Process for the preparation of 3-aryl-1-dihydrobenzofuran-2-(trifluoromethyl)propenones and their use

Abstract

The present application relates to a kind of new compound and its preparation method and application, specifically, it is related to ( E )‑3‑aryl‑1‑(2,2‑dimethyl‑2,3‑dihydrobenzofuran‑5‑yl)‑2‑(trifluoromethyl)prop‑2‑en‑1‑one derivatives and its preparation method and application.The present application compound shows good antitumor activity to HGC‑27 (human gastric cancer cell strain), MCF‑7 (human breast cancer cell strain), HCT‑116 (human colon cancer cell), DU145 (human prostate cancer cell), C‑33A (human cervical cancer cell), NCI‑H460 (human large cell lung cancer cell), and normal cell HaCat (human keratinocyte) has good safety, some drugs are superior to positive control drug cisplatin (DDP).The present application compound provides good lead compound basis for the research and development of antitumor drugs, and has wide application prospect.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, specifically to a class of ( E )-3-aryl-1-(2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one derivatives, their preparation methods and applications. Background Technology

[0002] Chalcones are a class of α,β-unsaturated ketones widely found in natural plants, with the basic structure of 1,3-diphenylpropenone. Studies have shown that chalcones possess a variety of pharmacological activities, including anticancer, anti-inflammatory, antihypertensive, antidiabetic, antiulcer, antioxidant, antimicrobial, and antimalarial activities, demonstrating broad medicinal prospects.

[0003] The presence of reactive α,β-unsaturated ketone groups in chalcones is the reason for their biological activity. This structure is highly heterogeneous, allowing them to interact with a variety of drug targets through different substitution modes, thus endowing these compounds with a wide range of biological functions. It is precisely because of this structural characteristic that chalcones and their derivatives have attracted widespread attention from synthetic chemists not only for their diverse chemical modification potential but also for their broad-spectrum biological activities, giving them an important place in the field of drug development.

[0004] Some chalcone compounds have been successfully used in clinical applications. For example, Metochalcone is used as a bile / diuretic agent for gastrolytic therapy, Sofalcone is a mucosal protectant based on soft ketones, and Hesperidinmethychalcone is used as a vascular protectant. These successful cases fully demonstrate the clinical potential of the chalcone skeleton in drug development [Biomolecules, 2021, 11(6): 894].

[0005] In recent years, research on structural modification using chalcone as a lead compound has made some progress. Liu, Z. et al. [Bioorg Chem, 2024, 147: 107310] designed and synthesized 16 novel imidazole-chalcone compounds as microtubule polymerization inhibitors, using chalcone scaffolds as lead compounds. Preliminary in vitro cytotoxicity results showed that compound 1 had a significant inhibitory effect on all four tested cancer cell types, with an inhibition index (RI) of 1.63 (IC50). 50 =2.28~7.77 μM), and also showed low toxicity to H8 cells (IC50). 50=47.51 μM), when used in combination with cisplatin, its RI decreased from 6.04 to 2.01. Yan, J. et al. [Eur J Med Chem, 2022, 227: 113897] modified the structure of chalcone compounds targeting both tubulin and thioredoxin reductase (TrxR). Among the synthesized compounds, compound 2 showed an IC50 of 47.51 μM against cisplatin, which decreased from 6.04 to 2.01. 50 The values ​​ranged from 6 to 35 nM, which was 2.4 to 9.7 times higher than the positive control drug.

[0006] ; Furthermore, the structure of chalcones holds significant potential value in drug synthesis and their anti-tumor applications. Chinese patents CN120208932A, CN105585563A, and CN105585562A disclose a series of chalcone compounds containing dihydrobenzofuran structures, which exhibit good inhibitory effects against breast cancer, gastric cancer, colorectal cancer, and non-small cell lung cancer. Chinese patent CN119732937A discloses the application of a chalcone compound in the preparation of a drug for treating cervical cancer. Chinese patent CN119613455A discloses a novel dual-target inhibitor of tubulin and metalloproteinases, its preparation method, and its application. By introducing new chalcone derivatives into aminophosphate derivatives, a novel dual-target inhibitor of tubulin and metalloproteinases is obtained as a compound with targeting function. Chinese patent CN119462575A discloses a chalcone derivative and its preparation method. Using 2,4-dihydroxyformaldehyde as the starting material, isopentenyl is first introduced into 2,4-dihydroxybenzaldehyde through Friedel-Crafts reaction, and then heterocyclic substituted formaldehyde is introduced into heterocycle through aldol condensation reaction to form a chalcone structure. Mechanistic studies have shown that it has good application prospects as an anticancer drug.

[0007] However, the existing chalcone derivatives still require further expansion in terms of structural types and target sites. Optimizing their antitumor activity, selectivity, and pharmacokinetic properties by introducing aromatic heterocyclic groups with specific spatial conformations and electronic effects remains an important research direction in this field. In particular, the modification strategy of introducing a trifluoromethyl group at the β-position of the chalcone skeleton, combined with a 2,2-dialkyl-2,3-dihydrobenzofuran structure, has not yet been systematically reported. The introduction of a trifluoromethyl group can enhance the compound's lipophilicity, metabolic stability, and hydrophobic interactions with target proteins, potentially significantly improving its antitumor activity and druggability. Therefore, developing a novel derivative containing a chalcone skeleton and exploring its antitumor applications is of great significance. Summary of the Invention

[0008] The purpose of this invention is to provide a novel type of ( EThe derivative of 3-aryl-1-(2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one has excellent antitumor activity, especially significant inhibitory effect on a variety of human tumor cells, while having good safety for normal cells.

[0009] Another object of the present invention is to provide a method for preparing the above-mentioned compound, which is simple to operate, has mild reaction conditions, uses readily available raw materials, and is suitable for industrial production.

[0010] Another object of the present invention is to provide a pharmaceutical composition comprising the above-mentioned compounds, and its use in the preparation of antitumor drugs.

[0011] To achieve the above objectives, the present invention adopts the following technical solution: The first aspect of the present invention is to provide a formula ( E Compounds with the )-I structure and their pharmaceutically acceptable salts have the following structural formulas: ; R1 is selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, nitro, cyano or hydroxy; R2 is selected from C1-C6 alkyl groups; n is selected from 0, 1, 2, 3, 4 or 5.

[0012] Preferably, R1 is selected from halogens, including chlorine, bromine, and fluorine.

[0013] Preferably, R1 is selected from C1-C6 alkyl or nitro groups, more preferably methyl or nitro groups.

[0014] Preferably, (R1) n Selected from: chlorine, 2,4-dichloro, 2-chloro-6-fluoro, bromine, fluorine, 2,4-difluoro, methoxy, ethoxy, methyl, 2,3,4-trimethoxy, 3,4,5-trimethoxy, nitro, trifluoromethyl; Preferably, R2 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, pentyl, isopentyl, and n-pentyl.

[0015] Preferably, the formula ( E Compounds with the )-I structure are selected from: ( E )-I1~( E )-I36; where, ( E )-I1 is ( E )-3-(4-chlorophenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I2 is ( E )-3-(3-chlorophenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I3 is ( E )-3-(2-chlorophenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I4 is ( E )-3-(2,4-dichlorophenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I5 is ( E )-3-(2-chloro-6-fluorophenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I6 is ( E )-3-(4-bromophenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I7 is ( E )-3-(3-bromophenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I8 is ( E )-3-(2-bromophenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I9 is ​​( E )-3-(4-fluorophenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I10 is ( E )-3-(3-fluorophenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E)-I11 is ( E )-3-(2-fluorophenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I12 is ( E )-3-(2,4-difluorophenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I13 is ( E )-3-(4-methoxyphenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I14 is ( E )-3-(3-methoxyphenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I15 is ( E )-3-(2-methoxyphenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I16 is ( E )-3-(3,4,5-trimethoxyphenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I17 is ( E )-3-(2,3,4-trimethoxyphenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I18 is ( E )-3-(4-ethoxyphenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I19 is ( E )-3-(3-ethoxyphenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I20 is ( E )-3-(2-ethoxyphenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I21 is ( E )-3-(4-methylphenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I22 is ( E )-3-(3-methylphenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E -I23 is ( E )-3-(2-methylphenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I24 is ( E )-3-(4-nitrophenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I25 is ( E )-3-(3-nitrophenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I26 is ( E )-3-phenyl-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I27 is ( E )-3-(3-thienyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E -I28 is ( E )-3-(3-trifluoromethylphenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; (E )-I29 is ( E )-3-(4-nitrophenyl)-1-(7-ethoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I30 is ( E )-3-(4-nitrophenyl)-1-(7-propoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I31 is ( E )-3-(4-nitrophenyl)-1-(7-isopropoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I32 is ( E )-3-(4-nitrophenyl)-1-(7-(tert-butoxy)-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I33 is ( E )-3-(4-nitrophenyl)-1-(7-butoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I34 is ( E )-3-(4-nitrophenyl)-1-(7-(pentoxy)-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I35 is ( E )-3-(4-nitrophenyl)-1-(7-(pent-2-oxy)-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I36 is ( E )-3-(4-nitrophenyl)-1-(7-(pent-3-oxy)-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one.

[0016] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the above general formula ( E The compound shown in )-I, its pharmaceutically acceptable salt, and pharmaceutically acceptable carriers, diluents, or excipients.

