Alpha-fluorochalcone derivative and application thereof

Abstract

The invention provides an alpha-fluorochalcone derivative and application thereof. The derivative comprises pharmaceutically acceptable salt of the derivative. The invention also provides an application of the derivative and the pharmaceutically acceptable salt thereof in preparation of drugs for treating PPAR receptor related diseases. The derivative provided by the invention has the characteristics of good in-vivo absorption, high bioavailability and strong drug effect, thereby having huge clinical application value.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and relates to an α-fluorochalcone derivative and its application. Specifically, the derivative relates to a pharmaceutically acceptable salt and a prodrug, which is a peroxisome proliferator-activated receptor (PPAR) agonist, has the use of treating diseases related to abnormal PPAR expression, and has great clinical application prospects. Background Art

[0002] Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in developed countries or regions. It refers to the accumulation of excess fat in the liver in the form of triglycerides (fatty degeneration > 5% of hepatocyte tissue). In addition to excess fat, patients with NAFLD are accompanied by liver cell damage and inflammation (steatohepatitis), the latter of which is nonalcoholic steatohepatitis (NASH). Simple fatty degeneration in NAFLD is not associated with increased short-term morbidity or mortality, but once it progresses to NASH, it significantly increases the risk of cirrhosis, liver failure and hepatocellular carcinoma (HCC). Cirrhosis caused by NASH is an increasing reason for liver transplantation. The morbidity and mortality caused by liver disease are greatly increased in NASH patients, and are closely related to the increased morbidity and mortality of cardiovascular diseases. Diagnosis of asymptomatic middle-aged male patients showed that 46% of patients had non-alcoholic fatty liver disease (NAFLD, and 12.2% had NASH. NAFLD patients were mostly male, elderly, hypertensive and diabetic. 60% to 76% of diabetic patients had NAFLD, and 22% had NASH. The number of pediatric patients with NAFLD is also increasing year by year, and 38% to 53% of obese children have NAFLD. In China, the incidence of non-alcoholic fatty liver disease has risen to the first place.

[0003] Currently, only obeticholic acid has been approved by the FDA to treat this disease. In China, liver-protecting drugs such as polyene phosphatidylcholine, silymarin, ursodeoxycholic acid, and glycyrrhizic acid are commonly used in clinical practice.

[0004] Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily. They are ligand-activated transcription factors that regulate gene expression. There are three main subtypes: α, γ, and δ (or β). The α subtype is mainly expressed in brown adipose tissue, liver, heart, and skeletal muscle, and plays a major role in the metabolism of bile acid, lipids, and sugars; the β subtype has no obvious expression specificity and may have anti-inflammatory effects; the γ subtype has a certain effect on insulin resistance. PPARs are 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 diseases, respiratory diseases, eye diseases, IBD (irritable bowel disease), ulcerative colitis, and Crohn's disease. From the perspective of the various conditional mechanisms of PPARs that are beneficial to liver function, PPAR agonists are one of the most effective potential drugs for the treatment of fatty liver.

[0005] Elafibranor (GFT-505) is a peroxisome proliferator-activated α and δ receptor (PPARα / δ) agonist developed by Genfit, France. It is currently in Phase III clinical studies for the treatment of non-alcoholic steatohepatitis (NASH) and Phase II clinical trials for the treatment of primary cholangitis (PBC). There has been no progress in clinical studies of elafibranor 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 in microvessels and macrovessels, such as high-density and low-density lipoprotein cholesterol, triglycerides and inflammation, and has shown positive effects on insulin resistance, diabetes and atherosclerosis in preclinical studies.

[0006] The following compounds are compounds reported in the literature for treating NASH.

[0007]

[0008] Some researchers at home and abroad have also conducted early research on PPAR agonist small molecule compounds. For example, CN108658908A discloses a compound with a bicyclic ring structure, and CN 1930122A discloses a 1,3-diphenylprop-2-ene-1-one derivative compound, which exhibits good biological activity against all or part of the three subtypes of PPAR, and WO2017143038 discloses a deuterated chalcone derivative. Summary of the invention

[0009] The present invention aims to provide a novel α-fluorochalcone derivative, which has the activity of activating PPAR.

[0010] In order to solve the above technical problems, the present invention adopts the following technical solutions:

[0011] An α-fluorochalcone derivative is a compound represented by formula I or a pharmaceutically acceptable salt thereof:

[0012]

[0013] Wherein: R1, R2 are independently selected from H, halogen, CF3, -CN, C 1-6 Alkoxy, CF3O, CHF2O, C 1-6 Alkylthio, CF3S, CHF2S, C 1-6 Alkyl, C 1-6 Alkyl sulfoxide-, CF3SO, C 1-6 alkylsulfone or CF3SO2, or selected from: 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;

[0014] R3 and R4 are independently selected from H, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, including but not limited to Cl, Br, I, CH3, Et, CH3O;

[0015] R5 and R6 are independently selected from H, C 1-6 Alkyl, C 1-6 Heteroalkyl, phenyl, 5-6 membered heteroaryl, R5, R6 can also be cyclic C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl; wherein R5 and R6 include but are not limited to methyl, ethyl, isopropyl, phenyl, pyrazolyl or pyridyl; R5 and R6 are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

[0016] R7 is selected from H or C 1-6 alkyl;

[0017] n is selected from 0, 1, 2, 3, 4, 5 or 6;

[0018] R is selected from H, F, Cl, Br, I, OH, CN, NH2, COOH, C(=O)NH2, Me, Et, CF3, CHF2, CH2F, NHCH3 or N(CH3)2.

[0019] In the preferred compounds of formula I, R1, R2 are selected from H, halogen, CF3, -CN, C 1-6 Alkoxy, CF3O, CHF2O, C 1-6 Alkylthio, CF3S, CHF2S, C 1-6 Alkyl, C 1-6 Alkyl sulfoxide-, CF3SO, C 1-6 Alkylsulfone or CF3SO2; wherein R1 and R2 are preferably selected from Cl, Me, Et, CH3O, EtO, n-Pr-O, i-PrO, CH3S, EtS, n-PrS, i-PrO, CH3SO, CH3SO2, CF3O, CHF2O, CF3S, CHF2S, CF3SO or CF3SO2.

[0020] In the preferred compounds of formula I, R3 and R4 are independently selected from H, halogen, C 1-4 Alkyl or C 1-4 alkoxy, or each independently selected from C optionally substituted by 1, 2 or 3 R 1-4 Alkyl, C 1-4 Alkoxy.

[0021] In the preferred compounds of formula I, R5 and R6 are independently selected from H, C 1-6 Alkyl, C 1-6 heteroalkyl, phenyl or 5-6 membered heteroaryl, R5 and R6 can also be cyclic C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, R5, R6 include but are not limited to methyl, ethyl, isopropyl, phenyl, pyrazolyl or pyridyl; or R5, R6 are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

[0022] Among the preferred compounds of formula I, Selected from:

[0023] Among the preferred compounds of formula I, Selected from:

[0024] An α-fluorochalcone derivative is a compound represented by formula II or a pharmaceutically acceptable salt thereof:

[0025]

[0026] Wherein, when R1 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, CF3, CHF2, CH2F, NHCH3 or N(CH3)2; then R2 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

[0027] When R2 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, CF3, CHF2, CH2F, NHCH3 or N(CH3)2; then R1 is selected from H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy;

[0028] R3 and R4 are independently selected from H, halogen, C 1-4 Alkyl or C 1-6 Alkoxy;

[0029] R5 and R6 are independently selected from H, C 1-6 Alkyl, phenyl or 5-6 membered heteroaryl, or R5 and R6 can also be ring-formed to form C 3-6 Cycloalkyl or 3- to 6-membered heterocycloalkyl;

[0030] R7 is selected from H or C 1-6 alkyl;

[0031] n is selected from 0, 1, 2, 3 or 4;

[0032] The heteroaryl group and the heterocycloalkyl group contain at least one heteroatom, and the heteroatom is selected from one or more of N, O, and S.

[0033] Preferably, it is a compound represented by Formula IIa or a pharmaceutically acceptable salt thereof:

[0034]

[0035] wherein R is selected from Me, Et, CF3, CHF2, CH2F, NHCH3 or N(CH3)2;

[0036] R2 is selected from H, halogen or C 1-6 alkyl;

[0037] R3 and R4 are independently selected from H, halogen or C 1-4 alkyl;

[0038] R5 and R6 are independently selected from H, C 1-6Alkyl, phenyl or 5-6 membered heteroaryl, or R5 and R6 can also be ring-formed to form C 3-6 Cycloalkyl or 3- to 6-membered heterocycloalkyl;

[0039] R7 is selected from H or C 1-6 alkyl;

[0040] The heteroaryl group and the heterocycloalkyl group contain at least one heteroatom, and the heteroatom is selected from one or more of N, O, and S.

[0041] Preferably, it is a compound represented by Formula IIb or a pharmaceutically acceptable salt thereof:

[0042]

[0043] wherein R is selected from Me, Et, CF3, CHF2, CH2F, NHCH3 or N(CH3)2;

[0044] R2 is selected from H, halogen or C 1-6 alkyl;

[0045] R3 and R4 are independently selected from H, halogen or C 1-4 alkyl;

[0046] R5 and R6 are independently selected from H, C 1-6 Alkyl, phenyl or 5-6 membered heteroaryl, or R5 and R6 can also be ring-formed to form C 3-6 Cycloalkyl or 3- to 6-membered heterocycloalkyl;

[0047] R7 is selected from H or C 1-6 alkyl;

[0048] The heteroaryl group and the heterocycloalkyl group contain at least one heteroatom, and the heteroatom is selected from one or more of N, O, and S.

[0049] Preferably, it is a compound represented by Formula IIc or a pharmaceutically acceptable salt thereof:

[0050]

[0051] wherein R is selected from Me, Et, CF3, CHF2, CH2F, NHCH3 or N(CH3)2;

[0052] R2 is selected from H, halogen or C 1-6 alkyl;

[0053] R3 and R4 are independently selected from H, halogen or C 1-4 alkyl;

[0054] R5 and R6 are independently selected from H, C 1-6 Alkyl, phenyl or 5-6 membered heteroaryl, or R5 and R6 can also be ring-formed to form C3-6 Cycloalkyl or 3- to 6-membered heterocycloalkyl;

[0055] R7 is selected from H or C 1-6 alkyl;

[0056] The heteroaryl group and the heterocycloalkyl group contain at least one heteroatom, and the heteroatom is selected from one or more of N, O, and S.

[0057] Preferably, it is a compound represented by Formula IId or a pharmaceutically acceptable salt thereof:

[0058]

[0059] wherein R1 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, CF3, CHF2, CH2F, NHCH3 or N(CH3)2;

[0060] R2 is selected from H, halogen or C 1-6 alkyl;

[0061] R3 and R4 are independently selected from H, halogen or C 1-4 alkyl;

[0062] R5 and R6 are independently selected from H, C 1-6 Alkyl, phenyl or 5-6 membered heteroaryl, or R5 and R6 can also be ring-formed to form C 3-6 Cycloalkyl or 3- to 6-membered heterocycloalkyl;

[0063] R7 is selected from H or C 1-6 alkyl;

[0064] The heteroaryl group and the heterocycloalkyl group contain at least one heteroatom, and the heteroatom is selected from one or more of N, O, and S.

[0065] An α-fluorochalcone derivative, which is a compound numbered P001-P098 or a pharmaceutically acceptable salt thereof:

[0066]

[0067]

[0068] 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.

[0069] The present invention also provides a use of the above-mentioned pharmaceutical composition in preparing a drug for treating PPAR receptor-related diseases.

[0070] Preferably, the PPAR receptor-related disease is: non-alcoholic steatohepatitis, liver fibrosis, insulin resistance, primary biliary cholangitis, dyslipidemia, hyperlipidemia, hypercholesterolemia, atherosclerosis, hypertriglyceridemia, cardiovascular disease, obesity, kidney disease or brain degenerative disease.

[0071] 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.

[0072] Compared with the prior art, the present invention has the following beneficial effects:

[0073] The present invention has developed a series of fluorinated chalcone derivatives based on the structure of GFT-505 and conducted relevant biological tests. The experimental results show that in the in vitro model, the inhibitory effect of α-fluorinated chalcone derivatives on liver fibrosis is stronger than that of the positive drug GFT-505; in the in vivo model, the bioavailability of α-fluorinated chalcone derivatives is also good.

[0074] Definition and explanation of relevant terms

[0075] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered to be uncertain or unclear in the absence of a special definition, but should be understood according to its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding commercial product or its active ingredient.

[0076] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0077] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the invention, prepared from a compound having a specific substituent discovered by the invention and a relatively non-toxic base. When the compound of the invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of a 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 salts, ammonium or organic amines.

[0078] In addition to the form of salts, compounds provided by the present invention also exist in prodrug forms. Prodrugs of compounds described herein easily undergo chemical changes under physiological conditions to be converted into compounds of the present invention. In addition, prodrugs can be converted to compounds of the present invention by chemical or biochemical methods in an in vivo environment.

[0079] Certain compounds of the present invention may exist in unsolvated as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to the unsolvated forms and are encompassed within the scope of the present invention.

[0080] The term "pharmaceutically acceptable carrier" refers to any preparation or carrier medium representative of a 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 on the host or patient, including water, oil, vegetables and minerals, cream bases, lotion bases, ointment bases, excipients, etc. These bases include suspending agents, viscosity enhancers, transdermal enhancers, etc. Their preparations are well known to those skilled in the art of cosmetics or topical drugs. For additional information about the carrier, reference may be made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

[0081] The term "excipient" generally refers to a carrier, diluent and / or vehicle required to formulate an effective pharmaceutical composition.

[0082] With respect to a drug or pharmacologically active agent, 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 oral dosage forms of the present invention, an "effective amount" of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the specific active substance. The appropriate effective amount in each case can be determined by a person skilled in the art based on routine experiments.

[0083] The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating a target disorder, disease, or condition.

[0084] The terms "optional", "optionally" or "preferably" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0085] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is a keto group (i.e., =O), it means that two hydrogen atoms are replaced, and keto substitution does not occur on an aromatic group. The term "optionally substituted" means that it may be substituted or not substituted, and unless otherwise specified, the type and number of the substituents may be arbitrary on the basis of chemical achievability.

[0086] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, and each occurrence of R has an independent definition. In addition, combinations of substituents and / or variants thereof are permitted only if such combinations result in stable compounds.

[0087] When the number of a linking group is 0, such as -(CRR)0-, it means that the linking group is a single bond.

[0088] The term "alkyl" refers to a straight-chain or branched saturated hydrocarbon group consisting 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 (including n-butyl, isobutyl, sec-butyl or tert-butyl), pentyl (including n-pentyl, isopentyl, neopentyl), n-hexyl, and 2-methylhexyl.

[0089] 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, cycloheptyl and cyclooctyl.

[0090] The term "alkoxy" refers to a straight or branched alkyl group connected by an oxygen atom, such as C1-C6 alkoxy, including but not limited to methoxy, ethoxy, n-propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, sec-butoxy or tert-butoxy), pentoxy (including n-pentoxy, isopentoxy, neopentoxy), n-hexyloxy, 2-methylhexyloxy, etc.

[0091] The term "amino" refers to -NH2.

[0092] The term "cycloalkyl" refers to a saturated monocyclic, bicyclic or polycyclic alkyl group consisting of carbon atoms and hydrogen atoms, and it can be connected to the rest of the molecule through a single bond via any suitable carbon atom; when it is polycyclic, it can be connected by a parallel ring, a bridge ring or a spiro ring. In a certain embodiment, typical monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0093] The term "heterocycloalkyl" refers to a saturated cyclic group with heteroatoms, containing one or more heteroatoms independently selected from N, O, and S, and a group of a stable 3-10-membered saturated heterocyclic ring system composed of the rest being carbon. Unless otherwise specified in this specification, the heterocycloalkyl group may be a monocyclic, bicyclic, or polycyclic ring system; when it is polycyclic, it may be connected in parallel, bridged, or spirocyclic. In a certain embodiment, typical 4-6-membered monocyclic heterocycloalkyl groups containing one or more heteroatoms independently selected from N, O, and S include, but are not limited to

[0094] In one embodiment, typical 7-10 membered bicyclic heterocycloalkyl groups containing one or more heteroatoms independently selected from N, O, and S include but are not limited to wait.

[0095] The term "aryl" refers to an all-carbon aromatic group with a completely conjugated π electron system, which may be a single ring or a fused ring, and generally has 6 to 14 carbon atoms, preferably 6 to 12 carbon atoms, and most preferably 6 carbon atoms. Examples of aryl include, but are not limited to, phenyl, naphthyl, and anthracenyl.

[0096] The term "heteroaryl" refers to an aromatic group containing heteroatoms, which may be a monocyclic or condensed ring, preferably a 5-12-membered heteroaryl containing 1-4 independently selected from N, O, and S, including but not limited to pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, triazolyl, indolyl, etc. In a certain embodiment, typical 5-6-membered monocyclic heteroaryl containing 1 or more heteroatoms independently selected from N, O, and S include but are not limited to wait.

[0097] The term "halogenated C1-C6 alkyl", "halogenated C1-C6 alkoxy" refers to a group in which one or more (especially 1 to 3) hydrogen atoms are replaced by halogen atoms, especially fluorine or chlorine atoms.

[0098] 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.

[0099] The pharmaceutical composition of the present invention can be manufactured by methods well known in the art, such as conventional mixing methods, dissolving methods, granulating methods, making sugar-coated pills methods, grinding methods, emulsifying methods, freeze-drying methods, etc.

[0100] The administration routes of the compounds of the present invention or their pharmaceutically acceptable salts or their pharmaceutical compositions include, but are not limited to, oral, rectal, transmucosal, enteral administration, or topical, transdermal, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration. The preferred administration route is oral administration.

[0101] For oral administration, the pharmaceutical composition can be prepared by mixing the active compound with a pharmaceutically acceptable carrier well known in the art. These carriers enable the compounds of the present invention to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients. For example, a pharmaceutical composition for oral administration can be obtained in the following manner: the active ingredient is combined with one or more solid carriers, the resulting mixture is granulated if necessary, and a small amount of excipients is added if necessary to process the mixture or granules to form tablets or tablet cores. The tablet core can be combined with an optional enteric coating material to be processed into a coated preparation form that is more conducive to absorption by an organism (e.g., a human). DETAILED DESCRIPTION

[0102] The following are specific embodiments of the present invention, which further describe the technical solution 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.

[0103] Example 1: Compound P001

[0104]

[0105] Step 1: Compound P001-b

[0106] At room temperature, compound P001-a (4.00 g, 24.06 mmol, 1.00 eq.), N-bromosuccinimide (NBS) (4.37 g, 24.54 mmol, 1.02 eq.) and p-toluenesulfonic acid monohydrate (4.58 g, 24.06 mmol, 1.00 eq.) were dissolved in 12.00 mL of anhydrous acetonitrile and heated to 50°C at room temperature 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), the organic phases were combined, washed with water until neutral, washed once 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 (petroleum ether: ethyl acetate = 95:5) to obtain compound P001-b. Yield: 60%.

[0107] MS m / s(ESI):268.9[M+23].

[0108] Step 2: Compound P001-c

[0109] At room temperature, compound P001-b (3.40 g, 13.87 mmol, 1.00 eq.), tetrabutylammonium fluoride (TBAF) (5.70 mL, 20.81 mmol, 1.50 eq.) and potassium fluoride (1.21 g, 20.81 mmol, 1.50 eq.) were dissolved in anhydrous acetonitrile (12.00 mL), and heated to 80 ° C under nitrogen protection for 24 hours. The reaction solution was concentrated under reduced pressure, mixed with 20 mL of water, extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with water until neutral, washed once 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 (petroleum ether: ethyl acetate = 95:5) to obtain compound P001-c. Yield: 34%.

[0110] MS m / s(ESI):207.2[M+23].

[0111] Step 3: Compound P001-d

[0112] At room temperature, compound P001-c (2.19 g, 11.89 mmol, 1.00 eq.) and 3,4-dimethyl-4-hydroxybenzaldehyde (1.79 g, 11.89 mmol, 1.00 eq.) were dissolved in anhydrous methanol (55.00 mL, 25.11 eqv.), piperidine (3.30 mL, 3.00 eqv.) was added, and the mixture was heated to room temperature under nitrogen protection for 96 hours. The reaction solution was concentrated under reduced pressure, mixed with 20 mL of water, extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with water until neutral, washed once 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 (petroleum ether: dichloromethane = 3:1) to obtain compound P001-d. Yield: 43%;

[0113] MS (ESI): 315.1 (M-1). 1 H-NMR (400MHz; (CDCl3)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=37.2Hz,1H,CF=CH),2.54(s,3H,SCH3),2.28(s,6H,ArCH3).

