Bysspectin a derivatives, methods of making and pharmaceutical uses thereof

Abstract

The present application belongs to the technical field of medicine, and relates to Bysspectin A derivatives with hCES2A inhibitory activity, a preparation method of a composition, and a pharmaceutical use thereof, in particular to the use of the Bysspectin A derivatives in the preparation of drugs for treating and / or preventing diseases (diarrhea, diarrhea side effects caused by cancer treatment) related to hCES2A inhibitory activity.

Description

Technical Field

[0001] This invention relates to bysspectin A derivatives or pharmaceutically acceptable salts, their preparation methods, and their pharmaceutical uses. Specifically, it relates to new compounds, new pharmaceutical effects, and their application in the preparation of remedies for the prevention, relief, and / or treatment of diseases associated with hCES2A inhibitory activity (diarrhea, diarrheal side effects from cancer treatment, etc.), belonging to the field of pharmaceutical technology. Background Technology

[0002] As is well known, carboxylesterases (CEs) are an important class of serine hydrolases distributed in the human body, catalyzing the hydrolysis of various exogenous and endogenous compounds containing ester bonds. They are mainly divided into carboxylesterase 1 (hCES1A) and carboxylesterase 2 (hCES2A). hCES1A is primarily highly expressed in the liver, while hCES2A is mainly distributed in the small intestine and colon. hCES2A is an important phase I drug-metabolizing enzyme, participating in the metabolic clearance and activation of various ester drugs, environmental toxins, and carcinogens. This enzyme can effectively catalyze the hydrolysis of exogenous substances containing carboxyl ester bonds, amide bonds, and thioester bonds. hCES2A plays a leading role in the metabolic activation of the antitumor drugs irinotecan and capecitabine, as well as the gemcitabine prodrug LY2334737. Its activity level has a crucial impact on the antitumor activity of these drugs and the incidence or severity of adverse reactions. Irinotecan, a broad-spectrum anticancer drug, has a structure with a small acyl group and a large hydroxyl group, making it a good substrate for hCES2A. In the intestine, it can be hydrolyzed by hCES2A to produce excessive SN38, causing severe delayed-type diarrhea. Therefore, combining irinotecan with an hCES2A inhibitor can significantly alleviate this severe side effect caused by SN-38.

[0003] Bysspectin A, a natural product, is a novel diketone derivative isolated in 2018 by Professor Lin Sheng's research group at the Institute of Materia Medica, Chinese Academy of Medical Sciences, from the endophytic fungus *Byssochlamys spectabilis*, which grows on the leaves of the traditional Chinese medicine *Edgeworthia chrysantha*. Its structural features include a 2-substituted benzofuran core and two long octanone substituents. It exhibits good selective inhibition of hCES2A (IC50). 50 =2.01 μM (Eur. J. Med. Chem., 2018, 145, 717-725). This compound is difficult to extract and separate. Its total synthesis was first reported by Professor Xie Ping's research group at the Institute of Materia Medica, Chinese Academy of Medical Sciences in 2019 (Tetrahedron, 2019, 75, 3101-3107). Summary of the Invention

[0004] The technical problem solved by this invention is to provide bysspectin A derivatives as shown in Formula I, their preparation methods, pharmaceutical compositions, and their use in medicaments for treating diseases related to hCES2A inhibitory activity (diarrhea, diarrheal side effects caused by cancer treatment, etc.).

[0005] To solve the technical problem of this invention, the present invention provides the following technical solution:

[0006] The first aspect of the present invention is to provide a compound as shown in general formula (I) or a pharmaceutically acceptable salt thereof:

[0007]

[0008] in:

[0009] R1 is independently selected from hydrogen, -COR6;

[0010] R2 is independently selected from hydrogen, C1-10 alkyl, C1-10 alkoxy, halogen, nitro, and cyano;

[0011] R3 is independently selected from hydrogen, -COR7;

[0012] R4 is independently selected from hydrogen, C1-10 alkyl, C1-10 alkoxy, halogen, nitro, and cyano;

[0013] R5 is independently selected from hydrogen, C1-10 alkoxy, and C1-10 acyl groups;

[0014] R6 and R7 are independently selected from C1-16 straight-chain or branched alkyl groups;

[0015] However, the following compounds are excluded:

[0016]

[0017] Wherein, R1 is independently selected from hydrogen, -COR6; R2 is independently selected from hydrogen, C1-8 alkyl, C1-8 alkoxy, halogen, nitro, cyano; R3 is independently selected from hydrogen, -COR7; R4 is independently selected from hydrogen, C1-8 alkyl, C1-8 alkoxy, halogen, nitro, cyano; R5 is independently selected from hydrogen, C1-8 alkoxy, C1-8 acyl; R6 and R7 are independently selected from C1-14 straight-chain or branched alkyl groups.

[0018] However, the following compounds are excluded:

[0019]

[0020] Preferably, R1 is independently selected from hydrogen, -COR6; R2 is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, 2-methyl-butyl, p-pentyl, n-hexyl, 2-methyl-pentyl, 3-methyl-pentyl, 2,2-dimethyl-butyl, 2,3-dimethyl-butyl, methoxy, ethoxy, propoxy, butoxy, sec-butoxy, tert-butoxy, n-pentoxy, 2-methyl-butoxy, p-pentyl Oxygen, n-hexyloxy, 2-methyl-pentoxy, 3-methyl-pentoxy, 2,2-dimethyl-butoxy, 2,3-dimethyl-butoxy; R3 is independently selected from hydrogen, -COR7 substituted; R4 is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, 2-methyl-butyl, tert-pentyl, n-hexyl, 2-methyl-pentyl, 3-methyl-pentyl, 2,2-dimethyl-butyl, 2,3-dimethyl 2-Butyl, methoxy, ethoxy, propoxy, butoxy, sec-butoxy, tert-butoxy, n-pentoxy, 2-methyl-butoxy, tert-pentoxy, n-hexyloxy, 2-methyl-pentoxy, 3-methyl-pentoxy, 2,2-dimethyl-butoxy, 2,3-dimethyl-butoxy, halogen, nitro, cyano; R5 is independently selected from hydrogen, methoxy, ethoxy, propoxy, butoxy, sec-butoxy, tert-butoxy, n-pentoxy, 2-methyl-butoxy Oxygen, pteropenoyl, n-hexyloxy, 2-methyl-pentoxy, 3-methyl-pentoxy, 2,2-dimethyl-butoxy, 2,3-dimethyl-butoxy, acetyl, propionyl, butyryl, sec-butyryl, tert-butyryl, n-pentanoyl, 2-methyl-butyryl, pteropenoyl, n-hexyl, 2-methyl-pentanoyl, 3-methyl-pentanoyl, 2,2-dimethyl-butyryl, 2,3-dimethyl-butyryl, halogen, nitro, cyano;R6 and R7 are independently selected from methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, n-pentyl, 2-methyl-butyl, tert-pentyl, n-hexyl, 2-methyl-pentyl, 3-methyl-pentyl, 2,2-dimethyl-butyl, 2,3-dimethyl-butyl, n-heptyl, 2-methyl-hexyl, 3-methylhexyl, 2,2-dimethyl-pentyl, 2,3-dimethyl-pentyl, 2,4-dimethyl-pentyl, n-octyl, 2-methyl-heptyl, 3-methyl-heptyl, 4-methyl-heptyl, 2,2-dimethyl-hexyl, 2,3-dimethyl-hexyl, 2,4-dimethyl-hexyl, 2,5-dimethyl-hexyl, 2,3,4-trimethyl-butyl, n-nonyl, 2-methyl-octyl, 3-methyl-octyl, 4-methyl-octyl, 2,2 -Dimethyl-heptyl, 2,3-dimethyl-hexyl, 2,4-dimethyl-hexyl, 2,5-dimethyl-hexyl, 2,3,4-trimethyl-pentyl, 2,3,5-trimethyl-pentyl, n-decyl, 2-methyl-decyl, 3-methyl-decyl, 4-methyl-decyl, 5-methyl-decyl, 2,2-dimethyl-octyl, 2,3-dimethyl-octyl, 2,4-dimethyl-octyl, 2,5-dimethyl-octyl, 2,6-dimethyl-octyl, 2,7-dimethyl-octyl, 2,3,4-trimethyl-heptyl, 2,3,5-trimethyl-heptyl, 2,3,6-trimethyl-heptyl, 3,4,5-trimethyl-heptyl, 3,4,6-trimethyl-heptyl, 2,3,4,5-tetramethyl-hexyl, undecyl, dodecyl;

[0021] However, the following compounds are excluded:

[0022]

[0023] The preferred compound is selected from

[0024]

[0025] The second aspect of the present invention is to provide a method for preparing the compound described in the first aspect:

[0026] Preparation of fragment A-1:

[0027] When R3 is hydrogen, compound III is first obtained by iodination of initial raw material II; compound III is deprotected to obtain compound IV; then it is coupled with trimethylsilylacetylene to obtain compound V; compound V is protected by hydroxyl groups to obtain compound VI; compound VI is finally deprotected by TMS to obtain fragment A-1;

[0028]

[0029] i. Iodination reaction; ii. Deprotection reaction; iii. Coupling reaction; iv. Adding a protecting group; v. Removing the TMS protecting group. Wherein, R4 is defined as in any one of claims 1-3; R8 is methyl, ethyl, triethylsilyl, tert-butyldimethylsilyl, triphenylsilyl, (trimethylsilyl)ethoxymethyl;

[0030] Preparation of fragment A-2:

[0031] When R3 is -COR7, compound VII is iodinated to give compound VIII, compound VIII is oxidized by an oxidizing agent to give compound IX, compound IX is deprotected to give compound X, compound X is coupled with trimethylsilylacetylene to give compound XI, compound XI is protected by a hydroxyl group to give compound XII, compound XII is introduced with an alkyl side chain by a Grignard reaction to give compound XIII, compound XIII is oxidized to give compound XIV, and compound XIV is deprotected by TMS to give fragment A-2;

[0032]

[0033] i. Iodination reaction; ii. Oxidation reaction; iii. Deprotection reaction; iv. Coupling reaction; v. Adding a protecting group; vi. Grignard reaction; vii. Oxidation reaction; viiii. Deprotection of TMS group. Wherein R4 and R7 are defined as in any one of claims 1-3; R8 is defined as methyl, ethyl, triethylsilyl, tert-butyldimethylsilyl, triphenylsilyl, (trimethylsilyl)ethoxymethyl;

[0034] Fragment B: Compound XVI is obtained by introducing an alkyl side chain from compound XV via a Grignard reaction, compound XVI is oxidized to obtain compound XVII, and compound XVII is deprotected to obtain fragment B;

[0035]

[0036] i. Grignard reaction; ii. Oxidation reaction; iii. Deprotection, wherein R2 and R6 are defined as in any one of claims 1-3; Synthesis of I: Benzofuran ring is generated by the Sonogashira coupling cyclization reaction of fragment A-1 or fragment A-2 and fragment B to obtain intermediate XVIII, intermediate XVIII is deprotected and acylated to obtain compound I;

[0037]

[0038] i. Sonogashira coupling cyclization reaction; ii. deprotection; iii. acylation. Wherein R1, R2, R3, R4, and R5 are defined as in any one of claims 1-3; R8 is defined as methyl, ethyl, triethylsilyl, tert-butyldimethylsilyl, triphenylsilyl, or (trimethylsilyl)ethoxymethyl.

[0039] A third aspect of the present invention is to provide a pharmaceutical composition comprising a preventive and / or therapeutically effective amount of the above-mentioned bysspectin A derivative, and optionally a pharmaceutically acceptable carrier and / or excipients.

[0040] In this invention, depending on the route of administration, the pharmaceutical composition of the 2-benzofuran compound may be in the following dosage forms: solution, suspension, emulsion, pill, capsule, powder, controlled release or sustained release formulation.

[0041] The bysspectin A derivative pharmaceutical compositions of the present invention can be formulated using known methods and administered to subjects via several routes, including but not limited to parenteral, oral, topical, intradermal, intramuscular, intraperitoneal, subcutaneous, intravenous, and intranasal routes.

[0042] The bysspectin A derivative pharmaceutical compositions of the present invention can optionally be formulated by any conventional method using one or more pharmaceutically acceptable carriers and / or excipients. Therefore, bysspectin A derivatives and their pharmaceutically acceptable salts can be specifically formulated for, for example, inhalation or blowing (through the mouth or nose) or oral, sublingual, parenteral, or rectal administration.