[0017] The "therapeutic effective dose" refers to the dosage of a compound that can effectively prevent, alleviate, or treat tumors. This dosage can be determined by a person skilled in the art based on factors such as the patient's age, weight, and the severity of their condition.

[0018] The term "pharmaceutically acceptable carrier" includes, but is not limited to: fillers, binders, disintegrants, lubricants, flow aids, coating materials, solvents, cosolvents, surfactants, preservatives, stabilizers, antioxidants, pH adjusters, isotonic adjusters, buffers, etc. These carriers and excipients are well-known in the art and can be selected according to the formulation type and route of administration.

[0019] The pharmaceutical compositions of the present invention can be administered via various routes of administration, including oral administration, parenteral administration (such as intravenous injection, intramuscular injection, subcutaneous injection), topical administration, and rectal administration. Corresponding dosage forms include, but are not limited to, tablets, capsules, granules, powders, injections, lyophilized powder for injection, ointments, patches, and suppositories.

[0020] The present invention also relates to the above formula ( E The use of the compound shown in (I) or a pharmaceutical composition thereof in the preparation of an antitumor drug. The tumors include, but are not limited to, gastric cancer, colon cancer, breast cancer, prostate cancer, cervical cancer, and lung cancer.

[0021] In a preferred embodiment of the invention, the tumor is cervical cancer, particularly a malignant tumor associated with C-33A human cervical cancer cells.

[0022] Preferably, the tumor is gastric cancer, particularly a malignant tumor associated with HGC-27 human gastric cancer cells.

[0023] Preferably, the tumor is colon cancer, particularly a malignant tumor associated with HCT-116 human colon cancer cells.

[0024] The compounds of this invention can exert anti-tumor effects through a variety of mechanisms, including but not limited to: inducing apoptosis, inhibiting cell proliferation, arresting the cell cycle, inhibiting angiogenesis, and regulating signal transduction pathways.

[0025] The (E)-I compound of the present invention (i.e., the -3-aryl-1-(2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one derivative) can be prepared by the following method, with the reaction formula as follows: ; Step i: Using compound A as a starting material, react with R1-I or R1-Br to undergo an etherification reaction to obtain intermediate compound B; Preferably, the etherification reaction is carried out in the presence of potassium iodide and a basic reagent; Preferably, the etherification reaction is carried out in the presence of a solvent, wherein the solvent is selected from one or more of methanol, ethanol, isopropanol, and butanol; Preferably, the alkaline reagent can be an inorganic or organic base. The inorganic base includes, but is not limited to, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, etc.; the organic base includes, but is not limited to, sodium methoxide, sodium ethoxide, potassium tert-butoxide, potassium ethoxide, etc. Sodium carbonate and potassium carbonate are preferred.

[0026] Preferably, the time and temperature of the etherification reaction can be adjusted by conventional technical means, such as reacting at 20~80°C for 1~12 hours; more preferably, reacting at 40~60°C for 4~8 hours; and most preferably, reacting at 50°C for 6 hours.

[0027] Step ii: Compound B undergoes a Friedel-Crafts acylation reaction to obtain intermediate compound C; Preferably, the reagent for the Friedel-Crafts acylation reaction is selected from acetyl chloride, acetic anhydride, or a mixture thereof; Preferably, the catalyst for the Friedel-Crafts acylation reaction is a Lewis acid, such as one or more of zinc chloride, aluminum trichloride, ferric chloride, tin tetrachloride, and boron trifluoride.

[0028] Step iii: Compound C and benzaldehyde derivative (R1) n -Ph-CHO reaction, Claisen-Schmidt condensation reaction under alkaline conditions, to prepare intermediate D; Preferably, the alkaline conditions can use inorganic or organic bases. The inorganic bases include, but are not limited to, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, and cesium carbonate; the organic bases include, but are not limited to, sodium methoxide, sodium ethoxide, potassium tert-butoxide, and potassium ethoxide. Sodium hydroxide, potassium hydroxide, sodium methoxide, or sodium ethoxide are preferred.

[0029] Preferably, the Claisen-Schmidt condensation reaction is carried out in the presence of a solvent, including but not limited to methanol, ethanol, n-propanol, isopropanol, butanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide, or mixtures thereof. Methanol, ethanol, or mixtures thereof are preferred.

[0030] Preferably, the reaction temperature is generally 0-80℃, and more preferably room temperature (20-25℃) to 60℃.

[0031] Preferably, the reaction time is generally 2-24 hours, and more preferably 4-12 hours.

[0032] Preferably, after the reaction is complete, post-processing and purification can be carried out by conventional methods, including but not limited to: quenching reaction, extraction, washing, drying, concentration, column chromatography, recrystallization, etc.

[0033] Step iv: Compound D was reacted with Togni reagent and cuprous iodide catalysis to prepare the target product shown in formula (E)-I.

[0034] Preferably, the Togni reagent is selected from 1-(trifluoromethyl)-1,2-benzyl-3(1H)-one; Preferably, after the reaction is completed, the product is extracted with deionized water and ethyl acetate. The organic phase is dried with anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by column chromatography to obtain the target product shown in formula (E)-I1. The definitions of R1 and R2 are as described above.

[0035] Compared with the prior art, the beneficial effects of the present invention are as follows: (1) This invention introduces a trifluoromethyl group into the β-position of the chalcone skeleton for the first time, and combines it with a 2,2-dimethyl-2,3-dihydrobenzofuran structure to construct a novel class of fluorinated chalcone derivatives. The introduction of the trifluoromethyl group enhances the lipophilicity and metabolic stability of the compound, which is beneficial to improving its pharmacokinetic properties.

[0036] (2) The compounds of this invention exhibit significant inhibitory activity against various human tumor cell lines (HGC-27 gastric cancer, HCT-116 colon cancer, MCF-7 breast cancer, DU145 prostate cancer, C-33A cervical cancer, and NCI-H460 large cell lung cancer). Among them, compound (E)-I24 shows significant inhibitory activity against C-33A cervical cancer cells at an IC50 of 100%. 50 The concentration reached 1.36 μM, which was superior to the positive control drug cisplatin (IC50). 50 =7.14μM), exhibiting excellent anti-cervical cancer activity.

[0037] (3) The compounds of the present invention exhibit varying degrees of inhibitory effects on six different types of human tumor cells, and have broad-spectrum anti-tumor activity, especially their inhibitory activity on C-33A cervical cancer and HGC-27 gastric cancer cells. Attached Figure Description

[0038] Figure 1The study investigated the apoptosis-inducing effect of compound (E)-I24 on C-33A cells, including: (a) the effect of different cell death inhibitors on cell viability after 48 h of treatment with C-33A cells alone; (b) the cell survival rate of C-33A cells after 48 h of combined treatment with compound (E)-I24 and the above four inhibitors; (c) the apoptosis status of cells after 18 h of drug treatment by flow cytometry; and (d) the total proportion of apoptotic cells. Figure 2 To demonstrate the inhibitory effect of compound (E)-I24 on tumor growth in vivo, (a) changes in mouse body weight over time, (b) tumor images of mice in each group after administration, (c) changes in tumor volume over time, and (d) weight of tumors removed in each group. Figure 3 H&E staining pathological observation of organ tissues from each group of mice. Detailed Implementation

[0039] Example 1: Synthesis of 2,2-dimethyl-2,3-dihydrobenzofuran-7-ether (B1~B9) Taking the synthesis of 2,2-dimethyl-2,3-dihydrobenzofuran-7-ether (B1) as an example: ; First, add 0.07 g (0.40 mmol) of potassium iodide and 2.76 g (20.0 mmol) of potassium carbonate to 15.00 mL of anhydrous ethanol. Then, add 1.64 g (10.0 mmol) of A while stirring at room temperature. After reacting for 0.5 h, add 2.84 g (20.0 mmol) of iodomethane. 50 o The mixture was stirred at C for 6 h. The reaction progress was monitored by thin-layer chromatography during the reaction. After the reaction was complete, the solvent was removed by rotary evaporation, the solution was dissolved in dichloromethane, allowed to stand, filtered, and the filtrate was collected. After removing the solvent again by rotary evaporation, a small amount of ice water was added, resulting in the precipitation of a brownish-red solid. The solid was air-dried to obtain B1, a brownish-red solid, with a yield of 86.7% and an mp of 42.6–43.7. o C. Molecular formula C 11 H 15 O2, HRMS-ESI m / z calcd for ( [M+H] + ) 179.1067, found 179.1065. Following the method used to prepare compound B1, compounds B2-B9 were prepared, and the results are shown in the table below: ; ; Example 2: Synthesis of 1-(7-alkoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)acetone (C1-C9) Taking the synthesis of 1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl) ethyl ketone (C1) as an example: ; First, 5.86 g (43.80 mmol) of anhydrous zinc chloride and 0.70 g (47.20 mmol) of acetyl chloride were dissolved in 60 mL of 1,2-dichloroethane. After stirring at room temperature for 0.5 h, 6.00 g (33.70 mmol) of compound B1 dissolved in 1,2-dichloroethane was added dropwise. The reaction was monitored by TLC until completion, approximately 10 h. The mixture was extracted with dilute hydrochloric acid, and the lower organic phase was collected. The filtrate was evaporated to dryness and recrystallized from anhydrous ethanol, or purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to give C1, a white needle-like solid, in 56.6% yield, mp 107.5–109.3. o C, mp98.3~101.6 o C. Molecular formula C 13 H 16 O3, HRMS-ESI m / z calcdfor ([M+Na) + ) 243.0997, found 243.0988.

