Sesquiterpene lactone scaberol C thioether derivative and preparation method and application thereof

Abstract

The present invention relates to sesquiterpene lactone scaberol C thioether derivatives and preparation methods and applications thereof, and belongs to the field of pharmaceutical technology. The existing scaberol C derivatives are limited by poor targeting, easy metabolic inactivation and other problems. The present invention chemically modifies the α-methylene-γ-lactone pharmacophore of scaberol C by Michael addition reaction and acylation or alkylation reaction, designs and synthesizes a series of thioether derivatives, and improves its anti-tumor effect and selectivity. These thioether derivatives can avoid inactivation by binding to high-content GSH in vivo, so as to better bind to targets in tumor cells. The present invention exhibits excellent anti-tumor activity and good biocompatibility, and provides valuable candidate compounds for the development of anti-tumor drugs.

Description

Technical Field

[0001] The invention belongs to the technical field of medicines, and in particular relates to a sesquiterpene lactone scaberol C thioether derivative and a preparation method and application thereof. Background Art

[0002] Intracellular oxidative stress is closely related to a variety of diseases such as cancer, inflammation, and neurodegenerative diseases. Especially in cancer cells, ROS and oxidative stress can induce the occurrence of cancer, and tumor cells produce more ROS than normal cells. At the same time, the expression of antioxidant defense systems such as TrxR and GSH in malignant tumors is greatly increased, and this highly expressed antioxidant defense system is essential for the survival and progression of tumor cells. The degree of intracellular oxidative stress mainly depends on the balance between the rate of ROS generation and the activity of the antioxidant defense system. Therefore, in view of the higher level of ROS in tumor cells, researchers have developed many chemotherapeutic agents that promote the generation of ROS or reduce the ability of intracellular ROS clearance, thereby pushing intracellular oxidative stress to a critical point and achieving the purpose of selectively killing tumor cells.

[0003] Scaberol C can be obtained from the crude extract of the whole plant of Scaber officinale by chemical modification, and its derivatives have significant anti-tumor activity and low toxicity. The structure-activity relationship of previous studies showed that the α-methylene-γ-butyrolactone fragment is the key pharmacophore for this type of sesquiterpene lactone to exert anti-tumor activity (J.Nat.Prod.2022,85,352-364; Eur.J.Pharmacol.2022,925:174989). However, α-methylene-γ-lactone, as a Michael addition receptor fragment, has the common shortcomings of covalent compounds, and its binding selectivity with the nucleophilic center in the body is poor, and its stability in plasma is poor. This greatly limits the application of this type of sesquiterpene lactone containing α-methylene-γ-butyrolactone fragment.

[0004] As a very important functional group in pharmacy, thioether is often introduced into drug molecules to improve the physicochemical properties of drug molecules, enhance their biological activity, and enhance the affinity and stability of drug molecules. Summary of the invention

[0005] The present invention designs to add the exocyclic double bond of α-methylene-γ-lactone to the thiol group, and the prepared thioether derivatives avoid being inactivated by the GSH with a high content in the body after entering the body, thereby achieving the purpose of better binding to the target.

[0006] The purpose of the present invention is to improve the electrophilic selectivity of the active center α-methylene-γ-lactone, by performing Michael addition modification on the exocyclic double bond of the active center, and then further diversifying the modification of C6-OH to obtain sesquiterpene lactone scaberol C thioether derivatives with better anti-tumor activity, and provide preparation methods and applications of these thioether derivatives.

[0007] The purpose of the invention is achieved through the following specific technical solutions:

[0008] Sesquiterpene lactone scaberol C sulfide derivative, the structure is shown in general formula I, general formula II, general formula III, or general formula IV:

[0009]

[0010] In the general formula I, the general formula II, the general formula III, or the general formula IV: R is cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, unsubstituted or substituted benzyl, C 1-8 Alkanoyl, unsubstituted or substituted benzoyl, unsubstituted or substituted cinnamoyl, benzyl, 1-naphthoyl, 2-naphthoyl, unsubstituted or substituted 4-pyridoyl, unsubstituted or substituted 3-pyridoyl, unsubstituted or substituted 2-furoyl, unsubstituted or substituted 2-thenoyl, unsubstituted or substituted 2-furylacryloyl, -CO(CH2) n COOH, -CO(CH2) m P + (Ph)3Br - , N-unsubstituted or substituted carbamoyl or unsubstituted or substituted oxyacyl;

[0011] R1 is C 1-8 straight-chain or branched alkyl, cyclopentyl, cyclopropyl, cyclohexyl, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, unsubstituted or substituted pyridyl, unsubstituted or substituted thienyl, unsubstituted or substituted furanyl;

[0012] R2 is -(CH2) p -, where p is an integer between 2 and 10;

[0013] Furthermore, in the general formula I, II, III or IV: when R is selected from -CO(CH2) n COOH, -CO(CH2) m P + (Ph)3Br - When n and m are independently integers between 2 and 10;

[0014] Furthermore, in the general formula I, II, III or IV: when R is selected from -CO(CH2) n COOH, -CO(CH2) m P + (Ph)3Br - When n=2-6, m=3-7;

[0015] Furthermore, in the general formula I, general formula II, general formula III or general formula IV:

[0016] R is benzoyl, 4-trifluoromethylbenzoyl, 3-trifluoromethylbenzoyl, 4-fluorobenzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl, 4-nitrobenzoyl, 4-acetylbenzoyl, cinnamoyl, 4-fluorocinnamoyl, 4-chlorocinnamoyl, 4-methoxycinnamoyl, 3-trifluoromethylcinnamoyl, 3,4-methylenedioxycinnamoyl, 3-methoxycinnamoyl, 4-dimethylaminocinnamoyl, 4-trifluoromethylcinnamoyl, 3,4-difluorocinnamoyl, 2-naphthoyl, 2,2-dimethylbutanoyl, 2-bromobutanoyl, cyclopropylcarbonyl, cyclohexanecarbonyl, 4,4-difluorocyclohexanecarbonyl, isovaleryl, hexanoyl, 5-bromovaleryl, unsubstituted or substituted 4-pyridinylcarbonyl, 2-furanoyl, 2-thenoyl, 4-pyridineoyl, 3-pyridineoyl, 4-pyridylacryloyl, 3-pyridylacryloyl, 2-furanacryloyl, 2-thiopheneacryloyl, -CO(CH2)2COOH, -CO(CH2)4COOH, -CO(CH2)6COOH, -CO(CH2)3P + (Ph)3Br - 、-CO(CH2)5P + (Ph)3Br - 、-CO(CH2)7P + (Ph)3Br, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-benzylcarbamoyl, N-p-fluorobenzylcarbamoyl, N-(3-pyridyl)carbamoyl, N-n-propylcarbamoyl, N-isopropylcarbamoyl, N-(2-furyl)carbamoyl, N-(2-thienyl)carbamoyl, p-methoxybenzyloxycarbamoyl, phenyloxycarbamoyl, phenylthiocarbamoyl, 2-thienylhydroxymethylcarbamoyl, 2-furylhydroxymethylcarbamoyl or hexylthiocarbamoyl.

[0017] R1 is methyl, ethyl, n-propyl, butyl, isopropyl, isobutyl, n-hexyl, phenyl, isopentenyl, p-bromophenyl, 3-bromophenyl, 3-fluorophenyl, p-fluorophenyl, p-chlorophenyl, 3-chlorophenyl, p-trifluoromethylphenyl, 3-trifluoromethylphenyl, p-nitrophenyl, 3-nitrophenyl, p-hydroxyphenyl, 3-hydroxyphenyl, p-methoxyphenyl, 3-methoxyphenyl, p-methylphenyl, 3-methylphenyl, 3-pyrrolidone, pyridyl, 2-thienyl, 2-furyl, benzyl, p-fluorobenzyl, 3-fluorobenzyl, p-chlorobenzyl, 3-chlorobenzyl, p-bromobenzyl, 3-bromobenzyl, p-trifluoromethylbenzyl, 3-trifluoromethylbenzyl, p-nitrobenzyl, 3-nitrobenzyl, p-hydroxybenzyl, 3-hydroxybenzyl, p-methoxybenzyl, 3-methoxybenzyl, p-methylbenzyl, 3-methylbenzyl, 3-pyridylmethyl, 2-thienylmethyl or 2-furylmethyl;

[0018] R2 is or -(CH2) p -, where p is an integer between 4 and 6.

[0019] The present invention includes but is not limited to the above substituents or side chains, and all derivatives that meet the requirements of the present invention should be included in the scope of protection of the present invention.

[0020] The sesquiterpene lactone scaberol C thioether derivative provided by the present invention is specifically selected from the following compounds:

[0021]

[0022]

[0023]

[0024]

[0025]

[0026] The present invention provides a method for preparing the above-mentioned sesquiterpene lactone scaberol C sulfide derivative, which specifically comprises the following steps:

[0027] Take the route shown below;

[0028] 1) Using scaberol C as a raw material, introducing different substituted thiol groups on the exocyclic double bond of the pharmacophore α-methylene-γ-lactone through a Michael addition reaction to obtain intermediates 1 and 2, respectively, and then introducing different acyl groups or alkyl groups on the hydroxyl groups of intermediates 1 and 2 through condensation or nucleophilic substitution reaction, respectively, to obtain the compounds represented by formulas I and III;

[0029] 2) The compounds of formula I and III are oxidized by m-CPBA to obtain compounds of formula II and IV.

[0030]

[0031] The present invention provides application of the sesquiterpene lactone scaberol C thioether derivative or a pharmaceutically acceptable salt thereof in preparing a drug for treating tumors.

[0032] The sesquiterpene lactone scaberol C thioether derivative or its pharmaceutically acceptable salt includes not only a single compound form, but also a mixture of multiple compounds whose structures meet the requirements of general formula I-IV; the pharmaceutically acceptable salt is selected from sulfate, hydrochloride, hydrobromide, phosphate, acetate, methanesulfonate, benzenesulfonate, toluenesulfonate, tartrate, maleate, benzoate, succinate, fumarate, tartrate, gallate, citrate, as well as ammonium salt, sodium salt and potassium salt.

[0033] The present invention provides a pharmaceutical composition, comprising the above-mentioned sesquiterpene lactone scaberol C thioether derivative or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant.

[0034] The pharmaceutical composition of the present invention comprises the compound of the general formula I-IV of the present invention and a conventional pharmaceutical carrier or excipient, and can be administered orally or parenterally.

[0035] The dosage form of the pharmaceutical composition of the present invention is capsule tablet, solution, suspension, granule or injection.

[0036] The present invention provides application of the above-mentioned pharmaceutical composition in preparing drugs for treating tumors.

[0037] Beneficial effects of the present invention:

[0038] The present invention can solve the problem that covalent compounds such as α-methylene-γ-butyrolactone fragments or α, β-unsaturated ketones are rapidly metabolized, inactivated and excreted from the body. At the same time, such thioether derivatives can release prototype compounds containing α-methylene-γ-butyrolactone fragments in the highly oxidized microenvironment of tumors, exert the irreversible binding effect of covalent compounds, and better bind to the target. DETAILED DESCRIPTION

[0039] The present invention is further described below by specific examples, which are not intended to further limit the present invention. It should be understood by those skilled in the art that equivalent replacements or corresponding improvements made to the technical features of the present invention still fall within the scope of protection of the present invention. Typical compounds of the present invention include the following compounds or pharmaceutically acceptable salts thereof, but are not limited to these:

[0040] Example 1: Preparation of Compound 1

[0041]

[0042] The synthesis method of scaberol C (SC) is based on the literature (J.Nat.Prod.2022,85,352-364). Compound SC (20 mg, 0.072 mmol), 4-fluorobenzenethiol (150.7 μL, 1.45 mmol), and anhydrous methanol 4 mL were added to a 10 mL round-bottom flask in sequence and stirred at room temperature for 24 h. After TLC confirmed that the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product intermediate 1. It was then prepared by reverse phase semi-preparative liquid phase, with the mobile phase MeCN-H2O (45:55, v / v) to obtain intermediate 1, and the structural identification data are as follows: m / z: [M+Na] + =427.1006, 1 H NMR (600MHz, CDCl3) δ7.51(dd,J=8.7,5.2Hz,2H),6.99(m,3H),5.35(d,J=3.0Hz,1H),5.01(d,J=9.2Hz,1H),4.27(t,J=9.8Hz,1H),3.83(s, 1H),3.38(ddd,J=42.9,13.3,4.4Hz,2H),3.13(d,J=6.1Hz,1H),2.95–2.85(m,3H),2.74(s,1H),2.24(dd,J=14.6,4.4Hz,1H),1.60(s,3H); 13 C NMR (150MHz, CDCl3) δ176.1,174.0,163.2,161.5,147.4,133.8,133.7,132.2,1 31.0,129.6,116.4,116.2,81.5,79.4,72.7,50.7,45.8,40.2,38.1,30.6,21.8.