[0114] Step 4: Compound P001-e

[0115] At room temperature, compound P001-d (0.50 g, 1.58 mmol, 1.00 eq.) and tert-butyl α-bromoisobutyrate (3.00 mL, 15.80 mmol, 10.00 eq.) were dissolved in anhydrous acetonitrile (15.00 mL, 30.00 eqv.), potassium carbonate (2.20 g, 10.00 eq.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 (petroleum ether: dichloromethane = 1:1) to obtain compound P001-e. Yield: 65%.

[0116] MS (ESI): 459.2 [M+1]. 1 H-NMR (400MHz; (CDCl3)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,SCH3), 2.26(s,6H,ArCH3), 1.52(s,9H,OC(CH3)3CO), 1.46(s,6H,C(CH3)2).

[0117] Step 5: Compound P001

[0118] At room temperature, compound P001-e (0.23 g, 0.51 mmol, 1.00 eq.) was dissolved in a 25% trifluoroacetic acid dichloromethane solution (4.00 mL) and reacted at room temperature for 1.5 hours. The reaction solution was diluted with 4 mL of dichloromethane, and then washed with 15 mL of saturated sodium bicarbonate solution until it was weakly alkaline, and then washed with saturated ammonium chloride solution to become weakly acidic, extracted with dichloromethane (10 mL × 3), the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound P001. Yield: 78%.

[0119] MS(ESI):401.7[M-1]. 1 H-NMR (400MHz; (CDCl3)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),2.54(s,3H,SCH3),2.28(s,6H,ArCH3),1.55(s,6H,CH3).

[0120] Example 2: Compound P002

[0121]

[0122] At room temperature, compound P001-d (100 mg, 0.32 mmol, 1.00 eq.) and isopropyl 2-bromoisobutyrate (510 μL, 3.16 mmol, 10.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium carbonate (437 mg, 10.00 eq.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P002. Yield: 81%.

[0123] MS (ESI): 445 (M+1). 1 H-NMR (400MHz; (CDCl3)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=38.4Hz,1H,CF =CH), 4.99 (m, 1H, OCH), 2.56 (s, 3H, SCH3), 2.17 (s, 6H, ArCH3), 1.39 (s, 6H, CH3), 1.26 (d, 6H, CH3).

[0124] Example 3: Compound P003

[0125]

[0126] Step 1: Compound P003-a

[0127] 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 potassium carbonate (2.20g, 10.00eq.) was added, and heated to 70°C at room temperature for 96 hours. The reaction solution was concentrated under reduced pressure, diluted with 40mL of water and mixed, extracted with ethyl acetate (10mL×3), the organic phases were combined, washed with water until neutral, washed once 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 (petroleum ether: dichloromethane = 1:10) to obtain compound P003-a. Yield: 87.9%.

[0128] MS (ESI): 445.2 [M+1].

[0129] Step 2: Compound P003

[0130] At room temperature, compound P003-a (0.51mmol, 1.00eq.) was dissolved in a 25% trifluoroacetic acid dichloromethane solution (4.00mL.), and reacted at room temperature for 1.5 hours. The reaction solution was diluted with 4mL of dichloromethane, and then washed with 15mL of saturated sodium bicarbonate solution to make it weakly alkaline, and then washed with saturated ammonium chloride solution to make it weakly acidic, extracted with dichloromethane (10mL×3), combined 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 P003. Yield: 98.6%.

[0131] MS(ESI):387.7[M-1]. 1 H NMR (400MHz, CDCl3)δ H =7.84(d,J=8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(d,J=8.3Hz,2H,ArH),6.77(d,J=36.8 Hz,1H,CF=CH),4.65(q,1H,OCH),2.55(s,3H,SCH3),2.32(s,6H,ArCH3),1.56(d,3H,CH3).

[0132] Compound P003-1

[0133]

[0134] Referring to the synthesis method of compound P003, tert-butyl 2-bromopropionate was replaced with S-tert-butyl 2-bromopropionate to obtain the chiral target compound P003-1.

[0135] MS(ESI):389.7[M+1]

[0136] Compound P003-2

[0137]

[0138] Referring to the synthesis method of compound P003, R-tert-butyl 2-bromopropionate was used instead of tert-butyl 2-bromopropionate to obtain the chiral target compound P003-2.

[0139] MS (ESI): 389.7 [M+1].

[0140] Example 4: Compound P004

[0141]

[0142] Step 1: Compound P004-a

[0143] At room temperature, compound P001-d (100 mg, 0.32 mmol, 1.00 eq.) and ethyl-1-bromobutanecarboxylate (510 μL, 3.16 mmol, 10.00 eq.) were dissolved in 6.00 mL of anhydrous ethyl acetate, and potassium carbonate (437 mg, 10.00 eq.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P004-a. Yield: 21%.

[0144] MS (ESI): 443.2 [M+1].

[0145] Step 2: Compound P004

[0146] At room temperature, compound P004-a (0.05mmol, 1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL, and reacted at room temperature for 3 hours. 30mL of saturated ammonium chloride solution was added to the reaction solution, extracted with dichloromethane (10mL×3), the organic phases were combined, 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%.

[0147] MS(ESI):413.7[M-1]. 1 H NMR (400MHz, CDCl3)δ H=7.84(d,J=8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(d,J=8.3Hz,2H,ArH),6.77(d,J=36.8Hz, 1H, CF=CH), 2.55 (s, 3H, SCH3), 2.52-2.62 (m, 4H, CH2), 2.32 (s, 6H, ArCH3), 1.56 (m, 2H, CH2).

[0148] Example 5: Compound P005

[0149]

[0150] At room temperature, compound P001-d (100 mg, 0.32 mmol, 1.00 eq.) and 5-chloro-2,2-dimethylvaleric acid isobutyl ester (214 μL, 0.95 mmol, 3.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium iodide (5 mg, 0.10 eq.) and potassium carbonate (437 mg, 10.00 eq.) were added, and heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P005. Yield: 81.2%.

[0151] MS (ESI): 501.7 [M+1]. 1 H NMR (400MHz, CDCl3)δ H =7.84(d,J=8.3,2H,ArH),7.40(s,2H,ArH),7.30(d,J=8.3Hz,2H,ArH),6.77(d,J=36.8Hz,1H,CF=CH),4.65(t,2H,OCH2),4.2 9(d,2H,OCH2),2.55(s,3H,SCH3),2.32(s,6H,ArCH3),1.92(m,1H,CH),1.85(m,4H,CH2),1.32(s,6H,CH3),1.02(d,6H,CH3).

[0152] Example 6: Compound P006

[0153]

[0154] Step 1: Compound P006-a

[0155] At room temperature, compound P001-d (100 mg, 0.32 mmol, 1.00 eq.) and tert-butyl 2-bromobutyrate (706 mg, 3.16 mmol, 10.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium carbonate (437 mg, 3.16 mmol, 10.00 eq.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P006-a. Yield: 80.2%.

[0156] MS (ESI): 459.5 [M+1].

[0157] Step 2: Compound P006

[0158] At room temperature, compound P006-a (0.23mmol, 1.00eq.) was dissolved in a 25% trifluoroacetic acid dichloromethane solution (4.00mL) and reacted at room temperature for 1.5 hours. The reaction solution was diluted with 4mL of dichloromethane, and then washed with 15mL of saturated sodium bicarbonate solution to make it weakly alkaline, and then washed with saturated ammonium chloride solution to make it weakly acidic, extracted with dichloromethane (10mL×3), combined 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 P006. Yield: 97.2%.

[0159] MS(ESI):401.3[M-1]. 1 H NMR (400MHz, CDCl3)δ H =7.84(d,J=8.3Hz,2H,ArH),7.40(s,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, SCH3), 2.32 (s, 6H, ArCH3), 1.83 (m, 2H, CH2), 1.56 (t, 3H, CH3).

[0160] Compound P006-1

[0161]

[0162] Referring to the synthesis method of compound P006, R-2-bromobutyric acid tert-butyl ester was used instead of 2-bromobutyric acid tert-butyl ester to obtain the chiral target compound P006-1.

[0163] MS(ESI):401.3[M-1]

[0164] Compound P006-2

[0165]

[0166] Referring to the synthesis method of compound P006, S-tert-butyl 2-bromobutyrate was used instead of tert-butyl 2-bromobutyrate to obtain the chiral target compound P006-1.

[0167] MS(ESI):401.3[M-1].

[0168] Example 7: Compound P007

[0169]

[0170] Step 1: Compound P007-a

[0171] At room temperature, compound P001-d (100 mg, 0.32 mmol, 1.00 eq.) and ethyl 2-bromoisovalerate (661 mg, 3.16 mmol, 10.00 eq.) were dissolved in 600 mL of anhydrous acetonitrile, and potassium carbonate (437 mg, 316 mmol, 1000 eq.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P007-a. Yield: 89.2%.

[0172] MS (ESI): 445.5 [M+1].

[0173] Step 2: Compound P007

[0174] At room temperature, compound P007-a (0.25mmol, 1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL, and reacted at room temperature for 3 hours. 30mL of saturated ammonium chloride solution was added to the reaction solution, extracted with dichloromethane (10mL×3), the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound P007. Yield: 95.3%.

[0175] MS(ESI):415.7[M-1]. 1 H NMR (400MHz, CDCl3)δ H=7.84(d,J=8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(d,J=7.5Hz,2H,ArH),6.77(d,J=36.8Hz,1H,C F=CH),4.63(d,1H,OCH),2.55(s,3H,SCH3),2.32(s,6H,ArCH3),1.65(m,1H,CH),1.10(d,6H,CH3).

[0176] Example 8: Compound P008

[0177]

[0178] Step 1: Compound P008-a

[0179] At room temperature, compound P001-d (100 mg, 0.32 mmol, 1.00 eq.) and ethyl 3-chloro-2,2-dimethylpropionate (157 mg, 0.95 mmol, 3.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium iodide (5 mg, 0.10 eq.) and potassium carbonate (437 mg, 3.16 mmol, 10.00 eq.) were added, and heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P008-a. Yield: 88%.

[0180] MS (ESI): 445.3 [M+1].

[0181] Step 2: Compound P008

[0182] At room temperature, compound P008-a (0.26mmol, 1.00eq.) was dissolved in 1.00mL of 10% sodium hydroxide solution and 1.00mL of tetrahydrofuran, and reacted at room temperature for 3 hours. 30mL of saturated ammonium chloride solution was added to the reaction solution, extracted with dichloromethane (10mL×3), the organic phases were combined, 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%.

[0183] MS(ESI):415.7[M-1]. 1 H-NMR (400MHz; (CDCl3)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=36.8H z,1H,CF=CH),4.45(s,2H,OCH2),2.54(s,3H,SCH3),2.28(s,6H,ArCH3),1.55(s,6H,CH3).

[0184] Example 9: Compound P009

[0185]

[0186] Step 1: Compound P009-a

[0187] At room temperature, compound P001-d (100 mg, 0.32 mmol, 1.00 eq.) and ethyl 3-chloropropionate (130 mg, 0.95 mmol, 3.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium iodide (5 mg, 0.032 mmol, 0.10 eq.) and potassium carbonate (437 mg, 10.00 eq.) were added, and heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P009-a. Yield: 89.1%.

[0188] MS (ESI): 417.7 [M+1].

[0189] Step 2: Compound P009

[0190] At room temperature, compound P009-a (0.26mmol, 1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL, and reacted at room temperature for 3 hours. 30mL of saturated ammonium chloride solution was added to the reaction solution, extracted with dichloromethane (10mL×3), the organic phases were combined, 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%.

[0191] MS(ESI):387.3[M-1]. 1 H NMR (400MHz, CDCl3)δ H=7.84(d,J=8.3,2H,ArH),7.40(s,2H,ArH),7.30(d,J=8.3Hz,2H,ArH),6.77(d,J=36.8Hz, 1H, CF=CH), 4.65 (t, 2H, OCH2), 4.45 (q, 2H, COCH2), 2.55 (s, 3H, SCH3), 2.32 (s, 6H, ArCH3).

[0192] Example 10: Compound P010

[0193]

[0194] Step 1: Compound P010-a

[0195] At room temperature, compound P001-d (100 mg, 0.32 mmol, 1.00 eq.) and methyl 1-bromocyclopentanecarboxylate (655 mg, 3.16 mmol, 10.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile (437 mg, 3.16 mmol, 10.00 eq.), and heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P010-a. Yield: 14%.

[0196] MS (ESI): 441.4 [M+1].

[0197] Step 2: Compound P010

[0198] At room temperature, compound P010-a (0.02mmol, 1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL, and reacted at room temperature for 3 hours. 30mL of saturated ammonium chloride solution was added to the reaction solution, extracted with dichloromethane (10mL×3), the organic phases were combined, 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%.

[0199] MS(ESI):427.2[M-1]. 1 H NMR (400MHz, CDCl3)δ H=7.84(d,J=8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(d,J=8.3Hz,2H,ArH),6.77(d,J =36.8Hz,1H,CF=CH),2.55(s,3H,SCH3),2.32(s,6H,ArCH3),1.96-1.56(m,8H,CH2).

[0200] Example 11: Compound P011

[0201]

[0202] Step 1: Compound P011-a

[0203] At room temperature, compound P001-d (100 mg, 0.32 mmol, 1.00 eq.) and methyl 1-bromocyclopropanecarboxylate (566 mg, 3.16 mmol, 10.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium carbonate (437 mg, 3.16 mmol, 10.00 eq.) was added, and heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P011-a. Yield: 15%.

[0204] MS (ESI): 415.3 [M+1].

[0205] Step 2: Compound P011

[0206] At room temperature, compound P011-a (0.03mmol, 1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL, and reacted at room temperature for 3 hours. 30mL of saturated ammonium chloride solution was added to the reaction solution, extracted with dichloromethane (10mL×3), the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P011. Yield: 90.5%.

[0207] MS(ESI):399.2[M-1]. 1 H NMR (400MHz, CDCl3)δ H=7.84(d,J=8.3Hz,2H,ArH),7.39(s,2H,ArH),7.30(d,J=8.3Hz,2H,ArH),6.77(d ,J=36.8Hz,1H,CF=CH),2.55(s,3H,SCH3),2.32(s,6H,ArCH3),1.54(m,4H,CH2).

[0208] Example 12: Compound P012

[0209]

[0210] Step 1: Compound P012-a

[0211] At room temperature, compound P001-d (100 mg, 0.32 mmol, 1.00 eq.) and tert-butyl bromoacetate (617 mg, 3.16 mmol, 10.00 eq.) were dissolved in anhydrous acetonitrile (15.00 mL, 30.00 eqv.), potassium carbonate (2.20 g, 10.00 eq.) was added, and the mixture was heated to 70 °C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 (petroleum ether: dichloromethane = 1:10) to obtain compound P012-a. Yield: 93.9%.

[0212] MS (ESI): 431.2 [M+1].

[0213] Step 2: Compound P012

[0214] At room temperature, compound P012-a (0.28mmol, 1.00eq.) was dissolved in a 25% trifluoroacetic acid dichloromethane solution (4.00mL.) and reacted at room temperature for 1.5 hours. The reaction solution was diluted with 4mL of dichloromethane, and then washed with 15mL of saturated sodium bicarbonate solution until it was weakly alkaline, and then washed with saturated ammonium chloride solution to become weakly acidic, extracted with dichloromethane (10mL×3), and the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P012. Yield: 95.6%.

[0215] MS(ESI):373.4[M-1]. 1 H NMR (400MHz, CDCl3)δ H=7.84(d,J=8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(d,J=8.3Hz,2H,ArH),6.77(d, J=36.8Hz,1H,CF=CH),4.89(s,2H,OCH2CO),2.55(s,3H,SCH3),2.32(s,6H,ArCH3).

[0216] Example 13: Compound P013

[0217]

[0218] Step 1: Compound P013-b

[0219] At room temperature, compound P013-a (5.00 g, 22.71 mmol, 1.00 eq.), N-bromosuccinimide (NBS) (4.12 g, 23.16 mmol, 1.02 eq.) and p-toluenesulfonic acid monohydrate (4.32 g, 22.71 mmol, 1.00 eq.) were dissolved in anhydrous acetonitrile (12.00 mL, 3.00 eqv.) 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), the organic phases were combined, washed with water until neutral, washed once 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 (petroleum ether: ethyl acetate = 95:5) to obtain compound P013-b. Yield: 70%; MS m / s (ESI): 322.9 [M+23].

[0220] Step 2: Compound P013-c

[0221] At room temperature, compound P013-b (3.50 g, 11.70 mmol, 1.00 eq.), tetrabutylammonium fluoride (TBAF) (5.00 mL, 17.55 mmol, 1.50 eq.) and potassium fluoride (1.05 g, 17.55 mmol, 1.50 eq.) were dissolved in anhydrous acetonitrile (12.00 mL, 3.53 eqv.) 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), the organic phases were combined, washed with water until neutral, washed once 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 (petroleum ether: ethyl acetate = 95:5) to obtain compound P013-c. Yield: 30%; MS m / s (ESI): 261.2 [M+23].

[0222] Step 3: Compound P013-d

[0223] At room temperature, compound P013-c (2.00 g, 8.40 mmol, 1.00 eq.) and 3,5-dimethyl-4-hydroxybenzaldehyde (1.79 g, 8.40 mmol, 1.00 eq.) were added with piperidine 2.30 mL, 3.00 eqv.) in anhydrous methanol (55.00 mL, 27.50 eqv.) and heated to room temperature under nitrogen protection for 96 hours. The reaction solution was concentrated under reduced pressure, mixed with 20 mL of water, extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with water until neutral, washed once 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 (petroleum ether: dichloromethane = 3:1) to obtain compound P013-d. Yield: 48%.

[0224] MS (ESI): 369.1 (M-1).

[0225] Step 4: Compound P013-e

[0226] At room temperature, compound P013-d (500 mg, 1.35 mmol, 1.00 eq.) and tert-butyl 2-bromoisobutyrate (2.60 mL, 13.50 mmol, 10.00 eq.) were dissolved in anhydrous acetonitrile (15.00 mL, 30.00 eqv.), and potassium carbonate (1.87 g, 10.00 eqv.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 (petroleum ether: dichloromethane = 1:1) to obtain compound P013-e. Yield: 67%.

[0227] MS (ESI): 513.2 [M+1].

[0228] Step 5: Compound P013

[0229] At room temperature, compound P013-e (300 mg, 0.59 mmol, 1.00 eq.) was dissolved in a 25% trifluoroacetic acid dichloromethane solution (4.00 mL) and reacted at room temperature for 1.5 hours. The reaction solution was diluted with 4 mL of dichloromethane, and then washed with 15 mL of saturated sodium bicarbonate solution until it was weakly alkaline, and then washed with saturated ammonium chloride solution to become weakly acidic, extracted with dichloromethane (10 mL × 3), and the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound P013. Yield: 77%.

[0230] MS(ESI):455.7[M-1]. 1H-NMR (400MHz; (CDCl3)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),2.28(s,6H,ArCH3),1.55(s,6H,CH3).

[0231] Example 14: Compound P014

[0232]

[0233] Step 1: Compound P014-b

[0234] At room temperature, compound P014-a (4.00 g, 19.78 mmol, 1.00 eq.), N-bromosuccinimide (NBS) (3.59 g, 20.18 mmol, 1.02 eq.) and p-toluenesulfonic acid monohydrate (3.84 g, 19.78 mmol, 1.00 eq.) were dissolved in anhydrous acetonitrile (12.00 mL, 3.00 eqv.) 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), the organic phases were combined, washed with water until neutral, washed once 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 (petroleum ether: ethyl acetate = 95:5) to obtain compound P014-b. Yield: 58%; MS m / s (ESI): 304.9 [M+23].

[0235] Step 2: Compound P014-c

[0236] At room temperature, compound P014-b (3.00 g, 10.67 mmol, 1.00 eq.), tetrabutylammonium fluoride (TBAF) (4.40 mL, 16.01 mmol, 1.50 eq.) and potassium fluoride (930 mg, 16.01 mmol, 1.50 eq.) were dissolved in anhydrous acetonitrile (12.00 mL) 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), the organic phases were combined, washed with water until neutral, washed once 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 (petroleum ether: ethyl acetate = 95:5) to obtain compound P014-c. Yield: 34%; MSm / s (ESI): 243.2 [M+23].