[0040] Following the method used to prepare compound C1, compounds C2-C9 were prepared, and the results are shown in the table below: ; ; Example 3: ( E Synthesis of 3-(4-phenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)prop-2-en-1-one (D1~D28, H2~H9) by( E Taking the synthesis of 3-(4-chlorophenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)prop-2-en-1-one (D1) as an example: ; 0.40 g (1.8 mmol) of C1, 0.17 g (2.4 mmol) of p-chlorobenzaldehyde, 0.05 g (1.4 mmol) of sodium hydroxide, and 2 mL of water were dissolved in 6 mL of anhydrous ethanol. The mixture was stirred at room temperature, and the reaction was monitored by TLC until completion, approximately 4 h. A yellow precipitate formed during the reaction. The precipitate was filtered to obtain a filter cake, which was washed with deionized water and a small amount of methanol. The filter cake was then dried in a vacuum drying oven to obtain D1, a pale yellow solid with a yield of 76.2% and an mp of 141.3–143.5 °C.

[0041] Following the method used to prepare compound D1, compounds D2~D28 and H2~H9 were prepared, and the results are shown in the table below: ; ; ; Example 4: ( E )-3-(4-phenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one (( E )-Ⅰ1~( E Synthesis of )-Ⅰ36) by( E )-3-(4-chlorophenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one (( E Taking the synthesis method of )-I1) as an example: ; Compound D1 0.10 g (0.30 mmol), Togni (1-(trifluoromethyl)-1,2-benzyl-3(1H)-one) 0.14 g (0.44 mmol), and CuI 0.03 g (0.15 mmol) were dissolved in 6 mL of DMF solvent. o The mixture was stirred at C and monitored by TLC until the reaction was complete, approximately 3 days later. After the reaction was complete, the mixture was extracted with deionized water and ethyl acetate. The lower organic phase was collected, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. Column chromatography (petroleum ether:ethyl acetate = 20:1) yielded ( E )-I1, yield 23.9%, pale yellow oily substance.