[0043] The intermediate 1 (15 mg, 0.037 mmol), cyclopropionic acid (14.8 μL, 0.19 mmol), EDCI (35.5 mg, 0.19 mmol), DMAP (2.3 mg, 0.019 mmol), and 3 mL of dry DCM were added to a 10 mL round-bottom flask and stirred at room temperature for 24 h. After TLC confirmed that the reaction was complete, 3 mL of water was added to terminate the reaction. The reaction solution was placed in a separatory funnel, the organic layer was taken, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined and placed in nitrogen blowing. The solvent was blown dry at room temperature to obtain a crude product 1. It was then prepared by reverse phase semi-preparative liquid phase, with the mobile phase MeCN-H2O (60:40, v / v) to obtain 1 monomer compound (11.3 mg, yield 64.6%), and the structural identification data are as follows: m / z: [M+Na] + =495.1245, 1 H NMR (600MHz, CDCl3) δ7.57–7.51(m,2H),7.04–6.98(m,2H),6.97(s,1H),5.36(d,J=4.2Hz,1H) ,5.32(t,J=10.3Hz,1H),4.91(d,J=9.8Hz,1H),3.90(dt,J=9.9,5.7Hz,1H),3.50(dd,J=13.2, 3.8Hz,1H),3.20(dd,J=13.2,5.0Hz,1H),3.04–2.98(m,1H),2.97–2.89(m,4H),2.24(dd,J=14 .7,4.7Hz,1H),1.68(d,J=0.9Hz,3H),1.50–1.43(m,1H),0.94–0.90(m,2H),0.88–0.83(m,2H);

[0044] Example 2: Preparation of Compound 2

[0045]

[0046] The operation was the same as in Example 1, except that 3-fluorobenzenethiol was used in the first step of the synthesis, cyclobutane acid was used in the second step of the synthesis, and the mobile phase was MeCN-H2O (50:50, v / v). The yield of monomer compound 2 was 64.8%, and the structural identification data were as follows: m / z: [M+Na] + =495.1245, 1H NMR (600MHz, CDCl3) δ7.64(s,1H),7.40(d,J=7.9Hz,1H),7.32(d,J=8.6Hz,1H),7.15(t,J=7.9Hz,1H),6.96 (s,1H),5.35(d,J=3.1Hz,1H),5.02(d,J=9.7Hz,1H),4.30(t,J=9.9Hz,1H),3.86–3.78(m,1H),3.48(dd,J= 13.3,4.6Hz,1H),3.40(dd,J=13.4,5.2Hz,1H),3.17(dt,J=6.9,4.9Hz,1H),3.12–3.06(m,1H),2.96–2.80( m,3H),2.70(dt,J=10.0,6.7Hz,1H),2.23–2.17(m,5H),2.01–1.95(m,1H),1.90–1.84(m,1H),1.61(s,3H);

[0047] Example 3: Preparation of Compound 3

[0048]

[0049] The operation was the same as in Example 1, except that 4-chlorothiophenol was used in the first step of the synthesis, cyclopentanoic acid was used in the second step of the synthesis, and the mobile phase was MeCN-H2O (50:50, v / v). The monomer compound 3 was obtained with a yield of 67.3%. The structural identification data are as follows: m / z: [M+Na] + =495.1245, 1 H NMR (600MHz, CDCl3) δ7.40(d,J=8.5Hz,2H),7.23(d,J=8.6Hz,2H),6.96(s,1H),5.32(d,J=4.2 Hz,1H),4.97(d,J=9.7Hz,1H),4.27(t,J=9.9Hz,1H),3.86–3.77(m,1H),3.45(dd,J=13.3,4.4H z,1H),3.34(dd,J=13.3,5.0Hz,1H),3.16(dt,J=7.2,4.7Hz,1H),2.92–2.81(m,3H),2.70–2.64 (m,2H),2.20(dd,J=14.8,4.6Hz,1H),1.91–1.84(m,2H),1.74–1.65(m,4H),1.60–1.54(m,5H);

[0050] Example 4: Preparation of Compound 4

[0051]

[0052] The operation was the same as in Example 1, except that 3-chlorothiophenol was used in the first step of the synthesis, cyclohexanoic acid was used in the second step of the synthesis, and the mobile phase was MeCN-H2O (50:50, v / v). The monomer compound 4 was obtained with a yield of 54.5%, and the structural identification data are as follows: m / z: [M+Na] + =495.1245, 1 H NMR (600MHz, CDCl3) δ7.63(s,1H),7.39(d,J=7.9Hz,1H),7.32(d,J=8.6Hz,1H),7.15(t,J=7.9Hz,1H),6.96(s,1H),5.35(d,J= 3.1Hz,1H),5.02(d,J=9.7Hz,1H),4.30(t,J=9.9Hz,1H),3.86–3.78(m,1H),3.48(dd,J=13.3,4.6Hz,1H),3.40(dd,J=13.4,5. 2Hz,1H),3.17(dt,J=6.9,4.9Hz,1H),2.96–2.80(m,3H),2.70(dt,J=10.0,6.7Hz,1H),2.28–2.22(m,2H),1.91–1.87(m,1H),1 .85–1.81(m,1H),1.76–1.72(m,2H),1.66–1.62(m,1H),1.61(s,3H),1.41–1.35(m,2H),1.30–1.24(m,2H),1.23–1.17(m,1H);

[0053] Example 5: Preparation of Compound 5

[0054]

[0055] The operation was the same as in Example 1, except that 4-bromothiophenol was used in the first step of the synthesis, benzoic acid was used in the second step of the synthesis, and the mobile phase was MeCN-H2O (55:45, v / v). The yield of monomer compound 4 was 84.4%, and the structural identification data were as follows: m / z: [M+Na] + =591.0500, 1H NMR (600MHz, CDCl3) δ7.84 (dd, J=8.2, 1.1Hz, 2H), 7.60–7.56 (m, 1H), 7.42–7. 35(m,6H),7.00(s,1H),5.64(t,J=10.3Hz,1H),5.38(d,J=4.3Hz,1H),5.03(d ,J=9.8Hz,1H),4.02–3.96(m,1H),3.53(dd,J=13.3,3.6Hz,1H),3.21–3.14(m ,2H),3.02–2.89(m,4H),2.27(dd,J=14.8,4.7Hz,1H),1.77(d,J=1.4Hz,3H);

[0056] Example 6: Preparation of Compound 6

[0057]

[0058] The operation was the same as in Example 1, except that 3-bromothiophenol was used in the first step of the synthesis, 4-methylbenzoic acid was used in the second step of the synthesis, and MeCN-H2O (60:40, v / v) was used as the mobile phase. The monomer compound 6 was obtained with a yield of 75.6%. The structural identification data are as follows: m / z: [M+Na] + =605.0733, 1 H NMR (600MHz, CDCl3) δ7.90 (dd, J=8.3, 1.1Hz, 2H), 7.59–7.56 (m, 1H), 7.44–7.41 (m, 3H), 7.36–7.3 3(m,1H),7.14(t,J=7.9Hz,1H),7.00(s,1H),5.65(t,J=10.3Hz,1H),5.38(d,J=4.3Hz,1H),5.03(d ,J=9.8Hz,1H),4.02–3.97(m,1H),3.53(dd,J=13.2,3.7Hz,1H),3.24(dd,J=13.2,5.1Hz,1H),3.19 –3.13(m,1H),3.04–2.89(m,4H),2.42(s,3H),2.27(dd,J=14.8,4.7Hz,1H),1.78(d,J=1.4Hz,3H);

[0059] Example 7: Preparation of Compound 7

[0060]

[0061] The operation was the same as in Example 1, except that 4-methoxythiophenol was used in the first step of the synthesis, and 4-methoxybenzoic acid was used in the second step of the synthesis. The mobile phase was MeCN-H2O (65:35, v / v). The yield of monomer compound 7 was 84.2%. The structural identification data are as follows: m / z: [M+Na] + =573.1142, 1 H NMR (600MHz, CDCl3) δ7.97(d,J=8.9Hz,2H),7.51(d,J=8.6Hz,2H),6.95(d,J=8.9Hz,2H),6.97(s,1H ),6.85(d,J=8.6Hz,2H),5.36(d,J=3.9Hz,1H),5.31(t,J=10.3Hz,1H),4.93(d,J=9.8Hz,1H),3.89( dt,J=10.5,5.2Hz,1H),3.87(s,3H),3.79(s,3H),3.46(dd,J=13.1,3.8Hz,1H),3.16(dd,J=13.1,5. 0Hz,1H),3.04(dt,J=10.8,6.6Hz,1H),3.01–2.88(m,4H),2.24(dd,J=14.8,4.6Hz,1H),1.68(s,3H);

[0062] Example 8: Preparation of Compound 8

[0063]

[0064] The operation was the same as in Example 1, except that 4-methoxythiophenol was used in the first step of the synthesis, 4-chlorobenzoic acid was used in the second step of the synthesis, and MeCN-H2O (65:35, v / v) was used as the mobile phase. The monomer compound 8 was obtained with a yield of 77.4%. The structural identification data are as follows: m / z: [M+Na] + =578.2253, 1H NMR (600MHz, CDCl3) δ7.97(d,J=8.3Hz,2H),7.51(d,J=8.6Hz,2H),7.31(d,J=7.3Hz,2H),6.97(s ,1H),6.85(d,J=8.6Hz,2H),5.36(d,J=3.9Hz,1H),5.31(t,J=10.3Hz,1H),4.93(d,J=9.8Hz,1H), 3.89(dt,J=10.5,5.2Hz,1H),3.79(s,3H),3.46(dd,J=13.1,3.8Hz,1H),3.16(dd,J=13.1,5.0Hz ,1H),3.04(dt,J=10.8,6.6Hz,1H),3.01–2.88(m,4H),2.24(dd,J=14.8,4.6Hz,1H),1.68(s,3H);

[0065] Example 9: Preparation of Compound 9

[0066]

[0067] The operation was the same as in Example 1, except that 4-nitrothiophenol was used in the first step of the synthesis, 4-pyridylcarboxylic acid was used in the second step of the synthesis, and the mobile phase was MeCN-H2O (55:45, v / v). The monomer compound 9 was obtained with a yield of 67.9%, and the structural identification data are as follows: m / z: [M+Na] + =559.1907, 1 H NMR (400MHz, CDCl3) δ8.84(s,2H),8.06(d,J=8.9Hz,2H),7.91(dd,J=8.2,1.1Hz,2H),7.84(d,J=2.9Hz ,2H),7.01(s,1H),5.69(t,J=10.0Hz,1H),5.39(d,J=4.1Hz,1H),5.04(d,J=9.8Hz,1H),4.01(dt,J=10 .9,4.6Hz,1H),3.58(dd,J=13.4,3.6Hz,1H),3.35(dd,J=13.4,4.6Hz,1H),3.11–3.06(m,2H),3.01(dd ,J=12.9,3.9Hz,1H),2.91(dd,J=13.1,8.4Hz,2H),2.28(dd,J=14.8,4.6Hz,1H),1.78(d,J=1.3Hz,3H);

[0068] Example 10: Preparation of Compound 10

[0069]