[0043] Bysspectin A derivative pharmaceutical compositions can also be in the form of solutions, suspensions, emulsions, pills, capsules, powders, controlled-release or sustained-release formulations. These formulations will contain a therapeutically effective amount of the bysspectin A derivative, preferably in a purified form, and an appropriate carrier to provide a suitable form of administration to the patient.

[0044] The fourth aspect of this invention is to provide the compounds described in the first aspect of this invention, or their pharmaceutically acceptable salts, for the prevention, relief, and / or treatment of diseases associated with hCES2A inhibitory activity (diarrhea, diarrheal side effects caused by cancer treatment, etc.). The use of these 2-benzofuran compounds and their salts in medicaments for the prevention, relief, and / or treatment of diseases associated with hCES2A inhibitory activity (diarrhea, diarrheal side effects caused by cancer treatment, etc.) falls within the scope of protection of this invention.

[0045] In this invention, the use of the medicament for preventing, alleviating and / or treating diarrhea, or diarrheal side effects caused by cancer treatment, is selected from those that inhibit the activity of hCES2A.

[0046] In this invention, the purified form of the bysspectin A derivative refers to a bysspectin A derivative that is substantially pure, particularly with a purity greater than 80%, preferably greater than 85%, particularly preferably greater than 90%, and even more preferably greater than 95%. The purity range of the purified form of the bysspectin A derivative can be, for example, 90-96%.

[0047] Beneficial technical effects:

[0048] The inventors discovered that new compounds obtained by structural optimization of the natural product bysspectin A have significantly enhanced hCES2A inhibitory activity compared to bysspectin A, with some compounds showing nearly 100 times stronger activity.

[0049] Bysspectin A derivatives of general formula I are novel monomeric compounds with advantages such as low toxicity and simple preparation process; they have good application and development prospects and are ideal for use in drugs to prevent, alleviate and / or treat diseases related to hCES2A inhibitory activity (diarrhea, diarrheal side effects caused by cancer treatment, etc.). They can be used in drug preparation. Detailed Implementation

[0050] Preparation Example

[0051] Preparation of intermediate 16:

[0052]

[0053] m-Methoxybenzyl alcohol (4.974 g, 36 mmol) was dissolved in 150 mL of anhydrous diethyl ether and placed in a 500 mL three-necked flask. n-BuLi (2.5 M, 31.8 mL, 79.2 mmol) was slowly added dropwise under argon protection at 0 °C. The mixture was stirred at room temperature for 3.5 h until the solution turned light brown. Iodine (9.41 g, 37.08 mmol) was dissolved in 100 mL of anhydrous diethyl ether and added to the reaction mixture. The mixture was stirred at room temperature for 15 min. The reaction was monitored by TLC until the reactants were completely reacted, at which point the reaction was stopped. Post-treatment: The reaction was quenched with ammonia-ammonium chloride buffer (pH = 8), extracted with methyl tert-butyl ether, and the organic phases were combined. The mixture was washed three times with saturated brine and dried over anhydrous Na₂SO₄. After filtration, the solvent was removed under reduced pressure, and the product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to give 6.7 g of the product as a white solid, with a yield of 70.5%.

[0054] 1 H NMR (400MHz, Chloroform-d) δ7.24 (dd, J=8.0, 5.7Hz, 1H), 6.98–6.87 (m, 2H), 6.86–6.78 (m, 1H), 4.64 (s, 2H), 3.78 (s, 3H).

[0055] Preparation of intermediate 17:

[0056]

[0057] Compound 16 (8.7 g, 32.9 mmol) was dissolved in 150 mL of dichloromethane and placed in a 250 mL single-necked flask. Dess-Martin oxidant (16.8 g, 39.5 mmol) was added at 0 °C, and the reaction was carried out at 0 °C for 1 h. The reaction was monitored by TLC until the starting material was completely reacted, at which point the reaction was stopped. Post-treatment: The reaction was quenched with saturated sodium sulfite, and the mixture was extracted three times with dichloromethane. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, the solvent was removed under reduced pressure, and the product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30:1) to give 5.92 g of the product, with a yield of 68.8%.

[0058] 1 H NMR (400MHz, Chloroform-d) δ10.19(d,0.8Hz,1H),7.50(dd,J=7.6,1.3Hz,1H),7.39(ddd,J=8.1Hz,7.6Hz,0.8Hz,1H),7.05(dd,J=8.1,1.3Hz,1H),3.95(s,3H).

[0059] Preparation of intermediate 18:

[0060]

[0061] Compound 17 (5.92 g, 22.6 mmol) was dissolved in 110 mL of anhydrous dichloromethane and placed in a 500 mL two-necked flask. Under argon protection at 0 °C, 1 M boron tribromide (dissolved in ultra-dry dichloromethane) (1 M, 56.5 mL, 56.5 mmol) was added dropwise. The mixture was heated to room temperature and stirred for 4 h. The reaction was monitored by TLC until the reactants were completely reacted, at which point the reaction was stopped. Post-treatment: The mixture was quenched with cold water, extracted three times with dichloromethane, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1) to give 4 g of the product, with a yield of 71.2%.

[0062] 1 H NMR (400MHz, Chloroform-d) δ10.03(d,J=0.7Hz,1H),7.46(dd,J=7.5,1.6Hz,1H),7.36(t,J=7.7Hz,1H),7.28(d,J=1.6Hz,1H),5.82(s,1H).

[0063] Preparation of intermediate 19:

[0064]

[0065] Compound 18 (4.0 g, 16.1 mmol) was dissolved in 80 mL of anhydrous tetrahydrofuran and placed in a 250 mL two-necked flask. After deoxygenation, Pd(PPh3)2Cl2 (226.0 mg, 0.322 mmol), CuI (122.65 mg, 0.644 mmol), and Et3N (8.05 mL) were added sequentially. After stirring for 20 min, trimethylsilylacetylene (11.27 mL) was added, and the mixture was heated to 50 °C and reacted for 5 h. TLC monitoring showed that the starting material had essentially disappeared, and the reaction was stopped. Post-treatment: The reaction solution was diluted with dichloromethane, the organic phase was washed three times with 0.5 N HCl, washed three times with saturated brine, and dried over anhydrous Na2SO4. After filtration, the solvent was removed by vacuum distillation, and the product was purified by silica gel column chromatography (pure petroleum ether) to obtain 3.22 g of product, with a yield of 92.1%.

[0066] 1 H NMR(400MHz,Chloroform-d)δ10.39(t,J=1.0Hz,1H),7.49(dt,J=7.7,1.3Hz,1H),7.37(tt,J=7.7 ,1.0Hz,1H),7.21(dt,J=8.1,1.2Hz,1H),3.75(ddt,J=6.6,4.2,1.2Hz,1H),0.32(d,J=1.5Hz,9H).

[0067] Preparation of intermediate 20:

[0068]

[0069] Compound 19 (100 mg, 0.5 mmol) was dissolved in 3 mL of anhydrous dichloromethane and placed in a 25 mL two-necked flask. Under argon protection, N,N-diisopropylethylamine (0.37 mL, 2.25 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (0.26 mL, 1.5 mmol) were added, and the mixture was stirred at room temperature for 2 h. The reaction was monitored by TLC until complete. Post-treatment: The reaction was quenched with cold water, and the mixture was extracted three times with dichloromethane. The combined organic phases were dried over anhydrous Na₂SO₄. The mixture was filtered, the solvent was removed under reduced pressure, and the product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 19:1) to give 100 mg of the product as a yellow oil, with a yield of 63.9%.

[0070] 1H NMR(400MHz,Chloroform-d)δ10.55(s,1H),7.56(d,J=4.5Hz,1H),7.37–7.34(m, 2H),5.33(s,2H),3.88–3.74(m,2H),1.02–0.89(m,2H),0.29(s,9H),0.01(s,9H).

[0071] Preparation of intermediate 21:

[0072]

[0073] Compound 20 (100 mg, 0.29 mmol) was dissolved in 3 mL of methyl tert-butyl ether and placed in a 10 mL two-necked flask. Under argon protection, octyl magnesium bromide (2 M, 0.348 mmol, 0.174 mL) was added dropwise at 0 °C, and the reaction was carried out at 0 °C for 0.5 h. The reaction was monitored by TLC until the starting material was completely reacted, at which point the reaction was stopped. Post-treatment: The reaction was quenched with cold ammonium chloride, extracted three times with methyl tert-butyl ether, and the organic phases were combined, dried over anhydrous Na₂SO₄, filtered, and the solvent was removed under reduced pressure. The product was purified by column chromatography (petroleum ether / ethyl acetate = 20:1) to give 80 mg of product, with a yield of 72.9%.

[0074] 1 H NMR(400MHz,Chloroform-d)δ7.24(d,J=8.0Hz,1H),7.11(d,J=7.7Hz,1H),6.99(d,J=8.3Hz,1H),5.28(s,2H),5.08(dt,J=9.0,4.6Hz,1H),3.86– 3.77(m,2H),3.70–3.58(m,1H),1.90–1.63(m,2H),1.59–1.43(m,1H),1. 32–1.23(m,12H),0.91–0.84(m,5H),0.27(s,9H),0.00(d,J=1.6Hz,9H).

[0075] Preparation of intermediate 22:

[0076]

[0077] Compound 22 (1.3 g, 93.5% yield) was prepared by oxidation of compound 21, following the synthetic method of compound 17.

[0078] 1H NMR(400MHz,Chloroform-d)δ7.26(d,J=8.4Hz,1H),7.11(d,J=8.4Hz,1H),7.10(dd,J=7.6Hz,J=1.2Hz,1H),5.28(s,2H),3.86–3. 77(m,2H),3.70–3.58(m,2H),1.63(m,2H),1.32–1.23(m,10H),0.98–0.94(m,2H),0.87(t,J=7.2Hz,3H),0.27(s,9H),0.00(s,9H).

[0079] Preparation of intermediate 23:

[0080]

[0081] Compound 22 (1.23 g, 3.3 mmol) was dissolved in 15 mL of methanol and placed in a 50 mL single-necked flask. Potassium carbonate (45.6 mg, 0.33 mmol) was added, and the mixture was stirred at room temperature for 1.5 h. The reaction was monitored by TLC until the starting material was completely reacted. Post-treatment: The potassium carbonate was filtered off, the methanol was evaporated to dryness, and the product was purified by column chromatography (petroleum ether / ethyl acetate = 50:1) to give 510 mg of the product as a yellow oil, with a yield of 89%.

[0082] 1 H NMR(400MHz,Chloroform-d)δ7.32(d,J=7.5Hz,1H),7.28(d,J=1.3Hz,1H),7.14(dd,J=7.5,1.3Hz,1H),5.33(s,2H),3.85–3.78(m,2H) ,3.51(s,1H),2.99(t,J=7.4Hz,2H),1.70(p,J=7.4Hz,2H),1.27(d,J=3.6Hz,10H),1.01–0.91(m,2H),0.91–0.83(m,3H),0.00(s,9H).

[0083] Preparation of intermediate 24:

[0084]

[0085] Compound 24 (368 mg, 81.6% yield) was prepared from compound 23 and magnesium octyl bromide using the same method as compound 21.

[0086] 1H NMR(400MHz,Chloroform-d)δ7.30(t,J=8.0Hz,1H),7.13(d,J=7.6Hz,1H),6.75(d,J=8.0Hz,1 H),5.02(m,1H),3.87(s,3H),2.08(s,1H),1.78–1.73(m,1H),1.64–1.26(m,13H),0.87(m,3H).

[0087] Preparation of intermediate 25:

[0088]

[0089] Compound 25 (369 mg, 98.6% yield) was prepared by oxidation of compound 24, following the synthetic method of compound 17.

[0090] 1 H NMR(400MHz,Chloroform-d)δ7.32(t,J=8.0Hz,1H),6.83(d,J=7.6Hz,2H),3.9(s ,3H),2.85(d,J=7.6Hz,2H),1.81–1.71(m,2H),1.37–1.26(m,10H),0.87(m,3H).