[0237] Step 3: Compound P014-d

[0238] At room temperature, compound P014-c (700 mg, 3.18 mmol, 1.00 eq.) and 3,5-dimethyl-4-hydroxybenzaldehyde (478 mg, 3.18 mmol, 1.00 eq.) were added with piperidine (873 μL, 3.00 eqv.) in anhydrous methanol (10.00 mL), and heated to room temperature under nitrogen protection for 96 hours. The reaction solution was concentrated under reduced pressure, mixed with 20 mL of water, extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with water until neutral, washed once 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 (petroleum ether: dichloromethane = 3:1) to obtain compound P014-d with a yield of 43%.

[0239] MS(ESI):351[M-1].

[0240] Step 4: Compound P014

[0241] At room temperature, compound P014-d (100 mg, 0.27 mmol, 1.00 eq.) and isopropyl 2-bromoisobutyrate (504 μL, 2.70 mmol, 10.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium carbonate (373 mg, 2.70 mmol, 10.00 eq.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P014. Yield: 81%.

[0242] MS(ESI):481[M+1]. 1 H-NMR (400MHz; (CDCl3)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,CHF2), 6.84(d,J=38.4Hz,1H,CF=CH),4.99(m,1H,OCH),2.17(s,6H,ArCH3),1.39(s,6H,CH3),1.26(d,6H,CH3).

[0243] Example 15: Compound P015

[0244]

[0245] Step 1: Compound P015-a

[0246] At room temperature, compound P013-d (100 mg, 0.27 mmol, 1.00 eq.) and tert-butyl 2-bromopropionate (2.70 mmol, 10.00 eq.) were dissolved in anhydrous acetonitrile (15.00 mL, 30.00 eqv.), and potassium carbonate (373 mg, 2.70 mmol, 10.00 eq.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 (petroleum ether: dichloromethane = 1:10) to obtain compound P015-a. Yield: 92.6%.

[0247] MS (ESI): 499.3 [M+1].

[0248] Step 2: Compound P015

[0249] At room temperature, compound P015-a (0.22mmol, 1.00eq.) was dissolved in a 25% trifluoroacetic acid dichloromethane solution (4.00mL.) and reacted at room temperature for 1.5 hours. The reaction solution was diluted with 4mL of dichloromethane, and then washed with 15mL of saturated sodium bicarbonate solution to make it weakly alkaline, and then washed with saturated ammonium chloride solution to make it weakly acidic, extracted with dichloromethane (10mL×3), combined organic phases, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P015. Yield: 90.6%.

[0250] MS(ESI):441.4[M-1]. 1 H NMR (400MHz, CDCl3)δ H =7.84(d,J=8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(d,J=8.3Hz,2H,ArH),6.77(d,J=36.8 Hz, 1H, CF=CH), 4.65 (q, J=6.6Hz, 1H, OCH), 2.32 (s, 6H, ArCH3), 1.56 (d, J=6.6Hz, 3H, CH3).

[0251] Example 16: Compound P016

[0252]

[0253] Step 1: Compound P016-a

[0254] At room temperature, compound P014-d (95 mg, 0.27 mmol, 1.00 eq.) and ethyl-1-bromocyclobutanecarboxylate (438 μL, 2.70 mmol, 10.00 eq.) were dissolved in anhydrous acetonitrile (6.00 mL), potassium carbonate (373 mg, 2.70 mmol, 10.00 eq.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P016-a. Yield: 26.0%.

[0255] MS (ESI): 479.2 [M+1].

[0256] Step 2: Compound P016

[0257] At room temperature, compound P016-a (0.05mmol, 1.00eq.) was dissolved in 1.00mL of 10% sodium hydroxide solution and 1.00mL of tetrahydrofuran, and reacted at room temperature for 3 hours. 30mL of saturated ammonium chloride solution was added to the reaction solution, extracted with dichloromethane (10mL×3), the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P016. Yield: 83.6%.

[0258] MS(ESI):449.7[M-1]. 1 H NMR (400MHz, CDCl3)δ H =7.84(d,J=8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(d,J=8.3Hz,2H,ArH),7.25(t,J=37.2Hz,1H,CHF2 ), 6.77 (d, J = 36.8Hz, 1H, CF = CH), 2.85-2.75 (m, 2H, CH2), 2.52-2.62 (m, 2H, CH2), 2.32 (s, 6H, ArCH3).

[0259] Example 17: Compound P017

[0260]

[0261] At room temperature, compound P013-d (100 mg, 0.27 mmol, 1.00 eq.) and 5-chloro-2,2-dimethylvaleric acid isobutyl ester (214 μL, 0.81 mmol, 3.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium iodide (5 mg, 0.032 mmol, 0.10 eq.) and potassium carbonate (373 mg, 2.70 mmol, 10.00 eq.) were added, and heated to 70 ° C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P017. Yield: 88.3%.

[0262] MS (ESI): 555.7 [M+1]. 1 H NMR (400MHz, CDCl3)δ H =7.84(d,J=8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(d,J=8.3Hz,2H,ArH),6.77(d,J=36.8Hz,1H,CF=CH),4.65(t,2H, OCH2),4.29(d,2H,OCH2),2.32(s,6H,ArCH3),1.92(m,1H,CH),1.85(m,4H,CH2),1.32(s,6H,CH3),1.02(d,6H,CH3).

[0263] Example 18: Compound P018

[0264]

[0265] Step 1: Compound P018-a

[0266] At room temperature, compound P014-d (95 mg, 0.27 mmol, 1.00 eq.) and tert-butyl 2-bromobutyrate (527 mg, 2.70 mmol, 10.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium carbonate (373 mg, 2.70 mmol, 10.00 eq.) was added, and heated to 70 ° C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P018-a. Yield: 80.1%.

[0267] MS (ESI): 495.5 [M+1].

[0268] Step 2: Compound P018

[0269] At room temperature, compound P018-a (0.19 mmol, 1.00 eq.) was dissolved in a 25% trifluoroacetic acid dichloromethane solution (4.00 mL) and reacted at room temperature for 1.5 hours. The reaction solution was diluted with 4 mL of dichloromethane, and then washed with 15 mL of saturated sodium bicarbonate solution until it was weakly alkaline, and then washed with saturated ammonium chloride solution to become weakly acidic, extracted with dichloromethane (10 mL × 3), and the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P018. Yield: 92.2%.

[0270] MS(ESI):437.3[M-1]. 1 H NMR (400MHz, CDCl3)δ H =7.84(d,J=8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(d,J=8.3Hz,2H,ArH),7.21(t,J=37.2Hz,1H,CHF2), 6.77(d,J=36.8Hz,1H,CF=CH),4.65(t,1H,OCH),2.32(s,6H,ArCH3),1.83(m,2H,CH2),1.56(t,3H,CH3).

[0271] Example 19: Compound P019

[0272]

[0273] Step 1: Compound P019-a

[0274] At room temperature, compound P013-d (100 mg, 0.27 mmol, 1.00 eq.) and ethyl 2-bromoisovalerate (565 mg, 2.70 mmol, 10.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium carbonate (373 mg, 2.70 mmol, 10.00 eq.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P019-a. Yield: 56.2%.

[0275] MS (ESI): 499.5 [M+1].

[0276] Step 2: Compound P019

[0277] 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. 30 mL of saturated ammonium chloride solution was added to the reaction solution, extracted with dichloromethane (10 mL×3), the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P019. Yield: 95.0%.

[0278] MS(ESI):469.7[M-1]. 1 H NMR (400MHz, CDCl3)δ H =7.84(d,J=8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(d,J=8.3Hz,2H,ArH),6.77(d,J=36. 8Hz,1H,CF=CH),4.63(d,1H,OCH),2.32(s,6H,ArCH3),1.65(m,1H,CH),1.10(d,6H,CH3).

[0279] Example 20: Compound P020

[0280]

[0281] Step 1: Compound P020-a

[0282] At room temperature, compound P014-d (100 mg, 0.27 mmol, 1.00 eq.) and ethyl 3-chloro-2,2-dimethylpropionate (134 mg, 0.81 mmol, 3.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium iodide (5 mg, 0.10 eq.) and potassium carbonate (373 mg, 2.70 mmol, 10.00 eq.) were added, and heated to 70 ° C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P020-a. Yield: 84%.

[0283] MS (ESI): 481.3 [M+1].

[0284] Step 2: Compound P020

[0285] At room temperature, compound P020-a (0.20mmol, 1.00eq.) was dissolved in 1.00mL of 10% sodium hydroxide solution and 1.00mL of tetrahydrofuran, and reacted at room temperature for 3 hours. 30mL of saturated ammonium chloride solution was added to the reaction solution, extracted with dichloromethane (10mL×3), the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P020. Yield: 80.0%.

[0286] MS(ESI):451.7[M-1]. 1 H-NMR (400MHz; (CDCl3)δ H =7.85(d,J=7.2Hz,2H,ArH),7.38(s,2H,ArH),7.30(d,J=7.2Hz,2H,ArH),7.21(t,J=37.5Hz,1H , CHF2), 6.77 (d, J=36.8Hz, 1H, CF=CH), 4.45 (s, 2H, OCH2), 2.28 (s, 6H, ArCH3), 1.55 (s, 6H, CH3).

[0287] Example 21: Compound P021

[0288]

[0289] Step 1: Compound P021-a

[0290] At room temperature, compound P013-d (100 mg, 0.27 mmol, 1.00 eq.) and ethyl 3-chloropropionate (111 mg, 0.81 mmol, 3.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium iodide (5 mg, 0.032 mmol, 0.10 eq.) and potassium carbonate (373 mg, 2.70 mmol, 10.00 eq.) were added, and heated to 70 ° C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P021-a. Yield: 93.1%.

[0291] MS (ESI): 471.7 [M+1].

[0292] Step 2: Compound P021

[0293] At room temperature, compound P021-a (0.21mmol, 1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL, and reacted at room temperature for 3 hours. 30mL of saturated ammonium chloride solution was added to the reaction solution, extracted with dichloromethane (10mL×3), the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P021. Yield: 52.2%.

[0294] MS(ESI):441.3[M-1]. 1 H NMR (400MHz, CDCl3)δ H =7.84(d,J=8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(d,J=8.3Hz,2H,ArH),6.77(d, J=36.8Hz,1H,CF=CH),4.65(t,2H,OCH2),4.45(q,2H,COCH2),2.32(s,6H,ArCH3).

[0295] Example 22: Compound P022

[0296]

[0297] Step 1: Compound P022-a

[0298] At room temperature, compound P013-d (100 mg, 0.27 mmol, 1.00 eq.) and methyl 1-bromocyclopentanecarboxylate (560 mg, 2.70 mmol, 10.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium carbonate (373 mg, 2.70 mmol, 10.00 eq.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P022-a. Yield: 10%.

[0299] MS (ESI): 497.4 [M+1].

[0300] Step 2: Compound P022

[0301] At room temperature, compound P022-a (0.01mmol, 1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL, and reacted at room temperature for 3 hours. 30mL of saturated ammonium chloride solution was added to the reaction solution, extracted with dichloromethane (10mL×3), the organic phases were combined, 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%.

[0302] MS(ESI):481.2[M-1]. 1 H NMR (400MHz, CDCl3)δ H =7.84(d,J=8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(d,J=8.3Hz,2H,ArH),6.77(d,J=36.8Hz,1H,CF=CH),2.32(s,6H,ArCH3),1.96-1.56(m,8H,CH2).

[0303] Example 23: Compound P023

[0304]

[0305] Step 1: Compound P023-a

[0306] At room temperature, compound P014-e (95 mg, 0.27 mmol, 1.00 eq.) and methyl 1-bromocyclopropanecarboxylate (483 mg, 2.70 mmol, 10.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium carbonate (373 mg, 2.70 mmol, 10.00 eq.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P023-a. Yield: 25%.

[0307] MS (ESI): 451.3 [M+1].

[0308] Step 2: Compound P023

[0309] At room temperature, compound P023-a (0.04mmol, 1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL, and reacted at room temperature for 3 hours. 30mL of saturated ammonium chloride solution was added to the reaction solution, extracted with dichloromethane (10mL×3), the organic phases were combined, 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%.

[0310] MS(ESI):435.2[M-1]. 1 H NMR (400MHz, CDCl3)δ H =7.84(d,J=8.3Hz,2H,ArH),7.39(s,2H,ArH),7.30(d,J=8.3Hz,2H,ArH),7.20(t,J=3 8.3Hz, 1H, CHF2), 6.77 (d, J = 36.8Hz, 1H, CF = CH), 2.32 (s, 6H, ArCH3), 1.54 (m, 4H, CH2).

[0311] Example 24: Compound P024

[0312]

[0313] Step 1: Compound P024-a

[0314] At room temperature, compound P013-d (100 mg, 0.27 mmol, 1.00 eq.) and tert-butyl bromoacetate (527 mg, 2.70 mmol, 10.00 eq.) were dissolved in anhydrous acetonitrile (15.00 mL, 30.00 eqv.), and potassium carbonate (373 mg, 2.70 mmol, 10.00 eq.) was added, and heated to 70 ° C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 (petroleum ether: dichloromethane = 1:10) to obtain compound P024-a. Yield: 93.8%.

[0315] MS (ESI): 485.2 [M+1].

[0316] Step 2: Compound P024

[0317] At room temperature, compound P024-a (0.23mmol, 1.00eq.) was dissolved in a 25% trifluoroacetic acid dichloromethane solution (4.00mL) and reacted at room temperature for 1.5 hours. The reaction solution was diluted with 4mL of dichloromethane, and then washed with 15mL of saturated sodium bicarbonate solution to make it weakly alkaline, and then washed with saturated ammonium chloride solution to make it weakly acidic, extracted with dichloromethane (10mL×3), combined organic phases, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P024. Yield: 95.6%.

[0318] MS(ESI):427.3[M-1]. 1 H NMR (400MHz, CDCl3)δ H =7.84(d,J=8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(d,J=8.3Hz,2H,ArH),6.77(d,J=36.8Hz,1H,CF=CH),4.89(s,2H,OCH2CO),2.32(s,6H,ArCH3).

[0319] Example 25: Compound P025

[0320]

[0321] Step 1: Compound P025-b

[0322] At room temperature, compound P025-a (5.00 g, 25.25 mmol, 1.00 eq.), N-bromosuccinimide (NBS) (4.587 g, 25.57 mmol, 1.02 eq.) and p-toluenesulfonic acid monohydrate (4.80 g, 25.25 mmol, 1.00 eq.) were dissolved in anhydrous acetonitrile (15.00 mL, 3.00 eqv.) 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), the organic phases were combined, washed with water until neutral, washed once 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 (petroleum ether: ethyl acetate = 95:5) to obtain compound P025-b. Yield: 60%; MS m / s (ESI): 300.9 [M+23].

[0323] Step 2: Compound P025-c

[0324] At room temperature, compound P025-b (3.50 g, 12.63 mmol, 1.00 eq.), tetrabutylammonium fluoride (TBAF) (5.20 mL, 18.94 mmol, 1.50 eq.) and potassium fluoride (1.10 g, 18.94 mmol, 1.50 eq.) were dissolved in anhydrous acetonitrile (18.00 mL, 5.14 eqv.) 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), the organic phases were combined, washed with water until neutral, washed once 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 (petroleum ether: ethyl acetate = 95:5) to obtain compound P025-c. Yield: 42%; MS m / s (ESI): 239.2 [M+23].

[0325] Step 3: Compound P025-d

[0326] At room temperature, compound P025-c (1.10 g, 5.09 mmol, 1.00 eq.) and 3,5-dimethyl-4-hydroxybenzaldehyde (764 mg, 5.09 mmol, 1.00 eq.) were added with piperidine (1.40 mL, 3.00 eqv.) in anhydrous methanol (27.50 mL, 25.00 eqv.), and heated to room temperature under nitrogen protection for 96 hours. The reaction solution was concentrated under reduced pressure, mixed with 20 mL of water, extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with water until neutral, washed once 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 (petroleum ether: dichloromethane = 3:1) to obtain compound P025-d. Yield: 53%.

[0327] MS (ESI): 347.1 (M-1).

[0328] Step 4: Compound P025-g

[0329] At room temperature, compound P025-d (0.50 g, 1.44 mmol, 1.00 eq.) and tert-butyl 2-bromoisobutyrate (2.70 mL, 14.35 mmol, 10.00 eq.) were dissolved in anhydrous acetonitrile (15.00 mL, 30.00 eqv.), and potassium carbonate (2.20 g, 10.00 eqv.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 (petroleum ether: dichloromethane = 1:1) to obtain compound P025-e. Yield: 67%.

[0330] MS (ESI): 491.2 [M+1].

[0331] Step 5: Compound P025

[0332] At room temperature, compound P025-e (0.25 g, 0.58 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 with 4 mL of dichloromethane, and then washed with 15 mL of saturated sodium bicarbonate solution until it was weakly alkaline, and then washed with saturated ammonium chloride solution to become weakly acidic, extracted with dichloromethane (10 mL × 3), and the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 25. Yield: 80%.

[0333] MS(ESI):433.4[M-1]. 1 H-NMR (400MHz; (CDCl3)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),3.32(s,3H,SO2CH3),2.28(s,6H,ArCH3),1.55(s,6H,CH3).

[0334] Example 26: Compound P026

[0335]

[0336] At room temperature, compound P025-d (100 mg, 0.29 mmol, 1.00 eq.) and isopropyl 2-bromoisobutyrate (463 μL, 2.87 mmol, 10.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium carbonate (397 mg, 2.87 mmol, 10.00 eq.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P026. Yield: 85%.

[0337] MS (ESI): 477 (M+1). 1 H-NMR (400MHz; (CDCl3)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=38.4Hz,1H,CF= CH),4.99(m,1H,OCH),3.32(s,3H,SO2CH3),2.17(s,6H,ArCH3),1.39(s,6H,CH3),1.26(d,6H,CH3).

[0338] Example 27: Compound P027

[0339]

[0340] Step 1: Compound P027-a

[0341] At room temperature, compound P025-d (100 mg, 0.29 mmol, 1.00 eq.) and tert-butyl 2-bromopropionate (477 mg, 2.87 mmol, 10.00 eq.) were dissolved in anhydrous acetonitrile (15.00 mL, 30.00 eqv.), and potassium carbonate (397 mg, 2.87 mmol, 10.00 eq.) was added, and heated to 70 ° C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 (petroleum ether: dichloromethane = 1:10) to obtain compound P027-a. Yield: 82.9%.

[0342] MS (ESI): 477.2 [M+1].

[0343] Step 2: Compound P027

[0344] At room temperature, compound P027-a (0.22mmol, 1.00eq.) was dissolved in a 25% trifluoroacetic acid dichloromethane solution (4.00mL) and reacted at room temperature for 1.5 hours. The reaction solution was diluted with 4mL of dichloromethane, and then washed with 15mL of saturated sodium bicarbonate solution to make it weakly alkaline, and then washed with saturated ammonium chloride solution to make it weakly acidic, extracted with dichloromethane (10mL×3), combined organic phases, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P027. Yield: 92.6%.

[0345] MS(ESI):419.7[M-1]. 1 H NMR (400MHz, CDCl3)δ H=8.54(d,J=8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(d,J=8.3Hz,2H,ArH),6.77(d,J=36.8H z,1H,CF=CH),4.65(q,1H,OCH),3.32(s,3H,SO2CH3),2.32(s,6H,ArCH3),1.56(d,3H,CH3).

[0346] Example 28: Compound P028

[0347]

[0348] Step 1: Compound P028-a

[0349] At room temperature, compound P025-d (100 mg, 0.29 mmol, 1.00 eq.) and ethyl-1-bromocyclobutanecarboxylate (465 μL, 2.87 mmol, 10.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium carbonate (397 mg, 2.87 mmol, 10.00 eq.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P028-a. Yield: 26%.

[0350] MS (ESI): 475.2 [M+1].

[0351] Step 2: Compound P028

[0352] At room temperature, compound P028-a (0.05mmol, 1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL, and reacted at room temperature for 3 hours. 30mL of saturated ammonium chloride solution was added to the reaction solution, extracted with dichloromethane (10mL×3), the organic phases were combined, 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%.