[0070] The operation was the same as in Example 1, except that 3-nitrothiophenol was used in the first step of the synthesis, 4-trifluoromethylbenzoic acid was used in the second step of the synthesis, and the mobile phase was MeCN-H2O (60:40, v / v). The monomer compound 10 was obtained with a yield of 77.9%, and the structural identification data are as follows: m / z: [M+Na] + =626.4704,8.12(d,J=8.2Hz,2H),7.83(s,1H),7.65(d,J=7.9Hz,1H),7.42–7.40(m,3H),7.25(t,J=7.9 Hz,1H),7.01(s,1H),5.69(t,J=10.0Hz,1H),5.39(d,J=4.1Hz,1H),5.04(d,J=9.8Hz,1H),4.01(dt,J=1 0.9,4.6Hz,1H),3.58(dd,J=13.4,3.6Hz,1H),3.35(dd,J=13.4,4.6Hz,1H),3.11–3.06(m,2H),3.01(dd ,J=12.9,3.9Hz,1H),2.91(dd,J=13.1,8.4Hz,2H),2.28(dd,J=14.8,4.6Hz,1H),1.78(d,J=1.3Hz,3H);

[0071] Example 11: Preparation of Compound 11

[0072]

[0073] The operation was the same as in Example 1, except that 4-hydroxythiophenol was used in the first step of the synthesis, 2-furancarboxylic acid was used in the second step of the synthesis, and the mobile phase was MeCN-H2O (60:40, v / v). The yield of monomer compound 11 was 84.5%, and the structural identification data were as follows: m / z: [M+Na] + =519.3490, 1H NMR (600MHz, CDCl3) δ8.05(d,J=4.9Hz,1H),7.84(d,J=7.4Hz,2H),7.66(d,J=4.4Hz,1H),7.46–7.37(m,2H),7. 01(s,1H),6.79(m,1H),6.11(s,1H),5.61(t,J=10.3Hz,1H),5.39(d,J=4.1Hz,1H),5.02(d,J=9.8Hz,1H),4.03 –3.95(m,1H),3.49(dd,J=13.4,3.2Hz,1H),3.29(dt,J=10.8,6.9Hz,1H),3.07(dd,J=13.4,5.2Hz,1H),3.03(d ,J=11.0Hz,1H),3.01–2.95(m,2H),2.91(d,J=14.8Hz,1H),2.27(dd,J=14.8,4.6Hz,1H),1.77(d,J=0.9Hz,3H);

[0074] Example 12: Preparation of Compound 12

[0075]

[0076] The operation was the same as in Example 1, except that 4-hydroxythiophenol was used in the first step of the synthesis, 2-thiophenecarboxylic acid was used in the second step of the synthesis, and MeCN-H2O (60:40, v / v) was used as the mobile phase. The monomer compound 12 was obtained with a yield of 43.6%. The structural identification data are as follows: m / z: [M+Na] + =535.6437, 1 H NMR (600MHz, CDCl3) δ8.07(d,J=4.8Hz,1H),7.84(d,J=7.4Hz,2H),7.64(d,J=4.2Hz,1H),7.46–7.37(m,2H),7. 01(s,1H),6.78(m,1H),6.11(s,1H),5.61(t,J=10.3Hz,1H),5.39(d,J=4.1Hz,1H),5.02(d,J=9.8Hz,1H),4.03 –3.95(m,1H),3.49(dd,J=13.4,3.2Hz,1H),3.29(dt,J=10.8,6.9Hz,1H),3.07(dd,J=13.4,5.2Hz,1H),3.03(d ,J=11.0Hz,1H),3.01–2.95(m,2H),2.91(d,J=14.8Hz,1H),2.27(dd,J=14.8,4.6Hz,1H),1.77(d,J=0.9Hz,3H);

[0077] Example 13: Preparation of Compound 13

[0078]

[0079] The operation was the same as in Example 1, except that 4-trifluoromethylthiophenol was used in the first step of the synthesis, 4-nitrobenzoic acid was used in the second step of the synthesis, and MeCN-H2O (70:30, v / v) was used as the mobile phase. The monomer compound 13 was obtained with a yield of 65.0%. The structural identification data are as follows: m / z: [M+Na] + =626.1648, 1 H NMR (400MHz, CDCl3) δ8.33(d,J=8.9Hz,2H),8.20(d,J=8.9Hz,2H),7.88(dd,J=8.3,1.2Hz,2H), 7.54–7.46(m,2H),7.01(s,1H),5.66(t,J=10.2Hz,1H),5.39(d,J=4.3Hz,1H),5.04(d,J=9.8Hz, 1H),4.03–3.96(m,1H),3.57(dd,J=13.3,3.9Hz,1H),3.28(dd,J=13.3,5.3Hz,1H),3.18–3.11(m ,1H),3.06–3.01(m,1H),3.01–2.89(m,3H),2.27(dd,J=14.8,4.6Hz,1H),1.78(d,J=1.4Hz,3H);

[0080] Example 14: Preparation of Compound 14

[0081]

[0082] The operation was the same as in Example 1, except that 4-trifluoromethylthiophenol was used in the first step of the synthesis, 4-methylbenzoic acid was used in the second step of the synthesis, and the mobile phase was MeCN-H2O (70:30, v / v). The monomer compound 14 was obtained with a yield of 85.8%, and the structural identification data are as follows: m / z: [M+Na] + =595.1265, 1H NMR(400MHz, CDCl3)δ7.90(d,J=8.2Hz,2H),7.88(dd,J=8.3,1.2Hz,2H),7.54–7.46(m,2H),7.27(d ,J=7.1Hz,2H),7.01(s,1H),5.66(t,J=10.2Hz,1H),5.39(d,J=4.3Hz,1H),5.04(d,J=9.8Hz,1H),4. 03–3.96(m,1H),3.57(dd,J=13.3,3.9Hz,1H),3.28(dd,J=13.3,5.3Hz,1H),3.18–3.11(m,1H),3.0 6–3.01(m,1H),3.01–2.89(m,3H),2.42(s,3H),2.27(dd,J=14.8,4.6Hz,1H),1.78(d,J=1.4Hz,3H);

[0083] Example 15: Preparation of Compound 15

[0084]

[0085] The operation was the same as in Example 1, except that 2-pyrimidinethiophenol was used in the first step of the synthesis, trans-cinnamic acid was used in the second step of the synthesis, and MeCN-H2O (65:35, v / v) was used as the mobile phase. The monomer compound 15 was obtained with a yield of 73.4%. The structural identification data are as follows: m / z: [M+H] + =519.1595, 1 H NMR (600MHz, CDCl3) δ8.50(d,J=4.8Hz,2H),7.81(d,J=16.0Hz,1H),7.52–7.47(m,2H),7.42–7. 36(m,3H),6.96(t,J=4.8Hz,1H),6.95(s,1H),6.35(d,J=16.0Hz,1H),5.48(t,J=10.3Hz,1H),5. 30(d,J=4.3Hz,1H),4.85(d,J=9.8Hz,1H),3.95–3.89(m,2H),3.59(dd,J=14.1,5.1Hz,1H),3.1 3(dt,J=7.0,4.9Hz,1H),2.95–2.78(m,4H),2.22(dd,J=14.8,4.6Hz,1H),1.74(d,J=1.4Hz,3H);

[0086] Example 16: Preparation of Compound 16

[0087]

[0088] The operation was the same as in Example 1, except that 2-pyrimidinethiophenol was used in the first step of the synthesis, 4-methyl trans-cinnamic acid was used in the second step of the synthesis, and the mobile phase was MeCN-H2O (65:35, v / v). The monomer compound 16 was obtained with a yield of 78.5%, and the structural identification data are as follows: m / z: [M+Na] + =555.3641, 1 H NMR (600MHz, CDCl3) δ8.55(d,J=4.8Hz,2H),7.64(d,J=15.9Hz,1H),7.45(d,J=8.7Hz,2H),7.03(t,J=4.8Hz ,1H),6.92(s,1H),6.89(d,J=8.7Hz,2H),6.28(d,J=15.9Hz,1H),5.34–5.30(m,1H),5.27(d,J=4.3Hz,1H), 4.77(d,J=9.8Hz,1H),3.87(dd,J=14.0,4.7Hz,1H),3.85–3.82(m,1H),3.63(dd,J=14.0,4.7Hz,1H),3.05( dt,J=7.0,4.7Hz,1H),2.91–2.78(m,4H),2.42(s,3H),2.20(dd,J=14.7,4.7Hz,1H),1.67(d,J=1.4Hz,3H);

[0089] Example 17: Preparation of Compound 17

[0090]

[0091] The operation was the same as in Example 1, except that 2-pyrimidinethiophenol was used in the first step of the synthesis, cyclopropylcarboxylic acid was used in the second step of the synthesis, and the mobile phase was MeCN-H2O (55:45, v / v). The monomer compound 17 was obtained with a yield of 57.8%. The structural identification data are as follows: m / z: [M+H] + =457.1420, 1H NMR(600MHz, CDCl3)δ8.55(d,J=4.8Hz,2H),7.03(t,J=4.8Hz,1H),6.92(s,1H),5.34–5.30(m, 1H),5.27(d,J=4.3Hz,1H),4.77(d,J=9.8Hz,1H),3.87(dd,J=14.0,4.7Hz,1H),3.85–3.82(m,1 H),3.63(dd,J=14.0,4.7Hz,1H),3.05(dt,J=7.0,4.7Hz,1H),2.91–2.78(m,4H),2.20(dd,J=14 .7,4.7Hz,1H),1.67(d,J=1.4Hz,3H),1.63–1.57(m,1H),1.08–0.97(m,2H),0.89–0.83(m,2H);

[0092] Example 18: Preparation of Compound 18

[0093]

[0094] The operation was the same as in Example 1, except that benzothiazole-2-thiol was used in the first step of the synthesis, 4-trifluoromethyl trans-cinnamic acid was used in the second step of the synthesis, and the mobile phase was MeCN-H2O (65:35, v / v). The monomer compound 18 was obtained with a yield of 46.3%. The structural identification data are as follows: m / z: [M+Na] + =535.6437, 1 H NMR (600MHz, CDCl3) δ7.69–7.62(m,5H),7.47–7.43(m,2H),7.32–7.28(m,2H),6.99(s,1H),6.4 7(d,J=16.0Hz,1H),5.36(d,J=4.4Hz,1H),5.28–5.22(m,1H),4.92–4.84(m,1H),4.81(d,J=9.8 Hz,1H),4.73(s,1H),3.92–3.87(m,1H),3.57(dd,J=14.5,7.8Hz,1H),3.03(dd,J=12.8,3.8Hz, 1H),2.98–2.93(m,1H),2.90–2.83(m,2H),2.23(dd,J=14.7,4.7Hz,1H),1.67(d,J=1.4Hz,3H);

[0095] Example 19: Preparation of Compound 19

[0096]

[0097] The operation was the same as in Example 1, except that benzothiazole-2-thiol was used in the first step of the synthesis, 4-methoxy trans-cinnamic acid was used in the second step of the synthesis, and the mobile phase was MeCN-H2O (70:30, v / v). The monomer compound 19 was obtained with a yield of 76.3%. The structural identification data are as follows: m / z: [M+Na] + =626.1543, 1 H NMR(600MHz, CDCl3)δ7.64(d,J=15.9Hz,1H),7.47–7.43(m,4H),7.32–7.28(m,2H),6.99(s,1H),6.91 (d,J=8.7Hz,2H),6.26(d,J=15.9Hz,1H),5.36(d,J=4.4Hz,1H),5.28–5.22(m,1H),4.92–4.84(m,1H), 4.81(d,J=9.8Hz,1H),4.73(s,1H),3.92–3.87(m,1H),3.57(dd,J=14.5,7.8Hz,1H),3.03(dd,J=12.8, 3.8Hz,1H),2.98–2.93(m,1H),2.90–2.83(m,2H),2.23(dd,J=14.7,4.7Hz,1H),1.67(d,J=1.4Hz,3H);

[0098] Example 20: Preparation of Compound 20

[0099]

[0100] The operation was the same as in Example 1, except that isobutyl mercaptan was used in the first step of the synthesis, 4-fluoro trans-cinnamic acid was used in the second step of the synthesis, and the mobile phase was MeCN-H2O (65:35, v / v). The monomer compound 20 was obtained with a yield of 59.4%, and the structural identification data are as follows: m / z: [M+Na] + =537.2548, 1H NMR (600MHz, CDCl3) δ7.65(d,J=16.0Hz,1H),7.52(dd,J=8.6,5.4Hz,2H),7.09(t,J=8.6Hz,2H),7.01(s,1H),6.32 (d,J=16.0Hz,1H),5.66–5.60(m,1H),5.37(d,J=4.4Hz,1H),5.07–5.03(m,1H),3.98–3.93(m,1H),3.14–3.02(m,3 H),2.99–2.94(m,2H),2.91(d,J=14.8Hz,1H),2.82(dd,J=13.6,4.5Hz,1H),2.62(dd,J=12.5,6.7Hz,1H),2.47(dd ,J=12.5,6.9Hz,1H),2.27(dd,J=14.8,4.7Hz,1H),1.85–1.78(m,1H),1.78(d,J=1.4Hz,3H),0.99(t,J=6.5Hz,6H);