[0091] Preparation of intermediate 26:

[0092]

[0093] Compound 25 (277 mg, 0.740 mmol) was dissolved in 20 mL of anhydrous dichloromethane and placed in a 100 mL two-necked flask. Under argon protection, 1 M boron tribromide (dissolved in ultra-dry dichloromethane) (1 M, 1.25 mL, 1.258 mmol) was added dropwise at -78 °C. The mixture was stirred at room temperature for 4 h, and the reaction was monitored by TLC until the reactants were completely reacted. The reaction was then stopped. Post-treatment: The mixture was quenched with cold water, extracted three times with dichloromethane, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to give 197 mg of the product as a brown oil, with a yield of 74.2%.

[0094] 1H NMR(400MHz,Chloroform-d)δ7.30–7.21(m,1H),7.14–7.05(m,1H),6.97(d,J=7.5Hz,1H),5.8 4(s,1H),2.87(t,J=7.3Hz,2H),1.71(p,J=7.3Hz,2H),1.43–1.07(m,10H),0.97–0.74(m,3H).

[0095] Preparation of Examples 1-14:

[0096] Example 1: Preparation of Compound 1

[0097] Step A: Following the synthetic method of compound 19, compound 27 (740 mg, 85.4% yield) was prepared from o-iodophenol (1 g, 4.55 mmol) and trimethylsilylacetylene.

[0098]

[0099] 1 H NMR(400MHz,Chloroform-d)δ7.34(dd,J=7.7,1.7Hz,1H),7.27–7.22(m,1H),6. 94(dd,J=8.4,1.1Hz,1H),6.85(td,J=7.5,1.1Hz,1H),5.84(s,1H),0.28(s,9H).

[0100] Step B: Following the synthetic method of compound 20, compound 28 (960 mg, 76.9% yield) was prepared from compound 27 (740 mg, 3.9 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (2.1 ml, 3 mmol).

[0101]

[0102] 1 H NMR(400MHz,Chloroform-d)δ7.43(dd,J=7.7,1.8Hz,1H),7.25–7.22(m,1H),7.08(dd,J=8.4,1.1Hz,1H),6.93 (td,J=7.5,1.1Hz,1H),5.29(s,2H),3.88–3.75(m,2H),1.04–0.89(m,2H),0.25(s,8H),0.00(d,J=2.2Hz,9H); 13C NMR (125MHz, CDCl3) δ158.4,134.1,129.9,121.7,115.5,113.9,101.5,98.4,93.5,66.5,18.2,0.2,-1.3; HRMS (ESIMS) m / z (M+H) + calcd for C 17 H 29 O2Si2:321.17006; Found:321.17068.

[0103] Step C: Following the synthetic method of compound 23, compound 29 (247 mg, 99% yield) was prepared from compound 28 (320.58 mg, 1 mmol).

[0104]

[0105] 1 H NMR(400MHz,Chloroform-d)δ7.46(dd,J=7.6,1.7Hz,1H),7.30(ddd,J=8.9,7.3,1.7Hz,1H),7.16(dd,J=8.4,1.1Hz,1H ),6.96(td,J=7.5,1.1Hz,1H),5.31(d,J=1.1Hz,2H),3.89–3.72(m,2H),3.27(s,1H),1.03–0.87(m,2H),-0.00(s,9H); 13 C NMR(100MHz,Chloroform-d)δ159.8,134.2,130.3,121.7,115.2,93.5,81.0,66.7,18.2,-1.3; HRMS(ESIMS)m / z(M+H) + calcd for C 14 H 21 O2Si:249.13053; Found:249.13042.

[0106] Step D: Compound 26 (144 mg, 0.4 mmol) was dissolved in 8 mL of anhydrous toluene and placed in a 50 mL three-necked flask. Ar gas was bubbled in. During this process, 8 mL solutions of [Cu(phen)(PPh3)2]NO3 (33 mg, 0.04 mmol), CsCO3 (260.7 mg, 0.8 mmol), and compound 29 (100 mg, 0.4 mmol) in anhydrous toluene were added sequentially. The reaction mixture was heated to 110 °C and stirred for 5 hours. The reaction was monitored by TLC until complete. Post-treatment: After cooling, the mixture was filtered, the solvent was removed under reduced pressure, and silica gel column chromatography (petroleum ether / ethyl acetate = 30:1) was performed to give 66 mg of the product as a pale yellow oil, with a yield of 34.3%.

[0107]

[0108] 1 H NMR(400MHz,Chloroform-d)δ8.10–8.06(m,2H),7.82(dd,J=7.7,0.9Hz,1H),7.69(dt,J=8.1,1.0Hz,1H),7.35–7.30(m,3H),7 .17–7.10(m,1H),5.47(s,2H),3.91–3.80(m,3H),3.12–3.03(m,2H),1.80(q,J=7.5Hz,2H),1.37–1.23(m,14H),-0.02(s,9H); 13 CNMR(100MHz,Chloroform-d)δ201.1,155.0,154.9,154.8,134.5,130.6,129.4,127.6,124.6,123.4,121.8,119.8, 115.3,115.2,,107.6,93.0,66.8,39.7,32.0,29.8,29.6,29.3,24.8,22.8,18.2,14.2,-1.3; HRMS(ESIMS)m / z(M+H) + calcd for C 29 H 41 O4Si:481.27686; Found:481.23761.

[0109] Step E: Compound 30 (50 mg, 0.1 mmol) was dissolved in 1.5 mL of methanol and 1.5 mL of tetrahydrofuran, placed in a 10 mL single-necked flask, and a methanol solution of sulfuric acid (0.1 mL dissolved in 1.5 mL of methanol) was added. The mixture was stirred at 20 °C for 2 h. The reaction was monitored by TLC until the starting material was completely reacted. Post-treatment: The reaction was quenched with cold sodium bicarbonate, extracted with ethyl acetate, the organic phases were combined, washed, dried, and subjected to column chromatography (petroleum ether / ethyl acetate = 8:1) to give 20 mg of the product as a yellow solid, with a yield of 57.1%.

[0110]

[0111] 1 H NMR(400MHz,Chloroform-d)δ7.99(d,J=0.8Hz,1H),7.87–7.80(m,2H),7.70(dd,J=8.0,0.8Hz,1H),7.46(s,1H),7.35(t,J=8. 0Hz,1H),7.31–7.27(m,1H),7.05–6.97(m,2H),3.12–3.03(m,2H),1.87–1.75(m,2H),1.39–1.23(m,10H),0.92–0.82(m,3H).; 13 CNMR(100MHz,Chloroform-d)δ201.7,156.8,154.8,154.0,130.8,129.8,128.6,127.6,125.2,123. 6,120.9,117.5,116.1,115.5,105.4,39.6,32.0,29.6,29.3,24.8,22.8,14.2; HRMS(ESI)m / z(M+H) + calcd for C 23 H 27 O3:351.19547; Found:351.19925.

[0112] Example 2 Preparation of Compound 2

[0113] Step A: Following the synthetic method for compound 30, compound 31 (47 mg, 36% yield) was prepared from compound 23 (100 mg, 0.258 mmol) and 2-iodophenol (56.8 mg, 0.258 mmol).

[0114]

[0115] 1H NMR(400MHz,Chloroform-d)δ7.63–7.59(m,1H),7.46–7.43(m,1H),7.34–7.29(m,1H),7.29–7.27(m,1H),7 .27–7.22(m,1H),7.15–7.12(m,1H),7.06(dd,J=7.3,1.4Hz,1H),5.32(d,J=1.4Hz,2H),3.86–3.78(m,1H),3 .78–3.70(m,1H),3.03–2.95(m,1H),2.44(dd,J=7.9,7.1Hz,1H),1.64(ddd,J=37.2,14.5,7.3Hz,3H),1.27( tdd,J=15.8,14.1,11.7,7.2Hz,6H),1.19–1.08(m,4H),1.00–0.91(m,2H),0.89–0.82(m,3H),-0.05(s,9H); 13 CNMR(100MHz,Chloroform-d)δ206.9,154.9,154.5,150.2,143.2,130.0,129.8,124.6,123.1,121.3,120.6,120.4 ,116.5,111.3,108.5,93.6,66.8,42.4,312.0,29.5,29.4,29.3,24.5,22.8,18.1,14.2,-1.4; HRMS(ESI)m / z(M+H) + calcd for C 29 H 41 O4Si:481.27686; Found:481.27954.

[0116] Step B: Following the synthetic method for compound 1, compound 2 (20 mg, 57.1% yield) was prepared from compound 31 (47 mg, 0.1 mmol)

[0117]

[0118] 1H NMR(400MHz,Chloroform-d)δ7.62(dd,J=8.0,0.8Hz,1H),7.50(dd,J=8.0,0.8Hz,1H),7.37–7.31(m,2H),7.29(dd,J=7.5,1.2Hz,1H),7.10(dd,J=8.3,1.2 Hz,1H),7.03(dd,J=7.5,1.2Hz,1H),6.95(d,J=1.2Hz,1H),6.56(s,1H),2.52 (m,2H),1.62–1.51(m,2H),1.28–1.23(m,2H),1.17–1.11(m,8H),0.85(t,3H).

[0119] 13 C NMR(100MHz,Chloroform-d)δ206.9,154.9,154.1,150.0,142.6,130.8,128.5,125.3,123.7,121. 5,119.5,118.5,114.1,111.4,108.0,42.7,31.9,29.3,29.2,24.6,22.7,14.2; HRMS(ESI)m / z(M+H) + calcd for C 23 H 27 O3:351.19547; Found:351.19925.

[0120] Example 3 Preparation of Compound 3

[0121] Following the synthetic method of compound 30, compound 3 (112 mg, 68.7% yield) was prepared from compound 26 (176 mg, 0.49 mmol) and phenylacetylene (50 mg, 0.49 mmol).

[0122]

[0123] 1 H NMR(400MHz,Chloroform-d)δ7.93(m,2H),7.86(s,1H),7.82(d,J=7.6Hz,1H),7.70(d,J=8.0Hz,1H),7.47(t,J= 7.6Hz,2H),7.39(m,1H),7.33(t,J=8.0Hz,1H),3.07(t,2H),1.80(m,2H),1.38–1.21(m,10H),0.92–0.83(m,3H); 13CNMR(100MHz,Chloroform-d)δ201.3,158.6,155.7,130.2,129.8,129.2,129.0,129.0,125.4, 124.8,123.5,115.7,103.1,39.5,32.0,29.7,29.6,29.3,24.7,22.8,14.2.HRMS(ESI)m / z(MH) - calcd for C 23 H 25 O2:333.18491; Found:333.18634

[0124] Example 4: Preparation of Compound 4

[0125] Step A: Dissolve 500 mg (2 mmol) of 3-iodo-4-methoxytoluene in anhydrous dichloromethane. Add 1 M boron tribromide (dissolved in dichloromethane) dropwise at 0 °C (1 M, 5 ml, 5 mmol) and stir for 1 h. Monitor the reaction by TLC until the starting material is completely reacted. Post-treatment: Quench the reaction with cold water, extract with dichloromethane, wash with saturated brine, dry with anhydrous sodium sulfate, and purify by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1) to give 465 mg of the product as a white solid, with a yield of 92.7%.

[0126]

[0127] 1 H NMR (400MHz, Chloroform-d) δ7.47(dd,J=2.1,0.8Hz,1H),7.04(ddd,J=8.2,2.1,0.8Hz,1H),6.88(d,J=8.2Hz,1H),5.15(s,1H),2.25(d,J=0.8Hz,3H).

[0128] Step B: Following the synthetic method of compound 30, compound 33 (83 mg, 43.1% yield) was prepared from compound 32 (90 mg, 0.39 mmol) and compound 23 (150 mg, 0.39 mmol).

[0129]

[0130] 1H NMR(500MHz,Chloroform-d)δ7.48(s,1H),7.46–7.42(m,1H),7.42–7.38(m,1H),7.33(t, J=7.5Hz,1H),7.24(d,J=5.8Hz,1H),7.17(dd,J=8.4,1.7Hz,1H),7.16–7.12(m,1H),5.39 (s,2H),3.86–3.77(m,2H),2.53(s,3H),2.50(t,J=7.5Hz,2H),1.72–1.60(m,2H),1.32(d ,J=6.8Hz,2H),1.28–1.15(m,8H),1.06–0.98(m,2H),0.94(t,J=7.2Hz,3H),0.05(s,9H); 13 C NMR (125MHz, CDCl3) δ206.9,154.8,153.0,150.2,132.5,129.8,129.2,128.3,125.9,125.4,121.1,120.4,116.5 ,110.8,108.3,93.5,66.8,42.7,31.9,29.4,29.3,29.2,24.5,22.7,21.5,18.1,14.2,-1.4; HRMS(ESI)m / z(M+H) + calcd forC 30 H 43 O4Si: 495.29251;

[0131] Found: 495.29279.

