R 2 is selected from H, halogen or C 1-6 alkyl;

R 3 and R 4 are each independently selected from H, halogen or C 1-4 alkyl;

R 5 and R 6 are each independently selected from H, C 1-6 alkyl, phenyl or 5-6 membered heteroaryl, or R 5 , R 6 may also form a ring of C 3-6 cycloalkyl or 3 ～6-membered heterocycloalkyl;

R 7 is selected from H or C 1-6 alkyl;

The heteroaryl group and heterocycloalkyl group contain at least one heteroatom, and the heteroatom is selected from one or more of N, O, and S.
The α-fluorochalcone derivatives according to claim 7, which is a compound represented by formula IId or a pharmaceutically acceptable salt thereof:

Wherein, R 1 is selected from H or -XR, X is selected from S, S(O), S(O) 2 or O, and R is selected from Me, Et, CF 3 , CHF 2 , CH 2 F, NHCH 3 or N (CH 3 ) 2 ;

R 2 is selected from H, halogen or C 1-6 alkyl;

R 3 and R 4 are each independently selected from H, halogen or C 1-4 alkyl;

R 5 and R 6 are each independently selected from H, C 1-6 alkyl, phenyl or 5-6 membered heteroaryl, or R 5 , R 6 may also form a ring of C 3-6 cycloalkyl or 3 ～6-membered heterocycloalkyl;

R 7 is selected from H or C 1-6 alkyl;

The heteroaryl group and heterocycloalkyl group contain at least one heteroatom, and the heteroatom is selected from one or more of N, O, and S.
An α-fluorochalcone derivative is a compound with the following structure or a pharmaceutically acceptable salt thereof:
A pharmaceutical composition comprising the compound according to any one of claims 1-12 or a pharmaceutically acceptable salt thereof as an active ingredient, and one or more pharmaceutically acceptable carriers.
A use of the compound according to any one of claims 1 to 12 or the pharmaceutical composition according to claim 13 in the preparation of a medicament for the treatment of PPAR receptor-related diseases.
The use according to claim 14, wherein the PPAR receptor related diseases are: non-alcoholic steatohepatitis, liver fibrosis, insulin resistance, primary biliary cholangitis, dyslipidemia, hyperlipidemia, Lipidemia, hypercholesterolemia, atherosclerosis, hypertriglyceridemia, cardiovascular disease, obesity, kidney disease, or degenerative brain disease.
The use according to claim 15, wherein the kidney disease is selected from chronic kidney disease and renal failure, and the brain degenerative disease is selected from Alzheimer's disease.