[0101] Example 21: Preparation of Compound 21

[0102]

[0103] The operation was the same as in Example 1, except that the second step synthesis method was as follows: the intermediate 1 (15 mg, 0.037 mmol), 1,1'-Carbonyl-di-(1,2,4-triazole) (12.2 mg, 0.074 mmol), cyclopropylamine (15.5 μL, 0.22 mmol), and 3 mL of dry DCM were added to a 10 mL round-bottom flask, and the mixture was stirred at room temperature for 24 h. After the reaction was confirmed to be complete by HPLC, the mixture was placed under nitrogen blowing and the solvent was blown off at room temperature to obtain a crude product 21. The product was then prepared by reverse phase semi-preparative liquid phase, with the mobile phase being MeCN-H2O (60:40, v / v), to obtain a monomer compound 21 with a yield of 68.3%, and the structural identification data are as follows: m / z: [M+H] + =488.1613, 1H NMR (400MHz, CDCl3) δ7.54–7.45(m,2H),7.03–6.96(m,3H),5.35(d,J=3.8Hz, 1H),5.21(t,J=9.6Hz,1H),4.87(d,J=11.0Hz,2H),3.94–3.85(m,1H),3.40(d, J=11.3Hz,1H),3.17(dd,J=13.2,4.7Hz,1H),3.01–2.83(m,5H),2.48(s,1H), 2.23(dd,J=14.7,4.6Hz,1H),1.69(d,J=1.2Hz,3H),0.67(s,2H),0.45(s,2H);

[0104] Example 22: Preparation of Compound 22

[0105]

[0106] The operation was the same as in Example 21, except that cyclohexyl mercaptan was used in the first step of the synthesis, cyclopentylamine was used in the second step of the synthesis, and MeCN-H2O (60:40, v / v) was used as the mobile phase. The monomer compound 22 was obtained with a yield of 57.7%. The structural identification data are as follows: m / z: [M+Na] + =526.1578, 1 H NMR (600MHz, CDCl3) δ7.00 (s, 1H), 5.66–5.59 (m, 1H), 5.37 (d, J = 4.4Hz, 1H), 5.07–5.02 (m, 1 H),3.98–3.92(m,1H),3.13–3.07(m,2H),3.04(t,J=12.0Hz,1H),2.98–2.88(m,3H),2.81(dd ,J=13.5,4.5Hz,1H),2.78–2.72(m,1H),2.26(dd,J=14.8,4.7Hz,1H),2.10–2.05(m,1H),2. 01–1.95(m,2H),1.80–1.73(m,9H),1.64–1.57(m,5H),1.40–1.29(m,4H),1.28–1.19(m,1H);

[0107] Example 23: Preparation of Compound 23

[0108]

[0109] The operation was the same as in Example 21, except that cyclohexyl mercaptan was used in the first step of the synthesis, n-propylamine was used in the second step of the synthesis, and the mobile phase was MeCN-H2O (55:45, v / v). The monomer compound 23 was obtained with a yield of 46.8%. The structural identification data are as follows: m / z: [M+Na] + =500.1248, 1 H NMR (600MHz, CDCl3) δ7.00 (s, 1H), 5.66–5.59 (m, 1H), 5.37 (d, J = 4.4Hz, 1H), 5.07–5.02 (m, 1H), 3.98–3. 92(m,1H),3.13–3.07(m,2H),3.11–3.01(m,3H),2.98–2.88(m,3H),2.81(dd,J=13.5,4.5Hz,1H),2.78–2 .72(m,1H),2.26(dd,J=14.8,4.7Hz,1H),2.10–2.05(m,1H),2.01–1.95(m,1H),1.80–1.73(m,5H),1.64 –1.57(m,1H),1.48(dd,J=14.6,7.3Hz,2H),1.40–1.29(m,4H),1.28–1.19(m,1H),0.88(t,J=7.4Hz,3H);

[0110] Example 24: Preparation of Compound 24

[0111]

[0112] The operation was the same as in Example 21, except that benzyl mercaptan was used in the first step of the synthesis, 2-thiophenemethylamine was used in the second step of the synthesis, and the mobile phase was MeCN-H2O (65:35, v / v). The monomer compound 24 was obtained with a yield of 57.4%, and the structural identification data are as follows: m / z: [M+Na] + =562.3326,7.34(d,J=8.2Hz,2H),7.23(t,J=7.1Hz,1H)7.31–7.27(m,2H),7.18(dd,J= 4.6,1.4Hz,1H),6.99(s,1H),6.93–6.90(m,2H),5.64–5.59(m,1H),5.39(d,J=4.4Hz,1 H),5.09–5.01(m,1H),4.01–3.94(m,3H),3.86(s,2H),3.11–3.04(m,2H),3.02–2.91(m ,4H),2.63(dd,J=13.7,3.9Hz,1H),2.28(dd,J=14.8,4.7Hz,1H),1.79(d,J=1.4Hz,3H);

[0113] Example 25: Preparation of Compound 25

[0114]

[0115] The operation was the same as Example 21, except that 4-chlorobenzyl mercaptan was used in the first step of the synthesis, 2-furylamine was used in the second step of the synthesis, and the mobile phase was MeCN-H2O (65:35, v / v). The monomer compound 25 was obtained with a yield of 66.9%. The structural identification data are as follows: m / z: [M+Na] + =581.4482, 1 H NMR (600MHz, CDCl3) δ7.39–7.35(m,2H),7.31–7.27(m,2H),7.19(dd,J=4.7,1.4Hz, 1H),7.02(s,1H),6.96–6.91(m,2H),5.64–5.59(m,1H),5.39(d,J=4.4Hz,1H),5.09 –5.01(m,1H),4.01–3.94(m,3H),3.86(s,2H),3.11–3.04(m,2H),3.02–2.91(m,4H) ,2.63(dd,J=13.7,3.9Hz,1H),2.28(dd,J=14.8,4.7Hz,1H),1.79(d,J=1.4Hz,3H);

[0116] Example 26: Preparation of Compound 26

[0117]

[0118] The operation was the same as in Example 21, except that 4-methoxybenzyl mercaptan was used in the first step of the synthesis, 4-pyridinemethylamine was used in the second step of the synthesis, and the mobile phase was MeCN-H2O (55:45, v / v). The monomer compound 26 was obtained with a yield of 36.8%, and the structural identification data are as follows: m / z: [M+Na] + =587.2264, 1H NMR (600MHz, CDCl3) δ8.94(d,J=1.4Hz,2H),8.45(d,J=1.4Hz,2H),7.32(d,J=8.6Hz,2H),6.9 7(s,1H),6.84(d,J=8.6Hz,2H),5.34(d,J=3.9Hz,1H),5.22(t,J=10.0Hz,1H),4.88(d,J=9.2 Hz,1H),4.78(d,J=1.3Hz,1H),3.94–3.88(m,3H),3.80(s,2H),3.78(s,3H),2.98–2.87(m,5H ),2.85–2.79(m,1H),2.55–2.44(m,1H),2.22(dd,J=14.7,4.6Hz,1H),1.68(d,J=0.8Hz,3H);

[0119] Example 27: Preparation of Compound 27

[0120]

[0121] The operation was the same as in Example 21, except that 4-methoxybenzyl mercaptan was used in the first step of the synthesis, benzylamine was used in the second step of the synthesis, and the mobile phase was MeCN-H2O (70:30, v / v). The monomer compound 27 was obtained with a yield of 78.0%. The structural identification data are as follows: m / z: [M+Na] + =586.1128, 1 H NMR (600MHz, CDCl3) δ7.98(d,J=7.5Hz,2H),7.46(t,J=7.5Hz,1H),7.41(t,J=7.7Hz,2H),7.32(d, J=8.6Hz,2H),6.97(s,1H),6.84(d,J=8.6Hz,2H),5.34(d,J=3.9Hz,1H),5.22(t,J=10.0Hz,1H),4. 88(d,J=9.2Hz,1H),4.78(d,J=1.3Hz,1H),3.94–3.88(m,3H),3.80(s,2H),3.78(s,3H),2.98–2.87 (m,5H),2.85–2.79(m,1H),2.55–2.44(m,1H),2.22(dd,J=14.7,4.6Hz,1H),1.68(d,J=0.8Hz,3H);

[0122] Example 28: Preparation of Compound 28

[0123]

[0124] The operation was the same as in Example 21, except that pentanethiol was used in the first step of the synthesis and 4-fluorobenzylamine was used in the second step of the synthesis. The mobile phase was MeCN-H2O (75:25, v / v). The monomer compound 28 was obtained with a yield of 81.4%. The structural identification data are as follows: m / z: [M+Na] + =554.4936, 1 H NMR (600MHz, CDCl3) δ7.37(dd,J=8.5,5.4Hz,2H),7.03(t,J=8.5Hz,2H),7.00(s,1H),5.67–5.61(m,1H),5.37(d, J=4.4Hz,1H),5.07–5.02(m,1H),3.98–3.93(m,3H),3.12–3.06(m,2H),3.04(d,J=11.3Hz,1H),2.99–2.94(m,2H) ,2.92(d,J=14.8Hz,1H),2.83(dd,J=13.6,4.5Hz,1H),2.69(dt,J=12.6,7.4Hz,1H),2.59(dt,J=12.5,7.5Hz,1H) ,2.27(dd,J=14.8,4.7Hz,1H),1.78(d,J=1.4Hz,3H),1.64–1.57(m,2H),1.39–1.28(m,4H),0.87(t,J=7.2Hz,3H);

[0125] Example 29: Preparation of Compound 29

[0126]

[0127] The operation was the same as in Example 21, except that pentanethiol was used in the first step of the synthesis and 4-methoxybenzylamine was used in the second step of the synthesis. The mobile phase was MeCN-H2O (75:25, v / v). The monomer compound 29 was obtained with a yield of 83.6%. The structural identification data are as follows: m / z: [M+Na] + =566.2349, 1H NMR (600MHz, CDCl3) δ7.48(d,J=8.7Hz,2H),7.00(s,1H),6.91(t,J=8.7Hz,2H),5.67–5.61(m,1H),5.37(d,J=4.4H z,1H),5.07–5.02(m,1H),3.98–3.93(m,3H),3.84(s,3H),3.12–3.06(m,2H),3.04(d,J=11.3Hz,1H),2.99–2.94(m, 2H),2.92(d,J=14.8Hz,1H),2.83(dd,J=13.6,4.5Hz,1H),2.69(dt,J=12.6,7.4Hz,1H),2.59(dt,J=12.5,7.5Hz,1H ),2.27(dd,J=14.8,4.7Hz,1H),1.78(d,J=1.4Hz,3H),1.64–1.57(m,2H),1.39–1.28(m,4H),0.89(t,J=7.2Hz,3H);

[0128] Example 30: Preparation of Compound 30

[0129]

[0130] The operation was the same as in Example 21, except that propanethiol was used in the first step of the synthesis, 4-trifluoromethylbenzylamine was used in the second step of the synthesis, and the mobile phase was MeCN-H2O (65:35, v / v). The monomer compound 30 was obtained with a yield of 67.0%, and the structural identification data are as follows: m / z: [M+Na] + =576.2269, 1H NMR (600MHz, CDCl3) δ8.06–8.01(m,2H),7.15(t,J=8.6Hz,2H),7.00(s,1H),5.67–5.61(m,1H),5.37(d,J=4.4H z,1H),5.07–5.02(m,1H),3.98–3.93(m,3H),3.12–3.06(m,2H),3.04(d,J=11.3Hz,1H),2.99–2.94(m,2H),2.9 2(d,J=14.8Hz,1H),2.83(dd,J=13.6,4.5Hz,1H),2.69(dt,J=12.6,7.4Hz,1H),2.59(dt,J=12.5,7.5Hz,1H),2 .27(dd,J=14.8,4.7Hz,1H),1.78(d,J=1.4Hz,3H),1.64–1.57(m,2H),1.39–1.28(m,2H),0.89(t,J=7.2Hz,3H);