[0353] MS(ESI):445.7[M-1]. 1 H NMR (400MHz, CDCl3)δ H=8.54(d,J=8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(d,J=8.3Hz,2H,ArH),6.77(d,J=36.8Hz,1H, CF=CH),3.32(s,3H,SO2CH3),2,85-2.75(m,4H,CH2),2.52-2.62(m,2H,CH2),2.32(s,6H,ArCH3).

[0354] Example 29: Compound P029

[0355]

[0356] At room temperature, compound P025-d (100 mg, 0.29 mmol, 1.00 eq.) and 5-chloro-2,2-dimethylvaleric acid isobutyl ester (195 μL, 0.86 mmol, 3.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium iodide (5 mg, 0.032 mmol, 0.10 eq.) and potassium carbonate (397 mg, 2.87 mmol, 10.00 eq.) were added, and heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P029. Yield: 82.6%.

[0357] MS (ESI): 533.7 [M+1]. 1 H NMR (400MHz, CDCl3)δ H =7.84(d,J=7.3,2H,ArH),7.40(s,2H,ArH),7.30(d,J=8.3Hz,2H,ArH),6.77(d,J=36.8Hz,1H,CF=CH),4.65(t,2H,OCH2),4.29 (d,2H,OCH2),3.32(s,3H,SO2CH3),2.32(s,6H,ArCH3),1.92(m,1H,CH),1.85(m,4H,CH2),1.32(s,6H,CH3),1.02(d,6H,CH3).

[0358] Example 30: Compound P030

[0359]

[0360] Step 1: Compound P030-a

[0361] At room temperature, compound P025-d (100 mg, 0.29 mmol, 1.00 eq.) and tert-butyl 2-bromobutyrate (560 mg, 2.87 mmol, 10.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium carbonate (397 mg, 2.87 mmol, 10.00 eq.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P030-a. Yield: 84.2%.

[0362] MS (ESI): 491.5 [M+1].

[0363] Step 2: Compound P030

[0364] At room temperature, compound P030-a (0.22mmol, 1.00eq.) was dissolved in a 25% trifluoroacetic acid dichloromethane solution (4.00mL) and reacted at room temperature for 1.5 hours. The reaction solution was diluted with 4mL of dichloromethane, and then washed with 15mL of saturated sodium bicarbonate solution to make it weakly alkaline, and then washed with saturated ammonium chloride solution to make it weakly acidic, extracted with dichloromethane (10mL×3), combined organic phases, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P030. Yield: 97.2%.

[0365] MS(ESI):433.3[M-1]. 1 H NMR (400MHz, CDCl3)δ H =8.54(d,J=8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(d,J=8.3Hz,2H,ArH),6.77(d,J=36.8Hz,1H,CF= CH),4.65(t,1H,OCH),3.34(s,3H,SO2CH3),2.32(s,6H,ArCH3),1.83(m,2H,CH2),1.56(d,3H,CH3).

[0366] Example 31: Compound P031

[0367]

[0368] Step 1: Compound P031-a

[0369] At room temperature, compound P025-d (100 mg, 0.29 mmol, 1.00 eq.) and ethyl 2-bromoisovalerate (601 mg, 2.87 mmol, 10.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium carbonate (397 mg, 2.87 mmol, 10.00 eq.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P031-a. Yield: 79.2%.

[0370] MS (ESI): 477.5 [M+1].

[0371] Step 2: Compound P031

[0372] At room temperature, compound P031-a (0.20mmol, 1.00eq.) was dissolved in 1.00mL of 10% sodium hydroxide solution and 1.00mL of tetrahydrofuran, and reacted at room temperature for 3 hours. 30mL of saturated ammonium chloride solution was added to the reaction solution, extracted with dichloromethane (10mL×3), the organic phases were combined, 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%.

[0373] MS(ESI):447.7[M-1]. 1 H NMR (400MHz, CDCl3)δ H =8.54(d,J=8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(d,J=8.3Hz,2H,ArH),6.77(d,J=36.8Hz,1H,CF =CH), 4.63 (d, 1H, OCH), 3.34 (s, 3H, SO2CH3), 2.32 (s, 6H, ArCH3), 1.65 (m, 1H, CH), 1.10 (d, 6H, CH3).

[0374] Example 32: Compound P032

[0375]

[0376] Step 1: Compound P032-a

[0377] At room temperature, compound P025-d (100 mg, 0.29 mmol, 1.00 eq.) and ethyl 3-chloro-2,2-dimethylpropionate (142 mg, 0.86 mmol, 3.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium iodide (5 mg, 0.10 eq.) and potassium carbonate (397 mg, 2.87 mmol, 10.00 eq.) were added, and heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P032-a. Yield: 82%.

[0378] MS (ESI): 477.3 [M+1].

[0379] Step 2: Compound P032

[0380] At room temperature, compound P032-a (0.21mmol, 1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL, and reacted at room temperature for 3 hours. 30mL of saturated ammonium chloride solution was added to the reaction solution, extracted with dichloromethane (10mL×3), the organic phases were combined, 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%.

[0381] MS(ESI):447.7[M-1]. 1 H-NMR (400MHz; (CDCl3)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,OCH2),3.34(s,3H,SO2CH3),2.28(s,6H,ArCH3),1.55(s,6H,CH3).

[0382] Example 33: Compound P033

[0383]

[0384] Step 1: Compound P033-a

[0385] At room temperature, compound P025-d (100 mg, 0.29 mmol, 1.00 eq.) and ethyl 3-chloropropionate (118 mg, 0.86 mmol, 3.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium iodide (5 mg, 0.032 mmol, 0.10 eq.) and potassium carbonate (397 mg, 2.87 mmol, 10.00 eq.) were added, and heated to 70 ° C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P033-a. Yield: 90.1%.

[0386] MS (ESI): 449.7 [M+1].

[0387] Step 2: Compound P033

[0388] At room temperature, compound P033-a (0.25mmol, 1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL, and reacted at room temperature for 3 hours. 30mL of saturated ammonium chloride solution was added to the reaction solution, extracted with dichloromethane (10mL×3), the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P033. Yield: 81.2%.

[0389] MS(ESI):419.3[M-1]. 1 H NMR (400MHz, CDCl3)δ H =8.54(d,J=7.3,2H,ArH),7.40(s,2H,ArH),7.30(d,J=8.3Hz,2H,ArH),6.77(d,J=36.8Hz,1 H,CF=CH),4.65(t,2H,OCH2),4.45(t,2H,COCH2),3.34(s,3H,SO2CH3),2.32(s,6H,ArCH3).

[0390] Example 34: Compound P034

[0391]

[0392] Step 1: Compound P034-a

[0393] At room temperature, compound P025-d (100 mg, 0.29 mmol, 1.00 eq.) and methyl 1-bromocyclopentanecarboxylate (600 mg, 2.87 mmol, 10.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium carbonate (397 mg, 2.87 mmol, 10.00 eq.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P034-a. Yield: 17%.

[0394] MS(ESI):475.4[M+1]

[0395] Step 2: Compound P034

[0396] At room temperature, compound P034-a (0.02mmol, 1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL, and reacted at room temperature for 3 hours. 30mL of saturated ammonium chloride solution was added to the reaction solution, extracted with dichloromethane (10mL×3), the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P034. Yield: 90.5%.

[0397] MS(ESI):459.2[M-1]. 1 H NMR (400MHz, CDCl3)δ H =8.54(d,J=8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(d,J=8.3Hz,2H,ArH),6.77(d,J= 36.8Hz,1H,CF=CH),3.34(s,3H,SO2CH3),2.32(s,6H,ArCH3),1.96-1.56(m,8H,CH2).

[0398] Example 35: Compound P035

[0399]

[0400] Step 1: Compound P035-a

[0401] At room temperature, compound P025-d (100 mg, 0.29 mmol, 1.00 eq.) and methyl 1-bromocyclohexanecarboxylate (636 mg, 2.87 mmol, 10.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium carbonate (397 mg, 2.87 mmol, 10.00 eq.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P035-a. Yield: 16%.

[0402] MS (ESI): 489.3 [M+1].

[0403] Step 2: Compound P035

[0404] At room temperature, compound P035-a (0.02mmol, 1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL, and reacted at room temperature for 3 hours. 30mL of saturated ammonium chloride solution was added to the reaction solution, extracted with dichloromethane (10mL×3), the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P035. Yield: 95.5%.

[0405] MS(ESI):473.2[M-1]. 1 H NMR (400MHz, CDCl3)δ H =8.54(d,J=8.3Hz,2H,ArH),7.39(s,2H,ArH),7.30(d,J=8.3Hz,2H,ArH),6.77(d,J=3 6.8Hz,1H,CF=CH),3.34(s,3H,SO2CH3),2.32(s,6H,ArCH3),1.94-1.50(m,10H,CH2).

[0406] Example 36: Compound P036

[0407]

[0408] Step 1: Compound P036-a

[0409] At room temperature, compound P025-d (100 mg, 0.29 mmol, 1.00 eq.) and tert-butyl bromoacetate (560 mg, 2.87 mmol, 10.00 eq.) were dissolved in anhydrous acetonitrile (15.00 mL, 30.00 eqv.), and potassium carbonate (397 mg, 2.87 mmol, 10.00 eq.) was added, and heated to 70 ° C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 (petroleum ether: dichloromethane = 1:10) to obtain compound P036-a. Yield: 50.9%.

[0410] MS (ESI): 463.2 [M+1].

[0411] Step 2: Compound P036

[0412] At room temperature, compound P036-a (0.12mmol, 1.00eq.) was dissolved in a 25% trifluoroacetic acid dichloromethane solution (4.00mL, 17.24eqv.), and reacted at room temperature for 1.5 hours. The reaction solution was diluted with 4mL of dichloromethane, and then washed with 15mL of saturated sodium bicarbonate solution until it was weakly alkaline, and then washed with saturated ammonium chloride solution to become weakly acidic, extracted with dichloromethane (10mL×3), and the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P036. Yield: 91.6%.

[0413] MS(ESI):405.4[M-1]. 1 H NMR (400MHz, CDCl3)δ H =8.54(d,J=8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(d,J=8.3Hz,2H,ArH),6.77(d,J =36.8Hz,1H,CF=CH),4.89(s,2H,OCH2CO),3.34(s,3H,SO2CH3),2.32(s,6H,ArCH3).

[0414] Example 37: Compound P037

[0415]

[0416] Step 1: Compound P037-b

[0417] At room temperature, compound P037-a (5.00 g, 33.29 mmol, 1.00 eq.), N-bromosuccinimide (NBS) (6.04 g, 33.96 mmol, 1.02 eq.) and p-toluenesulfonic acid monohydrate (6.33 g, 33.29 mmol, 1.00 eq.) were dissolved in anhydrous acetonitrile (15.00 mL, 3.00 eqv.) 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), the organic phases were combined, washed with water until neutral, washed once 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 (petroleum ether: ethyl acetate = 95:5) to obtain compound P037-b. Yield: 66%; MS m / s (ESI): 252.4 [M+23].

[0418] Step 2: Compound P037-c

[0419] At room temperature, compound P037-b (3.50 g, 15.28 mmol, 1.00 eq.), tetrabutylammonium fluoride (TBAF) (6.30 mL, 22.92 mmol, 1.50 eq.) and potassium fluoride (1.33 g, 22.92 mmol, 1.50 eq.) were dissolved in anhydrous acetonitrile (18.00 mL, 5.14 eqv.) 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), the organic phases were combined, washed with water until neutral, washed once 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 (petroleum ether: ethyl acetate = 95:5) to obtain compound P037-c. Yield: 32%; MS m / s (ESI): 191.2 [M+23].

[0420] Step 3: Compound P037-d

[0421] At room temperature, compound P037-c (1.50 g, 8.92 mmol, 1.00 eq.) and 3,5-dimethyl-4-hydroxybenzaldehyde (1.34 g, 8.92 mmol, 1.00 eq.) were added with piperidine (1.40 mL, 3.00 eqv.) in anhydrous methanol (30.00 mL, 20.00 eqv.), and heated to room temperature under nitrogen protection for 96 hours. The reaction solution was concentrated under reduced pressure, mixed with 20 mL of water, extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with water until neutral, washed once 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 (petroleum ether: dichloromethane = 3:1) to obtain compound P037-d. Yield: 43%.

[0422] MS (ESI): 299.1 (M-1).

[0423] Step 4: Compound P037-e

[0424] At room temperature, compound P037-d (500 mg, 1.66 mmol, 1.00 eq.) and tert-butyl 2-bromoisobutyrate (2.70 mL, 16.65 mmol, 10.00 eq.) were dissolved in anhydrous acetonitrile (15.00 mL, 30.00 eqv.), and potassium carbonate (2.30 g, 10.00 eq.) was added, and heated to 70 ° C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 (petroleum ether: dichloromethane = 1:1) to obtain compound P037-e. Yield: 60%.

[0425] MS (ESI): 443.2 [M+1].

[0426] Step 5: Compound P037

[0427] At room temperature, compound P037-e (250 mg, 0.56 mmol, 1.00 eq.) was dissolved in a 25% trifluoroacetic acid dichloromethane solution (4.00 mL.) and reacted at room temperature for 1.5 hours. The reaction solution was diluted with 4 mL of dichloromethane, and then washed with 15 mL of saturated sodium bicarbonate solution until it was weakly alkaline, and then washed with saturated ammonium chloride solution to become weakly acidic, extracted with dichloromethane (10 mL × 3), and the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound P037. Yield: 90%.

[0428] MS(ESI):385.4[M-1]. 1 H-NMR (400MHz; (CDCl3)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),3.70(s,3H,OCH3),2.28(s,6H,ArCH3),1.55(s,6H,CH3).

[0429] Example 38: Compound P038

[0430]

[0431] At room temperature, compound P037-d (100 mg, 0.33 mmol, 1.00 eq.) and isopropyl 2-bromoisobutyrate (537 μL, 3.33 mmol, 10.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium carbonate (460 mg, 10.00 eq.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P038. Yield: 83%.

[0432] MS (ESI): 429 (M+1). 1 H-NMR (400MHz; (CDCl3)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=38.4Hz,1H,CF =CH), 4.99 (m, 1H, OCH), 3.70 (s, 3H, OCH3), 2.17 (s, 6H, ArCH3), 1.39 (s, 6H, CH3), 1.26 (d, 6H, CH3).

[0433] Example 39: Compound P039

[0434]

[0435] Step 1: Compound P039-a

[0436] At room temperature, compound P037-d (100 mg, 0.33 mmol, 1.00 eq.) and tert-butyl 2-bromopropionate (553 mg, 3.33 mmol, 10.00 eq.) were dissolved in anhydrous acetonitrile (15.00 mL, 30.00 eqv.), potassium carbonate (460 mg, 10.00 eq.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 (petroleum ether: dichloromethane = 1:10) to obtain compound P039-a. Yield: 80.9%.

[0437] MS (ESI): 429.2 [M+1].

[0438] Step 2: Compound P039

[0439] At room temperature, compound P039-a (0.24mmol, 1.00eq.) was dissolved in a 25% trifluoroacetic acid dichloromethane solution (4.00mL.) and reacted at room temperature for 1.5 hours. The reaction solution was diluted with 4mL of dichloromethane, and then washed with 15mL of saturated sodium bicarbonate solution to make it weakly alkaline, and then washed with saturated ammonium chloride solution to make it weakly acidic, extracted with dichloromethane (10mL×3), combined organic phases, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P039. Yield: 94.6%.

[0440] MS(ESI):371.7[M-1]. 1 H NMR (400MHz, CDCl3)δ H =7.84(d,J=8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(d,J=8.3Hz,2H,ArH),6.77(d,J=36.8 Hz,1H,CF=CH),4.65(q,1H,OCH),3.70(s,3H,OCH3),2.32(s,6H,ArCH3),1.56(d,3H,CH3).

[0441] Example 40: Compound P040

[0442]

[0443] Step 1: Compound P040-a

[0444] At room temperature, compound P037-d (100 mg, 0.33 mmol, 1.00 eq.) and ethyl-1-bromocyclobutanecarboxylate (539 μL, 3.33 mmol, 10.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium carbonate (460 mg, 10.00 eq.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P040-a. Yield: 22%.

[0445] MS (ESI): 427.2 [M+1].

[0446] Step 2: Compound P040

[0447] At room temperature, compound P040-a (0.05mmol, 1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL, and reacted at room temperature for 3 hours. 30mL of saturated ammonium chloride solution was added to the reaction solution, extracted with dichloromethane (10mL×3), the organic phases were combined, 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%.

[0448] MS(ESI):397.7[M-1]. 1 H NMR (400MHz, CDCl3)δ H =7.84(d,J=8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(d,J=8.3Hz,2H,ArH),6.77(d,J=36.8Hz,1H ,CF=CH),3.70(s,3H,OCH3),2,85-2.75(m,2H,CH2),2.52-2.62(m,2H,CH2),2.32(s,6H,ArCH3).

[0449] Example 41: Compound P041

[0450]

[0451] At room temperature, compound P037-d (100 mg, 0.33 mmol, 1.00 eq.) and 5-chloro-2,2-dimethylvaleric acid isobutyl ester (225 μL, 1.00 mmol, 3.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium iodide (5 mg, 0.032 mmol, 0.10 eq.) and potassium carbonate (460 mg, 10.00 eq.) were added, and heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P041. Yield: 81.6%.

[0452] MS (ESI): 485.6 [M+1]. 1 H NMR (400MHz, CDCl3)δ H=7.84(d,J=7.3,2H,ArH),7.40(s,2H,ArH),7.30(d,J=8.3Hz,2H,ArH),6.77(d,J=36.8Hz,1H,CF=CH),4.65(t,2H,OCH2),4.2 9(d,2H,OCH2),3.70(s,3H,OCH3),2.32(s,6H,ArCH3),1.92(m,1H,CH),1.85(m,4H,CH2),1.32(s,6H,CH3),1.02(d,6H,CH3).

[0453] Example 42: Compound P042

[0454]

[0455] Step 1: Compound P042-a

[0456] At room temperature, compound P037-d (100 mg, 0.33 mmol, 1.00 eq.) and tert-butyl 2-bromobutyrate (650 mg, 3.33 mmol, 10.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium carbonate (460 mg, 10.00 eq.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P042-a. Yield: 87.2%.

[0457] MS (ESI): 443.5 [M+1].

[0458] Step 2: Compound P042

[0459] At room temperature, compound P042-a (0.26mmol, 1.00eq.) was dissolved in a 25% trifluoroacetic acid dichloromethane solution (4.00mL) and reacted at room temperature for 1.5 hours. The reaction solution was diluted with 4mL of dichloromethane, and then washed with 15mL of saturated sodium bicarbonate solution until it was weakly alkaline, and then washed with saturated ammonium chloride solution to become weakly acidic, extracted with dichloromethane (10mL×3), and the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P042. Yield: 93.2%.

[0460] MS(ESI):385.3[M-1]. 1 H NMR (400MHz, CDCl3)δ H=7.84(d,J=8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(d,J=8.3Hz,2H,ArH),6.77(d,J=36.8Hz,1H,CF =CH), 4.65 (t, 1H, OCH), 3.70 (s, 3H, OCH3), 2.32 (s, 6H, ArCH3), 1.83 (m, 2H, CH2), 1.56 (d, 3H, CH3).

[0461] Example 43: Compound P043

[0462]

[0463] Step 1: Compound P043-a

[0464] At room temperature, compound P037-d (100 mg, 0.33 mmol, 1.00 eq.) and ethyl 2-bromoisovalerate (696 mg, 3.33 mmol, 10.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium carbonate (460 mg, 10.00 eq.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P043-a. Yield: 75.2%.

[0465] MS (ESI): 429.5 [M+1].

[0466] Step 2: Compound P043

[0467] At room temperature, compound P043-a (0.22mmol, 1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL, and reacted at room temperature for 3 hours. 30mL of saturated ammonium chloride solution was added to the reaction solution, extracted with dichloromethane (10mL×3), the organic phases were combined, 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%.

[0468] MS(ESI):399.7[M-1]. 1 H NMR (400MHz, CDCl3)δ H=7.84(d,J=8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(d,J=8.3Hz,2H,ArH),6.77(d,J=36.8Hz,1H,C F=CH),4.63(d,1H,OCH),3.70(s,3H,OCH3),2.32(s,6H,ArCH3),1.65(m,1H,CH),1.10(d,6H,CH3).