[0042] ( E )-3-(4-chlorophenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one(( E)-Ⅰ1): Pale yellow oily substance, yield 23.9%. 1 H NMR (600 MHz, CDCl3) δ: 7.41 (s, 1H, H-9), 7.32 (s, 2H, H-4,6), 7.22 (q, J = 8.8 Hz, 4H, H-12,16,13,15), 3.87 (s, 3H, H-23), 2.98 (s, 2H, H-19), 1.51 (s, 6H, H-20,21). 13 C NMR (151 MHz, CDCl3) δ: 189.23, 152.58, 143.82, 135.10, 133.31, 133.25, 129.74, 129.70, 128.86, 128.05, 127.83, 127.22, 121.22, 120.52, 118.50, 110.93, 89.29, 54.93, 41.33, 27.23. Molecular formula C 21 H 18 ClF3O3, HRMS-ESI m / z calcd for [M+Na] + 433.0789, found 433.0796. ; (( E )-Ⅰ2): Pale yellow oily substance, yield 10.9%. 1 H NMR (600 MHz, CDCl3) δ: 7.40 (s, 1H, H-9), 7.33 (d, J = 1.3 Hz, 1H, H-16), 7.30 (s, 1H, H-6), 7.28 (s, 1H,H-12), 7.23 (dt, J = 6.8, 2.1 Hz, 1H, H-15), 7.16 (s, 1H, H-4), 7.14 (d, J =7.9 Hz, 1H, H-14), 3.87 (s, 3H, H-23), 2.98 (s, 2H, H-19), 1.50 (s, 6H, H-20,21). 13 C NMR (151 MHz, CDCl3) δ:188.95, 152.50, 143.81, 133.64, 133.28, 133.01, 129.83, 128.97, 128.93, 128.55, 127.91, 127.18, 126.24, 121.11, 120.47, 110.90, 89.28, 54.94, 41.33, 27.20. Molecular formula C 21 H 18 ClF3O3, HRMS-ESI m / z calcd for [M+H] + 411.0975, found 411.0974. ; (( E )-Ⅰ3): Pale yellow oily substance, yield 8.3%. 1 H NMR (600 MHz, CDCl3) δ: 7.65 (s,1H, H-9), 7.26 ((s, 1H, H-6), 7.25 (s, 1H, H-4), 7.20 (d, J = 3.1 Hz, 1H, H-15), 7.15 (d, J = 7.7 Hz, 1H, H-12), 7.11 (t, J = 7.7 Hz, 1H, H-13), 6.97 (t, J = 7.6 Hz, 1H, H-14), 3.77 (s, 3H, H-23), 2.89 (s, 2H, H-19), 1.41 (s, 6H, H-20,21). 13 C NMR (151 MHz, CDCl3) δ: 189.65, 153.17, 144.49, 133.71, 133.67, 133.63, 133.59, 131.84, 131.44, 131.36, 131.16, 130.92, 130.86, 130.53, 129.34, 129.27, 129.08, 128.12, 127.00, 124.76, 122.94, 121.74, 121.08, 119.30, 111.94, 90.20, 55.84, 42.29, 28.17. Molecular formula C 21 H 18 ClF3O3, HRMS-ESIm / z calcd for [M+H] + 411.0970, found 411.0979. ; (( E )-Ⅰ4): Pale yellow oily substance, yield 11.6%. 1 H NMR (600 MHz, CDCl3) δ 7.61 (s, 1H, H-9), 7.35 (d, J = 1.9 Hz, 1H, H-15), 7.29 (s, 1H, H-6), 7.26 (s, 1H,H-4), 7.17 (d, J = 8.4 Hz, 1H, H-12), 7.03 (dd, J = 8.4, 1.9 Hz, 1H, H-13), 3.85 (s, 3H, H-23), 2.97 (s, 2H, H-19), 1.49 (s, 6H, H-20,21). 13 C NMR (151MHz, CDCl3) δ: 188.31, 152.47, 143.60, 135.31, 133.40, 131.14, 130.88, 130.16, 128.88, 128.36, 127.81, 127.26, 126.46, 120.84, 120.06, 110.92, 89.32, 54.84, 41.27, 27.18. Molecular formula C 21 H 17 Cl2F3O3, HRMS-ESI m / z calcd for [M+H] + 445.0580, found 445.0590. ; (( E )-Ⅰ5): Pale yellow oily substance, yield 10.5%. 1 H NMR (600 MHz, CDCl3) δ: 7.53(s, 1H, H-9), 7.37 (s, 1H, H-6), 7.32 (s, 1H, H-4), 7.23 (td, J= 8.6, 6.5 Hz,1H, H-14), 6.82 – 6.76 (m, 1H, H-13), 6.70 – 6.65 (m, 1H, H-15), 3.87 (s, 3H,H-23), 2.99 (s, 2H, H-19), 1.50 (s, 6H, H-20,21). 13 C NMR (151 MHz, CDCl3) δ: 188.90, 163.71, 162.03, 160.73, 159.05, 152.55, 143.76, 130.12, 130.10, 130.06, 130.03, 127.77, 127.26, 126.50, 126.46, 126.42, 123.75, 121.93, 120.29, 120.11, 118.71, 115.98, 115.95, 115.90, 115.87, 111.07, 111.05, 110.91, 103.35, 103.18, 103.01, 89.33, 54.88, 41.33, 27.21. Molecular formula C 21 H 17 ClF4O3,HRMS-ESI m / z calcd for [M+Na] + 451.0700, found 451.0702. ; (( E )-Ⅰ6): Pale yellow oily substance, yield 15.2%. 1 H NMR (600 MHz, CDCl3) δ 7.41 (s, 1H, H-9), 7.36 (d, J = 8.5 Hz, 2H, H-15,13), 7.32 – 7.29 (m, 2H, H-6,4),7.16 (d, J = 8.5 Hz, 2H, H-12,16), 3.87 (s, 3H, H-23), 2.98 (s, 2H, H-19), 1.50 (s, 6H, H-20,21). 13 C NMR (151 MHz, CDCl3) δ:189.20, 152.61, 143.84, 136.98, 133.40, 133.36, 131.02, 130.13, 129.93, 127.81, 127.23, 123.48, 120.54, 110.93, 89.31, 54.94, 41.33, 27.24. Molecular formula C 21 H 18 BrF3O3, HRMS-ESI m / z calcd for [M+H] + 455.0464, found 455.0474. ; (( E )-Ⅰ7): Pale yellow oily substance, yield 4.6%. 1 H NMR (600 MHz, CDCl3) δ: 7.44 (s, 1H, H-9), 7.38 (d, J = 8.4 Hz, 2H, H-12,14), 7.32 (s, 1H, H-6), 7.30 (s, 1H,H-4), 7.21 (d, J = 7.8 Hz, 1H, H-16), 7.08 (t, J = 7.9 Hz, 1H, H-13), 3.87 (s,3H, H-23), 2.98 (s, 2H, H-19), 1.50 (s, 6H, H-20,21). 13 C NMR (151 MHz, CDCl3) δ: 188.94, 152.49, 143.81, 133.28, 133.25, 133.21, 133.17, 131.83, 131.51, 130.17, 129.97, 129.77, 129.57, 129.20, 127.94, 127.19, 126.62, 122.96, 122.01, 121.67, 120.46, 120.19, 118.83, 110.90, 89.29, 54.96, 41.34, 27.21. Molecular formula C 21 H 18 BrF3O3, HRMS-ESI m / z calcd for [M+H] +455.0464, found 455.0471. ; (( E )-Ⅰ8): Pale yellow oily substance, yield 15.5%. 1 H NMR (600 MHz, CDCl3) δ: 7.65(s, 1H, H-9), 7.51 – 7.47 (m, 1H, H-15), 7.31 (s, 1H, H-6), 7.24 (s, 1H, H-4), 7.21 – 7.19 (m, 1H, H-12), 7.09 – 7.06 (m, 2H, H-13,14), 3.84 (s, 3H, H-23), 2.95 (s, 2H, H-19), 1.47 (s, 6H, H-20,21). 13 C NMR (151 MHz, CDCl3) δ: 189.54, 153.14, 144.48, 135.88, 135.84, 135.80, 135.76, 133.26, 132.49, 131.39, 131.19, 131.00, 130.85, 130.72, 129.14, 128.08, 127.59, 124.72, 123.55, 122.90, 121.98, 121.15, 119.26, 111.86, 90.20, 55.90, 42.27, 28.16. Molecular formula C 21 H 18 BrF3O3, HRMS-ESI m / z calcd for [M+Na] + 477.0289, found 477.0291. ; (( E )-Ⅰ9): Pale yellow oily substance, yield 19.3%. 1 H NMR (600 MHz, CDCl3) δ : 7.42(s, 1H, H-9), 7.33 (s, 2H, H-6,4), 7.29 (dd, J = 8.6, 5.4 Hz, 2H, H-12,16),6.92 (t, J= 8.6 Hz, 2H, H-13,15), 3.86 (s, 3H, H-23), 2.98 (s, 2H, H-19), 1.50 (s, 6H, H-20,21). 13 C NMR (151 MHz, CDCl3) δ: 189.44, 163.27, 161.60, 152.51, 143.79, 133.53, 133.49, 133.45, 133.41, 130.60, 130.54, 128.56, 128.19, 127.99, 127.91, 127.79, 127.45, 127.43, 127.20, 120.49, 115.03, 114.89, 110.96, 89.25, 54.92, 41.34, 27.22. Molecular formula C 21 H 18 F4O3, HRMS-ESI m / z calcdfor [M+H] + 395.1270, found 395.1273. ; (( E )-Ⅰ10): Pale yellow oily substance, yield 21.4%. 1 H NMR (600 MHz, CDCl3) δ: 7.41(s, 1H, H-9), 7.36 – 7.29 (m, 2H, H-12,13), 7.21 (td, J = 8.0, 5.9 Hz, 1H, H-6), 7.08 (d, J = 7.8 Hz, 1H, H-14), 7.02 – 6.93 (m, 2H, H-4,16), 3.87 (s, 3H,H-23), 2.98 (s, 2H, H-19), 1.50 (s, 6H, H-20,21). 13 C NMR (151 MHz, CDCl3) δ:189.00, 162.35, 160.71, 152.54, 143.81, 133.34, 129.78, 129.58, 129.35, 127.89 (s), 127.20, 124.28, 123.87, 122.05, 120.50, 120.23, 118.41, 116.03, 115.89, 115.22, 115.07, 110.94, 89.28, 54.93, 41.33, 27.21. Molecular formula C 21 H 18 F4O3,HRMS-ESI m / z calcd for [M+H] + 395.1270, found 395.1272. ; (( E )-Ⅰ11): Pale yellow oily substance, yield 19.3%. 1 H NMR (600 MHz, CDCl3) δ : 7.62(s, 1H, H-9), 7.37 (s, 1H, H-6), 7.33 (s, 1H, H-4), 7.24 (dd, J = 8.2, 2.1 Hz,1H, H-14), 7.22 (d, J = 7.6 Hz, 1H, H-12), 7.04 – 6.99 (m, 1H, H-15), 6.92 (t, J = 7.6 Hz, 1H, H-13), 3.86 (s, 3H, H-23), 2.97 (s, 2H, H-19), 1.49 (s, 6H,H-20,21). 13 C NMR (151 MHz, CDCl3) δ: 189.00, 160.34, 158.67, 152.33, 143.65, 130.91, 130.86, 130.20, 130.00, 129.80, 129.60, 129.03, 127.93, 127.75, 127.71, 127.67, 127.15, 123.36, 123.34, 120.28, 119.65, 119.57, 114.59, 114.45, 110.93, 89.21, 54.85, 41.33, 27.18. Molecular formula C21 H 18 F4O3, HRMS-ESI m / z calcdfor [M+H] + 395.1270, found 395.1273. ; (( E )-Ⅰ12): Pale yellow oily substance, yield 21.5%. 1 H NMR (600 MHz, CDCl3) δ: 7.96(d, J = 16.0 Hz, 1H, H-12), 7.79 (d, J = 16.0 Hz, 1H, H-13), 7.54 (s, 1H, H-6), 7.53 (s, 1H, H-4), 7.27 (d, J = 2.2 Hz, 1H, H-15), 7.10 – 7.06 (m, 1H, H-13), 3.95 (s, 3H, H-23), 3.11 (s, 2H, H-19), 1.56 (s, 6H, H-20,21). 13 C NMR (151MHz, CDCl3) δ: 187.43, 161.84, 160.15, 151.18, 143.71, 135.46, 135.43, 132.32, 130.36, 129.45, 129.38, 127.91, 127.82, 126.83, 125.07, 125.05, 121.56, 121.47, 118.63, 113.88, 113.72, 110.65, 88.73, 54.97, 41.73, 27.26. Molecular formula C 21 H 17 F5O3, HRMS-ESI m / z calcd for [M+H] + 413.1176, found 413.1173. ; (( E )-Ⅰ13): Pale yellow oily substance, yield 51.3%. 1 H NMR (600 MHz, CDCl3) δ: 7.44(s, 1H, H-9), 7.38 (s, 1H, H-6), 7.30 (s, 1H, H-4), 7.23 (d, J = 8.6 Hz, 2H,H-12,16), 6.74 (d, J = 8.7 Hz, 2H, H-13,15), 3.86 (s, 3H, H-30), 3.75 (s, 3H,H-23), 2.98 (s, 2H, H-19), 1.50 (s, 6H, H-20,21). 13 C NMR (151 MHz, CDCl3) δ: 190.12, 159.91, 152.27, 143.71, 134.38, 134.35, 130.46, 129.39, 128.21, 127.12, 125.92, 125.73, 125.53, 125.33, 123.73, 120.49, 113.16, 111.01, 89.13, 54.89, 54.25, 41.38, 27.23. Molecular formula C 22 H 21 F3O4, HRMS-ESI m / z calcd for [M+H] + 407.1465, found 407.1474. ; (( E )-Ⅰ14): Pale yellow oily substance, yield 9.0%. 1 H NMR (600 MHz, CDCl3) δ: 7.42(s, 1H, H-9), 7.37 – 7.34 (m, 2H, H-15,6), 7.16 – 7.13 (m, 1H, H-12), 6.88(d, J = 7.7 Hz, 1H, H-16), 6.82 – 6.79 (m, 2H, H-14,4), 3.85 (s, 3H, H-30), 3.65 (s, 3H, H-23), 2.97 (s, 2H, H-19), 1.50 (s, 6H, H-20,21). 13 C NMR (151MHz, CDCl3) δ:189.54, 158.50, 152.30, 143.71, 134.78, 134.75, 134.71, 134.67, 132.48, 128.73, 128.47, 128.27, 128.18, 127.13, 121.13, 120.45, 115.25, 113.26, 110.89, 89.18, 54.90, 54.08, 41.35, 27.20. Molecular formula C 22 H 21 F3O4, HRMS-ESI m / z calcd for [M+Na] + 429.1284, found 429.1294. ; (( E )-Ⅰ15): Pale yellow oily substance, yield 49.9%. 1 H NMR (600 MHz, CDCl3) δ 7.74 (s, 1H, H-9), 7.33 (d, J = 3.1 Hz, 2H, H-12,6), 7.21 (dd, J = 11.3, 4.4 Hz, 1H,H-14), 7.14 (d, J = 7.7 Hz, 1H, H-15), 6.79 (d, J = 8.3 Hz, 1H, H-4), 6.71 (t, J = 7.5 Hz, 1H, H-13), 3.83 (s, 3H, H-30), 3.82 (s, 3H, H-23), 2.94 (s, 2H, H-19), 1.47 (s, 6H, H-20,21). 13 C NMR (151 MHz, CDCl3) δ:189.69, 156.33, 151.82, 143.35, 131.59, 131.55, 131.51, 131.47, 130.51, 130.43, 129.15, 128.35, 127.82, 127.58, 127.38, 127.19, 126.90, 120.78, 120.01, 119.56, 111.15, 109.36, 88.94, 54.74, 54.32, 41.40, 27.17. Molecular formula C 22 H 21 F3O4, HRMS-ESI m / z calcdfor [M+H] + 407.1465, found 407.1475. ; (( E )-Ⅰ16): Pale yellow oily substance, yield 62.1%. 1 H NMR (600 MHz, CDCl3) δ: 7.44(s, 1H, H-9), 7.37 (s, 1H, H-6), 7.29 (d, J = 1.2 Hz, 1H, H-4), 6.52 (s, 2H,H-12,16), 3.85 (s, 3H, H-23), 3.79 (s, 3H, H-35), 3.66 (s, 6H, H-37,39), 2.99(s, 2H, H-19), 1.51 (s, 6H, H-20,21). 13 C NMR (151 MHz, CDCl3) δ: 190.83, 153.45, 153.37, 153.05, 144.86, 139.54, 135.74, 135.71, 135.67, 135.63, 129.37, 128.71, 128.51, 128.32, 128.27, 128.04, 127.51, 126.54, 123.36, 122.31, 121.43, 111.78, 107.10, 90.30, 60.89, 56.37, 56.00, 55.93, 42.40, 28.23. Molecular formula C 24 H 25 F3O6, HRMS-ESI m / zcalcd for [M+Na] + 489.1501, found 489.1505. ; (( E )-Ⅰ17): Pale yellow oily substance, yield 45.2%. 1 H NMR (600 MHz, CDCl3) δ : 7.62(s, 1H, H-9), 7.37 (s, 1H, H-6), 7.33 (s, 1H, H-4), 6.88 (d, J = 8.8 Hz, 1H,H-12), 6.41 (d, J = 8.8 Hz, 1H, H-13), 3.93 (s, 3H, H-23), 3.85 (s, 3H, H-35), 3.78 (d, J = 4.1 Hz, 6H, H-39,44), 2.95 (s, 2H, H-19), 1.48 (s, 6H, H-20,21). 13 C NMR (151 MHz, CDCl3) δ: 190.02, 154.42, 151.95, 151.51, 143.54, 140.78, 130.47, 130.43, 128.39, 126.93, 126.78, 126.56, 126.36, 124.37, 123.85, 122.55, 120.73, 120.21, 118.52, 118.34, 111.01, 106.13, 89.01, 60.32, 59.79, 54.87, 54.85, 41.40, 27.18. Molecular formula C 24 H 25 F3O6, HRMS-ESI m / z calcd for [M+H] + 467.1676, found 467.1684. ; (( E )-Ⅰ18): Pale yellow oily substance, yield 40.6%. 1 H NMR (600 MHz, CDCl3) δ: 7.43(s, 1H, H-9), 7.37 (s, 1H, H-6), 7.30 (s, 1H, H-4), 7.21 (d, J = 8.7 Hz, 2H,H-12,16), 6.73 – 6.70 (m, 2H, H-13,15), 3.98 – 3.94 (m, 2H, H-30), 3.86 (d, J = 1.8 Hz, 3H, H-23), 2.97 (s, 2H, H-19), 1.50 (d, J = 1.9 Hz, 6H, H-20,21),1.35 (dt, J = 6.9, 3.4 Hz, 3H, H-31). 13 C NMR (151 MHz, CDCl3) δ : 190.17, 159.34, 152.24, 143.69, 134.48, 134.44, 130.47, 129.37, 128.23, 127.11, 125.75, 125.55, 125.36, 125.16, 123.54, 120.48, 113.60, 111.02, 89.11, 62.50, 54.88, 41.38, 27.22, 13.62. Molecular formula C 23 H 23 F3O4, HRMS-ESI m / z calcd for [M+H] + 421.1621, found 421.1632. ; (( E )-Ⅰ19): Pale yellow oily substance, yield 11.7%. 1 H NMR (600 MHz, CDCl3) δ: 7.42(s, 1H, H-9), 7.35 (s, 2H, H-6,4), 7.13 (dd, J = 8.9, 7.8 Hz, 1H, H-13), 6.86(d, J = 7.7 Hz, 1H, H-12), 6.80 – 6.77 (m, 2H, H-14,16), 3.85 (s, 3H, H-23), 3.82 (dd, J= 11.9, 4.9 Hz, 2H, H-30), 2.97 (s, 2H, H-19), 1.50 (s, 6H, H-20,21), 1.31 (t, J = 7.0 Hz, 3H, H-31). 13 C NMR (151 MHz, CDCl3) δ: 189.58, 157.85, 152.28, 143.71, 134.85, 134.82, 132.43, 128.71, 128.33, 128.20, 128.13, 127.13, 121.03, 120.45, 115.97, 113.73, 110.90, 89.17, 62.36, 54.90, 41.36, 27.19, 13.61. Molecular formula C 23 H 23 F3O4, HRMS-ESI m / z calcd for [M+Na] + 443.1446, found 443.1450. ; (( E )-Ⅰ20): Pale yellow oily substance, yield 58.6%. 