[0132] Step C: Following the synthetic method of compound 1, compound 4 (38 mg, 61.5% yield) was prepared from compound 33 (83 mg, 0.17 mmol).

[0133]

[0134] 1H NMR(400MHz,Chloroform-d)δ7.39–7.35(m,2H),7.31(t,J=7.6Hz,1H),7.13(dd,J=8.8,0.8Hz,1H),7.08(dd,J=8.8,0.8Hz,1H),6.99(dd, J=7.6,1.2Hz,1H),6.89(d,J=1.2Hz,1H),6.79(s,1H),2.53–2.46(m,2H),2.45(s,3H),1.56(m,2H),1.26(t,2H),1.14(m,8H),0.85(t,3H); 13 C NMR(100MHz,Chloroform-d)δ207.3,154.1,153.3,150.1,142.5,133.1,130.6,128.7,126.5,121.2,1 19.3,118.4,114.3,110.9,107.8,42.7,31.9,29.3,29.2,24.6,22.7,21.4,14.2; HRMS(ESI)m / z(M+H) + calcd for C 24 H 29 O3:365.21112; Found:365.21210

[0135] Example 5: Preparation of Compound 5

[0136] Step A: Following the synthetic method of compound 19, compound 34 (244 mg, 92.4% yield) was prepared from 2-iodo-5-methoxyphenol (300 mg, 1.2 mmol) and trimethylsilylacetylene.

[0137]

[0138] 1 H NMR (400MHz, Chloroform-d) δ7.24(d,J=8.5Hz,1H),6.49(d,J=2.4Hz,1H),6.42(dd,J=8.5,2.4Hz,1H),5.88(s,1H),3.78(s,3H),0.26(s,9H); 13 C NMR(100MHz,Chloroform-d)δ161.9,158.7,132.5,107.3,102.1,101.0,100.0,99.3,55.5,0.2; HRMS(ESI)m / z(M+H) + calcd for C 12 H17 O2Si:221.09817; Found:221.09923.

[0139] Step B: Following the synthetic method of compound 20, compound 35 (330 mg, 97.1% yield) was prepared from compound 34 (214 mg, 0.97 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (0.51 ml, 2.91 mmol).

[0140]

[0141] 1 H NMR(400MHz,Chloroform-d)δ7.34(d,J=8.5Hz,1H),6.66(d,J=2.4Hz,1H),6.48(dd,J=8.5,2.4H z,1H),5.27(s,2H),3.83–3.80(m,2H),3.79(s,3H),0.98–0.96(m,2H),0.24(s,9H),0.01(s,9H); 13 C NMR(100MHz,Chloroform-d)δ161.2,159.8,134.8,107.1,106.6,102.2,93.6, 91.7,77.5,77.2,76.8,66.6,55.5,18.2,0.3,-1.3,-1.3; HRMS(ESI)m / z(M+H) + calcd for C 18 H 31 O3Si2:351.18062; Found:351.18420.

[0142] Step C: Following the synthetic method of compound 23, compound 36 (270 mg, 97.1% yield) was prepared from compound 35 (340 mg, 0.97 mmol).

[0143]

[0144] 1 H NMR(400MHz,Chloroform-d)δ7.37(d,J=8.5Hz,1H),6.74(d,J=2.4Hz,1H),6.51(dd,J=8.5 ,2.4Hz,1H),5.30(s,2H),3.84–3.80(m,2H),3.80(s,3H),0.98–0.95(m,2H),0.00(s,9H); 13C NMR(100MHz,Chloroform-d)δ134.9,107.2,102.0,93.7,91.7,79.6,77.4,76.8,66.7,65.8,55.6,18.2,-1.3; HRMS(ESI)m / z(M+H) + calcd for C 15 H 23 O3Si:279.14110; Found:279.14008.

[0145] Step D: Following the synthetic method for compound 30, compound 37 (50 mg, 27.3% yield) was prepared from compound 26 (129 mg, 0.36 mmol) and compound 36.

[0146]

[0147] 1 H NMR(400MHz,Chloroform-d)δ7.98(d,J=8.8Hz,1H),7.93(d,J=1.1Hz,1H),7.80(dd,J=7 .8,0.9Hz,1H),7.65(dd,J=8.1,1.0Hz,1H),7.29(d,J=7.8Hz,1H),6.90(d,J=2.4Hz,1H) ,6.67(dd,J=8.8,2.4Hz,1H),5.44(s,2H),3.89–3.84(m,6H),3.11–3.02(m,2H),1.79(q ,J=7.5Hz,2H),1.47–1.21(m,12H),1.03–0.96(m,2H),0.93–0.84(m,4H),-0.01(s,9H); 13 CNMR(100MHz,Chloroform-d)δ201.2,161.4,156.4,155.3,154.6,129.7,129.6,128.4,124.5,122.8,115.0,113.0,1 07.1,105.7,101.8,93.2,66.8,55.6,39.7,32.0,29.8,29.6,29.3,24.8,22.8,18.2,14.2,-1.3; HRMS(ESI)m / z(M+H) + calcd forC 30 H 43O5Si: 511.28743; Found: 511.28793. Step E: Following the synthesis method of compound 1, compound 5 (22 mg, 57.9% yield) was prepared from compound 37 (50 mg, 0.1 mmol)

[0148]

[0149] 1 H NMR(400MHz,Chloroform-d)δ7.84(dd,J=7.8,0.9Hz,1H),7.80(d,J=0.9Hz,1H),7.72–7.64(m,2H),7.54(s,1H),7.3 1(t,J=7.8Hz,1H),6.62–6.54(m,2H),3.83(s,3H),3.07(t,2H),1.80(m,2H),1.38–1.22(m,10H),0.93–0.83(m,3H); 13 C NMR(100MHz,Chloroform-d)δ201.5,162.1,157.4,155.5,154.6,129.4,128.7,125.1,123.0,115.2,112 .0,109.1,107.9,103.2,102.3,55.6,39.5,32.0,29.6,29.6,29.3,24.8,22.8,14.2; HRMS(ESI)m / z(M+H) + calcd for C 24 H 29 O4:381.20604; Found:381.20447

[0150] Example 6 Preparation of Compound 6

[0151] Step A: Following the synthetic method of compound 19, compound 38 (330 mg, 95.4% yield) was prepared from compound 32 (400 mg, 1.7 mmol) and trimethylsilylacetylene.

[0152]

[0153] 1 H NMR (400MHz, Chloroform-d) δ7.15(d,J=2.3Hz,1H),7.04(dd,J=8.3,2.3Hz,1H),6.84(d,J=8.4Hz,1H),5.67(s,1H),2.24(s,3H),0.28(s,9H); 13C NMR(100MHz,Chloroform-d)δ155.1,131.8,131.6,129.6,114.4,109.2,102.0,99.4,20.4,0.1; HRMS(ESI)m / z(M+H) + calcd for C 12 H 17 OSi: 205.10432;

[0154] Found: 205.10493.

[0155] Step B: Following the synthetic method of compound 20, compound 39 (592 mg, 99.7% yield) was prepared from compound 38 (312 mg, 1.53 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (0.81 ml, 4.59 mmol).

[0156]

[0157] 1 H NMR(400MHz,Chloroform-d)δ7.25(d,J=2.3Hz,1H),7.05(dd,J=8.4,2.2Hz,1H),6.97(dd,J=8.4,1.4Hz,1H),5.25(d,J=1.3 Hz,2H),3.81(td,J=8.3,1.4Hz,2H),2.25(s,3H),0.96(td,J=8.4,1.3Hz,2H),0.25(d,J=1.3Hz,9H),0.01(d,J=1.4Hz,9H); 13 C NMR(100MHz,Chloroform-d)δ156.3,134.4,131.2,130.6,115.8,113.7,101.7,98.0,93.7,66.4,20.4,18.2,0.2,-1.3; HRMS(ESI)m / z(M+H) + calcd for C 18 H 31 O2Si2:335.18571; Found:335.18497.

[0158] Step C: Following the synthetic method of compound 23, compound 40 (385 mg, 88.9% yield) was prepared from compound 39 (552 mg, 1.65 mmol).

[0159]

[0160] 1H NMR(400MHz,Chloroform-d)δ7.27(dt,J=2.2,0.7Hz,1H),7.11–7.07(m,1H),7.05(d,J=8.5Hz,1H),5.28(d,J=1.0 Hz,2H),3.87–3.72(m,2H),3.24(d,J=0.8Hz,1H),2.26(t,J=0.8Hz,3H),1.04–0.87(m,2H),0.00(d,J=1.0Hz,9H); 13 C NMR(100MHz,Chloroform-d)δ156.7,134.5,131.1,130.9,115.4,112.3,93.7,80.7,80.5,66.5,20.4,18.2,-1.3; HRMS(ESI)m / z(M+H) + calcd for C 15 H 23 O2Si:263.14618; Found:263.14554.

[0161] Step D: Following the synthetic method of compound 30, compound 41 (105 mg, 55.9% yield) was prepared from compound 40 (100 mg, 0.38 mmol) and compound 26 (137 mg, 0.38 mmol).

[0162]

[0163] 1 H NMR(400MHz,Chloroform-d)δ8.06(d,J=1.1Hz,1H),7.88(d,J=2.2Hz,1H),7.82(d,J=7.7Hz, 1H),7.69(dd,J=8.1,1.3Hz,1H),7.32(t,J=7.9Hz,1H),7.21(d,J=8.4Hz,1H),7.13(dd,J=8. 5,2.2Hz,1H),5.42(s,2H),3.88–3.80(m,2H),3.07(t,J=7.5Hz,2H),2.39(s,3H),1.81(p,J= 7.4Hz,2H),1.36–1.27(m,10H),1.03–0.94(m,2H),0.94–0.84(m,3H),-0.03(d,J=1.0Hz,9H); 13C NMR(100MHz,Chloroform-d)δ201.1,155.1,154.8,153.0,131.1,130.6,130.0,129.4,127.9,124.5,123.3,119.5,1 15.3,115.2,107.5,93.2,66.6,39.7,32.0,30.3,29.6,29.3,24.8,22.8,20.8,18.2,14.2,-1.3; HRMS(ESI)m / z(M+H) + calcd for C 30 H 43 O4Si:495.29251; Found:495.29153.

[0164] Step E: Following the synthetic method of compound 1, compound 6 (33 mg, 90.7% yield) was prepared from compound 41 (73 mg, 0.1 mmol).

[0165]

[0166] 1 H NMR(500MHz,Chloroform-d)δ7.99(s,1H),7.84(d,1H),7.69(d,J=8.0Hz,1H),7.64(d,J=2.0Hz,1H),7.40(s,1H),7.34(t,J=8.0H z,1H),7.07(dd,J=8.3,2.0Hz,1H),6.92(d,J=8.3Hz,1H),3.08(t,2H),2.34(s,3H),1.80(m,2H),1.45–1.22(m,10H),0.88(t,3H); 13 C NMR(125MHz,Chloroform-d)δ201.7,157.0,154.8,151.9,131.5,129.9,129.6,128.7,127.6,125.1,123 .4,117.2,115.7,115.5,105.2,39.5,32.0,29.6,29.6,29.3,24.8,22.8,20.6,14.2; HRMS(ESI)m / z(M+H) + calcd for C 24 H 29 O3:365.21112; Found:365.21060

[0167] Example 7 Preparation of Compound 7

[0168] Step A: Following the synthetic method of compound 24, compound 42 (464 mg, 43.5% yield) was prepared from compound 17 (800 mg, 3.06 mmol) and hexyl magnesium bromide (1 M, 3.66 mmol, 3.66 ml).

[0169]

[0170] 1 H NMR(400MHz,Chloroform-d)δ7.29(t,J=7.9Hz,1H),7.12(dd,J=7.7,1.4Hz,1H), 6.73(dd,J=8.1,1.4Hz,1H),5.01(dt,J=7.6,3.4Hz,1H),3.88(s,3H),2.13(d,J=3 .3Hz,1H),1.76(dddd,J=13.9,10.0,5.9,4.0Hz,1H),1.62(ddt,J=13.9,10.0,5.3 Hz,1H),1.51(ddt,J=10.0,8.0,3.8Hz,1H),1.38–1.24(m,7H),0.92–0.82(m,3H); 13 C NMR (100MHz, Chloroform-d) δ157.7,149.0,129.5,119.4,109.9,90.4,77.7,56.7,37.8,31.9,29.3,26.0,22.7,14.2;

[0171] HRMS(ESI)m / z(M+) + calcd for C 14 H 21 O2I:348.05807; Found:348.05511.