[0469] Example 44: Compound P044

[0470]

[0471] Step 1: Compound P044-a

[0472] At room temperature, compound P037-d (100 mg, 0.33 mmol, 1.00 eq.) and ethyl 3-chloro-2,2-dimethylpropionate (165 mg, 1.00 mmol, 3.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium iodide (5 mg, 0.10 eq.) and potassium carbonate (460 mg, 10.00 eq.) were added, and heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P044-a. Yield: 87%.

[0473] MS (ESI): 429.3 [M+1].

[0474] Step 2: Compound P044

[0475] At room temperature, compound P044-a (0.26mmol, 1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL, and reacted at room temperature for 3 hours. 30mL of saturated ammonium chloride solution was added to the reaction solution, extracted with dichloromethane (10mL×3), the organic phases were combined, 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%.

[0476] MS(ESI):399.7[M-1]. 1 H-NMR (400MHz; (CDCl3)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,OCH2),2.28(s,6H,ArCH3),1.55(s,6H,CH3).

[0477] Example 45: Compound P045

[0478]

[0479] Step 1: Compound P045-a

[0480] At room temperature, compound P037-d (100 mg, 0.33 mmol, 1.00 eq.) and ethyl 3-chloropropionate (137 mg, 1.00 mmol, 3.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium iodide (5 mg, 0.032 mmol, 0.10 eq.) and potassium carbonate (460 mg, 10.00 eq.) were added, and heated to 70 ° C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P045-a. Yield: 91.5%.

[0481] MS (ESI): 401.7 [M+1].

[0482] Step 2: Compound P045

[0483] 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. 30 mL of saturated ammonium chloride solution was added to the reaction solution, and dichloromethane was extracted (10 mL×3). The organic phases were combined, 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%.

[0484] MS(ESI):371.3[M-1]. 1 H NMR (400MHz, CDCl3)δ H=7.84(d,J=7.3,2H,ArH),7.40(s,2H,ArH),7.30(d,J=8.3Hz,2H,ArH),6.77(d,J=36.8Hz, 1H, CF=CH), 4.65 (t, 2H, OCH2), 4.45 (t, 2H, COCH2), 3.70 (s, 3H, OCH3), 2.32 (s, 6H, ArCH3).

[0485] Example 46: Compound P046

[0486]

[0487] Step 1: Compound P046-a

[0488] At room temperature, compound P037-d (100 mg, 0.33 mmol, 1.00 eq.) and methyl 1-bromocyclopentanecarboxylate (690 mg, 3.33 mmol, 10.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium carbonate (460 mg, 10.00 eq.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P046-a. Yield: 19%.

[0489] MS (ESI): 427.4 [M+1].

[0490] Step 2: Compound P046

[0491] At room temperature, compound P046-a (0.04mmol, 1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL, and reacted at room temperature for 3 hours. 30mL of saturated ammonium chloride solution was added to the reaction solution, extracted with dichloromethane (10mL×3), the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P046. Yield: 90.0%.

[0492] MS(ESI):411.2[M-1]. 1 H NMR (400MHz, CDCl3)δ H=7.84(d,J=8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(d,J=8.3Hz,2H,ArH),6.77(d,J =36.8Hz,1H,CF=CH),3.70(s,3H,OCH3),2.32(s,6H,ArCH3),1.96-1.56(m,8H,CH2).

[0493] Example 47: Compound P047

[0494]

[0495] Step 1: Compound P047-a

[0496] At room temperature, compound P037-d (100 mg, 0.33 mmol, 1.00 eq.) and methyl 1-bromocyclohexanecarboxylate (737 mg, 3.33 mmol, 10.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium carbonate (460 mg, 10.00 eq.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P047-a. Yield: 17%.

[0497] MS (ESI): 441.3 [M+1].

[0498] Step 2: Compound P047

[0499] At room temperature, compound P047-a (0.03mmol, 1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL, and reacted at room temperature for 3 hours. 30mL of saturated ammonium chloride solution was added to the reaction solution, extracted with dichloromethane (10mL×3), the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P047. Yield: 90.5%.

[0500] MS(ESI):425.2[M-1]. 1 H NMR (400MHz, CDCl3)δ H=7.84(d,J=8.3Hz,2H,ArH),7.39(s,2H,ArH),7.30(d,J=8.3Hz,2H,ArH),6.77(d,J= 36.8Hz,1H,CF=CH),3.70(s,3H,OCH3),2.32(s,6H,ArCH3),1.94-1.50(m,10H,CH2).

[0501] Example 48: Compound P048

[0502]

[0503] Step 1: Compound P048-a

[0504] At room temperature, compound P037-d (100 mg, 0.33 mmol, 1.00 eq.) and tert-butyl bromoacetate (650 mg, 3.33 mmol, 10.00 eq.) were dissolved in anhydrous acetonitrile (15.00 mL, 30.00 eqv.), and potassium carbonate (460 mg, 10.00 eq.) was added, and heated to 70 ° C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 (petroleum ether: dichloromethane = 1:10) to obtain compound P0P48-a. Yield: 84.9%.

[0505] MS (ESI): 415.2 [M+1].

[0506] Step 2: Compound P048

[0507] At room temperature, compound P048-a (0.25mmol, 1.00eq.) was dissolved in a 25% trifluoroacetic acid dichloromethane solution (4.00mL) and reacted at room temperature for 1.5 hours. The reaction solution was diluted with 4mL of dichloromethane, and then washed with 15mL of saturated sodium bicarbonate solution until weak alkalinity, and then washed with saturated ammonium chloride solution to weak acidity, extracted with dichloromethane (10mL×3), combined organic phases, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P048. Yield: 90.6%.

[0508] MS(ESI):357.4[M-1]. 1 H NMR (400MHz, CDCl3)δ H=7.84(d,J=8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(d,J=8.3Hz,2H,ArH),6.77(d, J=36.8Hz,1H,CF=CH),4.89(s,2H,OCH2CO),3.70(s,3H,OCH3),2.32(s,6H,ArCH3).

[0509] Example 49: Compound P049

[0510]

[0511] Step 1: Compound P049-b

[0512] At room temperature, compound P049-a (5.00 g, 41.61 mmol, 1.00 eq.), N-bromosuccinimide (NBS) (7.56 g, 42.45 mmol, 1.02 eq.) and p-toluenesulfonic acid monohydrate (7.92 g, 41.61 mmol, 1.00 eq.) were dissolved in anhydrous acetonitrile (15.00 mL, 3.00 eqv.) 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), the organic phases were combined, washed with water until neutral, washed once 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 (petroleum ether: ethyl acetate = 95:5) to obtain compound P049-b. Yield: 62%; MS m / s (ESI): 222.4 [M+23].

[0513] Step 2: Compound P049-c

[0514] At room temperature, compound P049-b (3.00 g, 15.08 mmol, 1.00 eq.), tetrabutylammonium fluoride (TBAF) (6.20 mL, 22.61 mmol, 1.50 eq.) and potassium fluoride (1.31 g, 22.61 mmol, 1.50 eq.) were dissolved in anhydrous acetonitrile (18.00 mL, 6.00 eqv.) 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), the organic phases were combined, washed with water until neutral, washed once 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 (petroleum ether: ethyl acetate = 95:5) to obtain compound P049-c. Yield: 30%; MS m / s (ESI): 161.2 [M+23].

[0515] Step 3: Compound P049-d

[0516] At room temperature, compound P049-c (1.00 g, 7.24 mmol, 1.00 eq.) and 3,5-dimethyl-4-hydroxybenzaldehyde (1.09 g, 7.24 mmol, 1.00 eq.) were added with piperidine (2.00 mL, 3.00 eqv.) in anhydrous methanol (20.00 mL, 20.00 eqv.), and heated to room temperature under nitrogen protection for 96 hours. The reaction solution was concentrated under reduced pressure, mixed with 20 mL of water, extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with water until neutral, washed once 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 (petroleum ether: dichloromethane = 3:1) to obtain compound P049-d. Yield: 40%.

[0517] MS (ESI): 269.1 (M-1).

[0518] Step 4: Compound P049-e

[0519] At room temperature, compound P049-d (500 mg, 1.85 mmol, 1.00 eq.) and tert-butyl 2-bromoisobutyrate (3.50 mL, 18.50 mmol, 10.00 eq.) were dissolved in anhydrous acetonitrile (15.00 mL, 30.00 eqv.), and potassium carbonate (2.56 g, 10.00 eq.) was added, and heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 (petroleum ether: dichloromethane = 1:1) to obtain compound P049-e. Yield: 60%.

[0520] MS (ESI): 413.2 [M+1].

[0521] Step 5: Compound P049

[0522] At room temperature, compound P049-e (250 mg, 0.61 mmol, 1.00 eq.) was dissolved in a 25% trifluoroacetic acid dichloromethane solution (4.00 mL) and reacted at room temperature for 1.5 hours. The reaction solution was diluted with 4 mL of dichloromethane, and then washed with 15 mL of saturated sodium bicarbonate solution until it was weakly alkaline, and then washed with saturated ammonium chloride solution to become weakly acidic, extracted with dichloromethane (10 mL × 3), and the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P049. Yield: 92%.

[0523] MS(ESI):355.4[M-1]. 1H-NMR (400MHz; (CDCl3)δ H =7.85(d,J=7.2Hz,2H,ArH),7.38(s,2H,ArH),7.30(m,3H,ArH),6.77(d,J=36.8Hz,1H,CF=CH),2.28(s,6H,ArCH3),1.55(s,6H,CH3).

[0524] Example 50: Compound P050

[0525]

[0526] At room temperature, compound P049-d (100 mg, 0.37 mmol, 1.00 eq.) and isopropyl 2-bromoisobutyrate (734 mg, 3.70 mmol, 10.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium carbonate (511 mg, 10.00 eq.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P050. Yield: 80%.

[0527] MS (ESI): 399.4 (M+1). 1 H-NMR (400MHz; (CDCl3)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,1 H, CF=CH), 4.99 (q, 1H, OCH), 2.17 (s, 6H, ArCH3), 1.39 (s, 6H, CH3), 1.26 (d, 6H, CH3).

[0528] Example 51: Compound P051

[0529]

[0530] Step 1: Compound P051-a

[0531] At room temperature, compound P049-d (100 mg, 0.37 mmol, 1.00 eq.) and tert-butyl 2-bromopropionate (774 mg, 3.70 mmol, 10.00 eq.) were dissolved in anhydrous acetonitrile (15.00 mL, 30.00 eqv.), and potassium carbonate (511 mg, 10.00 eq.) was added, and heated to 70 ° C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 (petroleum ether: dichloromethane = 1:10) to obtain compound P051-a. Yield: 81.9%.

[0532] MS (ESI): 399.2 [M+1].

[0533] Step 2: Compound P051

[0534] At room temperature, compound P051-a (0.27mmol, 1.00eq.) was dissolved in a 25% trifluoroacetic acid dichloromethane solution (4.00mL) and reacted at room temperature for 1.5 hours. The reaction solution was diluted with 4mL of dichloromethane, and then washed with 15mL of saturated sodium bicarbonate solution until it was weakly alkaline, and then washed with saturated ammonium chloride solution to become weakly acidic, extracted with dichloromethane (10mL×3), and the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P051. Yield: 97.6%.

[0535] MS(ESI):341.7[M-1]. 1 H NMR (400MHz, CDCl3)δ H =7.84(d,J=8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(m,3H,ArH),6.77(d,J=36.8Hz,1H,CF=CH),4.65(q,1H,OCH),2.32(s,6H,ArCH3),1.56(d,3H,CH3).

[0536] Example 52: Compound P052

[0537]

[0538] Step 1: Compound P052-a

[0539] At room temperature, compound P049-d (100 mg, 0.37 mmol, 1.00 eq.) and ethyl-1-bromocyclobutanecarboxylate (767 mg, 3.70 mmol, 10.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium carbonate (511 mg, 10.00 eq.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P052-a. Yield: 20%.

[0540] MS (ESI): 397.2 [M+1].

[0541] Step 2: Compound P052

[0542] At room temperature, compound P052-a (0.05mmol, 1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL, and reacted at room temperature for 3 hours. 30mL of saturated ammonium chloride solution was added to the reaction solution, extracted with dichloromethane (10mL×3), the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P052. Yield: 94.0%.

[0543] MS(ESI):367.7[M-1]. 1 H NMR (400MHz, CDCl3)δ H =7.84(d,J=8.3Hz,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,CH2),2.52-2.62(m,2H,CH2),2.32(s,6H,ArCH3),2.10-1.93(m,2H,CH2),1.56(d,3H,CH3).

[0544] Example 53: Compound P053

[0545]

[0546] At room temperature, compound P049-d (100 mg, 0.37 mmol, 1.00 eq.) and 5-chloro-2,2-dimethylvaleric acid isobutyl ester (817 mg, 1.00 mmol, 3.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium iodide (5 mg, 0.032 mmol, 0.10 eq.) and potassium carbonate (511 mg, 10.00 eq.) were added, and heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P053. Yield: 86.6%.

[0547] MS (ESI): 455.5 [M+1]. 1 H NMR (400MHz, CDCl3) δH=7.84(d,J=7.3,2H,ArH),7.40(s,2H,ArH),7.30(m,3H,ArH),6.77(d,J=36.8Hz,1H,CF=CH),4.65( t,2H,OCH2),4.29(d,2H,OCH2),2.32(s,6H,ArCH3),1.92(m,1H,CH),1.85(m,4H,CH2),1.32(s,6H,CH3),1.02(d,6H,CH3).

[0548] Example 54: Compound P054

[0549]

[0550] Step 1: Compound P054-a

[0551] At room temperature, compound P049-d (100 mg, 0.37 mmol, 1.00 eq.) and tert-butyl 2-bromobutyrate (722 mg, 3.70 mmol, 10.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium carbonate (511 mg, 10.00 eq.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P054-a. Yield: 84.2%.

[0552] MS (ESI): 413.5 [M+1].

[0553] Step 2: Compound P054

[0554] At room temperature, compound P054-a (0.28mmol, 1.00eq.) was dissolved in a 25% trifluoroacetic acid dichloromethane solution (4.00mL) and reacted at room temperature for 1.5 hours. The reaction solution was diluted with 4mL of dichloromethane, and then washed with 15mL of saturated sodium bicarbonate solution to make it weakly alkaline, and then washed with saturated ammonium chloride solution to make it weakly acidic, extracted with dichloromethane (10mL×3), combined organic phases, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P054. Yield: 86.2%.

[0555] MS(ESI):355.3[M-1]. 1 H NMR (400MHz, CDCl3)δ H =7.84(d,J=8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(m,3H,ArH),6.77(d,J=36.8Hz,1 H, CF=CH), 4.65 (t, 1H, OCH), 2.32 (s, 6H, ArCH3), 1.83 (m, 2H, CH2), 1.56 (d, 3H, CH3).

[0556] Example 55: Compound P055

[0557]

[0558] Step 1: Compound P055-a

[0559] At room temperature, compound P049-d (100 mg, 0.37 mmol, 1.00 eq.) and ethyl 2-bromoisovalerate (774 mg, 3.70 mmol, 10.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium carbonate (511 mg, 10.00 eq.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P055-a. Yield: 70.0%.

[0560] MS (ESI): 399.5 [M+1].

[0561] Step 2: Compound P055

[0562] At room temperature, compound P055-a (0.23mmol, 1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL, and reacted at room temperature for 3 hours. 30mL of saturated ammonium chloride solution was added to the reaction solution, extracted with dichloromethane (10mL×3), the organic phases were combined, 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%.

[0563] MS(ESI):369.7[M-1]. 1 H NMR (400MHz, CDCl3)δ H =7.84(d,J=8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(m,3H,ArH),6.77(d,J=36.8Hz, 1H, CF=CH), 4.63 (d, 1H, OCH), 2.32 (s, 6H, ArCH3), 1.65 (m, 1H, CH), 1.10 (d, 6H, CH3).

[0564] Example 56: Compound P056

[0565]

[0566] Step 1: Compound P056-a

[0567] At room temperature, compound P049-d (100 mg, 0.37 mmol, 1.00 eq.) and ethyl 3-chloro-2,2-dimethylpropionate (183 mg, 1.11 mmol, 3.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium iodide (5 mg, 0.10 eq.) and potassium carbonate (511 mg, 10.00 eq.) were added, and heated to 70 ° C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P056-a. Yield: 89%.

[0568] MS (ESI): 399.3 [M+1].

[0569] Step 2: Compound P056

[0570] At room temperature, compound P056-a (0.31mmol, 1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL, and reacted at room temperature for 3 hours. 30mL of saturated ammonium chloride solution was added to the reaction solution, extracted with dichloromethane (10mL×3), the organic phases were combined, 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%.

[0571] MS(ESI):369.7[M-1]. 1 H-NMR (400MHz; (CDCl3)δ H =7.85(d,J=7.2Hz,2H,ArH),7.38(s,2H,ArH),7.30(m,3H,ArH),6.77(d,J=36.8Hz,1H,CF=CH),4.45(s,2H,OCH2),2.28(s,6H,ArCH3),1.55(s,6H,CH3).

[0572] Example 57: Compound P057

[0573]

[0574] Step 1: Compound P057-a

[0575] At room temperature, compound P049-d (100 mg, 0.37 mmol, 1.00 eq.) and ethyl 3-chloropropionate (152 mg, 1.11 mmol, 3.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium iodide (5 mg, 0.032 mmol, 0.10 eq.) and potassium carbonate (511 mg, 10.00 eq.) were added, and heated to 70 ° C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P057-a. Yield: 90.5%.

[0576] MS (ESI): 471.7 [M+1].

[0577] Step 2: Compound P057

[0578] 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. 30 mL of saturated ammonium chloride solution was added to the reaction solution, extracted with dichloromethane (10 mL×3), the organic phases were combined, 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%.

[0579] MS(ESI):341.3[M-1]. 1 H NMR (400MHz, CDCl3)δ H =7.84(d,J=7.3,2H,ArH),7.40(s,2H,ArH),7.30(m,3H,ArH),6.77(d,J=36.8Hz,1H,CF=CH),4.65(t,2H,OCH2),4.45(t,2H,COCH2),2.32(s,6H,ArCH3).

[0580] Example 58: Compound P058

[0581]

[0582] Step 1: Compound P058-a

[0583] At room temperature, compound P049-d (100 mg, 0.37 mmol, 1.00 eq.) and methyl 1-bromocyclopentanecarboxylate (766 mg, 3.70 mmol, 10.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium carbonate (511 mg, 10.00 eq.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P058-a. Yield: 20%.

[0584] MS (ESI): 397.4 [M+1].

[0585] Step 2: Compound P058

[0586] At room temperature, compound P058-a (0.05mmol, 1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL, and reacted at room temperature for 3 hours. 30mL of saturated ammonium chloride solution was added to the reaction solution, extracted with dichloromethane (10mL×3), the organic phases were combined, 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%.

[0587] MS(ESI):381.2[M-1]. 1 H NMR (400MHz, CDCl3)δ H =7.84(d,J=8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(m,3H,ArH),6.77(d,J=36.8Hz,1H,CF=CH),2.32(s,6H,ArCH3),1.96-1.56(m,8H,CH2).

[0588] Example 59: Compound P059

[0589]

[0590] Step 1: Compound P059-a

[0591] At room temperature, compound P049-d (100 mg, 0.37 mmol, 1.00 eq.) and methyl 1-bromocyclopropanecarboxylate (662 mg, 3.70 mmol, 10.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium carbonate (511 mg, 10.00 eq.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P059-a. Yield: 35%.

[0592] MS (ESI): 369.3 [M+1].

[0593] Step 2: Compound P059

[0594] 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. 30 mL of saturated ammonium chloride solution was added to the reaction solution, extracted with dichloromethane (10 mL×3), the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P059. Yield: 90.0%.

[0595] MS(ESI):353.2[M-1]. 1 H NMR (400MHz, CDCl3)δ H =7.84(d,J=8.3Hz,2H,ArH),7.39(s,2H,ArH),7.30(m,3H,ArH),6.77(d,J=36.8Hz,1H,CF=CH),2.32(s,6H,ArCH3),1.54(m,4H,CH2).

[0596] Example 60: Compound P060

[0597]

[0598] Step 1: Compound P060-a

[0599] At room temperature, compound P049-d (100 mg, 0.37 mmol, 1.00 eq.) and tert-butyl bromoacetate (722 mg, 3.70 mmol, 10.00 eq.) were dissolved in anhydrous acetonitrile (15.00 mL, 30.00 eqv.), and potassium carbonate (511 mg, 10.00 eq.) was added, and heated to 70 ° C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 (petroleum ether: dichloromethane = 1:10) to obtain compound P060-a. Yield: 85.9%.