1 H NMR (600 MHz, CDCl3) δ 7.78 (s, 1H, H-9), 7.33 (d, J = 4.2 Hz, 2H, H-12, 6), 7.21 – 7.16 (m, 1H, H-14),7.13 (d, J = 7.6 Hz, 1H, H-15), 6.77 (d, J = 8.3 Hz, 1H, H-13), 6.68 (t, J = 7.5Hz, 1H, H-13), 4.07 (q, J = 7.0 Hz, 2H, H-30), 3.82 (s, 3H, H-23), 2.93 (s,2H, H-19), 1.47 (s, 6H, H-20,21), 1.46 (d, J = 7.0 Hz, 3H, H-31). 13 C NMR (151MHz, CDCl3) δ:189.83, 155.79, 151.83, 143.35, 131.74, 131.70, 131.65, 131.62, 130.36, 129.08, 128.36, 127.54, 127.35, 127.15, 126.89, 120.89, 120.04, 119.39, 111.19, 110.30, 88.93, 62.92, 54.71, 41.38, 27.16, 13.75. Molecular formula C 23 H 23 F3O4, HRMS-ESI m / z calcd for [M+Na] + 443.1446, found 443.1449. ; (( E )-Ⅰ21): Pale yellow oily substance, yield 19.8%. 1 H NMR (600 MHz, CDCl3) δ 7.43 (s, 1H, H-9), 7.35 (d, J = 10.7 Hz, 2H, H-12,16), 7.18 (d, J = 8.1 Hz, 2H, H-13,15), 7.03 (d, J = 8.0 Hz, 2H, H-4,6), 3.86 (s, 3H, H-23), 2.97 (s, 2H, H-19), 2.27 (s, 3H, H-24), 1.50 (s, 6H, H-20,21). 13 C NMR (151 MHz, CDCl3) δ 189.87, 152.25, 143.68, 139.40, 134.79, 134.75, 128.63, 128.46, 128.39, 128.16, 127.34, 127.14, 127.09, 126.94, 126.75, 124.26, 122.44, 120.62, 120.49, 118.80, 110.99, 89.12, 54.88, 41.37, 27.21, 20.31. Molecular formula C 22 H 21 F3O3,HRMS-ESI m / z calcd for [M+H]+ 391.1516, found 391.1526. ; (( E )-Ⅰ22): Pale yellow oily substance, yield 10.7%. 1 H NMR (600 MHz, CDCl3) δ: 7.40 (s, 1H, H-9), 7.36 (d, J = 1.1 Hz, 1H, H-12), 7.34 (s, 1H, H-6), 7.09 (dd, J =6.6, 3.8 Hz, 3H, H-13,14,15), 7.07 (s, 1H, H-4), 3.85 (s, 3H, H-23), 2.96 (s,2H, H-19), 2.22 (s, 3H, H-24), 1.49 (s, 6H, H-20,21). 13 C NMR (151 MHz, CDCl3) δ: 189.68, 152.17, 143.64, 137.30, 135.14, 135.10, 135.06, 135.02, 131.17, 129.75, 129.48, 128.21, 128.00, 127.81, 127.57, 127.05, 125.46, 120.39, 110.95, 89.10, 54.87, 41.35, 27.18, 20.17. Molecular formula C 22 H 21 F3O3, HRMS-ESI m / z calcdfor [M+H] + 391.1521, found 391.1524. ; (( E )-Ⅰ23): Pale yellow oily substance, yield 11.7%. 1 H NMR (600 MHz, CDCl3) δ : 7.62(s, 1H, H-9), 7.26 – 7.22 (m, 2H, H-12,6), 7.10 (dd, J = 12.0, 5.5 Hz, 3H, H-13,15 4), 6.93 (t, J= 7.0 Hz, 1H, H-14), 3.81 (s, 3H, H-23), 2.92 (s, 2H, H-19), 2.38 (s, 3H, H-24), 1.46 (s, 6H, H-20,21). 13 C NMR (151 MHz, CDCl3) δ: 189.29, 151.93, 143.43, 135.46, 134.31, 134.27, 130.70, 129.06, 128.79, 128.40, 128.03, 126.82, 125.13, 124.07, 122.25, 120.43, 119.97, 118.61, 110.91, 89.01, 54.79, 41.32, 27.15, 18.81. Molecular formula C 22 H 21 F3O3, HRMS-ESI m / z calcd for [M+Na] + 413.1340, found 413.1341. ; (( E )-Ⅰ24): Pale yellow oily substance, yield 26.0%. Purity: 94.86% (HPLC). 1 H NMR (600 MHz, CDCl3) δ : 8.11 (s, 1H, H-9), 8.10 (s, 1H, H-6), 7.48 (d, J = 8.7 Hz,2H, H-13,15), 7.41 (d, J = 7.6 Hz, 2H, H-12,16), 7.30 (s, 1H, H-4), 3.88 (s,3H, H-23), 2.98 (s, 2H, H-19), 1.50 (s, 6H, H-20,21). 13 C NMR (151 MHz, CDCl3) δ:188.29, 152.97, 147.18, 143.97, 137.45, 132.02, 131.98, 131.94, 131.90, 129.18, 129.13, 127.53, 127.38, 127.17, 122.93, 122.51, 121.71, 120.54, 119.89, 119.51, 118.07, 110.91, 89.50, 54.98, 41.28, 27.23, 27.21. Molecular formula C 21 H 18 F3NO5, HRMS-ESI m / z calcd for [M+H] + 422.1210, found 422.1219. ; (( E )-Ⅰ25): Pale yellow oily substance, yield 4.6%. 1 H NMR (600 MHz, CDCl3) δ: 8.17(s, 1H, H-9), 8.11 (dd, J = 8.2, 0.8 Hz, 1H, H-13), 7.61 (d, J = 7.8 Hz, 1H, H-14), 7.42 (dd, J = 9.8, 5.9 Hz, 3H, H-12,16,6), 7.31 (s, 1H, H-4), 3.87 (s,3H, H-23), 2.97 (s, 2H, H-19), 1.49 (s, 6H, H-20,21). 13 C NMR (151 MHz, CDCl3) δ : 188.42, 152.84, 147.26, 143.97, 133.68, 132.89, 132.08, 132.04, 131.93, 131.75, 131.54, 131.32, 128.89, 127.71, 127.34, 123.62, 123.41, 123.31, 121.80, 120.50, 119.97, 118.15, 110.89, 89.47, 55.00, 41.29, 27.20. Molecular formula C 21 H 18 F3NO5, HRMS-ESIm / z calcd for [M+H] + 422.1215, found 422.1218. ; (( E )-Ⅰ26): Pale yellow oily substance, yield 21.1%. 1 H NMR (600 MHz, CDCl3) δ : 7.33(s, 1H, H-9), 7.30 (s, 1H, H-14), 7.21 (s, 1H, H-6), 7.20 (s, 1H, H-4), 7.18– 7.10 (m, 4H, H-12,13,15,16), 3.77 (s, 3H, H-23), 2.88 (s, 2H, H-19), 1.40 (s, 6H, H-20,21). 13 C NMR (151 MHz, CDCl3) δ: 189.57, 152.31, 143.69, 134.84, 134.80, 131.24, 128.98, 128.55, 128.06, 127.71, 127.10, 120.51, 110.99, 89.15, 54.89, 41.34, 27.20. Molecular formula C 21 H 19 F3O3, HRMS-ESI m / z calcd for [M+H] + 377.1365, found 377.1369. ; (( E )-Ⅰ27): Pale yellow oily substance, yield 14.1%. 1 H NMR (600 MHz, CDCl3) δ: 7.48(s, 1H, H-9), 7.45 – 7.35 (m, 2H, H-34,6), 7.33 (s, 1H, H-4), 7.17 (dd, J =5.1, 3.0 Hz, 1H, H-32), 6.93 (d, J= 5.1 Hz, 1H, H-31), 3.89 (s, 3H, H-23), 3.01 (s, 2H, H-19), 1.52 (s, 6H, H-20,21). 13 C NMR (151 MHz, CDCl3) δ: 189.72, 152.52, 143.87, 132.87, 128.49, 128.21, 128.18, 128.14, 128.10, 128.06, 127.23, 126.53, 125.75, 122.45, 122.16, 120.68, 110.87, 89.25, 54.95, 41.39, 27.25. Molecular formula C 19 H 17 F3O3S, HRMS-ESI m / z calcd for [M+H] + 383.0929, found 383.0930. ; (( E )-Ⅰ28): Pale yellow oily substance, yield 13.0%. 1 H NMR (400 MHz, CDCl3) δ: 7.54 (s, 1H, H-9), 7.50 (d, J = 7.6 Hz, 1H, H-14), 7.46 (s, 1H, H-16), 7.43 (s, 1H,H-6), 7.37 (s, 1H, H-12), 7.33 (d, J = 7.5 Hz, 1H, H-13), 7.29 (s, 1H, H-4), 3.84 (s, 3H, H-23), 2.95 (s, 2H, H-19), 1.48 (s, 6H, H-20,21). 13 C NMR (101MHz, CDCl3) δ:189.79, 153.58, 144.86, 134.31, 133.16, 132.15, 131.66, 131.35, 131.01, 129.29, 128.88, 128.27, 126.40, 124.86, 123.45, 122.15, 121.43, 120.73, 112.00, 90.30, 55.93, 42.30, 28.12. Molecular formula C 22 H 18 O3F6, HRMS-ESI m / z calcdfor [M+H] + 445.1233, found 445.1238. ; (( E )-Ⅰ29): Pale yellow oily substance, yield 21.0%. 1 H NMR (600 MHz, CDCl3) δ 8.10(d, J = 8.8 Hz, 2H, H-13,15), 7.47 (d, J = 8.8 Hz, 2H, H-12,16), 7.41 (s, 1H,H-9), 7.38 (s, 1H, H-6), 7.30 (s, 1H, H-4), 4.11 (q, J = 7.0 Hz, 2H, H-23),2.97 (s, 2H, H-19), 1.50 (s, 6H, H-20,21), 1.42 (t, J = 5.3 Hz, 3H, H-24). 13 CNMR (151 MHz, CDCl3) δ : 189.33, 154.33, 148.19, 144.15, 138.49, 133.69, 133.49, 133.29, 133.08, 132.95, 132.92, 132.88, 132.84, 130.15, 128.68, 128.46, 124.47, 123.93, 122.74, 121.21, 120.92, 119.10, 90.30, 64.60, 42.37, 28.26, 14.63. Molecular formula C 22 H 20 NO5F3, HRMS-ESIm / z calcd for [M+H] + 436.1366, found 436.1376. ; (( E )-Ⅰ30): Pale yellow oily substance, yield 11.6%. 1 H NMR (600 MHz, CDCl3) δ: 8.10(d, J = 8.8 Hz, 2H, H-13,15), 7.48 (d, J = 8.8 Hz, 2H, H-12,16), 7.41 (s, 1H,H-9), 7.38 (s, 1H, H-6), 7.29 (s, 1H, H-4), 3.99 (t, J = 6.8 Hz, 2H, H-23), 2.97 (s, 2H, H-19), 1.81 (dd, J = 14.4, 7.1 Hz, 2H, H-24), 1.50 (s, 6H, H-20,21), 1.01 (t, J = 7.4 Hz, 3H, H-25). 13 C NMR (151 MHz, CDCl3) δ: 189.33, 154.46, 148.18, 144.32, 138.51, 133.70, 133.50, 133.30, 133.10, 132.93, 132.90, 132.86, 132.82, 130.15, 128.71, 128.42, 124.47, 123.93, 122.74, 121.22, 120.92, 119.10, 113.85, 90.22, 70.69, 42.36, 28.25, 22.25, 10.36. Molecular formula C 23 H 22 NO5F3, HRMS-ESI m / z calcd for [M+H] + 450.1523, found 450.1529. ; (( E )-Ⅰ31): Pale yellow oily substance, yield 14.4%. 1H NMR (600 MHz, CDCl3) δ: 8.09(d, J = 8.7 Hz, 2H, H-13,15), 7.47 (d, J = 8.7 Hz, 2H, H-12,16), 7.41 (s, 1H,H-9), 7.35 (s, 1H, H-6), 7.33 (s, 1H, H-4), 4.55 (dt, J = 12.2, 6.1 Hz, 1H, H-23), 2.97 (s, 2H, H-19), 1.49 (s, 6H, H-20,21), 1.30 (s, 3H, H-24), 1.29 (s,3H, H-25). 13 C NMR (151 MHz, CDCl3) δ: 189.34, 155.36, 148.17, 142.81, 138.51, 133.68, 133.48, 133.27, 133.07, 132.94, 132.90, 132.86, 132.82, 130.17, 129.30, 128.42, 124.56, 123.90, 122.74, 120.99, 120.92, 119.10, 117.27, 90.07, 71.81, 42.35, 28.22, 21.92. Molecular formula C 23 H 22 NO5F3, HRMS-ESI m / z calcd for [M+H] + 450.1523, found 450.1531. ; (( E )-Ⅰ32): Pale yellow oily substance, yield 24.6%. 1 H NMR (600 MHz, CDCl3) δ: 8.09(d, J = 8.8 Hz, 2H, H-13,15), 7.48 (d, J = 8.8 Hz, 2H, H-12,16), 7.41 (s, 1H,H-9), 7.34 (s, 1H, H-6), 7.33 (s, 1H, H-4), 4.30 (dd, J= 12.2, 6.1 Hz, 1H, H-23), 2.96 (s, 2H, H-19), 1.75 – 1.69 (m, 1H, H-24), 1.57 (dd, J = 14.2, 7.0Hz, 1H, H-24), 1.48 (d, J = 3.5 Hz, 6H, H-20,21), 1.24 (d, J = 6.1 Hz, 3H, H-25), 0.93 (t, J = 7.5 Hz, 3H, H-26). 13 C NMR (151 MHz, CDCl3) δ: 189.33, 155.41, 148.16, 143.14, 138.53, 133.68, 133.48, 133.28, 133.08, 132.93, 132.89, 132.85, 132.82, 130.17, 128.40, 124.57, 123.89, 120.94, 119.10, 117.43, 90.00, 42.33, 28.98, 28.20, 28.19, 19.28, 9.79. Molecular formula C 24 H 24 NO5F3, HRMS-ESI m / z calcd for [M+H] + 464.1685, found 464.1690. ; (( E )-Ⅰ33): Pale yellow oily substance, yield 15.8%. 1 H NMR (600 MHz, CDCl3) δ: 8.10(d, J = 8.8 Hz, 2H, H-13,15), 7.48 (d, J = 8.7 Hz, 2H, H-12,16), 7.41 (s, 1H,H-9), 7.38 (s, 1H, H-6), 7.29 (s, 1H, H-4), 4.03 (s, 2H, H-23), 2.96 (s, 2H,H-19), 1.79 – 1.74 (m, 2H, H-24), 1.49 (s, 6H, H-20,21), 1.46 (dd, J= 15.0,7.5 Hz, 2H, H-25), 0.96 (t, J = 7.4 Hz, 3H, H-26). 13 C NMR (151 MHz, CDCl3) δ: 189.34, 154.47, 148.18, 144.35, 138.50, 133.70, 133.50, 133.29, 133.09, 132.93, 132.89, 132.85, 132.81, 130.15, 128.70, 128.41, 124.56, 123.93, 122.74, 121.20, 120.92, 119.10, 113.84, 90.21, 68.96, 42.36, 30.97, 28.24, 19.10, 13.83. Molecular formula C 24 H 24 NO5F3, HRMS-ESI m / z calcd for [M+H] + 464.1685, found 464.1689. ; (( E )-Ⅰ34): Pale yellow oily substance, yield 19.1%. 1 H NMR (600 MHz, CDCl3) δ: 8.09(d, J = 8.7 Hz, 2H, H-13,15), 7.47 (d, J = 8.8 Hz, 2H, H-12,16), 7.41 (s, 1H,H-9), 7.37 (s, 1H, H-6), 7.29 (s, 1H, H-4), 4.02 (t, J = 6.9 Hz, 2H, H-23),2.96 (s, 2H, H-19), 1.81 – 1.76 (m, 2H, H-24), 1.49 (s, 6H, H-20,21), 1.40(ddd, J = 10.5, 7.2, 4.6 Hz, 4H, H-25,26), 0.91 (t, J = 6.9 Hz, 3H, H-27). 13 CNMR (151 MHz, CDCl3) δ189.33, 154.46, 148.17, 144.32, 138.50, 133.67, 133.47, 133.27, 133.07, 132.94, 132.91, 132.87, 132.83, 130.16, 128.71, 128.42, 124.57, 123.92, 122.75, 121.20, 120.92, 119.10, 113.87, 90.21, 69.26, 42.35, 28.62, 28.23, 27.97, 22.43, 22.41, 22.40, 13.98. Molecular formula C 25 H 26 NO5F3, HRMS-ESI m / z calcd for [M+H] + 478.1841, found 478.1843. ; (( E )-Ⅰ35): Pale yellow oily substance, yield 18.6%. 1 H NMR (600 MHz, CDCl3) δ: 8.09(d, J = 8.8 Hz, 2H, H-13,15), 7.48 (d, J = 8.7 Hz, 2H, H-12,16), 7.41 (s, 1H,H-9), 7.34 (s, 1H, H-6), 7.34 – 7.33 (m, 1H, H-4), 4.37 (dd, J = 12.3, 6.1 Hz,1H, H-23), 2.97 (s, 2H, H-19), 1.52 (dd, J = 10.2, 5.8 Hz, 2H, H-24), 1.48 (d, J = 3.5 Hz, 6H, H-20,21), 1.25 (s, 3H, H-27), 1.25 (s, 2H, H-25), 0.90 (t, J =7.3 Hz, 3H, H-26). 13 C NMR (151 MHz, CDCl3) δ: 189.34, 155.40, 148.17, 143.15, 138.52, 133.71, 133.51, 133.30, 133.10, 132.90, 132.86, 132.82, 132.78, 130.16, 129.33, 128.41, 124.56, 123.90, 120.91, 119.10, 117.43, 89.99, 75.72, 42.34, 38.39, 28.22, 28.20, 19.77, 18.72, 13.96. Molecular formula C 25 H 26 NO5F3, HRMS-ESI m / z calcd for [M+H] + 478.1841, found 478.1846. ; (( E )-Ⅰ36): Pale yellow oily substance, yield 19.5%. 1 H NMR (600 MHz, CDCl3) δ: 8.09(d, J = 8.8 Hz, 2H, H-13,15), 7.47 (d, J = 8.7 Hz, 2H, H-12,16), 7.41 (s, 1H,H-9), 7.34 (s, 1H, H-6), 7.33 (s, 1H, H-4), 4.11 (p, J = 5.9 Hz, 1H, H-23), 2.97 (s, 2H, H-19), 1.63 (ddd, J = 15.0, 13.8, 7.3 Hz, 4H, H-24,26), 1.48 (s,6H, H-20,21), 0.91 (t, J = 7.4 Hz, 6H, H-25,27). 13 C NMR (151 MHz, CDCl3) δ:189.33, 155.39, 148.16, 143.69, 138.53, 133.72, 133.52, 133.32, 133.12, 132.90, 132.86, 132.82, 132.78, 130.16, 129.38, 128.39, 124.47, 123.89, 122.75, 120.92, 120.80, 119.10, 117.70, 89.93, 82.54, 42.34, 28.19, 26.22, 9.63. Molecular formula C 25 H 26 NO5F3, HRMS-ESI m / z calcd for [M+H] + 478.1841, found 478.1844. Example 5 Assay of the antitumor activity of 3-aryl-1-(2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-trifluoromethylpropenone derivatives 1. Mechanism of antitumor activity The MTT assay was used in this experiment. Thirty-six target compounds ((E)-Ⅰ1 to (E)-Ⅰ36) were dissolved in DMSO and then diluted with culture medium to a series of concentrations of 100, 50, 25, 12.5, 6.25, and 3.125 (1.563, 0.781, and 0.391) μM for later use. IC50 50 Calculation of IC50 values: A curve was fitted to the logarithm of drug concentration and the cell inhibition rate to calculate the IC50 of the target compound against different tumor cells and normal cells. 50 Each experimental group was measured in parallel three times.