[0172] Step B: Following the synthesis method of compound 25, compound 43 (446 mg, 98.1% yield) was prepared by oxidation of compound 42 (464 mg, 1.33 mmol).

[0173]

[0174] 1H NMR(400MHz,Chloroform-d)δ7.32(dd,J=8.2,7.5Hz,1H),6.82(ddd,J=8.8,7.9,1.4Hz,2H),3.89(s,3H),2.85(t ,J=7.4Hz,2H),1.76–1.66(m,2H),1.37(dddd,J=12.9,6.8,5.0,2.4Hz,2H),1.34–1.23(m,4H),0.93–0.82(m,3H); 13 CNMR(100MHz,Chloroform-d)δ206.5,158.3,148.6,129.7,119.2,111.7,83.1,56.8,42.8,31.7,28.9,24.0,22.6,14.2; HRMS(ESI)m / z(M+H) + calcd for C 14 H 20 O2I:347.05025; Found:347.05090.

[0175] Step C: Following the synthesis method of compound 26, compound 44 (146 mg, 41.5% yield) was prepared from compound 43 (366 mg, 1.06 mmol) and boron tribromide (1 M, 2.6 ml, 2.65 mmol).

[0176]

[0177] 1 H NMR(400MHz,Chloroform-d)δ7.25–7.22(m,1H),7.07(dd,J=8.2,1.5Hz,1H),6.95(dd,J=7.5,1.5H z,1H),6.10(s,1H),2.87(t,J=7.4Hz,2H),1.76–1.64(m,2H),1.41–1.21(m,6H),0.93–0.83(m,3H); 13 C NMR(100MHz,Chloroform-d)δ205.1,155.7,145.3,129.9,120.1,117.0,83.7,42.1,31.7,29.0,24.2,22.6,14.1; HRMS(ESI)m / z(M+H) + calcdfor C 13 H 18 O2I:333.03460; Found:333.03506.

[0178] Step D: Following the synthetic method of compound 30, compound 45 (69 mg, 39.0% yield) was prepared from compound 44 (102 mg, 0.3 mmol) and compound 23 (120 mg, 0.3 mmol).

[0179]

[0180] 1 H NMR(400MHz,Chloroform-d)δ7.92(d,J=1.0Hz,1H),7.84(dd,J=7.7,0.8Hz,1H),7.62(dt,J=8.2 ,0.9Hz,1H),7.40–7.31(m,3H),7.07(dd,J=6.2,2.5Hz,1H),5.35(s,2H),3.81–3.70(m,2H),3.1 1–3.03(m,2H),2.43(t,J=7.4Hz,2H),1.79(q,J=7.5Hz,2H),1.57(q,J=7.2Hz,2H),1.45–1.39(m ,2H),1.26(dt,J=5.5,1.9Hz,2H),1.13(dq,J=6.5,3.7Hz,8H),0.97–0.80(m,12H),-0.06(s,9H); 13 C NMR(100MHz,Chloroform-d)δ206.6,200.9,155.2,155.1,152.8,143.2,130.4,130.2,128.6,124.8,123.7,120.4,117.4,116.8,115.6 ,109.7,93.5,66.9,53.6,42.6,39.5,31.9,31.7,29.4,29.3,29.2,24.6,24.5,22.7,22.7,18.1,14.2,14.2,-1.4; HRMS(ESI)m / z(M+H) + calcd for C 36 H 53 O5Si:593.36568; Found:593.36450.

[0181] Step E: Following the synthetic method for compound 1, compound 7 (41 mg, 99% yield) was prepared from compound 45 (70 mg, 0.11 mmol)

[0182]

[0183] 1H NMR(400MHz,Chloroform-d)δ7.91(d,J=0.9Hz,1H),7.85(dd,J=7.7,0.9Hz,1H),7.65–7.61(m ,1H),7.36(d,J=7.9Hz,1H),7.34–7.29(m,2H),7.13(dd,J=8.3,1.2Hz,1H),7.02(dd,J=7.5,1. 1Hz,1H),3.10–3.01(m,2H),2.53(t,J=7.4Hz,2H),1.84–1.72(m,2H),1.65–1.54(m,2H),1.46 –1.37(m,2H),1.37–1.28(m,4H),1.22–1.08(m,10H),0.91–0.86(m,3H),0.84(t,J=7.1Hz,3H); 13 CNMR(100MHz,Chloroform-d)δ206.6,201.7,155.4,154.6,152.9,142.4,130.7,130.0,128.3,125.2,124.0,119.4,118.6,1 15.9,114.2,108.9,42.5,39.5,31.9,31.81,29.4,29.2,29.2,29.2,24.7,24.5,22.7,22.7,14.2,14.2; HRMS(ESI)m / z(M+H) +

[0184] calcd for C 30 H 39 O4:463.28429; Found:463.28438

[0185] Example 8: Preparation of Compound 8

[0186] Step A: Following the synthetic method of compound 21, compound 46 (153 mg, 33.9% yield) was prepared from compound 20 (400 mg, 1.15 mmol) and propylmagnesium bromide (2 M, 0.69 ml, 1.38 mmol).

[0187]

[0188] 1H NMR (400MHz, Chloroform-d) δ7.22 (ddd, J=8.1, 4.8, 3.2Hz, 1H), 7.10 (dt, J=7.5, 1.3Hz, 1H ),6.98–6.93(m,1H),5.28–5.22(m,2H),5.10(dd,J=8.0,4.8Hz,1H),3.84–3.74(m,2H),2. 45(d,J=35.4Hz,1H),1.80–1.65(m,2H),1.51(dddd,J=14.9,7.4,6.1,3.7Hz,1H),1.46–1. 30(m,1H),0.94(td,J=6.1,5.2,3.2Hz,5H),0.25(d,J=1.9Hz,9H),-0.01(d,J=1.9Hz,9H); 13 C NMR(100MHz,Chloroform-d)δ158.4,149.7,129.6,118.7,113.6,111.1,104.2 ,99.1,93.4,72.2,66.5,40.2,19.4,18.1,14.0,0.1,-1.3; HRMS(ESI)m / z(M+H) + calcd for C 21 H 37 O3Si2:393.22757; Found:393.22809

[0189] Step B: Following the synthesis method of compound 22, compound 47 (225 mg, 92% yield) was prepared by oxidation of compound 46 (250 mg, 0.64 mmol).

[0190]

[0191] 1 H NMR(400MHz,Chloroform-d)δ7.33–7.28(m,2H),7.21–7.17(m,1H),7.13–7.08(m,1H),5.39–5.26(m,2H),3.90–3.75( m,2H),3.13–2.99(m,2H),1.73(dq,J=10.0,7.4,6.7Hz,2H),1.05–0.91(m,4H),0.32–0.23(m,9H),0.08–-0.02(m,9H); 13C NMR(100MHz,Chloroform-d)δ204.9,159.0,145.2,129.6,120.6,117.2,111.2, 105.0,99.1,93.5,66.7,44.6,18.1,18.0,13.9,-0.1,-1.3; HRMS(ESI)m / z(M+H) + calcd for C 21 H 35 O3Si2:391.21192; Found:391.20993

[0192] Step C: Following the synthetic method for compound 23, compound 48 (125 mg, 80.6% yield) was prepared from compound 47 (190 mg, 0.49 mmol)

[0193]

[0194] 1 H NMR(400MHz,Chloroform-d)δ7.34–7.29(m,1H),7.27(t,J=1.4Hz,1H),7.15–7.11(m,1H),5.36–5.25(m,2H),3.80(ddt,J=10.1,7.0 ,1.5Hz,2H),3.52–3.46(m,1H),3.02–2.90(m,2H),1.73(dddd,J=11.1,9.3,5.6,1.8Hz,2H),1.04–0.85(m,5H),0.04–-0.08(m,9H); 13 CNMR(100MHz,Chloroform-d)δ204.2,159.5,145.1,129.8,120.5,117.1,109.9,93.6,86.5,77.9,66.8,44.2,18.1,17.8,13.8,-1.3; HRMS(ESI)m / z(M+H) + calcdfor C 18 H 27 O3Si:319.17240; Found:319.17111.

[0195] Step D: Following the synthetic method of compound 30, compound 49 (89 mg, 52.4% yield) was prepared from compound 26 (113 mg, 0.31 mmol) and compound 48 (100 mg, 0.31 mmol).

[0196]

[0197] 1 H NMR(500MHz,Chloroform-d)δ7.93(s,1H),7.85(d,J=7.6Hz,1H),7.62(d,J=8.2Hz,1H),7.42–7.37(m ,2H),7.34(t,J=7.9Hz,1H),7.08(dd,J=6.3,2.3Hz,1H),5.35(s,2H),3.80–3.68(m,2H),3.07(t,J=7 .5Hz,2H),2.44(t,J=7.3Hz,2H),1.80(p,J=7.5Hz,2H),1.69–1.56(m,2H),1.42(td,J=8.4,8.0,5.0H z,2H),1.39–1.21(m,8H),0.99–0.91(m,2H),0.91–0.85(m,3H),0.81(t,J=7.4Hz,3H),-0.06(s,9H); 13 C NMR(100MHz,Chloroform-d)δ206.4,201.0,155.2,155.1,152.8,143.1,130.4,130.2,128.6,124.9,123.8,120.5,118.0,116 .8,115.6,109.7,93.5,66.9,44.5,39.6,32.0,29.6,29.6,29.3,24.7,22.8,18.1,17.9,14.2,13.9,-1.4; HRMS(ESI)m / z(M+H) + calcd for C 33 H 47 O5Si:551.31873; Found:551.31873.

[0198] Step E: Following the synthetic method for compound 1, compound 8 (23 mg, 60.7% yield) was prepared from compound 49 (50 mg, 0.09 mmol)

[0199]

[0200] 1H NMR(400MHz,Chloroform-d)δ7.89–7.84(m,2H),7.66–7.62(m,1H),7.35(dddd,J=15.8,8.1,3.0,1.4Hz,2H),7.15–7.11(m,1H),7.08–7.04(m,1H ),6.91(s,1H),3.07(t,J=7.4Hz,2H),2.55(t,J=7.2Hz,2H),1.79(t,J=7 .4Hz,2H),1.64(q,J=7.4Hz,2H),1.37–1.21(m,10H),0.90–0.81(m,6H); 13 C NMR (125MHz, CDCl3) δ206.1,201.6,155.4,154.4,152.7,142.4,130.8,130.1,128.2,125.2,124.2,119.6,118 .7,115.9,114.1,108.8,44.2,39.5,32.0,29.6,29.6,29.3,24.7,22.8,17.9,14.2,13.9; HRMS(ESI)m / z(M+H) + calcd for C 27 H 33 O4:421.23734; Found:421.23682

[0201] Example 9: Preparation of Compound 9

[0202] Step A: Following the synthetic method of compound 24, compound 50 (374 mg, 40.1% yield) was prepared from compound 17 (800 mg, 3.06 mmol) and propylmagnesium bromide (2 M, 1.82 ml, 3.66 mmol).

[0203]

[0204] 1 H NMR(500MHz,Chloroform-d)δ7.29(t,J=7.9Hz,1H),7.12(d,J=7.6Hz,1H),6.73(d,J=8.0Hz,1H) ,5.03(dd,J=8.4,4.0Hz,1H),3.88(s,3H),2.11(s,1H),1.79–1.41(m,4H),0.97(t,J=7.4Hz,3H); 13C NMR (125MHz, CDCl3) δ157.7,149.0,129.4,119.4,109.9,90.4,77.4,56.7,39.9,19.2,14.1; HRMS (ESI) m / z (M+Na) + calcd for C 11 H 15 O2INa:329.00089; Found:329.00381.

[0205] Step B: Following the synthesis method of compound 25, compound 51 (412 mg, 85.1% yield) was prepared by oxidation of compound 50 (486 mg, 1.59 mmol).