[0600] MS (ESI): 385.2 [M+1].

[0601] Step 2: Compound P060

[0602] At room temperature, compound P060-a (0.30mmol, 1.00eq.) was dissolved in a 25% trifluoroacetic acid dichloromethane solution (4.00mL) and reacted at room temperature for 1.5 hours. The reaction solution was diluted with 4mL of dichloromethane, and then washed with 15mL of saturated sodium bicarbonate solution to make it weakly alkaline, and then washed with saturated ammonium chloride solution to make it weakly acidic, extracted with dichloromethane (10mL×3), combined organic phases, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P060. Yield: 90.0%.

[0603] MS(ESI):327.4[M-1]. 1 H NMR (400MHz, CDCl3)δ H =7.84(d,J=8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(m,3H,ArH),6.77(d,J=36.8Hz,1H,CF=CH),4.89(s,2H,OCH2CO),2.32(s,6H,ArCH3).

[0604] Example 61: Compound P061

[0605]

[0606] Step 1: Compound P061-b

[0607] At room temperature, compound P061-a (4.00 g, 21.95 mmol, 1.00 eq.), N-bromosuccinimide (NBS) (4.00 g, 22.39 mmol, 1.02 eq.) and p-toluenesulfonic acid monohydrate (4.17 g, 21.95 mmol, 1.00 eq.) were dissolved in anhydrous acetonitrile (12.00 mL, 3.00 eqv.) 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), the organic phases were combined, washed with water until neutral, washed once 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 (petroleum ether: ethyl acetate = 95:5) to obtain compound P061-b. Yield: 69%; MS m / s (ESI): 260.9 [M-1].

[0608] Step 2: Compound P061-c

[0609] At room temperature, compound P061-b (3.50 g, 13.40 mmol, 1.00 eq.), tetrabutylammonium fluoride (TBAF) (5.60 mL, 20.10 mmol, 1.50 eq.) and potassium fluoride (1.17 g, 20.10 mmol, 1.50 eq.) were dissolved in anhydrous acetonitrile (14.00 mL, 4.00 eqv.) 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), the organic phases were combined, washed with water until neutral, washed once 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 (petroleum ether: ethyl acetate = 95:5) to obtain compound P061-c. Yield: 30%; MS m / s (ESI): 199.2 [M-1].

[0610] Step 3: Compound P061-d

[0611] At room temperature, compound P061-c (2.00 g, 9.99 mmol, 1.00 eq.) and 3,5-dimethyl-4-hydroxybenzaldehyde (1.50 g, 9.99 mmol, 1.00 eq.) were added with piperidine (2.80 mL, 3.00 eqv.) in anhydrous methanol (50.00 mL, 25.00 eqv.), and heated to room temperature under nitrogen protection for 96 hours. The reaction solution was concentrated under reduced pressure, mixed with 20 mL of water, extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with water until neutral, washed once 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 (petroleum ether: dichloromethane = 3:1) to obtain compound P061-d. Yield: 48%.

[0612] MS (ESI): 331.1 (M-1).

[0613] Step 4: Compound P061-e

[0614] At room temperature, compound P061-d (0.50 g, 1.50 mmol, 1.00 eq.) and tert-butyl 2-bromoisobutyrate (3.00 mL, 15.04 mmol, 10.00 eq.) were dissolved in anhydrous acetonitrile (15.00 mL, 30.00 eqv.), and potassium carbonate (2.08 g, 10.00 eqv.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 (petroleum ether: dichloromethane = 1:1) to obtain compound P061-e. Yield: 60%.

[0615] MS(ESI):473.2[M-1].

[0616] Step 5: Compound P061

[0617] At room temperature, compound P061-e (200 mg, 0.42 mmol, 1.00 eq.) was dissolved in a 25% trifluoroacetic acid dichloromethane solution (4.00 mL.) and reacted at room temperature for 1.5 hours. The reaction solution was diluted with 4 mL of dichloromethane, and then washed with 15 mL of saturated sodium bicarbonate solution until it was weakly alkaline, and then washed with saturated ammonium chloride solution to become weakly acidic, extracted with dichloromethane (10 mL × 3), and the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P061. Yield: 88%.

[0618] MS(ESI):417.7[M-1]. 1 H-NMR (400MHz; (CDCl3)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),2.54(s,3H,SCH3),2.28(s,6H,ArCH3),1.55(s,6H,CH3).

[0619] Example 62: Compound P062

[0620]

[0621] At room temperature, compound P061-d (100 mg, 0.30 mmol, 1.00 eq.) and isopropyl 2-bromoisobutyrate (629 mg, 3.01 mmol, 10.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium carbonate (416 mg, 3.01 mmol, 10.00 eqv.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P062. Yield: 80%.

[0622] MS(ESI):459(M-1). 1 H-NMR (400MHz; (CDCl3)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,SCH3)2.17(s 6H ArCH3)1.39(s 6H OC(CH3)2)1.26(d6H CH3).

[0623] Example 63: Compound P063

[0624]

[0625] Step 1: Compound P063-a

[0626] At room temperature, compound P061-d (100 mg, 0.30 mmol, 1.00 eq.) and tert-butyl 2-bromopropionate (630 mg, 3.01 mmol, 10.00 eq.) were dissolved in anhydrous acetonitrile (15.00 mL, 30.00 eqv.), potassium carbonate (416 mg, 10.00 eqv.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 (petroleum ether: dichloromethane = 1:10) to obtain compound P063-a. Yield: 80.5%.

[0627] MS(ESI):459.2[M-1].

[0628] Step 2: Compound P063

[0629] At room temperature, compound P063-a (0.22mmol, 1.00eq.) was dissolved in a 25% trifluoroacetic acid dichloromethane solution (4.00mL, 17.24eqv.), and reacted at room temperature for 1.5 hours. The reaction solution was diluted with 4mL of dichloromethane, and then washed with 15mL of saturated sodium bicarbonate solution until it was weakly alkaline, and then washed with saturated ammonium chloride solution to become weakly acidic, extracted with dichloromethane (10mL×3), and the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P063. Yield: 92.6%.

[0630] MS(ESI):403.7[M-1]. 1 H NMR (400MHz, CDCl3)δ H=7.84(d,J=8.3Hz,1H,ArH),7.40(s,2H,ArH),7.30(d,J=8.3Hz,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, SCH3), 2.32 (s, 6H, ArCH3), 1.56 (d, 3H, CH3).

[0631] Example 64: Compound P064

[0632]

[0633] Step 1: Compound P064-a

[0634] At room temperature, compound P061-d (100 mg, 0.30 mmol, 1.00 eq.) and ethyl-1-bromocyclobutanecarboxylate (624 mg, 3.01 mmol, 10.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium carbonate (416 mg, 10.00 eqv.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P064-a. Yield: 18%.

[0635] MS(ESI):457.2[M-1].

[0636] Step 2: Compound P064

[0637] At room temperature, compound P064-a (0.03mmol, 1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL, and reacted at room temperature for 3 hours. 30mL of saturated ammonium chloride solution was added to the reaction solution, extracted with dichloromethane (10mL×3), the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P064. Yield: 950%.

[0638] MS(ESI):429.7[M-1]. 1 H NMR (400MHz, CDCl3)δ H=7.84(d,J=8.3Hz,1H,ArH),7.40(s,2H,ArH),7.30(d,J=8.3Hz,1H,ArH),6.77(d,J=36.8Hz,1H,CF=CH), 6.75(s,1H,ArH),2.55(s,3H,SCH3),2,85-2.75(m,4H,CH2),2.52-2.62(m,2H,CH2),2.32(s,6H,ArCH3).

[0639] Example 65: Compound P065

[0640]

[0641] Step 1: Compound P065

[0642] At room temperature, compound P061-d (100 mg, 0.30 mmol, 1.00 eq.) and 5-chloro-2,2-dimethylvaleric acid isobutyl ester (199 mg, 0.90 mmol, 3.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium iodide (5 mg, 0.032 mmol, 0.10 eq.) and potassium carbonate (416 mg, 10.00 eqv.) were added, and heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P065. Yield: 93.2%.

[0643] MS(ESI):515.3[M-1]. 1 H NMR (400MHz, CDCl3)δ H =7.84(d,J=8.3Hz,1H,ArH),7.40(s,2H,ArH),7.30(d,J=8.3Hz,1H,ArH),6.77(d,J=36.8Hz,1H,CF=CH),6.75(s,1H,ArH),4.65(t,2H, OCH2),4.29(d,2H,OCH2),2.55(s,3H,SCH3),2.32(s,6H,ArCH3),1.92(m,1H,CH),1.85(m,4H,CH2),1.32(s,6H,CH3),1.02(d,6H,CH3).

[0644] Example 66: Compound P066

[0645]

[0646] Step 1: Compound P066-a

[0647] At room temperature, compound P061-d (100 mg, 0.30 mmol, 1.00 eq.) and tert-butyl 2-bromobutyrate (588 mg, 3.01 mmol, 10.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium carbonate (416 mg, 10.00 eq.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P066-a. Yield: 88.2%.

[0648] MS(ESI):473.5[M-1].

[0649] Step 2: Compound P066

[0650] At room temperature, compound P066-a (0.24mmol, 1.00eq.) was dissolved in a 25% trifluoroacetic acid dichloromethane solution (4.00mL) and reacted at room temperature for 1.5 hours. The reaction solution was diluted with 4mL of dichloromethane, and then washed with 15mL of saturated sodium bicarbonate solution to make it weakly alkaline, and then washed with saturated ammonium chloride solution to make it weakly acidic, extracted with dichloromethane (10mL×3), combined organic phases, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P066. Yield: 91.2%.

[0651] MS(ESI):417.3[M-1]. 1 H NMR (400MHz, CDCl3)δ H =7.84(d,J=8.3Hz,1H,ArH),7.40(s,2H,ArH),7.30(d,J=8.3Hz,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,SCH3),2.32(s,6H,ArCH3),1.83(m,2H,CH2),1.56(d,3H,CH3).

[0652] Example 67: Compound P067

[0653]

[0654] Step 1: Compound P067-a

[0655] At room temperature, compound P061-d (100 mg, 0.30 mmol, 1.00 eq.) and ethyl 2-bromoisovalerate (630 mg, 3.01 mmol, 10.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium carbonate (416 mg, 10.00 eq.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P067-a. Yield: 83.2%.

[0656] MS(ESI):459.5[M-1].

[0657] Step 2: Compound P067

[0658] At room temperature, compound P067-a (0.22mmol, 1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL, and reacted at room temperature for 3 hours. 30mL of saturated ammonium chloride solution was added to the reaction solution, extracted with dichloromethane (10mL×3), the organic phases were combined, 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%.

[0659] MS(ESI):431.7[M-1]. 1 H NMR (400MHz, CDCl3)δ H =7.84(d,J=8.3Hz,1H,ArH),7.40(s,2H,ArH),7.30(d,J=8.3Hz,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,SCH3),2.32(s,6H,ArCH3),1.65(m,1H,CH),1.10(d,6H,CH3).

[0660] Example 68: Compound P068

[0661]

[0662] Step 1: Compound P068-a

[0663] At room temperature, compound P061-d (100 mg, 0.30 mmol, 1.00 eq.) and ethyl 3-chloro-2,2-dimethylpropionate (149 mg, 0.90 mmol, 3.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium iodide (5 mg, 0.10 eq.) and potassium carbonate (416 mg, 10.00 eq.) were added, and heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P068-a. Yield: 84%.

[0664] MS(ESI):459.3[M-1].

[0665] Step 2: Compound P068

[0666] At room temperature, compound P068-a (0.23mmol, 1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL, and reacted at room temperature for 3 hours. 30mL of saturated ammonium chloride solution was added to the reaction solution, extracted with dichloromethane (10mL×3), the organic phases were combined, 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%.

[0667] MS(ESI):431.7[M-1]. 1 H-NMR (400MHz; (CDCl3)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, OCH2), 2.54 (s, 3H, SCH3), 2.28 (s, 6H, ArCH3), 1.55 (s, 6H, CH3).

[0668] Example 69: Compound P069

[0669]

[0670] Step 1: Compound P069-a

[0671] At room temperature, compound P061-d (100 mg, 0.30 mmol, 1.00 eq.) and ethyl 3-chloropropionate (123 mg, 0.90 mmol, 3.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium iodide (5 mg, 0.032 mmol, 0.10 eq.) and potassium carbonate (416 mg, 10.00 eqv.) were added, and heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P069-a. Yield: 81.6%.

[0672] MS(ESI):431.7[M-1].

[0673] Step 2: Compound P069

[0674] At room temperature, compound P069-a (0.22mmol, 1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL, and reacted at room temperature for 3 hours. 30mL of saturated ammonium chloride solution was added to the reaction solution, extracted with dichloromethane (10mL×3), the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P069. Yield: 86.2%.

[0675] MS(ESI):403.3[M-1]. 1 H NMR (400MHz, CDCl3)δ H =7.84(d,J=8.3Hz,1H,ArH),7.40(s,2H,ArH),7.30(d,J=8.3Hz,1H,ArH),6.77(d,J=36.8Hz,1H,CF= CH),6.75(s,1H,ArH),4.65(t,2H,OCH2),4.45(t,2H,COCH2),2.55(s,3H,SCH3),2.32(s,6H,ArCH3).

[0676] Example 70: Compound P070

[0677]

[0678] Step 1: Compound P070-a

[0679] At room temperature, compound P061-d (100 mg, 0.30 mmol, 1.00 eq.) and methyl 1-bromocyclopentanecarboxylate (624 mg, 3.01 mmol, 10.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium carbonate (416 mg, 10.00 eqv.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P070-a. Yield: 29%.

[0680] MS(ESI):457.4[M-1].

[0681] Step 2: Compound P070

[0682] At room temperature, compound P070-a (0.06mmol, 1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL, and reacted at room temperature for 3 hours. 30mL of saturated ammonium chloride solution was added to the reaction solution, extracted with dichloromethane (10mL×3), the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P070. Yield: 90.5%.

[0683] MS(ESI):443.2[M-1]. 1 H NMR (400 MHz, CDCl3) δ H =7.84(d,J=8.3Hz,1H,ArH), 7.40(s,2H,ArH), 7.30(d,J=8.3Hz,1H,ArH), 6.77(d,J=36.8Hz, 1H, CF=CH), 6.75 (s, 1H, ArH), 2.55 (s, 3H, SCH3), 2.32 (s, 6H, ArCH3), 1.96-1.56 (m, 8H, CH2).

[0684] Example 71: Compound P071

[0685]

[0686] Step 1: Compound P071-a

[0687] At room temperature, compound P061-d (100 mg, 0.30 mmol, 1.00 eq.) and methyl 1-bromocyclohexanecarboxylate (666 mg, 3.01 mmol, 10.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium carbonate (416 mg, 10.00 eqv.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P071-a. Yield: 19%.

[0688] MS(ESI):471.3[M-1].

[0689] Step 2: Compound P071

[0690] At room temperature, compound P071-a (0.03mmol, 1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL, and reacted at room temperature for 3 hours. 30mL of saturated ammonium chloride solution was added to the reaction solution, extracted with dichloromethane (10mL×3), the organic phases were combined, 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%.

[0691] MS(ESI):457.2[M-1]. 1 H NMR (400MHz, CDCl3)δ H =7.84(d,J=8.3Hz,1H,ArH),7.39(s,2H,ArH),7.30(d,J=8.3Hz,1H,ArH),6.77(d,J=36.8Hz, 1H, CF=CH), 6.75 (s, 1H, ArH), 2.55 (s, 3H, SCH3), 2.32 (s, 6H, ArCH3), 1.94-1.50 (m, 10H, CH2).

[0692] Example 72: Compound P072

[0693]

[0694] Step 1: Compound P072-a

[0695] At room temperature, compound P061-d (100 mg, 0.30 mmol, 1.00 eq.) and tert-butyl bromoacetate (588 mg, 3.01 mmol, 10.00 eq.) were dissolved in anhydrous acetonitrile (15.00 mL, 30.00 eqv.), potassium carbonate (416 mg, 10.00 eqv.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 (petroleum ether: dichloromethane = 1:10) to obtain compound P072-a. Yield: 90.9%.

[0696] MS(ESI):445.2[M-1].

[0697] Step 2: Compound P072

[0698] At room temperature, compound P072-a (0.27mmol, 1.00eq.) was dissolved in a 25% trifluoroacetic acid dichloromethane solution (4.00mL, 17.24eqv.), and reacted at room temperature for 1.5 hours. The reaction solution was diluted with 4mL of dichloromethane, and then washed with 15mL of saturated sodium bicarbonate solution until it was weakly alkaline, and then washed with saturated ammonium chloride solution to become weakly acidic, extracted with dichloromethane (10mL×3), and the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P072. Yield: 90.6%.

[0699] MS(ESI):389.4[M-1]. 1 H NMR (400MHz, CDCl3)δ H =7.84(d,J=8.3Hz,1H,ArH),7.40(s,2H,ArH),7.30(d,J=8.3Hz,1H,ArH),6.77(d,J=36.8Hz ,1H,CF=CH),6.75(s,1H,ArH),4.89(s,2H,OCH2CO),2.55(s,3H,SCH3),2.32(s,6H,ArCH3).

[0700] Example 73: Compound P073

[0701]

[0702] Step 1: Compound P073-a

[0703] At room temperature, compound P001-c (2.50 g, 13.57 mmol, 1.00 eq.) and 3-methyl-4-hydroxybenzaldehyde (1.85 g, 13.57 mmol, 1.00 eq.) were added with piperidine (3.30 mL, 3.00 eqv.) in anhydrous methanol (55.00 mL, 25.11 eqv.), and heated to room temperature under nitrogen protection for 96 hours. The reaction solution was concentrated under reduced pressure, mixed with 20 mL of water, extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with water until neutral, washed once 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 (petroleum ether: dichloromethane = 3:1) to obtain compound P073-a. Yield: 42%.

[0704] MS (ESI): 301.1 (M-1).

[0705] Step 2: Compound P073-b

[0706] At room temperature, compound P073-a (0.50 g, 1.29 mmol, 1.00 eq.) and tert-butyl 2-bromoisobutyrate (2.40 mL, 12.87 mmol, 10.00 eq.) were dissolved in anhydrous acetonitrile (15.00 mL, 30.00 eqv.), and potassium carbonate (1.78 g, 10.00 eqv.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 (petroleum ether: dichloromethane = 1:1) to obtain compound P073-b. Yield: 60%.

[0707] MS (ESI): 445.2 [M+1].

[0708] Step 3: Compound P073

[0709] At room temperature, compound P073-a (100 mg, 0.22 mmol, 1.00 eq.) was dissolved in a 25% trifluoroacetic acid dichloromethane solution (4.00 mL, 17.24 eqv.) and reacted at room temperature for 1.5 hours. The reaction solution was diluted with 4 mL of dichloromethane, and then washed with 15 mL of saturated sodium bicarbonate solution until it was weakly alkaline, and then washed with saturated ammonium chloride solution to become weakly acidic, extracted with dichloromethane (10 mL × 3), and the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P073. Yield: 80%.

[0710] MS(ESI):387.7[M-1]. 1H-NMR (400MHz; (CDCl3)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,SCH3),2.28(s,3H,ArCH3),1.55(s,6H,CH3).

[0711] Example 74: Compound P074

[0712]

[0713] At room temperature, compound P073-a (100 mg, 0.33 mmol, 1.00 eq.) and isopropyl 2-bromoisobutyrate (534 μL, 3.31 mmol, 10.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium carbonate (457 mg, 10.00 eq.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P074. Yield: 80%.

[0714] MS (ESI): 431 (M+1). 1 H-NMR (400MHz; (CDCl3)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=C H),6.58(d,J=8.2Hz,1H,ArH),4.99(m,1H,OCH),2.56(s,3H,SCH3),2.17(s,3H,ArCH3),1.39(s,6H,C(CH3)2),1.26(d,6H,CH3).

[0715] Example 75: Compound P075

[0716]

[0717] Step 1: Compound P075-a

[0718] At room temperature, compound P073-a (100 mg, 0.33 mmol, 1.00 eq.) and tert-butyl 2-bromopropionate (550 μL, 3.31 mmol, 10.00 eq.) were dissolved in anhydrous acetonitrile (3.00 mL, 30.00 eqv.), and potassium carbonate (457 mg, 10.00 eq.) was added, and heated to 70 ° C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 (petroleum ether: dichloromethane = 1:10) to obtain compound P075-a. Yield: 80.0%.