[0043] The antitumor activity of this series of compounds was determined by the MTT assay, and the inhibition rates against six different human tumor cell lines and one human normal cell line are shown in the table below: Table 1. In vitro antiproliferative activity (IC50) of the target compounds against different cell lines 50 (μM) ; Using the MTT assay, the 36 target compounds synthesized all exhibited varying degrees of inhibitory activity against six different tumor cell types, indicating that the target compounds possess broad-spectrum antitumor activity. Overall, they showed the best in vitro antitumor activity against C-33A and HGC-27 cells, with compound (…) being the most effective. E )-Ⅰ24 showed the best activity, and it was effective against IC50 in C-33A cells. 50The value was 1.36 ± 0.02 μM, which was superior to the positive control drug DDP (IC50). 50 =7.14±0.3μM). Furthermore, among all tumor cells tested, this series of compounds exhibited the best inhibitory activity against C-33A cells; therefore, the compounds of this invention have potential significance for inhibiting tumor proliferation.

[0044] Example 6 Determination of compounds ( E The antitumor activity mechanism of C-33A cells was investigated using the MTT assay. C-33A cells in logarithmic growth phase were seeded at an appropriate density into 96-well plates and incubated at 37°C. o After culturing in a 5% CO2 incubator for 24 h, cells were treated with 100, 50, 25, 12.5, 6.25, 3.125, 1.563, 0.781, and 0.391 μM of the drug in well plates at 0, 12, 24, and 36 h. After adding MTT, the OD values ​​of different concentration groups were measured using a microplate reader. The data were analyzed to calculate cell viability. Subsequently, cells treated with 0, 0.5, 1, 2, and 5 μM of the drug were photographed under a fluorescence inverted microscope, and cell morphology was observed and compared at 10× and 20× magnification.