[0206]

[0207] 1 H NMR(400MHz,Chloroform-d)δ7.32(dd,J=8.3,7.5Hz,1H),6.82(ddd,J=8.7,7.9,1.3Hz ,2H),3.89(s,3H),2.83(t,J=7.3Hz,2H),1.74(h,J=7.4Hz,2H),0.99(t,J=7.4Hz,3H); 13 C NMR(100MHz,Chloroform-d)δ206.3,158.3,148.5,129.7,119.2,111.7,83.1,56.8,44.7,17.5,13.9; HRMS(ESI)m / z(M+H) + calcd for C 11 H 14 O2I:305.00330;Found:305.00443

[0208] Step C: Following the synthesis method of compound 26, compound 52 (100 mg, 29.7% yield) was prepared from compound 51 (360 mg, 1.18 mmol) and boron tribromide (1 M, 2.96 ml, 2.96 mmol).

[0209]

[0210] 1H NMR(400MHz,Chloroform-d)δ7.25(dd,J=8.2,7.5Hz,1H),7.07(dd,J=8.1,1.5Hz,1H),6.95(dd,J =7.5,1.5Hz,1H),6.27(s,1H),2.87(t,J=7.3Hz,2H),1.76(p,J=7.3Hz,2H),1.00(t,J=7.4Hz,3H); 13 C NMR(100MHz,Chloroform-d)δ205.1,155.8,145.3,129.9,120.1,117.0,83.5,43.9,17.7,13.9; HRMS(ESI)m / z(M+H) + calcd for C 10 H 12 O2I:305.00330;Found:305.00443

[0211] Step D: Following the synthetic method of compound 30, compound 53 (43 mg, 24.3% yield) was prepared from compound 52 (87.1 mg, 0.3 mmol) and compound 23 (120 mg, 0.3 mmol).

[0212]

[0213] 1 H NMR(400MHz,Chloroform-d)δ7.92(d,J=0.9Hz,1H),7.85(dd,J=7.7,0.9Hz,1H),7.62(dt,J=8.2, 0.9Hz,1H),7.41–7.38(m,2H),7.36–7.31(m,1H),7.08(dd,J=6.4,2.2Hz,1H),5.35(s,2H),3.78–3 .72(m,2H),3.06(t,J=7.3Hz,2H),2.43(t,J=7.5Hz,2H),1.84(h,J=7.4Hz,2H),1.27–1.24(m,2H) ,1.18–1.10(m,8H),1.05(t,J=7.4Hz,3H),0.96–0.90(m,3H),0.84(t,J=7.1Hz,4H),-0.06(s,9H); 13C NMR(100MHz,Chloroform-d)δ209.0,201.6,155.2,154.8,152.7,143.2,130.4,130.2,124.9,123.8,120.5,116.8,115 .7,109.7,93.5,66.9,42.7,41.5,31.9,29.4,29.3,29.2,24.5,22.7,18.1,18.0,14.2,14.1,-1.4; HRMS(ESI)m / z(M+H) + calcd for C 33 H 47 O5Si:551.31873; Found:551.35278

[0214] Step E: Following the synthetic method for compound 1, compound 9 (17 mg, 67.3% yield) was prepared from compound 53 (35 mg, 0.06 mmol)

[0215]

[0216] 1 H NMR(400MHz,Chloroform-d)δ7.89–7.84(m,2H),7.65(dd,J=8.2,1.0Hz,1H),7.41–7.34(m,2H),7.13(dd,J=8.2,1 .0Hz,1H),7.08(m,1H),3.05(t,2H),2.54(t,2H),1.82(m,2H),1.60(m,4H),1.15(t,9H),1.05(t,3H),0.84(t,3H); 13 CNMR(150MHz,Chloroform-d)δ205.8,200.9,155.6,154.2,152.5,142.4,131.0,130.2,128.0,125.2,124.3,119.9 ,118.7,115.9,114.0,108.7,42.3,41.4,31.9,29.4,29.2,29.2,24.5,22.7,18.0,14.2,14.1; HRMS(ESI)m / z(M+H) + calcd for C 27 H 33 O4:421.23734; Found:421.23676

[0217] Example 10: Preparation of Compound 10

[0218] Step A: Iodine (253.8 mg, 1 mmol) was dissolved in 5 mL of chloroform and placed in a 10 mL single-necked flask. The solution was stirred at room temperature for 1.5 h to obtain solution 1. m-Methoxyphenol (124.12 mg, 1 mmol) and Ag(CO2CF3)2 (220.88 mg, 1 mmol) were dissolved in 5 mL of chloroform and placed in a 25 mL single-necked flask. The solution was stirred for 1.5 h to obtain solution 2. Solution 1 was added dropwise to solution 2, and the mixture was stirred overnight at room temperature. The reaction was monitored by TLC until the reactants were completely reacted, at which point the reaction was stopped. Post-treatment: The mixture was quenched with saturated Na2S2O3, extracted three times with dichloromethane, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50:1) to obtain 154 mg of a yellow solid, with a yield of 61%.

[0219]

[0220] 1 H NMR (400MHz, Chloroform-d) δ7.49 (d, J = 8.8 Hz, 1H), 6.60 (d, J = 2.8 Hz, 1H), 6.34 (dd, J = 8.8, 2.8 Hz, 1H), 5.23 (d, J = 2.1 Hz, 1H), 3.77 (s, 3H).

[0221] Step B: Following the synthetic method of compound 30, compound 55 (66 mg, 33.3% yield) was prepared from compound 23 (150 mg, 0.39 mmol) and compound 54 (97.5 mg, 0.39 mmol) and compound 54.

[0222]

[0223] 1 H NMR(500MHz,Chloroform-d)δ7.47(d,J=8.5Hz,1H),7.35–7.31(m,2H),7.08(s,1H) ,7.05(dd,J=7.2,1.5Hz,1H),6.99(d,J=2.3Hz,1H),6.89(dd,J=8.5,2.3Hz,1H),5. 32(s,2H),3.85(s,3H),3.75(t,J=8.3Hz,2H),2.43(t,J=7.5Hz,2H),1.64–1.52(m, 2H),1.30–1.08(m,10H),0.94(t,J=8.3Hz,2H),0.85(t,J=7.1Hz,3H),-0.06(s,9H); 13CNMR(125MHz, CDCl3)δ207.1,158.4,155.6,154.6,149.2,142.9,129.5,128.6,122.5,121.4,120.4,116.5,112. 5,108.4,95.7,93.5,66.8,55.8,42.7,31.9,29.4,29.3,29.2,24.6,22.7,18.1,14.2,-1.3; HRMS(ESI)m / z(M+H) + calcd for C 30 H 43 O5Si:511.28743; Found:511.28989.

[0224] Step C: Following the synthetic method of compound 1, compound 10 (13 mg, 26.1% yield) was prepared from compound 55 (66 mg, 0.13 mmol).

[0225]

[0226] 1 H NMR(500MHz,Chloroform-d)δ7.47(d,J=8.5Hz,1H),7.34(t,J=8.0Hz,1H),7.10(d,J=8.0Hz,1H),7.04–7.00(m,2H),6.92(dd ,J=8.5,2.2Hz,1H),6.87(s,1H),6.46(s,1H),3.86(s,3H),2.49(t,2H),1.62(s,2H),1.56-1.15(m,10H),0.90–0.78(m,3H); 13 CNMR(150MHz,Chloroform-d)δ206.9,158.8,156.0,153.8,148.8,142.4,133.6,130.5,121.6,119.5,11 8.4,114.2,113.0,107.9,95.8,55.9,42.6,31.9,29.4,29.2,29.2,24.6,22.7,14.2; HRMS(ESI)m / z(M+H) + calcd for C 24 H 29 O4:381.20604; Found:381.20447

[0227] Example 11 Preparation of Compound 11

[0228] Step A: Dissolve p-methoxyphenol (1 g, 8.1 mmol) in 40 mL of anhydrous dichloromethane in a 100 mL single-necked flask, cool to 0 °C, add N,N-diisopropylethylamine (2.67 mL, 16.2 mmol) and chloromethyl methyl ether (0.79 mL, 10.53 mmol), and react at room temperature for 1 h. Monitor the reaction by TLC until the starting material is completely reacted, then stop the reaction. Post-treatment: Dilute with 60 mL each of dichloromethane and water, separate the aqueous and organic phases, wash the organic phase with water / saturated sodium bicarbonate (1:1), dry with anhydrous sodium sulfate, filter, remove solvent under reduced pressure, and purify by silica gel column chromatography (petroleum ether / ethyl acetate (10:1)) to obtain 536 mg of product, with a yield of 39.4%.

[0229]

[0230] 1 H NMR (400MHz, Chloroform-d) δ6.98 (d, J = 9.1 Hz, 2H), 6.83 (d, J = 9.1 Hz, 2H), 5.11 (s, 2H), 3.77 (s, 3H), 3.48 (s, 3H).

[0231] Step B: Compound 56 (0.98 g, 5.8 mmol) was dissolved in 25 mL of anhydrous methyl tert-butyl ether in a 50 mL three-necked flask. Under argon protection at 0 °C, n-Buli (2.8 mL, 7.0 mmol) was added dropwise. The reaction was carried out at 0 °C for 3.5 h. The solution color changed from clear and transparent to milky white, then to pale yellow. Iodine (1.5 g, 5.97 mmol) in anhydrous methyl tert-butyl ether solution was added, and the solution gradually turned pale brownish-yellow. The reaction was monitored by TLC until the reactants were completely reacted, at which point the reaction was stopped. Post-treatment: The reaction was terminated with an ammonia-ammonium chloride buffer solution. Methyl tert-butyl ether was extracted three times, and the crude product was used directly in the next step.

[0232]

[0233] Step C: The crude compound 57 (686 mg, 3.8 mmol) was dissolved in 8 mL of methanol and placed in a 25 mL single-necked flask. 10% hydrochloric acid (3.2 N) was added at 23 °C, and the mixture was heated under reflux for 20 min. The reaction was monitored by TLC until complete. Post-treatment: The reaction mixture was cooled to room temperature, the methanol was evaporated to dryness, water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried, filtered, evaporated to dryness, and purified by column chromatography (petroleum ether / ethyl acetate = 10:1) to give 488 mg of the product, with a yield of 51.4%.

[0234]

[0235] 1H NMR (400MHz, Chloroform-d) δ6.94 (dd, J=8.8, 0.5Hz, 1H), 6.86 (dd, J=8.8, 3.0Hz, 1H), 6.84–6.81 (m, 1H), 5.79 (s, 1H), 3.79 (s, 3H); 13 C NMR (100MHz, Chloroform-d) δ154.3,146.7,125.2,117.9,116.0,115.6,55.9.

[0236] Step D: Following the synthetic method of compound 30, compound 59 (74 mg, 37.2% yield) was prepared from compound 23 (150 mg, 0.39 mmol) and compound 58 (96.6 mg, 0.39 mmol).

[0237]

[0238] 1 H NMR(400MHz,Chloroform-d)δ7.39–7.30(m,3H),7.08(dd,J=4.7,1.7Hz,2H),7. 05(dd,J=7.2,1.4Hz,1H),6.89(dd,J=8.9,2.6Hz,1H),5.32(s,2H),3.85(s,3H) ,3.78–3.69(m,2H),2.42(t,J=7.5Hz,2H),1.58(t,J=7.2Hz,2H),1.27–1.22(m, 2H),1.20–1.08(m,8H),0.97–0.90(m,2H),0.85(t,J=7.1Hz,3H),-0.04(s,9H); 13 C NMR(100MHz,Chloroform-d)δ206.9,156.2,154.8,151.0,149.6,143.1,129.9,129.7,120.4,117.8,116.5,113.5,1 11.8,108.6,103.5,93.5,66.8,56.0,42.7,31.9,29.4,29.3,29.2,24.5,22.7,18.1,14.2,-1.3; HRMS(ESI)m / z(M+H) + calcd for C 30 H 43 O5Si:511.28743; Found:511.28638

[0239] Step E: Following the synthetic method of compound 1, compound 11 (18 mg, 59.2% yield) was prepared from compound 59 (40 mg, 0.08 mmol).