[0719] MS (ESI): 431.2 [M+1].

[0720] Step 2: Compound P075

[0721] At room temperature, compound P075-a (0.24mmol, 1.00eq.) was dissolved in a 25% trifluoroacetic acid dichloromethane solution (4.00mL) and reacted at room temperature for 1.5 hours. The reaction solution was diluted with 4mL of dichloromethane, and then washed with 15mL of saturated sodium bicarbonate solution until weak alkalinity, and then washed with saturated ammonium chloride solution to weak acidity, extracted with dichloromethane (10mL×3), and the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P0P75. Yield: 96.6%.

[0722] MS (ESI): 373.7 [M+1]. 1 H NMR (400MHz, CDCl3)δ H =7.84(d,J=8.3Hz,2H,ArH),7.82(d,J=8.2Hz,1H,ArH),7.40(s,1H,ArH),7.30(d,J=8.3Hz,2H,ArH),6.77(d,J=36.8 Hz,1H,CF=CH),6.58(d,J=8.2Hz,1H,ArH),4.65(q,1H,OCH),2.55(s,3H,SCH3),2.32(s,3H,ArCH3),1.56(d,3H,CH3).

[0723] Example 76: Compound P076

[0724]

[0725] Step 1: Compound P076-a

[0726] At room temperature, compound P073-a (100 mg, 0.33 mmol, 1.00 eq.) and ethyl-1-bromocyclobutanecarboxylate (536 μL, 3.31 mmol, 10.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium carbonate (457 mg, 10.00 eq.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P076-a. Yield: 20%.

[0727] MS (ESI): 429.2 [M+1].

[0728] Step 2: Compound P076

[0729] At room temperature, compound P076-a (0.05mmol, 1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL, and reacted at room temperature for 3 hours. 30mL of saturated ammonium chloride solution was added to the reaction solution, extracted with dichloromethane (10mL×3), the organic phases were combined, 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%.

[0730] MS(ESI):399.7[M-1]. 1 H NMR (400MHz, CDCl3)δ H =7.84(d,J=8.3Hz,2H,ArH),7.82(d,J=8.2Hz,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,SCH3),2,85-2.75(m,4H,CH2),2.52-2.62(m,2H,CH2),2.32(s,3H,ArCH3).

[0731] Example 77: Compound P077

[0732]

[0733] At room temperature, compound P073-a (100 mg, 0.33 mmol, 1.00 eq.) and 5-chloro-2,2-dimethylvaleric acid isobutyl ester (224 μL, 0.99 mmol, 3.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium iodide (5 mg, 0.032 mmol, 0.10 eq.) and potassium carbonate (457 mg, 10.00 eq.) were added, and heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P077. Yield: 80.2%.

[0734] MS (ESI): 487.3 [M+1]. 1 H NMR (400MHz, CDCl3)δ H =7.84(d,J=7.3,2H,ArH),7.82(d,J=8.2Hz,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,A rH),4.65(t,2H,OCH2),4.29(d,2H,OCH2),2.55(s,3H,SCH3),2.32(s,3H,Ar CH3),1.92(m,1H,CH),1.85(m,4H,CH2),1.32(s,6H,CH3),1.02(d,6H,CH3).

[0735] Example 78: Compound P078

[0736]

[0737] Step 1: Compound P078-a

[0738] At room temperature, compound P073-a (100 mg, 0.33 mmol, 1.00 eq.) and tert-butyl 2-bromobutyrate (646 mg, 3.31 mmol, 10.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium carbonate (457 mg, 10.00 eq.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P078-a. Yield: 83.2%.

[0739] MS (ESI): 445.5 [M+1].

[0740] Step 2: Compound P078

[0741] At room temperature, compound P078-a (0.25mmol, 1.00eq.) was dissolved in a 25% trifluoroacetic acid dichloromethane solution (4.00mL) and reacted at room temperature for 1.5 hours. The reaction solution was diluted with 4mL of dichloromethane, and then washed with 15mL of saturated sodium bicarbonate solution to make it weakly alkaline, and then washed with saturated ammonium chloride solution to make it weakly acidic, extracted with dichloromethane (10mL×3), combined organic phases, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P078. Yield: 90.0%.

[0742] MS(ESI):387.3[M-1]. 1 H NMR (400MHz, CDCl3)δ H =7.84(d,J=8.3Hz,2H,ArH),7.82(d,J=8.2Hz,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, SCH3), 2.32 (s, 3H, ArCH3), 1.83 (m, 2H, CH2), 1.56 (d, 3H, CH3).

[0743] Example 79: Compound P079

[0744]

[0745] Step 1: Compound P079-a

[0746] At room temperature, compound P073-a (100 mg, 0.33 mmol, 1.00 eq.) and ethyl 2-bromoisovalerate (693 mg, 3.31 mmol, 10.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium carbonate (457 mg, 10.00 eq.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P079-a. Yield: 89.0%.

[0747] MS (ESI): 431.5 [M+1].

[0748] Step 2: Compound P079

[0749] At room temperature, compound P079-a (0.27mmol, 1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL, and reacted at room temperature for 3 hours. 30mL of saturated ammonium chloride solution was added to the reaction solution, extracted with dichloromethane (10mL×3), the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P079. ​​Yield: 95.3%.

[0750] MS(ESI):401.7[M-1]. 1 H NMR (400MHz, CDCl3)δ H =7.84(d,J=8.3Hz,2H,ArH),7.82(d,J=8.2Hz,1H,ArH),7.40(s,1H,ArH),7.30(d,J=8.3Hz,2H,ArH),6.77(d,J=36.8Hz,1H,C F=CH),6.58(d,J=8.2Hz,1H,ArH),4.63(d,1H,OCH),2.55(s,3H,SCH3),2.32(s,3H,ArCH3),1.65(m,1H,CH),1.10(d,6H,CH3).

[0751] Example 80: Compound P080

[0752]

[0753] Step 1: Compound P080-a

[0754] At room temperature, compound P073-a (100 mg, 0.33 mmol, 1.00 eq.) and ethyl 3-chloro-2,2-dimethylpropionate (163 mg, 0.99 mmol, 3.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium iodide (5 mg, 0.10 eq.) and potassium carbonate (457 mg, 10.00 eq.) were added, and heated to 70 ° C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P080-a. Yield: 83%.

[0755] MS (ESI): 431.3 [M+1].

[0756] Step 2: Compound P080

[0757] At room temperature, compound P080-a (0.25mmol, 1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL, and reacted at room temperature for 3 hours. 30mL of saturated ammonium chloride solution was added to the reaction solution, extracted with dichloromethane (10mL×3), the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P080. Yield: 80.0%.

[0758] MS(ESI):401.7[M-1]. 1 H-NMR (400MHz; (CDCl3)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=36.8H z,1H,CF=CH),6.58(d,J=8.2Hz,1H,ArH),4.45(s,2H,OCH2),2.54(s,3H,SCH3),2.28(s,3H,ArCH3),1.55(s,6H,CH3).

[0759] Example 81: Compound P081

[0760]

[0761] Step 1: Compound P081-a

[0762] At room temperature, compound P073-a (100 mg, 0.33 mmol, 1.00 eq.) and ethyl 3-chloropropionate (136 mg, 0.99 mmol, 3.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium iodide (5 mg, 0.10 eq.) and potassium carbonate (457 mg, 10.00 eq.) were added, and heated to 70 ° C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P081-a. Yield: 89.0%.

[0763] MS (ESI): 403.7 [M+1].

[0764] Step 2: Compound P081

[0765] At room temperature, compound P081-a (0.27mmol, 1.00eq.) was dissolved in 1.00mL of 10% sodium hydroxide solution and 1.00mL of tetrahydrofuran, and reacted at room temperature for 3 hours. 30mL of saturated ammonium chloride solution was added to the reaction solution, extracted with dichloromethane (10mL×3), the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P081. Yield: 88%.

[0766] MS(ESI):373.3[M-1]. 1 H NMR (400MHz, CDCl3)δ H =7.84(d,J=8.3Hz,2H,ArH),7.82(d,J=8.2Hz,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,OCH2),4.45(t,2H,COCH2),2.55(s,3H,SCH3),2.32(s,3H,ArCH3).

[0767] Example 82: Compound P082

[0768]

[0769] Step 1: Compound P082-a

[0770] At room temperature, compound P073-a (100 mg, 0.33 mmol, 1.00 eq.) and methyl 1-bromocyclopentanecarboxylate (686 mg, 3.31 mmol, 10.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium carbonate (457 mg, 10.00 eq.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P082-a. Yield: 29%.

[0771] MS (ESI): 429.4 [M+1].

[0772] Step 2: Compound P082

[0773] 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. 30 mL of saturated ammonium chloride solution was added to the reaction solution, extracted with dichloromethane (10 mL×3), the organic phases were combined, 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%.

[0774] MS(ESI):413.2[M-1]. 1 H NMR (400MHz, CDCl3)δ H =7.84(d,J=8.3Hz,2H,ArH),7.82(d,J=8.2Hz,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,SCH3),2.32(s,3H,ArCH3),1.96-1.56(m,8H,CH2).

[0775] Example 83: Compound P083

[0776]

[0777] Step 1: Compound P083-a

[0778] At room temperature, compound P073-a (100 mg, 0.33 mmol, 1.00 eq.) and methyl 1-bromocyclohexanecarboxylate (732 mg, 3.31 mmol, 10.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium carbonate (457 mg, 10.00 eq.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P083-a. Yield: 18%.

[0779] MS (ESI): 443.3 [M+1].

[0780] Step 2: Compound P083

[0781] At room temperature, compound P083-a (0.04mmol, 1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL, and reacted at room temperature for 3 hours. 30mL of saturated ammonium chloride solution was added to the reaction solution, extracted with dichloromethane (10mL×3), the organic phases were combined, 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%.

[0782] MS(ESI):427.2[M-1]. 1 H NMR (400MHz, CDCl3)δ H =7.84(d,J=8.3Hz,2H,ArH),7.82(d,J=8.2Hz,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,SCH3),2.32(s,3H,ArCH3),1.94-1.50(m,10H,CH2).

[0783] Example 84: Compound P084

[0784]

[0785] Step 1: Compound P084-a

[0786] At room temperature, compound P073-a (100 mg, 0.33 mmol, 1.00 eq.) and tert-butyl bromoacetate (648 mg, 3.31 mmol, 10.00 eq.) were dissolved in anhydrous acetonitrile (15.00 mL, 30.00 eqv.), and potassium carbonate (457 mg, 10.00 eq.) was added, and heated to 70 ° C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 (petroleum ether: dichloromethane = 1:10) to obtain compound P084-a. Yield: 94%.

[0787] MS (ESI): 417.2 [M+1].

[0788] Step 2: Compound P084

[0789] At room temperature, compound P084-a (0.29mmol, 1.00eq.) was dissolved in a 25% trifluoroacetic acid dichloromethane solution (4.00mL) and reacted at room temperature for 1.5 hours. The reaction solution was diluted with 4mL of dichloromethane, and then washed with 15mL of saturated sodium bicarbonate solution to make it weakly alkaline, and then washed with saturated ammonium chloride solution to make it weakly acidic, extracted with dichloromethane (10mL×3), combined organic phases, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P084. Yield: 95.0%.

[0790] MS(ESI):359.4[M-1]. 1 H NMR (400MHz, CDCl3)δ H =7.84(d,J=8.3Hz,2H,ArH),7.82(d,J=8.2Hz,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, OCH2CO), 2.55 (s, 3H, SCH3), 2.32 (s, 3H, ArCH3).

[0791] Example 85: Compound P085

[0792]

[0793] Step 1: Compound P085-a

[0794] At room temperature, compound P001-c (2.50 g, 13.57 mmol, 1.00 eq.) and p-hydroxybenzaldehyde (1.66 g, 13.57 mmol, 1.00 eq.) were added with piperidine (3.80 mL, 3.00 eqv.) in anhydrous methanol (55.00 mL, 25.11 eqv.), and heated to room temperature under nitrogen protection for 96 hours. The reaction solution was concentrated under reduced pressure, mixed with 20 mL of water, extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with water until neutral, washed once 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 (petroleum ether: dichloromethane = 3:1) to obtain compound P085-a. Yield: 52%.

[0795] MS (ESI): 287.1 (M-1).

[0796] Step 2: Compound P085-b

[0797] At room temperature, compound P085-a (0.50 g, 1.73 mmol, 1.00 eq.) and tert-butyl 2-bromoisobutyrate (3.30 mL, 17.34 mmol, 10.00 eq.) were dissolved in anhydrous acetonitrile (15.00 mL, 30.00 eqv.), and potassium carbonate (2.40 g, 10.00 eqv.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 (petroleum ether: dichloromethane = 1:1) to obtain compound P085-b. Yield: 65%.

[0798] MS (ESI): 431.2 [M+1].

[0799] Step 3: Compound P085

[0800] Compound P085-b (100 mg, 0.23 mmol, 1.00 eq.) was dissolved in a 25% trifluoroacetic acid dichloromethane solution (4.00 mL) at room temperature and reacted at room temperature for 1.5 hours. The reaction solution was diluted with 4 mL of dichloromethane, and then washed with 15 mL of saturated sodium bicarbonate solution until it was weakly alkaline, and then washed with saturated ammonium chloride solution to become weakly acidic, extracted with dichloromethane (10 mL × 3), and the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P085. Yield: 90%.

[0801] MS(ESI):373.7[M-1]. 1H-NMR (400MHz; (CDCl3)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, SCH3), 1.55 (s, 6H, CH3).

[0802] Example 86: Compound P086

[0803]

[0804] At room temperature, compound P085-a (100 mg, 0.35 mmol, 1.00 eq.) and isopropyl 2-bromoisobutyrate (560 μL, 3.47 mmol, 10.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium carbonate (457 mg, 10.00 eq.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P086. Yield: 80%.

[0805] MS (ESI): 417 (M+1). 1 H-NMR (400MHz; (CDCl3)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,SCH3),1.39(s,6H,C(CH3)2),1.26(d,6H,CH3).

[0806] Example 87: Compound P087

[0807]

[0808] Step 1: Compound P087-a

[0809] At room temperature, compound P085-a (100 mg, 0.35 mmol, 1.00 eq.) and tert-butyl 2-bromopropionate (576 μL, 3.47 mmol, 10.00 eq.) were dissolved in anhydrous acetonitrile (3.00 mL, 30.00 eqv.), and potassium carbonate (480 mg, 10.00 eq.) was added, and heated to 70 ° C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 (petroleum ether: dichloromethane = 1:10) to obtain compound P087-a. Yield: 80.0%.

[0810] MS (ESI): 417.2 [M+1].

[0811] Step 2: Compound P087

[0812] At room temperature, compound P087-a (0.25mmol, 1.00eq.) was dissolved in a 25% trifluoroacetic acid dichloromethane solution (4.00mL) and reacted at room temperature for 1.5 hours. The reaction solution was diluted with 4mL of dichloromethane, and then washed with 15mL of saturated sodium bicarbonate solution to make it weakly alkaline, and then washed with saturated ammonium chloride solution to make it weakly acidic, extracted with dichloromethane (10mL×3), combined organic phases, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P087. Yield: 90.6%.

[0813] MS (ESI): 359.7 [M+1]. 1 H NMR (400MHz, CDCl3)δ H =7.84(d,J=8.3Hz,2H,ArH),7.82(d,J=8.2Hz,2H,ArH),7.40(d,J=8.2Hz,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,SCH3),1.56(d,3H,CH3).

[0814] Example 88: Compound P088

[0815]

[0816] Step 1: Compound P088-a

[0817] At room temperature, compound P085-a (100 mg, 0.35 mmol, 1.00 eq.) and ethyl-1-bromocyclobutanecarboxylate (562 μL, 3.47 mmol, 10.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium carbonate (480 mg, 10.00 eq.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P088-a. Yield: 30%.

[0818] MS (ESI): 415.2 [M+1].

[0819] Step 2: Compound P088

[0820] 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. 30 mL of saturated ammonium chloride solution was added to the reaction solution, extracted with dichloromethane (10 mL×3), the organic phases were combined, 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%.

[0821] MS(ESI):385.7[M-1]. 1 H NMR (400MHz, CDCl3)δ H =7.84(d,J=8.3Hz,2H,ArH),7.82(d,J=8.2Hz,2H,ArH),7.40(d,J=8.2Hz,2H,ArH),7.30(d,J=8.3Hz,2H , ArH), 6.77 (d, J = 36.8Hz, 1H, CF = CH), 2.55 (s, 3H, SCH3), 2, 85-2.75 (m, 4H, CH2), 2.52-2.62 (m, 2H, CH2).

[0822] Example 89: Compound P089

[0823]

[0824] At room temperature, compound P085-a (100 mg, 0.35 mmol, 1.00 eq.) and 5-chloro-2,2-dimethylvaleric acid isobutyl ester (235 μL, 1.04 mmol, 3.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium iodide (5 mg, 0.10 eq.) and potassium carbonate (480 mg, 10.00 eq.) were added, and heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P089. Yield: 82%.

[0825] MS (ESI): 473.3 [M+1]. 1 H NMR (400MHz, CDCl3)δ H =7.84(d,J=8.3Hz,2H,ArH),7.82(d,J=8.2Hz,2H,ArH),7.40(d,2H,J=8.2Hz,ArH),7.30(d,J=8.3Hz,2H,ArH),6.77(d,J=36.8Hz,1H,C F=CH),4.65(t,2H,OCH2),4.29(d,2H,OCH2),2.55(s,3H,SCH3),1.92(q,1H,CH),1.85(m,4H,CH2),1.32(s,6H,CH3),1.02(d,6H,CH3).

[0826] Example 90: Compound P090

[0827]

[0828] Step 1: Compound P090-a

[0829] At room temperature, compound P085-a (100 mg, 0.35 mmol, 1.00 eq.) and tert-butyl 2-bromobutyrate (677 mg, 3.47 mmol, 10.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium carbonate (480 mg, 10.00 eq.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P090-a. Yield: 83%.

[0830] MS (ESI): 431.5 [M+1].

[0831] Step 2: Compound P090

[0832] At room temperature, compound P090-a (0.27mmol, 1.00eq.) was dissolved in a 25% trifluoroacetic acid dichloromethane solution (4.00mL) and reacted at room temperature for 1.5 hours. The reaction solution was diluted with 4mL of dichloromethane, and then washed with 15mL of saturated sodium bicarbonate solution until weak alkalinity, and then washed with saturated ammonium chloride solution to weak acidity, extracted with dichloromethane (10mL×3), combined organic phases, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P090. Yield: 90.0%.

[0833] MS(ESI):373.3[M-1]. 1 H NMR (400MHz, CDCl3)δ H =7.84(d,J=8.3Hz,2H,ArH),7.82(d,J=8.2Hz,2H,ArH),7.40(d,J=8.2Hz,2H,ArH),7.30(d,J=8.3Hz,2H,Ar H), 6.77 (d, J = 36.8Hz, 1H, CF = CH), 4.65 (t, 1H, OCH), 2.55 (s, 3H, SCH3), 1.83 (m, 2H, CH2), 1.56 (d, 3H, CH3).

[0834] Example 91: Compound P091

[0835]

[0836] Step 1: Compound P091-a

[0837] At room temperature, compound P085-a (100 mg, 0.35 mmol, 1.00 eq.) and ethyl 2-bromoisovalerate (726 mg, 3.47 mmol, 10.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium carbonate (480 mg, 10.00 eq.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P091-a. Yield: 85.0%.

[0838] MS (ESI): 417.5 [M+1].

[0839] Step 2: Compound P091

[0840] 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. 30 mL of saturated ammonium chloride solution was added to the reaction solution, extracted with dichloromethane (10 mL×3), the organic phases were combined, 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%.

[0841] MS(ESI):387.7[M-1]. 1 H NMR (400MHz, CDCl3)δ H =7.84(d,J=8.3Hz,2H,ArH),7.82(d,J=8.2Hz,2H,ArH),7.40(d,J=8.2Hz,2H,ArH),7.30(d,J=8.3Hz,2H,A rH), 6.77 (d, J = 36.8Hz, 1H, CF = CH), 4.63 (d, 1H, OCH), 2.55 (s, 3H, SCH3), 1.65 (m, 1H, CH), 1.10 (d, 6H, CH3).