[0045] Table 2. Compounds at different concentrations and times ( E )-I24's in vitro antiproliferative activity against C-33A cells IC50 50 Value (μM) ; Experimental results showed that at the same time point, cell viability decreased gradually with increasing drug concentration; at the same concentration, the antiproliferative activity of the drug gradually increased with prolonged treatment time, which also confirmed the activity of the compound (…). E The antiproliferative effect of )-I24 is typically concentration- and time-dependent.

[0046] Example 7 Preliminary analysis of cell death was conducted using inhibitors of four cell death pathways: Ferrostatin-1, the caspase inhibitor Z-VAD-FMK, Spautin-1 (an autophagy inhibitor), and Necrostatin-1 (a TNF-alpha inhibitor). Cell viability was assessed after pretreatment with these inhibitors at safe concentrations (10 μM) for 48 h. Subsequently, C-33A cells were seeded at appropriate densities in 96-well plates at a concentration of 2 μM of the target compound (E)-Ⅰ24 and cultured at 37 °C in a 5% CO2 incubator for 24 h. After incubation, the cells were incubated with the four inhibitors, the four drug-treated inhibitors, or only complete culture medium. Cell viability was determined using the MTT assay after incubation. Cell death was observed and plotted, with each experiment performed in triplicate.

[0047] The results showed that, compared with other inhibitors, Z-VAD-FMK pretreatment partially attenuated the antiproliferative effect of (E)-I24, while the other inhibitors did not show significant antagonistic effects. This result suggests that compound (E)-I24 may exert its antitumor activity by inducing apoptosis. To further verify this hypothesis, we used Annexin V-FITC / PI double staining combined with flow cytometry to detect and analyze the apoptosis rate.