[0240]

[0241] 1 H NMR(400MHz,Chloroform-d)δ7.38(dt,J=9.0,0.9Hz,1H),7.33(dd,J=8.2,7.5Hz,1H),7.08(dd,J=8.2,1.1Hz,1H),7.05(d,J=2.6Hz,1H),7.00(dd,J=7.5, 1.1Hz,1H),6.93(dd,J=9.0,2.6Hz,1H),6.89(d,J=0.9Hz,1H),6.66(s,1H),3 .85(s,3H),2.50(t,2H),1.56(t,2H),1.26(t,2H),1.15(m,8H),0.85(t,3H); 13 C NMR(150MHz,Chloroform-d)δ206.9,156.6,154.0,150.7,149.9,142.6,130.8,129.0,119.5,118.5,114 .2,114.1,112.0,108.1,103.6,56.0,42.7,31.9,29.4,29.2,29.2,24.6,22.7,14.2; HRMS(ESI)m / z(M+H) + calcd for C 24 H 29 O4:381.20604; Found:381.20526

[0242] Example 12 Preparation of Compound 12

[0243] Step A: Following the synthesis method of compound 19, compound 60 (250 mg, 98.8% yield) was prepared from compound 58 (288 mg, 1.15 mmol) and trimethylsilylacetylene.

[0244]

[0245] Step B: Following the synthesis method of compound 20, compound 61 (332 mg, 99.7% yield) was prepared from compound 60 (213 mg, 0.97 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride.

[0246] 1H NMR (400MHz, Chloroform-d) δ7.25(m,3H),5.92(d,J=1.9Hz,1H),4.15(d,J=0.7Hz,3H),0.72–0.63(m,9H); 13 C NMR(100MHz,Chloroform-d)δ153.0,151.6,118.1,115.6,115.2,109.5,102.3,99.3,55.9,0.1; HRMS(ESI)m / z(M+H) + calcd for C 12 H 17 O2Si:221.09923; Found:221.09895.

[0247]

[0248] Step C: Following the synthetic method for compound 23, compound 62 (232 mg, 80.3% yield) was prepared from compound 61 (349 mg, 1.04 mmol)

[0249] 1 H NMR(400MHz,Chloroform-d)δ7.01(d,J=9.0Hz,1H),6.94(d,J=3.1Hz,1H),6.81(dd,J=9.0,3.1H z,1H),5.21(s,2H),3.84–3.78(m,2H),3.76(s,3H),0.99–0.89(m,2H),0.26(s,9H),0.01(s,9H); 13 C NMR(100MHz,Chloroform-d)δ153.8,117.9,116.5,115.5,114.4,113.8,94.4,66.4,55.9,18.2,0.2,-1.2; HRMS(ESI)m / z(M+H) + calcd forC 18 H 31 O3Si2:351.18062; Found:351.17798.

[0250]

[0251] 1H NMR(400MHz,Chloroform-d)δ7.08(d,J=9.1Hz,1H),6.98(d,J=3.1Hz,1H),6.85(dd,J=9.1,3.1Hz,1 H),5.23(s,2H),3.85–3.78(m,2H),3.75(s,3H),3.70–3.58(m,1H),0.98–0.91(m,2H),-0.00(s,9H); 13 C NMR(100MHz,Chloroform-d)δ154.2,153.0,118.3,117.3,116.6,113.4,94.4,81.0,80.2,66.5,55.8,18.2,-1.3; HRMS(ESI)m / z(M+H) + calcd for C 15 H 23 O3Si: 279.14110;

[0252] Found: 279.13962.

[0253] Step D: Following the synthetic method of compound 30, compound 63 (87 mg, 47.4% yield) was prepared from compound 26 (129.5 mg, 0.36 mmol) and compound 62 (100 mg, 0.39 mmol).

[0254]

[0255] 1 H NMR(500MHz,Chloroform-d)δ8.14–8.11(m,1H),7.85(d,J=7.6Hz,1H),7.72(d,J=8.1Hz,1H),7 .63(d,J=3.2Hz,1H),7.36(t,J=7.9Hz,1H),7.30–7.26(m,1H),6.92(dd,J=9.0,3.1Hz,1H),5.41 (s,2H),3.91(s,3H),3.90–3.84(m,2H),3.79(s,1H),3.10(t,J=7.5Hz,2H),1.84(p,J=7.5Hz,2 H),1.50–1.43(m,2H),1.43–1.25(m,8H),1.05–0.96(m,3H),0.92(t,J=6.7Hz,3H),0.01(s,9H); 13C NMR (125MHz, CDCl3) δ201.0,154.8,154.7,154.5,149.4,130.1,129.3,124.6,123.5,120.6,116.9,115.8,11 5.3,112.1,107.9,93.7,66.6,56.0,39.7,32.0,29.6,29.3,24.8,22.8,18.2,14.2,-1.3; HRMS(ESI)m / z(M+H) + calcd for C 30 H 43 O5Si:511.28743; Found:511.28989

[0256] Step E: Following the synthetic method of compound 1, compound 12 (20 mg, 52.5% yield) was prepared from compound 63 (50 mg, 0.1 mmol).

[0257]

[0258] 1 H NMR(400MHz,Chloroform-d)δ7.97(d,J=0.9Hz,1H),7.86(dd,J=7.8,0.9Hz,1H),7.70(dt,J=8.2,0.9Hz,1H),7.36(t,J=7.8Hz,1H),7.31(d,J=3.0 Hz,1H),6.96–6.92(m,2H),6.87(dd,J=8.2,3.0Hz,1H),3.84(s,3H),3.1 3–3.04(m,2H),1.87–1.73(m,2H),1.47–1.22(m,10H),0.91–0.83(m,3H); 13 C NMR(100MHz,Chloroform-d)δ201.5,156.7,154.8,153.7,148.2,129.9,128.8,125.2,123.7,118.5, 117.9,115.5,111.0,105.5,56.1,39.5,32.0,29.6,29.6,29.3,24.7,22.8,14.2; HRMS(ESI)m / z(M+H) + calcd for C 24 H 29 O4:381.20604; Found:381.20615

[0259] Example 13 Preparation of Compound 13

[0260] Step A: Following the synthetic method of compound 21, compound 64 (254 mg, 50.9% yield) was prepared from compound (400 mg, 1.15 mmol) and hexyl magnesium bromide (1 M, 1.38 mmol, 1.38 ml).

[0261]

[0262] 1 H NMR(400MHz,Chloroform-d)δ7.24(d,J=8.0Hz,1H),7.11(dt,J=7.8,0.8Hz,1H),6.99(dd,J=8.3,1.1Hz,1H),5.28(s,2H),5.13–5.04(m,1H),3.87–3.7 5(m,2H),2.21(d,J=4.6Hz,1H),1.77(tdd,J=19.8,10.4,5.3Hz,2H),1.42–1 .16(m,8H),1.01–0.92(m,2H),0.92–0.83(m,3H),0.27(s,9H),0.00(s,9H); 13 CNMR(100MHz,Chloroform-d)δ158.6,149.6,129.7,118.8,113.7,111.2,104.4,99.1,9 3.5,72.8,66.6,38.2,32.0,29.4,26.3,22.7,18.1,14.2,0.2,-1.3; HRMS(ESI)m / z(M+H) + calcd for C 24 H 43 O3Si2:435.27452; Found:435.27460

[0263] Step B: Following the synthesis method of compound 22, compound 65 (167 mg, 75.9% yield) was prepared by oxidation of compound 64 (220 mg, 0.51 mmol).

[0264]

[0265] 1H NMR(400MHz,Chloroform-d)δ7.30–7.27(m,1H),7.18(dd,J=8.4,1.2Hz,1H),7.09(dd,J=7.6,1.2Hz,1H),5.29(s,2H),3.85–3.75(m,2 H),3.06(dd,J=7.9,7.2Hz,2H),1.72–1.60(m,2H),1.37–1.24(m,6H),0.98–0.92(m,2H),0.90–0.84(m,3H),0.25(s,9H),0.00(s,9H); 13 C NMR(100MHz,Chloroform-d)δ205.1,159.0,145.2,129.6,120.6,117.2,111.2,105.0,99 .1,93.5,66.7,42.8,31.8,29.1,24.5,22.7,18.1,14.2,-0.1,-1.3; HRMS(ESI)m / z(M+H) + calcd for C 24 H 41 O3Si2:433.25887; Found:433.25995

[0266] Step C: Following the synthetic method for compound 23, compound 66 (108 mg, 96.5% yield) was prepared from compound 65 (133 mg, 0.31 mmol)

[0267]

[0268] 1 H NMR(400MHz,Chloroform-d)δ7.32–7.28(m,1H),7.25(dd,J=8.5,1.4Hz,1H),7.12(dd,J=7.5,1.3Hz,1H),5.30(s,2H),3.85–3.74(m ,2H),3.50(s,1H),2.98(t,J=7.4Hz,2H),1.72–1.63(m,2H),1.34–1.23(m,6H),0.97–0.89(m,2H),0.89–0.83(m,3H),-0.02(s,9H); 13CNMR(100MHz,Chloroform-d)δ204.3,159.5,145.1,134.5,129.7,120.5,117.1,109.9 ,93.5,86.5,66.7,42.3,31.7,28.9,24.3,22.6,18.1,14.1,-1.4; HRMS(ESI)m / z(M+H) + calcd for C 21 H 33 O3Si:361.21935; Found:361.21970

[0269] Step D: Following the synthetic method of compound 30, compound 67 (33 mg, 19.9% ​​yield) was prepared from compound 66 (100 mg, 0.28 mmol) and compound 26 (100 mg, 0.28 mmol).

[0270]

[0271] 1 H NMR(400MHz,Chloroform-d)δ7.92(d,J=0.9Hz,1H),7.85(dd,J=7.7,0.9Hz,1H),7.65–7.60(m,1H) ,7.40–7.37(m,2H),7.37–7.31(m,1H),7.08(dd,J=6.3,2.4Hz,1H),5.35(s,2H),3.82–3.71(m,2H) ,3.10–3.01(m,2H),2.49–2.38(m,2H),1.80(p,J=7.5Hz,2H),1.57(q,J=7.3Hz,2H),1.36–1.23(m, 10H),1.20–1.07(m,6H),0.96–0.92(m,2H),0.90–0.85(m,3H),0.78(t,J=7.0Hz,3H),-0.06(s,9H); 13 C NMR(100MHz,Chloroform-d)δ206.6,201.0,155.2,155.1,152.8,143.2,130.3,130.2,128.6,124.9,123.8,120.5,117.4,116.8,115.6 ,109.7,93.5,66.9,42.6,39.6,32.0,31.6,29.6,29.6,29.3,28.9,24.7,24.4,22.8,22.5,18.1,14.2,14.1,-1.4; HRMS(ESI)m / z(M+H)+ calcd for C 36 H 53 O5Si: 593.36568; Found: 593.36414. Step E: Following the synthesis method of compound 1, compound 13 (23 mg, 82.8% yield) was prepared from compound 67 (35 mg, 0.06 mmol)

[0272]

[0273] 1 H NMR(400MHz,Chloroform-d)δ7.89–7.84(m,2H),7.65(dt,J=8.2,0.9Hz,1H),7.40–7.31(m,2H),7.15–7.11(m,1H),7.06(dd,J=7.5,0.9Hz,1H),6. 82(s,1H),3.06(t,2H),2.57–2.49(m,2H),1.84–1.74(m,2H),1.60(q,2H ),1.45–1.22(m,10H),1.22–1.07(m,6H),0.93–0.84(m,3H),0.79(t,3H); 13 C NMR(100MHz,Chloroform-d)δ206.1,201.4,155.5,154.4,152.7,142.5,130.9,130.2,128.2,125.2,124.2,119.7,118.7,1 15.9,114.1,108.8,42.3,39.5,32.0,31.6,29.6,29.6,29.3,28.9,24.7,24.4,22.8,22.4,14.2,14.1; HRMS(ESI)m / z(M+H) + calcd for C 36 H 53 O5Si:593.36568; Found:593.36414.

[0274] Example 14 Preparation of Compound 14

[0275] Step A: Following the synthetic method of compound 30, compound 68 (130 mg, 37.5% yield) was prepared from compound 26 (200 mg, 0.56 mmol) and compound 23 (217 mg, 0.56 mmol).

[0276]

[0277] 1H NMR(400MHz,Chloroform-d)δ7.92(s,1H),7.85(d,J=7.6Hz,1H),7.65–7.60(m,1H), 7.39(d,J=6.7Hz,2H),7.35(s,1H),7.08(dd,J=6.3,2.3Hz,1H),5.35(s,2H),3.80–3. 70(m,2H),3.07(t,J=7.5Hz,2H),2.43(t,J=7.4Hz,2H),1.87(m,2H),1.59-1.57(m,2H ),1.44-1.41(m,2H),1.26(s,17H),0.94(d,J=8.4Hz,3H),0.84(s,3H),-0.05(s,9H).