[0131] Example 31: Preparation of Compound 31

[0132]

[0133] The operation was the same as in Example 21, except that propanethiol was used in the first step of the synthesis and isopropylamine was used in the second step of the synthesis. The mobile phase was MeCN-H2O (55:45, v / v). The monomer compound 31 was obtained with a yield of 45.7%. The structural identification data are as follows: m / z: [M+Na] + =460.1365, 1 H NMR(600MHz, CDCl3)δ7.00(s,1H),5.67–5.61(m,1H),5.37(d,J=4.4Hz,1H),5.07–5.02(m,1H),3.98–3.9 3(m,3H),3.12–3.06(m,2H),3.04(d,J=11.3Hz,1H),2.99–2.94(m,2H),2.92(d,J=14.8Hz,1H),2.83(dd,J =13.6,4.5Hz,1H),2.69(dt,J=12.6,7.4Hz,1H),2.59(dt,J=12.5,7.5Hz,1H),2.27(dd,J=14.8,4.7Hz,1 H),1.78(d,J=1.4Hz,3H),1.75–1.70(m,1H),1.64–1.57(m,2H),1.39–1.28(m,8H),0.89(t,J=7.2Hz,3H);

[0134] Example 32: Preparation of Compound 32

[0135]

[0136] The operation was the same as in Example 21, except that benzenethiol was used in the first step of the synthesis and propargylamine was used in the second step of the synthesis. The mobile phase was MeCN-H2O (65:35, v / v). The monomer compound 32 was obtained with a yield of 24.7%. The structural identification data are as follows: m / z: [M+Na] + =490.4462, 1 H NMR (600MHz, CDCl3) δ7.38–7.35(m,2H),7.24(t,J=7.4Hz,1H),7.13–7.10(m,2H),6.97(s,1H),5.35(d ,J=4.3Hz,1H),5.19(dd,J=10.9,10.0Hz,1H),5.03(d,J=9.8Hz,1H),4.07(d,J=4.8Hz,2H),3.88(dd,J =8.9,2.4Hz,1H),3.86–3.82(m,1H),3.47(dd,J=8.9,2.9Hz,1H),2.96–2.92(m,2H),2.88(s,1H),2.87 (s,1H),2.78–2.75(m,1H),2.48(t,J=2.5Hz,1H),2.26(dd,J=14.7,4.7Hz,1H),1.70(d,J=1.3Hz,3H);

[0137] Example 33: Preparation of Compound 33

[0138]

[0139] The operation was the same as in Example 21, except that p-methoxybenzenethiol was used in the first step of the synthesis, cyclopropanol was used in the second step of the synthesis, and the mobile phase was MeCN-H2O (65:35, v / v). The monomer compound 33 was obtained with a yield of 79.4%, and the structural identification data are as follows: m / z: [M+Na] + =523.1422, 1H NMR (600MHz, CDCl3) δ7.51(d,J=8.6Hz,2H),6.97(s,1H),6.85(d,J=8.6Hz,2H),5.36(d,J=3.9Hz,1H ),5.31(t,J=10.3Hz,1H),4.93(d,J=9.8Hz,1H),3.89(dt,J=10.5,5.2Hz,1H),3.79(s,3H),3.46(dd ,J=13.1,3.8Hz,1H),3.16(dd,J=13.1,5.0Hz,1H),3.04(dt,J=10.8,6.6Hz,1H),3.01–2.88(m,4H), 2.24(dd,J=14.8,4.6Hz,1H),1.68(s,3H),1.49–1.44(m,1H),0.94–0.89(m,2H),0.86–0.82(m,2H);

[0140] Example 34: Preparation of Compound 34

[0141]

[0142] The operation was the same as in Example 21, except that 4-fluorobenzenethiol was used in the first step of the synthesis and cyclopentanol was used in the second step of the synthesis. The mobile phase was MeCN-H2O (70:30, v / v). The monomer compound 34 was obtained with a yield of 81.5%. The structural identification data are as follows: m / z: [M+Na] + =539.1368, 1 H NMR (400MHz, CDCl3) δ7.54–7.45(m,2H),7.03–6.96(m,3H),5.35(d,J=3.8Hz,1H) ,5.21(t,J=9.6Hz,1H),4.87(d,J=11.0Hz,2H),3.94–3.85(m,1H),3.40(d,J=11.3 Hz,1H),3.17(dd,J=13.2,4.7Hz,1H),3.01–2.83(m,5H),2.72–2.67(m,2H),2.23 (dd,J=14.7,4.6Hz,1H),1.91–1.84(m,2H),1.74–1.65(m,7H),1.60–1.54(m,2H);

[0143] Example 35: Preparation of Compound 35

[0144]

[0145] The operation was the same as in Example 21, except that 4-bromobenzenethiol was used in the first step of the synthesis, benzyl alcohol was used in the second step of the synthesis, and the mobile phase was MeCN-H2O (75:25, v / v). The monomer compound 35 was obtained with a yield of 84.2%. The structural identification data are as follows: m / z: [M+Na] + =622.4833, 1 H NMR (600MHz, CDCl3) δ7.43–7.37(m,4H),7.32(t,J=7.3Hz,2H),7.27(d,J=7.3Hz,1H),7.23(d ,J=7.3Hz,2H),6.97(s,1H),5.36(d,J=4.4Hz,1H),5.32(t,J=10.2Hz,1H),4.93–4.90(m,1H) ,3.92–3.87 (m, 1H), 3.85–3.79 (m, 2H), 3.51 (dd, J = 13.2, 3.9 Hz, 1H), 3.25 (dd, J = 13.2, 4.9 Hz, 1H), 3.00–2.88 (m, 5H), 2.24 (dd, J = 14.7, 4.7 Hz, 1H), 1.68 (d, J = 1.4 Hz, 3H); Example 36: Preparation of Compound 36

[0146]

[0147] The operation was the same as in Example 21, except that 4-trifluoromethylbenzenethiol was used in the first step of the synthesis, 4-pyridinemethanol was used in the second step of the synthesis, and the mobile phase was MeCN-H2O (70:30, v / v). The monomer compound 36 was obtained with a yield of 76.9%. The structural identification data are as follows: m / z: [M+Na] + =612.2259, 1 H NMR (400MHz, CDCl3) δ8.93(d,J=1.4Hz,2H),8.42(d,J=1.4Hz,2H),7.58–7.51(m,4H),6.97(s,1H),5.34(dd,J=16.4,6.5Hz,2H),4.92(d,J=9.8Hz,1H) ,3.95–3.86(m,3H),3.56(dd,J=13.2,4.0Hz,1H),3.35(dd,J=13.2,4.5Hz, 1H),3.00–2.86(m,5H),2.24(dd,J=14.8,4.6Hz,1H),1.69(d,J=1.4Hz,3H);

[0148] Example 37: Preparation of Compound 37

[0149]

[0150] The operation was the same as in Example 21, except that benzyl mercaptan was used in the first step of the synthesis, 2-thiophene methanol was used in the second step of the synthesis, and the mobile phase was MeCN-H2O (65:35, v / v). The monomer compound 37 was obtained with a yield of 65.0%. The structural identification data are as follows: m / z: [M+Na] + =563.1244, 1 H NMR (600MHz, CDCl3) δ7.38–7.35(m,2H),7.34(dd,J=5.1,1.2Hz,1H),7.24(t,J=7.4Hz,1H),7.13–7.10(m,2H), 7.09(d,J=3.0Hz,1H),6.98(dd,J=5.1,3.5Hz,1H),6.97(s,1H),5.35(d,J=4.3Hz,1H),5.19(dd,J=10.9,10.0H z,1H),5.03(d,J=9.8Hz,1H),3.88(dd,J=8.9,2.4Hz,1H),3.86–3.82(m,1H),3.47(dd,J=8.9,2.9Hz,1H),2.96 –2.92(m,4H),2.88(s,1H),2.87(s,1H),2.78–2.75(m,1H),2.26(dd,J=14.7,4.7Hz,1H),1.70(d,J=1.3Hz,3H);

[0151] Example 38: Preparation of Compound 38

[0152]

[0153] The operation was the same as in Example 21, except that isopentenyl mercaptan was used in the first step of the synthesis, 2-furanmethanol was used in the second step of the synthesis, and the mobile phase was MeCN-H2O (65:35, v / v). The monomer compound 38 was obtained with a yield of 79.4%. The structural identification data are as follows: m / z: [M+Na] + =525.1369, 1H NMR (400MHz, CDCl3) δ7.34 (dd, J=5.1, 1.2Hz, 1H), 7.09 (d, J=3.0Hz, 1H), 6.98–6. 97(m,2H),5.42–5.31(m,3H),4.91(d,J=9.8Hz,1H),3.90–3.83(m,1H),3.48–3.34 (m,2H),3.12–3.03(m,3H),2.94–2.87(m,4H),2.85–2.78(m,1H),2.77–2.70(m,1 H),2.23(dd,J=14.8,4.6Hz,1H),1.74(s,3H),1.70(s,3H),1.68(d,J=1.3Hz,3H);

[0154] Example 39: Preparation of Compound 39

[0155]

[0156] The operation was the same as in Example 21, except that 4-methylbenzenethiol was used in the first step of the synthesis, phenol was used in the second step of the synthesis, and MeCN-H2O (75:25, v / v) was used as the mobile phase. The monomer compound 39 was obtained with a yield of 34.6%. The structural identification data are as follows: m / z: [M+Na] + =543.2259, 1 H NMR(600MHz, CDCl3)δ7.30(t,J=7.4Hz,2H),7.26–7.20(m,3H),7.11(s,4H),7.06(s,1H),6.34(d,J=2.5Hz,1H ),5.90(d,J=1.8Hz,1H),5.36(d,J=3.9Hz,1H),5.29–5.24(m,2H),4.94(d,J=9.7Hz,1H),4.30(dd,J=14.8,5.7 Hz,1H),4.21(dd,J=14.8,5.7Hz,1H),3.86(dt,J=11.3,4.1Hz,1H),3.24–3.17(m,1H),2.95(dd,J=12.8,3.5H z,1H),2.91(d,J=14.8Hz,1H),2.70(t,J=12.1Hz,1H),2.31(s,3H),2.25(dd,J=14.8,4.7Hz,1H),1.70(s,3H);

[0157] Example 40: Preparation of Compound 40

[0158]

[0159] The operation was the same as in Example 21, except that cyclopropylthiol was used in the first step of the synthesis and 4-fluorobenzyl alcohol was used in the second step of the synthesis. The mobile phase was MeCN-H2O (65:35, v / v). The monomer compound 40 was obtained with a yield of 68.5%. The structural identification data are as follows: m / z: [M+Na] + =525.3369, 1 H NMR (600MHz, CDCl3) δ7.37(dd,J=8.5,5.4Hz,2H),7.03(t,J=8.5Hz,2H),6.97(s,1H),5.33(d,J=4.4H z,1H),5.12(dd,J=11.0,9.9Hz,1H),4.94(d,J=9.7Hz,1H),4.06–4.02(m,1H),3.83(dd,J=8.9,2.4Hz, 1H),3.82–3.78(m,3H),3.44(dd,J=8.9,2.9Hz,1H),2.91(d,J=14.8Hz,1H),2.87–2.83(m,3H),2.68–2 .64(m,1H),2.25(dd,J=14.8,4.7Hz,1H),1.71(d,J=1.4Hz,3H),0.74–0.72(m,2H),0.71–0.68(m,2H);

[0160] Example 41: Preparation of Compound 41

[0161]