[0842] Example 92: Compound P092

[0843]

[0844] Step 1: Compound P092-a

[0845] At room temperature, compound P085-a (100 mg, 0.35 mmol, 1.00 eq.) and ethyl 3-chloro-2,2-dimethylpropionate (172 mg, 1.04 mmol, 3.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium iodide (5 mg, 0.10 eq.) and potassium carbonate (480 mg, 10.00 eq.) were added, and heated to 70 ° C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P092-a. Yield: 86%.

[0846] MS (ESI): 417.3 [M+1].

[0847] Step 2: Compound P092

[0848] 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. 30 mL of saturated ammonium chloride solution was added to the reaction solution, extracted with dichloromethane (10 mL×3), the organic phases were combined, 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%.

[0849] MS(ESI):387.7[M-1]. 1 H-NMR (400MHz; (CDCl3)δ H =7.85(d,J=7.2Hz,2H,ArH),7.82(d,J=8.2Hz,2H,

[0850] 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, OCH2), 2.54 (s, 3H, SCH3), 1.55 (s, 6H, CH3).

[0851] Example 93: Compound P093

[0852]

[0853] Step 1: Compound P093-a

[0854] At room temperature, compound P085-a (100 mg, 0.35 mmol, 1.00 eq.) and ethyl 3-chloropropionate (143 mg, 1.04 mmol, 3.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium iodide (5 mg, 0.10 eq.) and potassium carbonate (480 mg, 10.00 eq.) were added, and heated to 70 ° C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P093-a. Yield: 80.0%.

[0855] MS (ESI): 389.7 [M+1].

[0856] Step 2: Compound P093

[0857] At room temperature, compound P093-a (0.27mmol, 1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL, and reacted at room temperature for 3 hours. 30mL of saturated ammonium chloride solution was added to the reaction solution, extracted with dichloromethane (10mL×3), the organic phases were combined, 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%.

[0858] MS(ESI):359.3[M-1]. 1 H NMR (400MHz, CDCl3)δ H =7.84(d,J=7.3,2H,ArH),7.82(d,J=8.2Hz,2H,ArH),7.40(s,J=8.2Hz,2H,ArH),7.30(d,J=8.3Hz,2H,ArH),6.7 7(d,J=36.8Hz,1H,CF=CH),6.58(d,J=8.2Hz,1H,ArH),4.65(t,2H,OCH2),4.45(t,2H,COCH2),2.55(s,3H,SCH3).

[0859] Example 94: Compound P094

[0860]

[0861] Step 1: Compound P094-a

[0862] At room temperature, compound P085-a (100 mg, 0.35 mmol, 1.00 eq.) and methyl 1-bromocyclopentanecarboxylate (719 mg, 3.47 mmol, 10.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium carbonate (480 mg, 10.00 eq.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P094-a. Yield: 30%.

[0863] MS (ESI): 415.4 [M+1].

[0864] Step 2: Compound P094

[0865] 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. 30 mL of saturated ammonium chloride solution was added to the reaction solution, extracted with dichloromethane (10 mL×3), the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P094. Yield: 90.0%.

[0866] MS(ESI):399.2[M-1]. 1 H NMR (400MHz, CDCl3)δ H =7.84(d,J=8.3Hz,2H,ArH),7.82(d,J=8.2Hz,2H,ArH),7.40(d,J=8.2Hz,1H,ArH),7.30(d,J=8.3Hz,2H,A rH), 6.77 (d, J = 36.8Hz, 1H, CF = CH), 6.58 (d, J = 8.2Hz, 1H, ArH), 2.55 (s, 3H, SCH3), 1.96-1.56 (m, 8H, CH2).

[0867] Example 95: Compound P095

[0868]

[0869] Step 1: Compound P095-a

[0870] At room temperature, compound P085-a (100 mg, 0.35 mmol, 1.00 eq.) and methyl 1-bromocyclohexanecarboxylate (768 mg, 3.47 mmol, 10.00 eq.) were dissolved in 6.00 mL of anhydrous acetonitrile, and potassium carbonate (480 mg, 10.00 eq.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 preparative chromatography (petroleum ether: dichloromethane = 1:10) to obtain compound P095-a. Yield: 20%.

[0871] MS (ESI): 387.3 [M+1].

[0872] Step 2: Compound P095

[0873] At room temperature, compound P095-a (0.05mmol, 1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL, and reacted at room temperature for 3 hours. 30mL of saturated ammonium chloride solution was added to the reaction solution, extracted with dichloromethane (10mL×3), the organic phases were combined, 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%.

[0874] MS(ESI):371.2[M-1]. 1 H NMR (400MHz, CDCl3)δ H =7.84(d,J=8.3Hz,2H,ArH),7.82(d,J=8.2Hz,2H,ArH),7.39(d,J=8.2Hz,2H,ArH),7.30(d,J=8.3Hz,2 H, ArH), 6.77 (d, J = 36.8Hz, 1H, CF = CH), 6.58 (d, J = 8.2Hz, 1H, ArH), 2.55 (s, 3H, SCH3), 1.55 (m, 4H, CH2).

[0875] Example 96: Compound P096

[0876]

[0877] Step 1: Compound P096-a

[0878] At room temperature, compound P085-a (100 mg, 0.35 mmol, 1.00 eq.) and tert-butyl bromoacetate (677 mg, 3.47 mmol, 10.00 eq.) were dissolved in anhydrous acetonitrile (15.00 mL, 30.00 eqv.), and potassium carbonate (480 mg, 10.00 eq.) was added, and heated to 70 ° C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 (petroleum ether: dichloromethane = 1:10) to obtain compound P096-a. Yield: 94%.

[0879] MS (ESI): 403.2 [M+1].

[0880] Step 2: Compound P096

[0881] At room temperature, compound P096-a (0.30mmol, 1.00eq.) was dissolved in a 25% trifluoroacetic acid dichloromethane solution (4.00mL) and reacted at room temperature for 1.5 hours. The reaction solution was diluted with 4mL of dichloromethane, and then washed with 15mL of saturated sodium bicarbonate solution until it was weakly alkaline, and then washed with saturated ammonium chloride solution to become weakly acidic, extracted with dichloromethane (10mL×3), and the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P096. Yield: 91.0%.

[0882] MS(ESI):345.4[M-1]. 1 H NMR (400MHz, CDCl3)δ H =7.84(d,J=8.3Hz,2H,ArH),7.82(d,J=8.2Hz,2H,ArH),7.40(d,J=8.2Hz,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, OCH2CO), 2.55 (s, 3H, SCH3).

[0883] Example 97: Compound P097

[0884]

[0885] Step 1: Compound P097-a

[0886] At room temperature, compound P001-c (2.00 g, 10.86 mmol, 1.00 eq.) and 3,5-dichloro-4-hydroxybenzaldehyde (2.08 g, 10.86 mmol, 1.00 eq.) were added with piperidine (3.00 mL, 3.00 eqv.) in anhydrous methanol (50.00 mL, 25.11 eqv.), and heated to room temperature under nitrogen protection for 96 hours. The reaction solution was concentrated under reduced pressure, mixed with 20 mL of water, extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with water until neutral, washed once 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 (petroleum ether: dichloromethane = 3:1) to obtain compound P097-a. Yield: 38%.

[0887] MS (ESI): 356.1 (M-1).

[0888] Step 2: Compound P097-b

[0889] At room temperature, compound P097-a (0.50 g, 1.40 mmol, 1.00 eq.) and tert-butyl 2-bromoisobutyrate (2.70 mL, 14.00 mmol, 10.00 eq.) were dissolved in anhydrous acetonitrile (15.00 mL, 30.00 eqv.), and potassium carbonate (1.94 g, 10.00 eqv.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 (petroleum ether: dichloromethane = 1:1) to obtain compound P097-b. Yield: 60%.

[0890] MS (ESI): 500.2 [M+1].

[0891] Step 3: Compound P097

[0892] At room temperature, compound P097-b (200 mg, 0.40 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 with 4 mL of dichloromethane, and then washed with 15 mL of saturated sodium bicarbonate solution until it was weakly alkaline, and then washed with saturated ammonium chloride solution to become weakly acidic, extracted with dichloromethane (10 mL × 3), and the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P097. Yield: 79%.

[0893] MS(ESI):442.7[M-1]. 1 H-NMR (400MHz; (CDCl3)δ H =8.10(s,2H,ArH),7.85(d,J=7.2Hz,2H,ArH),7.30(d,J=7.2Hz,2H,ArH),6.77(d,J=36.8Hz,1H,CF=CH),2.54(s,3H,SCH3),1.55(s,6H,CH3).

[0894] Example 98: Compound P098

[0895]

[0896] Step 1: Compound P098-a

[0897] At room temperature, compound P001-c (2.00 g, 10.86 mmol, 1.00 eq.) and 2-methyl-4-hydroxybenzaldehyde (1.48 g, 10.86 mmol, 1.00 eq.) were added with piperidine (3.00 mL, 3.00 eqv.) in anhydrous methanol (50.00 mL, 25.11 eqv.), and heated to room temperature under nitrogen protection for 96 hours. The reaction solution was concentrated under reduced pressure, mixed with 20 mL of water, extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with water until neutral, washed once 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 (petroleum ether: dichloromethane = 3:1) to obtain compound P098-a. Yield: 37%.

[0898] MS (ESI): 301.1 (M-1).

[0899] Step 2: Compound P098-b

[0900] At room temperature, compound P098-a (0.50 g, 1.65 mmol, 1.00 eq.) and tert-butyl 2-bromoisobutyrate (3.10 mL, 16.54 mmol, 10.00 eq.) were dissolved in anhydrous acetonitrile (15.00 mL, 30.00 eqv.), and potassium carbonate (2.29 g, 10.00 eqv.) was added, and the mixture was heated to 70°C under nitrogen protection 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), the organic phases were combined, washed with water until neutral, washed once 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 (petroleum ether: dichloromethane = 1:1) to obtain compound P098-b. Yield: 60%.

[0901] MS (ESI): 445.2 [M+1].

[0902] Step 3: Compound P098

[0903] At room temperature, compound P098-b (200 mg, 0.45 mmol, 1.00 eq.) was dissolved in a 25% trifluoroacetic acid dichloromethane solution (4.00 mL) and reacted at room temperature for 1.5 hours. The reaction solution was diluted with 4 mL of dichloromethane, and then washed with 15 mL of saturated sodium bicarbonate solution until it was weakly alkaline, and then washed with saturated ammonium chloride solution to become weakly acidic, extracted with dichloromethane (10 mL × 3), and the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain P098. Yield: 75%.

[0904] MS(ESI):387.7[M-1]. 1H-NMR (400MHz; (CDCl3)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, SCH3), 2.32 (s, 3H, ArCH3), 1.55 (s, 6H, CH3).

[0905] Example 99 Activity of the compounds of the present invention on PPAR

[0906] Plasmid vectors containing PPARα(Kanamycin+), PPARδ(Kanamycin+), and pPPRE3-TK_Luciferase(Kanamycin+) were introduced into DH5a competent cells, and the target plasmids were obtained by monoclonal cloning and amplification culture. The target plasmids were extracted using Plasmid Miniprep Kit, and the luciferase and PPAR expression vectors were transfected into Hela cells. After transfection for 24 hours, the cells were cultured at 5*10 5 / ml was inoculated into a 96-well plate, and the compound of the present invention and the positive compound were added 12 hours later. The initial concentration of the compound was 10000nM, and it was diluted into 10 concentration gradients at a ratio of 1:2. After 24 hours of incubation in an incubator, luciferase detection reagent was added, and the luminescence intensity was detected by a Tecan Spark microplate reader to calculate the EC 50 The results are shown in Table 1.

[0907] Table 1 The agonist activity of the compounds of the present invention on PPARα and δ (EC 50 Value, nM)

[0908] Compound No. PPARα PPARδ GFT-505 +++ + P001 ++++ ++ P002 ++++ ++ P003 ++++ +++ P004 +++ ++ P006 +++ ++ P007 +++ ++ P008 +++ ++ P010 +++ + P013 +++ ++ P015 +++ ++ P018 +++ + P025 ++ + P030 ++ + P037 +++ ++ P039 +++ ++ P045 +++ + P049 ++ + P051 +++ + P057 +++ + P061 +++ ++ P063 +++ ++ P073 +++ ++ P085 +++ + P087 ++++ + P090 +++ ++ P092 ++ + P097 +++ + P098 +++ +

[0909]

Note

[0910] +++: stands for EC 50 The value is greater than or equal to 10nM and less than 50nM;

[0911] ++: stands for EC 50 The value is greater than or equal to 50nM and less than 100nM;

[0912] +: represents EC 50 The value is greater than or equal to 100nM and less than 500nM.

[0913] The experimental results show that the EC of the compounds of the present invention for the agonist effect on PPARα and PPARδ 50 The value is better than that of the positive control drug, indicating that the compound of the present invention has stronger activity.

[0914] Example 100 Animal Bioavailability of the Compounds of the Invention

[0915] Rats were fasted but not watered for 12 hours. After administration, about 400 μL of blood was collected from the eye sockets of each animal, and EDTA-Na2 was used for anticoagulation. The blood was collected at 2 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 24 hours and 30 hours after administration of the test substance for the intravenous administration group; and at 5 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 24 hours and 30 hours after administration of the test substance for the oral administration group. After collection, the blood was placed in an ice bath and centrifuged within 1 hour to separate the plasma (centrifugation conditions: 6000 rpm, 8 minutes, 4°C). Vortex mix at 2500rpm for 1min, take 100.0μL plasma sample in a 1.5mL centrifuge tube, add 10.0μL internal standard working solution (1.000μg / mL), vortex at 2500rpm for 1min, then centrifuge at 17000×g, 4℃ for 15min, take the supernatant and analyze it by UHPLC-MS / MS, inject 2.0μL. Data were analyzed and processed by WinNonLin7.0 pharmacokinetic software.

[0916] The results of the pharmacokinetic study of compound P001 in SD rats (n=3) showed that after intravenous administration (dose of 1.0 mg / kg), the half-life of compound P001 in rats was T 1 / 2 1.63±0.15h, C max The half-life of compound P001 in rats after intragastric administration (dose of 10.0 mg / kg) was T 1 / 2 1.46±0.37h, C max It is 4603.24±1048.8ng / mL, and the absolute bioavailability is 40.88%.

[0917] Document CN108658908 A reported that after oral administration of 20 mg / kg, the Cmax of GFT-505 was 1138 ng / mL, indicating that the blood concentration of the compound P001 of the present invention was higher and its effect was better than that of GFT-505.

[0918] Example 101 Effect of the compounds of the present invention on collagen I protein expression

[0919] A blank control group, a TGFβ1 model group, a GFT-505 positive control group and a compound of the present invention group were set up. LX-2 (hepatic stellate cells) were plated in 6-well plates, with 5*10 5 cells, discarded the original culture medium after 12 hours, added culture medium containing 2% serum, added GFT-505 and the compounds of the present invention P001, P002, P003, the final concentration was 10μM, and the blank control group was replaced with an equal amount of culture medium. After 1 hour, the blank control group was replaced with an equal amount of culture medium, and TGFβ1 was added to the other groups, the final concentration was 1ng / ml. After 48 hours, the cells were digested with trypsin, and the expression of CollagenⅠ protein was detected by Western Blot method. The relative expression level of CollagenⅠ protein in each group is shown in Table 2.

[0920] Table 2 Relative expression levels of Collagen Ⅰ protein in each group

[0921] Group sample Relative protein expression level Blank group control group Culture medium 0.18 Model Group TGFβ1 0.71 Positive control group GFT-505 0.52 Embodiment 1 of the present invention P001 0.38 Embodiment 2 of the present invention P002 0.33 Embodiment 3 of the present invention P003 0

[0922] The compounds P001, P002 and P003 of the present invention can effectively reduce the expression of Collagen Ⅰ protein, and the effects are obvious. Compared with the positive control drug GFT-505, the activity is stronger, and the effect of compound P003 is the best.

Claims

1. An α-fluorochalcone derivative, which is a compound represented by formula I or a pharmaceutically acceptable salt thereof: in: R1 and R2 are independently selected from H, halogen, CF3, -CN, C 1-6 Alkoxy, CF3O, CHF2O, C 1-6 Alkylthio, CF3S, CHF2S, C 1-6 Alkyl, C 1-6 Alkyl sulfoxide-, CF3SO, C 1-6 alkylsulfone or CF3SO2, or selected from: 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; R3 and R4 are independently selected from H, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, including but not limited to Cl, Br, I, CH3, Et, CH3O; R5 and R6 are independently selected from H, C 1-6 Alkyl, C 1-6 Heteroalkyl, phenyl, 5-6 membered heteroaryl, R5 and R6 can also form a ring to form C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl; wherein R5 and R6 include but are not limited to methyl, ethyl, isopropyl, phenyl, pyrazolyl or pyridyl; R5 and R6 are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, R7 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, NH2, COOH, C(=O)NH2, Me, Et, CF3, CHF2, CH2F, NHCH3 Or N(CH3)2.

2. The α-fluorochalcone derivative according to claim 1, characterized in that: It is a compound represented by formula IA or a pharmaceutically acceptable salt thereof: wherein R1 is selected from H; R2 is selected from H, halogen or C 1-6 alkyl; R3 and R4 are independently selected from H, halogen or C 1-4 alkyl; R5 and R6 are independently selected from H, C 1-6 Alkyl, phenyl or 5-6 membered heteroaryl, or R5 and R6 can also be ring-formed to form C 3-6 Cycloalkyl or 3- to 6-membered heterocycloalkyl; R7 is selected from H or C 1-6 alkyl; n is selected from 0 or 1; 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.

3. The α-fluorochalcone derivative according to claim 1, characterized in that: It is a compound represented by formula IB or a pharmaceutically acceptable salt thereof: wherein R is selected from Me, Et or CF3; R2 is selected from OH; R3 and R4 are independently selected from H, halogen or C 1-4 alkyl; R5 and R6 are independently selected from H, C 1-6 Alkyl, phenyl or 5-6 membered heteroaryl, or R5 and R6 can also be ring-formed to form C 3-6 Cycloalkyl or 3- to 6-membered heterocycloalkyl; R7 is selected from H or C 1-6 alkyl; n is selected from 0 or 1; 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.

4. The α-fluorochalcone derivative according to claim 1, characterized in that: It is a compound represented by formula IC or a pharmaceutically acceptable salt thereof: wherein R is selected from Me, Et or CF3; R2 is selected from H, halogen or C 1-6 alkyl; When R3 is H, R4 is C 1-4 Alkyl; or R3 is C 1-4 When alkyl, R4 is H; or R3 is C 1-4 When alkyl, R4 is C 1-4 alkyl; R5 and R6 are independently selected from H, C 1-6 Alkyl, phenyl or 5-6 membered heteroaryl, or R5 and R6 can also be ring-formed to form C 3-6 Cycloalkyl or 3- to 6-membered heterocycloalkyl; R7 is selected from H or C 1-6 alkyl; n is selected from 1; 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.

5. The α-fluorochalcone derivative according to claim 1, characterized in that: It is a compound represented by formula ID or a pharmaceutically acceptable salt thereof: wherein R is selected from Me, Et, CF3, CHF2, CH2F, NHCH3 or N(CH3)2; R2 is selected from H, halogen or C 1-6 alkyl; R3 and R4 are independently selected from H, halogen or C 1-4 alkyl; R5 and R6 are independently selected from H, C 1-6 Alkyl, phenyl or 5-6 membered heteroaryl, or R5 and R6 can also be ring-formed to form C 3-6 Cycloalkyl or 3- to 6-membered heterocycloalkyl; R7 is selected from H or C 1-6 alkyl; n is selected from 0, 1, 2 or 3; 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.

6. An α-fluorochalcone derivative, which is a compound of the following structure or a pharmaceutically acceptable salt thereof:

7. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof as an active ingredient, and one or more pharmaceutically acceptable carriers.

8. Use of the compound according to any one of claims 1 to 6 or the pharmaceutical composition according to claim 7 in the preparation of a medicament for treating PPAR receptor-related diseases.

9. The use according to claim 8, characterized in that The PPAR receptor-related diseases are: non-alcoholic fatty hepatitis, liver fibrosis, insulin resistance, primary biliary cholangitis, dyslipidemia, hyperlipidemia, hypercholesterolemia, atherosclerosis, hypertriglyceridemia, cardiovascular disease, obesity, kidney disease or brain degenerative disease.

10. The use according to claim 9, characterized in that The kidney disease is selected from chronic kidney disease and renal failure, and the brain degenerative disease is selected from Alzheimer's disease.

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