[0048] Annexin V-FITC / PI double-stained cells were analyzed by flow cytometry to quantitatively detect the apoptosis rate induced by compound (E)-I24. Drug concentration gradients of 0.5, 1, and 2 μM and a blank control group were set up. The results showed that ( Figure 1 After 18 hours of drug treatment, the apoptotic proportion of C-33A cells (Q2+Q3) increased in a dose-dependent manner. Specifically, the proportion of apoptotic cells increased from 14.96% to 35.20%. With increasing drug concentration, the early and late apoptosis rates and the total apoptosis rate of C-33A cells in each group increased significantly; the number of normal cells decreased significantly with increasing drug concentration.

[0049] These results indicate that compound (E)-I24 can induce apoptosis.

[0050] Example 8 After culturing the cells to a suitable inoculation state, the cell concentration was adjusted to 2 × 10⁷ cells / mL, and 2 × 10⁶ cells were subcutaneously injected into each mouse. The first observation was conducted on day 7 post-inoculation, followed by observations every 2 days; when tumor growth approached the grouping criteria, observations and measurements were taken daily. Once the tumor model was successfully established, the mice in each group were weighed, tumor volume was measured, and they were randomly assigned to different groups on the same day (grouping details are shown in Table 3-3).

[0051] Table 3 Animal Experiment Grouping ; Note: ip: intraperitoneal administration.

[0052] Following treatment, tumor size was measured every 3 days, mouse weight was recorded, and tumor photographs were taken to calculate tumor volume. After treatment, tumor-bearing mice were euthanized, tumor tissue was dissected, weighed, and photographed. Furthermore, organs and tumor tissue from each group of mice were dissected, fixed with paraformaldehyde, and used for H&E staining analysis. Blood was collected from 5 additional mice in each group; a portion was used for routine blood tests, and the remaining portion was separated into serum for later use.

[0053] All animal experiments in this study were conducted in strict accordance with relevant regulations on laboratory animal ethics and welfare. During the experiments, the number of animals used was minimized, and all possible measures were taken to reduce their suffering. All animals were housed in an environment meeting SPF standards, with free access to food and water, and were kept in a circadian rhythm with alternating 12-hour light and 12-hour dark conditions.

[0054] The results showed that (E)-I24 significantly inhibited tumor growth in a dose-dependent manner. Figure 2 The tumor inhibition rates in the 10 mg / kg and 30 mg / kg groups reached 65.9% and 72.6%, respectively, both superior to the 59.0% in the cisplatin group. Histopathological observation further confirmed that the tumor tissue in the (E)-I24 treatment group showed obvious map-like necrosis, pyknosis or dissolution of tumor cell nuclei, and increased eosinophilicity of the cytoplasm, while the tumor cells in the model control group had typical morphology and dense structure.

[0055] In vivo safety evaluation showed that mice in all (E)-I24 dose groups experienced steady weight gain and normal mental status and activity during treatment, while mice in the cisplatin group showed progressive weight loss. H&E staining results of major organs showed ( Figure 3 No significant tissue damage or pathological changes were observed in the heart, liver, spleen, lungs, and kidneys at any of the (E)-I24 dosage groups, indicating that the compound exhibits good in vivo tolerability and biocompatibility at the specified dosages. In summary, compound (E)-I24 demonstrates significantly superior antitumor activity compared to cisplatin in vivo, with good safety profile, and thus has potential for further development.

Claims

1. A kind of formula ( E Compounds with the )-I structure and their pharmaceutically acceptable salts have the following structural formulas: ； in, R1 is selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, nitro, cyano or hydroxy; R2 is selected from C1-C6 alkyl groups; n is selected from 0, 1, 2, 3, 4 or 5.

2. The formula according to claim 1 ( E Compounds with a )-I structure, characterized in that, (R1) n R2 is selected from: chlorine, 2,4-dichloro, 2-chloro-6-fluoro, bromine, fluorine, 2,4-difluoro, methoxy, ethoxy, methyl, 2,3,4-trimethoxy, 3,4,5-trimethoxy, nitro, trifluoromethyl; R2 is selected from methyl, ethyl, propyl, butyl, pentyl; R2 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, pentyl, isopentyl, n-pentyl.

3. The formula according to claim 1 ( E Compounds with a )-I structure, characterized in that, Selected from: ( E )-I1~( E )-I36; where, ( E )-I1 is ( E )-3-(4-chlorophenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I2 is ( E )-3-(3-chlorophenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I3 is ( E )-3-(2-chlorophenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I4 is ( E )-3-(2,4-dichlorophenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I5 is ( E )-3-(2-chloro-6-fluorophenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I6 is ( E )-3-(4-bromophenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I7 is ( E )-3-(3-bromophenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I8 is ( E )-3-(2-bromophenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I9 is ​​( E )-3-(4-fluorophenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I10 is ( E )-3-(3-fluorophenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I11 is ( E )-3-(2-fluorophenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I12 is ( E )-3-(2,4-difluorophenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I13 is ( E )-3-(4-methoxyphenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I14 is ( E )-3-(3-methoxyphenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I15 is ( E )-3-(2-methoxyphenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I16 is ( E )-3-(3,4,5-trimethoxyphenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I17 is ( E )-3-(2,3,4-trimethoxyphenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I18 is ( E )-3-(4-ethoxyphenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I19 is ( E )-3-(3-ethoxyphenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I20 is ( E )-3-(2-ethoxyphenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I21 is ( E )-3-(4-methylphenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I22 is ( E )-3-(3-methylphenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E -I23 is ( E )-3-(2-methylphenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I24 is ( E )-3-(4-nitrophenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I25 is ( E )-3-(3-nitrophenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I26 is ( E )-3-phenyl-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I27 is ( E )-3-(3-thienyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E -I28 is ( E )-3-(3-trifluoromethylphenyl)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I29 is ( E )-3-(4-nitrophenyl)-1-(7-ethoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I30 is ( E )-3-(4-nitrophenyl)-1-(7-propoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I31 is ( E )-3-(4-nitrophenyl)-1-(7-isopropoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I32 is ( E )-3-(4-nitrophenyl)-1-(7-(tert-butoxy)-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I33 is ( E )-3-(4-nitrophenyl)-1-(7-butoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I34 is ( E )-3-(4-nitrophenyl)-1-(7-(pentoxy)-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I35 is ( E )-3-(4-nitrophenyl)-1-(7-(pent-2-oxy)-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one; ( E )-I36 is ( E )-3-(4-nitrophenyl)-1-(7-(pent-3-oxy)-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(trifluoromethyl)prop-2-en-1-one.

4. A method for preparing the (E)-I compound according to claim 1, characterized in that, It is prepared by the following method, with the reaction formula as follows: ； In the formula, the bases R1 and R2 are defined as described in claim 1; Step i: Using compound A as a starting material, react with R1-I or R1-Br to undergo an etherification reaction to obtain intermediate compound B; step ii: Compound B was subjected to a Friedel-Crafts acylation reaction to obtain intermediate compound C; Step iii: Compound C and benzaldehyde derivative (R1) n -Ph-CHO reaction, Claisen-Schmidt condensation reaction under alkaline conditions, to prepare intermediate D; Step iv: Compound D was reacted with Togni reagent and cuprous iodide catalysis to prepare the target product shown in formula (E)-I.

5. The method for preparing the (E)-I compound according to claim 4, characterized in that: Step i: The etherification reaction is carried out in the presence of potassium iodide and an alkaline reagent; the etherification reaction is carried out in the presence of a solvent, the solvent being selected from one or more of methanol, ethanol, isopropanol, and butanol; the alkaline reagent is selected from sodium carbonate and potassium carbonate; the etherification reaction is carried out at 40~60℃ for 4~8 hours. Step ii: The reagent for the Friedel-Crafts acylation reaction is selected from acetyl chloride, acetic anhydride, or a mixture thereof; the catalyst for the Friedel-Crafts acylation reaction is one or more of zinc chloride, aluminum trichloride, ferric chloride, tin tetrachloride, and boron trifluoride. Step iii: The Claisen-Schmidt condensation reaction is carried out in the presence of a solvent selected from methanol, ethanol, n-propanol, isopropanol, butanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide, or mixtures thereof. Step iv: The Togni reagent is selected from 1-(trifluoromethyl)-1,2-benzyl-3(1H)-one; after the reaction, the product is extracted with deionized water and ethyl acetate, the organic phase is dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by column chromatography to obtain the target product shown in formula (E)-I1.

6. A pharmaceutical composition comprising: (a) a therapeutically effective amount of the compound according to any one of claims 1-3; and a pharmaceutically acceptable carrier.

7. Use of the compound according to any one of claims 1-3 or the pharmaceutical composition according to claim 6 in the preparation of a medicament for treating or preventing tumors.

8. The use according to claim 7, characterized in that, The tumor is selected from gastric cancer, colon cancer, breast cancer, prostate cancer, cervical cancer, or lung cancer.

9. The application according to claim 7, characterized in that, The tumors were selected from HGC-27 human gastric cancer, HCT-116 human colon cancer, MCF-7 human breast cancer, DU145 human prostate cancer, C-33A human cervical cancer, or NCI-H460 human large cell lung cancer.

10. The application according to claim 7, characterized in that, The tumors mentioned are cervical cancer and stomach cancer.

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