[0162] The operation was the same as in Example 21, except that 4-methoxythiophenol was used in the first step of the synthesis, and pentanethiol was used in the second step of the synthesis. The mobile phase was MeCN-H2O (70:30, v / v). The yield of monomer compound 41 was 71.4%. The structural identification data are as follows: m / z: [M+Na] + =569.2248, 1H NMR (600MHz, CDCl3) δ7.51(d,J=8.6Hz,2H),6.97(s,1H),6.85(d,J=8.6Hz,2H),5.36(d,J=3.9Hz,1H),5. 31(t,J=10.3Hz,1H),4.93(d,J=9.8Hz,1H),3.89(dt,J=10.5,5.2Hz,1H),3.79(s,3H),3.46(dd,J=13.1,3 .8Hz,1H),3.16(dd,J=13.1,5.0Hz,1H),3.04(dt,J=10.8,6.6Hz,1H),3.01–2.88(m,4H),2.84–2.74(m,2H ),2.24(dd,J=14.8,4.6Hz,1H),1.68(s,3H),1.62–1.56(m,2H),1.34–1.28(m,4H),0.87(t,J=7.1Hz,3H);

[0163] Example 42: Preparation of Compound 42

[0164]

[0165] The operation was the same as in Example 21, except that 4-fluorobenzenethiol was used in the first step of the synthesis, isobutyl mercaptan was used in the second step of the synthesis, and the mobile phase was MeCN-H2O (65:35, v / v). The monomer compound 42 was obtained with a yield of 78.3%. The structural identification data are as follows: m / z: [M+Na] + =543.6275, 1 H NMR (600MHz, CDCl3) δ7.57–7.51(m,2H),7.04–6.98(m,2H),6.97(s,1H),5.36(d,J=4.2Hz, 1H),5.32(t,J=10.3Hz,1H),4.91(d,J=9.8Hz,1H),3.90(dt,J=9.9,5.7Hz,1H),3.50(dd,J =13.2,3.8Hz,1H),3.20(dd,J=13.2,5.0Hz,1H),3.04–2.98(m,3H),2.97–2.89(m,4H),2.2 4(dd,J=14.7,4.7Hz,1H),1.85–1.78(m,1H),1.68(d,J=0.9Hz,3H),0.99(t,J=6.5Hz,6H);

[0166] Example 43: Preparation of Compound 43

[0167]

[0168] Compound 17 (20 mg, 0.044 mmol), m-CPBA (15.1 mg, 0.088 mmol), and 4 mL of dry dichloromethane were added to a 10 mL round-bottom flask in sequence and stirred at room temperature for 4 h. After TLC confirmed that the reaction was complete, 3 mL of saturated sodium bicarbonate was added to terminate the reaction. The mixture was then extracted with ethyl acetate and the solvent was removed by distillation under reduced pressure to obtain a crude product 43. The product was then prepared by reverse phase semi-preparative liquid chromatography with a mobile phase of MeCN-H2O (55:45, v / v) to obtain the final product 43 with a yield of 82.3%. The structural identification data are as follows: m / z: [M+Na] + =511.1147, 1 H NMR(600MHz,DMSO-d6)δ9.09(d,J=4.9Hz,2H),7.87(t,J=4.9Hz,1H),7.46(s,1H),5.54(t,J=10 .1Hz,1H),5.41(d,J=4.2Hz,1H),4.40(d,J=9.8Hz,1H),4.32(dd,J=15.6,5.8Hz,1H),4.01(dd,J =15.6,4.0Hz,1H),4.00–3.96(m,1H),3.35–3.30(m,1H),2.83(dd,J=12.4,3.8Hz,1H),2.69–2.6 0(m,3H),2.23(dd,J=14.8,4.6Hz,1H),1.64–1.59(m,4H),0.87–0.83(m,2H),0.83–0.76(m,2H);

[0169] Example 44: Preparation of Compound 44

[0170]

[0171] The operation was the same as in Example 43, and the mobile phase was MeCN-H2O (60:40, v / v). The yield of monomer compound 44 was 82.5%, and the structural identification data were as follows: m / z: [M+Na] + =489.3245, 1H NMR(600MHz, CDCl3)δ6.97(s,1H),5.40–5.34(m,2H),4.95–4.90(m,1H),3.99( dt,J=9.8,5.9Hz,1H),3.54–3.50(m,2H),3.17–3.09(m,3H),3.00–2.93(m,3H) ,2.93–2.90(m,1H),2.45–2.37(m,1H),2.24(dd,J=14.7,4.6Hz,1H),1.70(d,J =1.4Hz,3H),1.62–1.57(m,1H),1.14(dd,J=6.7,5.4Hz,6H),1.01–0.85(m,4H).

[0172] Example 45: Preparation of Compound 45

[0173]

[0174] The operation was the same as in Example 43, and the mobile phase was MeCN-H2O (60:40, v / v). The yield of monomer compound 45 was 86.3%. The structural identification data are as follows: m / z: [M+Na] + =527.2249, 1 H NMR (600MHz, CDCl3) δ7.87–7.85(m,2H),7.35–7.33(m,2H),6.97(s,1H),5.36(d,J=4.2Hz,1H) ,5.32(t,J=10.3Hz,1H),4.91(d,J=9.8Hz,1H),3.90(dt,J=9.9,5.7Hz,1H),3.50(dd,J=13.2, 3.8Hz,1H),3.20(dd,J=13.2,5.0Hz,1H),3.04–2.98(m,1H),2.97–2.89(m,4H),2.24(dd,J=14 .7,4.7Hz,1H),1.68(d,J=0.9Hz,3H),1.50–1.43(m,1H),0.94–0.90(m,2H),0.88–0.83(m,2H);

[0175] Example 46: Preparation of Compound 46

[0176]

[0177] Compound SC (20 mg, 0.072 mmol), 3,6-dioxa-1,8-octanedithiol (117.2 μL, 0.72 mmol), and anhydrous methanol 4 mL were added to a 10 mL round-bottom flask in sequence and stirred at room temperature for 24 h. After TLC confirmed that the reaction was complete, the solvent was removed by vacuum distillation to obtain a crude intermediate 2. The intermediate 2 was then prepared by reverse phase semi-preparative liquid phase, with the mobile phase MeCN-H2O (55:45, v / v). The structural identification data are as follows: m / z: [M+H] + =735.2501, 1 H NMR (600MHz, CDCl3) δ7.00(s,1H),5.34(d,J=4.0Hz,1H),4.98(d,J=9.7Hz,1H),4.27(t,J=1 0.0Hz,1H),3.83(dt,J=10.5,5.2Hz,1H),3.73–3.66(m,2H),3.65–3.58(m,2H),3.17(dd,J=1 1.0,4.4Hz,1H),3.11(dd,J=13.8,4.1Hz,1H),3.04(dd,J=13.8,4.4Hz,1H),2.91–2.82(m,4H ),2.80–2.73(m,1H),2.62–2.56(m,1H),2.23(dd,J=14.7,4.7Hz,1H),1.60(d,J=1.1Hz,3H);

[0178] The intermediate 1 obtained above (15 mg, 0.02 mmol), cyclopropionic acid (16.3 μL, 0.2 mmol), EDCI (39.2 mg, 0.2 mmol), DMAP (25.0 mg, 0.2 mmol), and 3 mL of dry DCM were added to a 10 mL round-bottom flask and stirred at room temperature for 24 h. After TLC confirmed that the reaction was complete, 3 mL of water was added to terminate the reaction. The reaction solution was placed in a separatory funnel, the organic layer was taken, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined and placed in nitrogen blowing. The solvent was blown dry at room temperature to obtain a crude product 46. It was then prepared by reverse phase semi-preparative liquid phase, with the mobile phase MeCN-H2O (60:40, v / v) to obtain the monomer compound 46 (13.4 mg, yield 75.3%), and the structural identification data are as follows: m / z: [M+H] + =871.3019, 1H NMR (600MHz, CDCl3) δ6.97 (s, 1H), 5.35–5.29 (m, 2H), 4.91 (d, J = 9.8Hz, 1H), 3.90–3.85(m,1H),3.69(t,J=6.7Hz,2H),3.64(s,2H),3.20–3.15(m,1H),3.0 0–2.86(m,7H),2.78(dt,J=13.5,6.8Hz,1H),2.23(dd,J=14.7,4.7Hz,1H),1. 68(d,J=1.4Hz,3H),1.59–1.54(m,1H),0.97–0.92(m,2H),0.92–0.86(m,2H);

[0179] Example 47: Preparation of Compound 47

[0180]

[0181] The operation was the same as Example 46, except that benzoic acid was used in the second step of the synthesis, and the mobile phase was MeCN-H2O (70:30, v / v). The monomer compound 47 was obtained with a yield of 64.3%. The structural identification data are as follows: m / z: [M+Na] + =965.2837, 1 H NMR (600MHz, CDCl3) δ7.97 (dd, J=8.3, 1.2Hz, 2H), 7.61–7.56 (m, 1H), 7.45 (t, J=7.8Hz, 2H), 7. 01(s,1H),5.62(t,J=10.3Hz,1H),5.36(d,J=4.3Hz,1H),5.02(d,J=9.8Hz,1H),3.98–3.94(m,1 H),3.65(t,J=6.7Hz,2H),3.60(s,2H),3.13(dd,J=13.6,3.4Hz,1H),3.08–2.94(m,4H),2.93– 2.85(m,3H),2.75(dt,J=13.5,6.7Hz,1H),2.26(dd,J=14.8,4.7Hz,1H),1.78(d,J=1.4Hz,3H);

[0182] Example 48: Preparation of Compound 48

[0183]

[0184] The operation was the same as Example 46, except that trans-cinnamic acid was used in the second step of the synthesis, and the mobile phase was MeCN-H2O (75:25, v / v). The monomer compound 48 was obtained with a yield of 55.2%. The structural identification data are as follows: m / z: [M+Na]+ =1017.3069, 1 H NMR(600MHz, CDCl3)δ7.67(d,J=16.0Hz,1H),7.52(dd,J=6.7,2.9Hz,2H),7.40–7.38(m,3H),6.99(s ,1H),6.37(d,J=16.0Hz,1H),5.50(t,J=10.0Hz,1H),5.35(d,J=4.3Hz,1H),4.98(d,J=9.8Hz,1H),3 .95–3.90 (m, 1H), 3.66 (t, J = 6.7 Hz, 2H), 3.60 (s, 2H), 3.14 (dd, J = 13.2, 2.7 Hz, 1H), 3.01–2.86 (m, 7H), 2.77 (dt, J = 13.6, 6.8 Hz, 1H), 2.25 (dd, J = 14.8, 4.7 Hz, 1H), 1.75 (d, J = 1.4 Hz, 3H); Example 49: Preparation of Compound 49

[0185]

[0186] The operation was the same as Example 46, except that 1,5-pentanedithiol was used in the first step of the synthesis, and the mobile phase was MeCN-H2O (65:35, v / v). The monomer compound 49 was obtained with a yield of 45.7%. The structural identification data are as follows: m / z: [M+Na] + =847.2742, 1 HNMR(600MHz, CDCl3)δ6.96(s,1H),5.35–5.29(m,2H),4.95–4.88(m,1H),3.89–3.83(m,1H),3.11( dd,J=13.6,3.3Hz,1H),3.01–2.95(m,1H),2.95–2.86(m,4H),2.81(dd,J=13.6,4.3Hz,1H),2.73(d t, J = 12.6, 7.3 Hz, 1H), 2.60 (dt, J = 12.6, 7.4 Hz, 1H), 2.23 (dd, J = 14.7, 4.7 Hz, 1H), 1.68 (d, J = 1.4 Hz, 3H), 1.66-1.61 (m, 2H), 1.59-1.49 (m, 2H), 0.97-0.93 (m, 2H), 0.93-0.87 (m, 2H); Example 50: Preparation of Compound 50

[0187]

[0188] The operation was the same as Example 47, except that 1,5-pentanedithiol was used in the first step of the synthesis, and the mobile phase was MeCN-H2O (70:30, v / v). The monomer compound 50 was obtained with a yield of 66.8%. The structural identification data are as follows: m / z: [M+Na] + =919.2741, 1 HNMR(600MHz, CDCl3)δ7.97(dd,J=8.3,1.2Hz,2H),7.63–7.55(m,1H),7.46(t,J=7.8Hz,2H),6.99(s,1 H),5.66–5.59(m,1H),5.36(d,J=4.3Hz,1H),5.05(d,J=9.8Hz,1H),3.98–3.92(m,1H),3.12–3.02(m,3 H),2.99–2.94(m,2H),2.92(d,J=14.7Hz,1H),2.83(dd,J=13.7,4.5Hz,1H),2.73–2.67(m,1H),2.62–2 .55(m,1H),2.26(dd,J=14.8,4.7Hz,1H),1.78(d,J=1.4Hz,3H),1.66–1.58(m,2H),1.51–1.44(m,1H);