[0278] Step B: Following the synthetic method for compound 1, compound 69 (90 mg, 91.6% yield) was prepared from compound 68 (130 mg, 0.2 mmol)

[0279]

[0280] 1 H NMR(500MHz,Chloroform-d)δ7.87(d,J=7.5Hz,1H),7.84(s,1H),7.66(d,J=8.0Hz,1H ),7.44–7.34(m,2H),7.14(d,J=8.2Hz,1H),7.10(d,J=7.5Hz,1H),6.35(s,1H),3.07( t,J=7.4Hz,2H),2.54(t,J=7.4Hz,2H),1.79(t,J=7.5Hz,2H),1.59(t,J=7.2Hz,2H),1 .41(d,J=7.8Hz,2H),1.38–1.15(m,18H),0.89(d,J=5.4Hz,3H),0.84(d,J=7.2Hz,3H).

[0281] Step C: Compound 69 (60 mg, 0.12 mmol) was dissolved in 0.5 mL of anhydrous methyl tert-butyl ether and placed in a 10 mL single-necked flask. Trifluoroacetic acid (15 mg, 0.15 mmol, 0.02 mL) and acetyl chloride (11.8 mg, 0.01 mL, 0.15 mmol) were added at 0 °C. The mixture was then moved to room temperature and reacted. The reaction was stopped by TLC monitoring until the starting material was completely reacted. Post-treatment: The reaction was quenched with water, extracted with ethyl acetate, and the organic phases were combined, dried, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1) to give 51 mg of the product, with a yield of 79.7%.

[0282]

[0283] 1 H NMR(500MHz,Chloroform-d)δ7.85(d,J=7.6Hz,1H),7.82(s,1H),7.62(d,J=8.2Hz,1H),7.50(t,J=7.8Hz,1H),7.37(t,J=8.1Hz,2H),7.30(d,J=8.1Hz,1H) ,3.06(t,J=7.5Hz,2H),2.50(t,J=7.4Hz,2H),2.32(s,3H),1.78(q,J=7.5Hz, 2H),1.59(t,J=7.2Hz,2H),1.38–1.06(m,20H),0.86(dt,J=18.3,6.9Hz,6H); 13 C NMR (125MHz, CDCl3) δ205.3,200.9,169.3,155.5,151.8,148.6,143.1,130.3,128.1,125.2,125.2,125.0,124.3,121.3,115.8, 109.2,42.4,39.5,32.0,31.9,29.6,29.6,29.4,29.3,29.2,29.2,24.7,24.3,22.8,22.7,21.3,14.2,14.2; HRMS(ESI)m / z(M+H) + calcd for C 34 H 45 O5:533.32615; Found:533.32672

[0284] Example 15 Preparation of Compound 15

[0285] Compound 15 (68.2 mg, 80.1% yield) was prepared from compound 23 (37.9 mg, 0.139 mmol) and compound 25 (50 mg, 0.139 mmol) using the same method as compound 30.

[0286]

[0287] 1H NMR(400MHz,Chloroform-d)δ7.95(s,1H),7.84(d,J=7.6Hz,1H),7.61(d,J=8.0Hz ,1H),7.41(t,J=8.0Hz,1H),7.33(t,J=7.9Hz,1H),7.09(d,J=8.4Hz,1H),7.02(d,J =7.6Hz,1H),3.96(s,3H),3.07(t,J=7.4Hz,2H),2.43(t,J=7.4Hz,2H),1.80(t,J=7 .4Hz,2H),1.59(t,J=7.2Hz,2H),1.39–1.06(m,20H),0.86(dt,J=17.8,6.6Hz,6H).

[0288] Evaluation of the inhibitory effect of compounds 1-15 on hCES2A in Experiment Example 1

[0289] Using fluorescein diacetate (FD), a commercial probe for hCES2A, as a substrate, the IC50 of the inhibitory activity of a series of compounds against hCES2A was determined. 50 :

[0290] a. The total volume of the in vitro reaction system was 200 μL, which contained phosphate buffer at pH 7.4, a final concentration of hCES2A of 1 μg / mL, and a final concentration of fluorescent substrate FD of 8 μM;

[0291] b. First, add all substances except FD to a 96-well plate and incubate at 37°C for 3 min. Then add 2 μl of FD (final concentration of 8 μM) to start the reaction.

[0292] c. Use a multi-functional microplate reader to continuously detect the fluorescein of the metabolic hydrolysis products of FD for 30 min (excitation wavelength 480 nm, emission wavelength 525 nm).

[0293] d. Plot the inhibitor concentration on the x-axis and the remaining enzyme activity on the y-axis, and use software to calculate the IC50. 50 Value. The formula for calculating remaining enzyme activity is:

[0294] Remaining enzyme activity (%) = (F0 - F1) / F0 × 100%

[0295] F0 is the fluorescence intensity value measured in the pre-incubation solution without the addition of inhibitors, and F1 is the fluorescence intensity value measured in the pre-incubation solution with the addition of inhibitors of various concentrations.

[0296] Table 1 IC50 of the inhibitory activity of Bysspectin A and its derivatives against hCES2A 50 value

[0297]

Claims

1. A compound as shown in general formula I, or a pharmaceutically acceptable salt thereof: I in: R1 is independently selected from -COR 6； R2 is independently selected from hydrogen, C 1-10 Alkyl, C 1-10 Alkoxy; R3 is independently selected from hydrogen, -COR 7； R4 is independently selected from hydrogen, C 1-10 Alkyl, C 1-10 Alkyl groups; R5 is independently selected from acetyl, propionyl, butyryl, sec-butyryl, tert-butyryl, n-valeryl, 2-methyl-butyryl, tert-valeryl, n-hexanoyl, 2-methyl-valeryl, 3-methyl-valeryl, 2,2-dimethyl-butyryl, 2,3-dimethyl-butyryl; R6 and R7 are independently selected from C. 1-16 Straight-chain or branched alkyl groups.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, R1 is independently selected from -COR6; R2 is independently selected from hydrogen, C 1-8 Alkyl, C 1-8 alkoxy group; R3 is independently selected from hydrogen, -COR7; R4 is independently selected from hydrogen, C 1-8 Alkyl, C 1-8 Alkyl groups; R6 and R7 are independently selected from C 1-14 Straight-chain or branched alkyl groups.

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, characterized in that: R1 is independently selected from -COR6; R2 is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, 2-methyl-butyl, p-pentyl, n-hexyl, 2-methyl-pentyl, 3-methyl-pentyl, 2,2-dimethyl-butyl, 2,3-dimethyl-butyl, methoxy, ethoxy, propoxy, butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, 2-methyl-butoxy, p-pentoxy, n-hexyloxy, 2-methyl-pentoxy, 3-methyl-pentoxy, 2,2-dimethyl-butoxy, 2,3-dimethyl-butoxy; R3 is independently selected from hydrogen. -COR7 substitution; R4 is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, 2-methyl-butyl, p-pentyl, n-hexyl, 2-methyl-pentyl, 3-methyl-pentyl, 2,2-dimethyl-butyl, 2,3-dimethyl-butyl, methoxy, ethoxy, propoxy, butoxy, sec-butoxy, tert-butoxy, n-pentoxy, 2-methyl-butoxy, p-pentoxy, n-hexoxy, 2-methyl-pentoxy, 3-methyl-pentoxy, 2,2-dimethyl-butoxy R6 and R7 are independently selected from methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, n-pentyl, 2-methyl-butyl, tert-pentyl, n-hexyl, 2-methyl-pentyl, 3-methyl-pentyl, 2,2-dimethyl-butyl, 2,3-dimethyl-butyl, n-heptyl, 2-methyl-hexyl, 3-methylhexyl, 2,2-dimethyl-pentyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, n-octyl, 2-methyl-heptyl, 3-methyl-heptyl, 4 -Methyl-heptyl, 2,2-dimethyl-hexyl, 2,3-dimethyl-hexyl, 2,4-dimethyl-hexyl, 2,5-dimethyl-hexyl, 2,3,4-trimethyl-butyl, n-nonyl, 2-methyl-octyl, 3-methyl-octyl, 4-methyl-octyl, 2,2-dimethyl-heptyl, 2,3-dimethyl-hexyl, 2,4-dimethyl-hexyl, 2,5-dimethyl-hexyl, 2,3,4-trimethyl-pentyl, 2,3,5-trimethyl-pentyl, n-decyl, 2-methyl-decyl, 3-methyl 2,2-Dimethyl-octyl, 2,3-Dimethyl-octyl, 2,4-Dimethyl-octyl, 2,5-Dimethyl-octyl, 2,6-Dimethyl-octyl, 2,7-Dimethyl-octyl, 2,3,4-Trimethyl-heptyl, 2,3,5-Trimethyl-heptyl, 2,3,6-Trimethyl-heptyl, 3,4,5-Trimethyl-heptyl, 3,4,6-Trimethyl-heptyl, 2,3,4,5-Tetramethyl-hexyl, Undecyl, Dodecyl.

4. The compound shown below or a pharmaceutically acceptable salt thereof, characterized in that, The compound is selected from 。 5. A method for preparing the compound according to any one of claims 1-3, comprising the following steps: Preparation of fragment A-1: When R3 is hydrogen, compound III is obtained by first iodizing commercially available starting material II. Compound III was deprotected to give compound IV; then coupled with trimethylsilylacetylene to give compound V; compound V was protected with a hydroxyl group to give compound VI, and compound VI was finally deprotected with TMS to give fragment A-1; i. Iodination reaction; ii. Deprotection reaction; iii. Coupling reaction; iv. Adding a protecting group; v. Removing the TMS protecting group; wherein R4 is defined as in any one of claims 1-3; R8 is methyl, ethyl, triethylsilyl, tert-butyldimethylsilyl, triphenylsilyl, (trimethylsilyl)ethoxymethyl; Preparation of fragment A-2: When R3 is -COR7, compound VII is iodinated to give compound VIII, compound VIII is oxidized by an oxidizing agent to give compound IX, compound IX is deprotected to give compound X, compound X is coupled with trimethylsilylacetylene to give compound XI, compound XI is protected by a hydroxyl group to give compound XII, compound XII is introduced with an alkyl side chain by a Grignard reaction to give compound XIII, compound XIII is oxidized to give compound XIV, and compound XIV is deprotected by TMS to give fragment A-2; i. Iodination reaction; ii. Oxidation reaction; iii. Deprotection; iv. Coupling reaction; v. Adding a protecting group; vi. Grignard reaction; vii. Oxidation reaction; viiii. Removing the TMS protecting group; wherein R4 and R7 are defined as in any one of claims 1-3; R8 is defined as methyl, ethyl, triethylsilyl, tert-butyldimethylsilyl, triphenylsilyl, (trimethylsilyl)ethoxymethyl; Fragment B: Compound XVI is obtained by introducing an alkyl side chain from compound XV via a Grignard reaction, compound XVI is oxidized to obtain compound XVII, and compound XVII is deprotected to obtain fragment B; i. a reaction in the form of a grid; ii. an oxidation reaction; iii. a deprotection reaction, wherein R2 and R6 are defined as in any one of claims 1-3; Synthesis of I: The benzofuran ring is generated by the Sonogashira coupling cyclization reaction of fragment A-1 or fragment A-2 and fragment B to give intermediate XVIII. Intermediate XVIII is deprotected and acylated to give compound I. i Sonogashira coupling cyclization reaction; ii. Deprotection; iii. Acylation; wherein R1, R2, R3, R4, and R5 are defined as in any one of claims 1-3; R8 is defined as methyl, ethyl, triethylsilyl, tert-butyldimethylsilyl, triphenylsilyl, or (trimethylsilyl)ethoxymethyl.

6. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises a compound of any one of claims 1-4 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

7. The pharmaceutical composition according to claim 6, characterized in that, The pharmaceutical composition includes tablets, capsules, pills, or injections.

8. The pharmaceutical composition according to claim 6, characterized in that, The pharmaceutical composition is selected from solutions, suspensions, emulsions, powders, controlled-release formulations, or sustained-release formulations.

9. Use of the compound of any one of claims 1-4 or a pharmaceutically acceptable salt thereof in the preparation of a medicament having hCES2A inhibitory activity.

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