[0189] Example 51: Preparation of Compound 51

[0190]

[0191] The operation was the same as Example 48, except that 1,5-pentanedithiol was used in the first step of the synthesis, and the mobile phase was MeCN-H2O (75:25, v / v). The yield of monomer compound 51 was 72.4%, and the structural identification data were as follows: m / z: [M+Na] + =971.3102, 1HNMR(600MHz, CDCl3)δ7.67(d,J=16.0Hz,1H),7.53–7.50(m,2H),7.42–7.38(m,3H),6.98(s,1H),6.35(d, J=16.0Hz,1H),5.50(t,J=10.3Hz,1H),5.35(d,J=2.7Hz,1H),4.99(d,J=9.8Hz,1H),3.97–3.88(m,1H),3.0 8(dd,J=13.6,3.5Hz,1H),3.05–2.89(m,5H),2.83(dd,J=13.6,4.4Hz,1H),2.70(dt,J=12.6,7.3Hz,1H),2. 65–2.55(m,1H),2.25(dd,J=14.8,4.7Hz,1H),1.75(d,J=1.4Hz,3H),1.68–1.59(m,2H),1.54–1.45(m,1H);

[0192] Example 52: Preparation of Compound 52

[0193]

[0194] The operation was the same as in Example 46, except that 1,6-hexanedithiol was used in the first step of the synthesis, and the mobile phase was MeCN-H2O (65:35, v / v). The monomer compound 52 was obtained with a yield of 78.5%. The structural identification data are as follows: m / z: [M+Na] + =861.2939, 1 HNMR (600MHz, CDCl3) δ6.97 (s, 1H), 5.36–5.29 (m, 2H), 4.92 (d, J = 9.8Hz, 1H), 3.91–3.81 (m, 1H), 3.11 (dd,J=13.6,3.3Hz,1H),2.98(t,J=11.9Hz,1H),2.94–2.85(m,4H),2.80(dd,J=13.6,4.3Hz,1H),2.7 1(dt,J=12.7,7.3Hz,1H),2.59(dt,J=12.5,7.4Hz,1H),2.23(dd,J=14.7,4.7Hz,1H),1.68(d,J=1.2H z,3H),1.65–1.59(m,2H),1.58–1.52(m,1H),1.44–1.39(m,2H),0.97–0.93(m,2H),0.92–0.87(m,2H);

[0195] Example 53: Preparation of Compound 53

[0196]

[0197] The operation was the same as in Example 47, except that 1,6-hexanedithiol was used in the first step of the synthesis, and the mobile phase was MeCN-H2O (70:30, v / v). The monomer compound 53 was obtained with a yield of 82.3%. The structural identification data are as follows: m / z: [M+Na] + =933.2959, 1 HNMR (600MHz, CDCl3) δ7.97–7.95(m,2H),7.58(t,J=7.5Hz,1H),7.45(t,J=7.8Hz,2H),7.01(s,1H),5.63(t ,J=10.3Hz,1H),5.36(d,J=4.3Hz,1H),5.04(d,J=9.8Hz,1H),3.99–3.92(m,1H),3.11–3.01(m,3H),2.98–2 .94(m,2H),2.91(d,J=14.7Hz,1H),2.82(dd,J=13.7,4.5Hz,1H),2.69(dt,J=12.7,7.3Hz,1H),2.58(dt,J= 12.5,7.4Hz,1H),2.26(dd,J=14.8,4.7Hz,1H),1.78(d,J=1.3Hz,3H),1.63–1.55(m,2H),1.40–1.35(m,2H);

[0198] Example 54: Preparation of Compound 54

[0199]

[0200] The operation was the same as in Example 48, except that 1,6-hexanedithiol was used in the first step of the synthesis, and the mobile phase was MeCN-H2O (75:25, v / v). The yield of monomer compound 54 was 85.9%, and the structural identification data were as follows: m / z: [M+Na] + =985.3265, 1HNMR (600MHz, CDCl3) δ7.66 (d, J=16.0Hz, 1H), 7.51 (dd, J=6.5, 2.8Hz, 2H), 7.41–7.38 (m, 3H), 6.99 (s, 1H), 6. 35(d,J=16.0Hz,1H),5.50(t,J=10.3Hz,1H),5.35(d,J=3.9Hz,1H),4.99(d,J=9.8Hz,1H),3.96–3.89(m,1H), 3.08(dd,J=13.6,3.5Hz,1H),3.03–2.89(m,5H),2.83(dd,J=13.6,4.4Hz,1H),2.69(dt,J=12.7,7.3Hz,1H),2 .58(dt,J=12.5,7.4Hz,1H),2.25(dd,J=14.8,4.6Hz,1H),1.74(s,3H),1.64–1.54(m,2H),1.42–1.35(m,2H);

[0201] Example 55: Preparation of Compound 55

[0202]

[0203] The operation was the same as in Example 46, except that 1,8-octanedithiol was used in the first step of the synthesis, and the mobile phase was MeCN-H2O (65:35, v / v). The monomer compound 55 was obtained with a yield of 74.3%. The structural identification data are as follows: m / z: [M+Na] + =889.3279, 1 HNMR (600MHz, CDCl3) δ6.97 (s, 1H), 5.38–5.29 (m, 2H), 4.92 (d, J = 9.8Hz, 1H), 3.90–3.83 (m, 1H), 3. 10(dd,J=13.6,3.2Hz,1H),2.98(t,J=11.9Hz,1H),2.93–2.85(m,4H),2.80(dd,J=13.6,4.3Hz,1H), 2.73–2.67(m,1H),2.58(dt,J=12.6,7.4Hz,1H),2.23(dd,J=14.7,4.6Hz,1H),1.68(s,3H),1.63–1. 57(m,2H),1.57–1.52(m,1H),1.42–1.34(m,2H),1.29(s,2H),0.97–0.93(m,2H),0.90–0.86(m,2H);

[0204] Example 56: Preparation of Compound 56

[0205]

[0206] The operation was the same as in Example 47, except that 1,8-octanedithiol was used in the first step of the synthesis, and the mobile phase was MeCN-H2O (70:30, v / v). The monomer compound 56 was obtained with a yield of 79.6%. The structural identification data are as follows: m / z: [M+Na] + =961.3264, 1 HNMR (600MHz, CDCl3) δ7.97(d,J=7.4Hz,2H),7.58(t,J=7.5Hz,1H),7.44(t,J=7.7Hz,2H),7.01(s,1H),5.63(t ,J=10.3Hz,1H),5.36(d,J=4.0Hz,1H),5.04(d,J=9.8Hz,1H),3.99–3.93(m,1H),3.12–3.00(m,3H),2.98–2.93 (m,2H),2.91(d,J=14.7Hz,1H),2.82(dd,J=13.6,4.5Hz,1H),2.69(dt,J=12.7,7.4Hz,1H),2.58(dt,J=12.5,7 .4Hz,1H),2.26(dd,J=14.8,4.6Hz,1H),1.78(s,3H),1.62–1.56(m,2H),1.39–1.32(m,2H),1.31–1.26(m,2H);

[0207] Example 57: Preparation of Compound 57

[0208]

[0209] The operation was the same as in Example 48, except that 1,8-octanedithiol was used in the first step of the synthesis, and the mobile phase was MeCN-H2O (75:25, v / v). The monomer compound 57 was obtained with a yield of 86.3%. The structural identification data are as follows: m / z: [M+Na] + =991.3738, 1HNMR(600MHz, CDCl3) δ7.66(d,J=16.0Hz,1H),7.51(dd,J=6.6,2.6Hz,2H),7.39(dd,J=5.1,1.5Hz,3H),7.00(s,1H),6. 35(d,J=16.0Hz,1H),5.50(t,J=10.3Hz,1H),5.36(d,J=3.8Hz,1H),4.99(d,J=9.8Hz,1H),3.96–3.88(m,1H),3.08(dd, J=13.6,3.4Hz,1H),3.03–2.90(m,5H),2.83(dd,J=13.6,4.4Hz,1H),2.69(dt,J=12.7,7.3Hz,1H),2.58(dt,J=12.5,7. 5Hz,1H),2.25(dd,J=14.8,4.6Hz,1H),1.75(d,J=0.8Hz,3H),1.63–1.56(m,2H),1.38–1.32(m,2H),1.30–1.22(m,2H);

[0210] Example 58: Preparation of Compound 58

[0211]

[0212] The operation was the same as in Example 46, except that 1,8-decanedithiol was used in the first step of the synthesis, and the mobile phase was MeCN-H2O (65:35, v / v). The monomer compound 58 was obtained with a yield of 67.2%. The structural identification data are as follows: m / z: [M+Na] + =917.3550, 1 HNMR(600MHz, CDCl3) δ6.97(s,1H),5.33(dd,J=18.1,7.8Hz,2H),4.92(d,J=9.8Hz,1H),3.91–3.82(m ,1H),3.11(dd,J=13.6,3.4Hz,1H),2.98(t,J=11.9Hz,1H),2.95–2.86(m,4H),2.80(dd,J=13.6,4.4Hz ,1H),2.73–2.68(m,1H),2.61–2.56(m,1H),2.23(dd,J=14.7,4.7Hz,1H),1.68(d,J=1.3Hz,3H),1.64– 1.57(m,2H),1.57–1.52(m,1H),1.40–1.34(m,2H),1.26(s,4H),0.97–0.93(m,2H),0.90–0.86(m,2H);

[0213] Example 59: Preparation of Compound 59

[0214]

[0215] The operation was the same as Example 47, except that 1,8-decanedithiol was used in the first step of the synthesis, and the mobile phase was MeCN-H2O (70:30, v / v). The monomer compound 59 was obtained with a yield of 79.5%. The structural identification data are as follows: m / z: [M+Na] + =989.3564, 1 HNMR (600MHz, CDCl3) δ7.97–7.94(m,2H),7.60–7.56(m,1H),7.44(t,J=7.8Hz,2H),7.01(s,1H),5.65– 5.59(m,1H),5.36(d,J=4.3Hz,1H),5.03(d,J=9.8Hz,1H),3.98–3.93(m,1H),3.11–3.00(m,3H),2.98–2 .93(m,2H),2.90(d,J=14.7Hz,1H),2.81(dd,J=13.6,4.5Hz,1H),2.70–2.66(m,1H),2.59–2.55(m,1H), 2.26(dd,J=14.8,4.7Hz,1H),1.77(d,J=1.4Hz,3H),1.62–1.54(m,2H),1.37–1.32(m,2H),1.25(s,4H);

[0216] Example 60: Preparation of Compound 60

[0217]

[0218] The operation was the same as in Example 48, except that 1,8-decanedithiol was used in the first step of the synthesis, and the mobile phase was MeCN-H2O (80:20, v / v). The monomer compound 60 was obtained with a yield of 76.5%. The structural identification data are as follows: m / z: [M+Na] + =1041.3882, 1HNMR(600MHz, CDCl3)δ7.66(d,J=16.0Hz,1H),7.51(dd,J=7.1,2.3Hz,2H),7.41–7.37(m,3H),7.00(s,1H),6.35(d,J= 16.0Hz,1H),5.51(t,J=10.3Hz,1H),5.36(d,J=4.2Hz,1H),4.99(d,J=9.8Hz,1H),3.95–3.90(m,1H),3.09(dd,J=13.6, 3.5Hz,1H),3.03–2.97(m,2H),2.96–2.89(m,3H),2.83(dd,J=13.6,4.4Hz,1H),2.70(dt,J=12.5,7.3Hz,1H),2.62–2.5 6(m,1H),2.25(dd,J=14.8,4.7Hz,1H),1.75(d,J=1.3Hz,3H),1.64–1.56(m,2H),1.38–1.32(m,2H),1.27–1.20(m,4H);

[0219] Example 61: Preparation of Compound 61

[0220]

[0221] The operation was the same as in Example 46, except that 1,4-benzenedithiol was used in the first step of the synthesis, and the mobile phase was MeCN-H2O (65:35, v / v). The yield of monomer compound 61 was 71.6%, and the structural identification data were as follows: m / z: [M+Na] + =853.2325, 1 HNMR (600MHz, CDCl3) δ7.44 (s, 2H), 6.96 (s, 1H), 5.35 (d, J = 3.7Hz, 1H), 5.32 (t, J = 1 0.1Hz,1H),4.92(d,J=9.8Hz,1H),3.89(dt,J=10.4,5.1Hz,1H),3.49(dd,J=13.0,3. 9Hz,1H),3.27(dd,J=13.0,4.9Hz,1H),2.99–2.88(m,5H),2.24(dd,J=14.7,4.6Hz, 1H),1.69(s,3H),1.52–1.46(m,1H),0.94–0.91(m,2H),0.86(dt,J=7.6,4.1Hz,2H);

[0222] Example 62: Preparation of Compound 62

[0223]

[0224] The operation was the same as Example 47, except that 1,4-benzenedithiol was used in the first step of the synthesis, and the mobile phase was MeCN-H2O (70:30, v / v). The monomer compound 62 was obtained with a yield of 84.3%. The structural identification data are as follows: m / z: [M+Na] + =925.2319, 1 HNMR(600MHz, CDCl3)δ7.86(d,J=7.2Hz,2H),7.57(t,J=7.5Hz,1H),7.42–7.35(m,4H) ,7.00(s,1H),5.63(t,J=10.3Hz,1H),5.38(d,J=4.0Hz,1H),5.04(d,J=9.8Hz,1H),3. 99(dt,J=10.6,5.4Hz,1H),3.51(dd,J=13.1,3.7Hz,1H),3.24–3.14(m,2H),3.02–2.9 6(m,3H),2.92(d,J=14.7Hz,1H),2.27(dd,J=14.8,4.7Hz,1H),1.78(d,J=1.0Hz,3H);

[0225] Example 63: Preparation of Compound 63

[0226]

[0227] The operation was the same as in Example 48, except that 1,4-benzenedithiol was used in the first step of the synthesis, and the mobile phase was MeCN-H2O (80:20, v / v). The yield of monomer compound 63 was 72.6%, and the structural identification data were as follows: m / z: [M+Na] + =977.2640, 1 HNMR(600MHz, CDCl3)δ7.62(d,J=16.0Hz,1H),7.46(dd,J=6.6,2.9Hz,2H),7.41–7.38(m,5H ),6.98(s,1H),6.28(d,J=16.0Hz,1H),5.50(t,J=10.2Hz,1H),5.36(d,J=4.1Hz,1H),4.99(d ,J=9.8Hz,1H),3.97–3.92(m,1H),3.46(dd,J=13.0,4.0Hz,1H),3.24(dd,J=13.0,5.3Hz,1H ),3.06–3.01(m,1H),2.99–2.90(m,4H),2.25(dd,J=14.8,4.7Hz,1H),1.74(d,J=1.2Hz,3H);

[0228] Example 64: Preparation of Compound 64

[0229]

[0230] The operation was the same as in Example 46, except that 4,4'-thiobisthiophenol was used in the first step of the synthesis, and the mobile phase was MeCN-H2O (70:30, v / v). The monomer compound 64 was obtained with a yield of 71.7%, and the structural identification data are as follows: m / z: [M+Na] + =961.2345, 1 HNMR(600MHz, CDCl3)δ7.43(d,J=8.4Hz,2H),7.25(d,J=6.1Hz,2H),6.96(s,1H),5.35(d, J=4.1Hz,1H),5.32(t,J=10.1Hz,1H),4.90(d,J=9.8Hz,1H),3.92–3.86(m,1H),3.50(dd, J=13.2,3.8Hz,1H),3.28(dd,J=13.2,4.7Hz,1H),3.00–2.86(m,5H),2.23(dd,J=14.7,4. 7Hz,1H),1.68(d,J=1.2Hz,3H),1.51–1.44(m,1H),0.95–0.90(m,2H),0.88–0.83(m,2H);

[0231] Example 65: Preparation of Compound 65

[0232]

[0233] The operation was the same as Example 47, except that 4,4'-thiobisthiophenol was used in the first step of the synthesis, and the mobile phase was MeCN-H2O (75:25, v / v). The monomer compound 65 was obtained with a yield of 82.5%. The structural identification data are as follows: m / z: [M+Na] + =1033.2353, 1HNMR(600MHz, CDCl3)δ7.89–7.86(m,2H),7.56(t,J=7.5Hz,1H),7.43–7.37(m,4H),7.22( d,J=8.4Hz,2H),7.00(s,1H),5.63(t,J=10.3Hz,1H),5.38(d,J=4.2Hz,1H),5.02(d,J=9. 8Hz,1H),4.01–3.96(m,1H),3.52(dd,J=13.2,3.7Hz,1H),3.21(dd,J=13.3,5.3Hz,1H),3 .19–3.15(m,1H),3.02–2.89(m,4H),2.26(dd,J=14.8,4.6Hz,1H),1.78(d,J=1.3Hz,3H);

[0234] Example 66: Preparation of Compound 66

[0235]

[0236] The operation was the same as in Example 48, except that 4,4'-thiobisthiophenol was used in the first step of the synthesis, and the mobile phase was MeCN-H2O (85:15, v / v). The monomer compound 66 was obtained with a yield of 76.5%. The structural identification data are as follows: m / z: [M+Na] + =1085.2668, 1 HNMR (600MHz, CDCl3) δ7.62 (d, J=16.0Hz, 1H), 7.46–7.43 (m, 2H), 7.43–7.37 (m, 5H), 7.21 (d, J= 8.4Hz,2H),6.98(s,1H),6.28(d,J=16.0Hz,1H),5.50(t,J=10.2Hz,1H),5.37(d,J=4.1Hz,1H), 4.98(d,J=9.8Hz,1H),3.98–3.92(m,1H),3.50(dd,J=13.1,4.0Hz,1H),3.27(dd,J=13.1,5.1Hz ,1H),3.08–3.03(m,1H),2.99–2.89(m,4H),2.26(dd,J=14.8,4.6Hz,1H),1.75(d,J=1.2Hz,3H).

[0237] Example 67: Antitumor activity screening experiment

[0238] The cell proliferation activity was detected by MTT method, and the in vitro antitumor activity of 66 tested compounds (1-66) was screened.

[0239] 1. Experimental materials:

[0240] (1) Test cell lines: human lung cancer cells A549, human lung cancer cells H460, human lung cancer cells H1299, cervical cancer cells HeLa, human liver cancer cells HepG2, human liver cancer cells Hep3B, human leukemia cells HL60, human breast cancer cells MCF-7, human breast cancer cells MDA-MB-231, human colon cancer cells SW620, and normal lung epithelial cells Beas-2B.

[0241] (2) Test drug: sesquiterpene lactone scaberol C thioether derivative (1-66) synthesized by the present invention.

[0242] (3) Positive control: cisplatin.

[0243] 2. Experimental methods:

[0244] (1) Preparation of test drugs: Accurately weigh 1-2 mg of each test sample, prepare it into a 50 mM stock solution with DMSO, and prepare it into working solutions of different concentrations with basal culture medium.

[0245] (2) Cell proliferation inhibition experiment: Cells in the logarithmic growth phase were inoculated into 96-well plates. After overnight culture, different concentrations of compounds were added and incubated for 24 h. Then, 20 μL of MTT was added to each well and incubated for 4 h. The supernatant was discarded, and 150 μL of DMSO was added. The cells were vortexed and dissolved for 10 min. The OD value was detected at 490 nm using an enzyme reader, and the IC value of the corresponding compound was calculated using GraphPad. 50 value.

[0246] 3. The activity results are shown in Table 1

[0247] Table 1 Inhibitory activity of scaberol C thioether derivatives on different tumor cells (IC 50 ,μM)

[0248]

[0249]

[0250]

[0251] The results of activity tests showed that the screened compounds showed good inhibitory activity against a variety of tumor cells and low toxicity to normal cells. The activity of some test compounds was better than that of the positive drug cisplatin. Therefore, the test compounds have the potential to be developed into new drugs for the treatment of cancer.

Claims

1. A sesquiterpene lactone scaberol C sulfide derivative, characterized in that: The structure is shown in Formula I, Formula II, Formula III or Formula IV, Wherein, R is cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, 4,4-difluorocyclohexanecarbonyl, benzyl, C1-8alkanoyl, benzoyl, 4-trifluoromethylbenzoyl, 3-trifluoromethylbenzoyl, 4-fluorobenzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl, 4-nitrobenzoyl, 4-acetylbenzoyl, cinnamoyl, 4-fluorocinnamoyl, 4-chlorocinnamoyl, 4-methoxycinnamoyl, 3-trifluoromethylcinnamoyl, 3,4-methylenedioxycinnamoyl, 3-methoxycinnamoyl, 4-dimethylaminocinnamoyl, 4-trifluoromethylcinnamoyl, 3,4-difluorocinnamoyl, biphenylyl, 1-naphthoyl, 2-naphthoyl, 2,2-dimethylbutanoyl, 2-bromobutanoyl, isovaleryl, hexanoyl, 5-bromovaleryl, 4-picolinyl, 3-picolinyl, 4-pyridylacryloyl, 3-pyridylacryloyl, 2-furoyl, 2-thiophenecarboxyl, 2-furylacryloyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-benzylcarbamoyl, N-p-fluorobenzylcarbamoyl, N-(3-pyridyl)carbamoyl, N-n-propylcarbamoyl, N-isopropylcarbamoyl, N-(2-furyl)carbamoyl, N-(2-thiophenyl)carbamoyl, p-methoxybenzyloxycarbamoyl, phenyloxycarbamoyl, phenylthiocarbamoyl, 2-thiophenylhydroxymethylcarbamoyl, 2-furylhydroxymethylcarbamoyl or hexylthiocarbamoyl. R1 is C 1-8 a straight chain or branched chain alkyl group, a cyclopentyl group, a cyclopropyl group, a cyclohexyl group, a phenyl group, a benzyl group, a pyridyl group, a thienyl group, a furyl group, a prenyl group, a p-bromophenyl group, a 3-bromophenyl group, a 3-fluorophenyl group, a p-fluorophenyl group, a p-chlorophenyl group, a 3-chlorophenyl group, a p-trifluoromethylphenyl group, a 3-trifluoromethylphenyl group, a p-nitrophenyl group, a 3-nitrophenyl group, a p-hydroxyphenyl group, a 3-hydroxyphenyl group, a p-methoxyphenyl group, a 3-methoxyphenyl group, a p-methylphenyl group, a 3-methylphenyl group, a p-fluorobenzyl group, a 3-fluorobenzyl group, a p-chlorobenzyl group, a 3-chlorobenzyl group, a p-bromobenzyl group, a 3-bromobenzyl group, a p-trifluoromethylbenzyl group, a 3-trifluoromethylbenzyl group, a p-nitrobenzyl group, a 3-nitrobenzyl group, a p-hydroxybenzyl group, a 3-hydroxybenzyl group, a p-methoxybenzyl group, a 3-methoxybenzyl group, a p-methylbenzyl group, a 3-methylbenzyl group, a 3-pyridylmethyl group, a 2-thienylmethyl group, or a 2-furylmethyl group. R2 is -(CH2) p -, where p is an integer between 2 and 10.

2. A sesquiterpene lactone scaberol C sulfide derivative, characterized in that: Specifically selected from the following compounds:

3. Use of the sesquiterpene lactone scaberol C thioether derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 in the preparation of a drug for treating tumors.

4. Use of the sesquiterpene lactone scaberol C thioether derivative or a pharmaceutically acceptable salt thereof according to claim 3 in the preparation of a drug for treating tumors, characterized in that: The pharmaceutically acceptable salt of the sesquiterpene lactone scaberol C thioether derivative is selected from sulfate, hydrochloride, hydrobromide, phosphate, acetate, methanesulfonate, benzenesulfonate, toluenesulfonate, tartrate, maleate, benzoate, succinate, fumarate, tartrate, gallate, citrate, as well as ammonium salt, sodium salt and potassium salt.

5. A pharmaceutical composition comprising the sesquiterpene lactone scaberol C thioether derivative according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient; The dosage form of the pharmaceutical composition is capsule tablet, solution, suspension, granule or injection; The pharmaceutical composition can be administered orally or parenterally.

6. Use of the pharmaceutical composition according to claim 5 in the preparation of drugs for treating tumors.

Images