Sesquiterpene lactone scaberol C dithiocarbamate derivatives and preparation method and application thereof

Abstract

The present invention relates to a sesquiterpene lactone scaberol C dithiocarbamate derivative and a preparation method and application thereof, and belongs to the field of pharmaceutical technology. Aiming at the problems of poor targeting and easy inactivation by nucleophilic molecules in vivo in existing scaberol C derivatives, the present invention obtains a series of sesquiterpene lactone scaberol C dithiocarbamate derivatives by performing Michael addition modification on the exocyclic double bond of the active center and performing diversified modification on C6-OH in the scaberol C molecule. These derivatives can not only release prototype compounds and dithiocarbamates in the highly oxidized state environment of tumor cells, synergistically exert anti-tumor effects, but also show good biocompatibility and safety, providing a new path for 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 dithiocarbamate derivative and a preparation method and application thereof. Background Art

[0002] Disulfiram is a dimer of diethyldithiocarbamate (DDC), which was initially used in the clinic to treat alcohol dependence. Subsequent studies have found that disulfiram can exert anti-tumor effects by inhibiting tumor stem cells and NF-κB-related signaling pathways, and then study the activity of its metabolites. Studies have shown that the monomer DDC of disulfiram can quickly form a very stable chelate with copper ions in the blood in vivo, which can exert a significant anti-tumor effect. The design of this type of dithiocarbamate derivatives has once again attracted widespread attention.

[0003] Scaberol C is a class of sesquiterpene lactone compounds containing α-methylene-γ-butyrolactone fragments found in the herb Eleutherococcus spp. Previous studies have shown that modified scaberol C derivatives have good anti-lung cancer activity, but these covalent compounds have the same poor targeting and are easily inactivated by nucleophilic molecules in the body. Currently, there are few studies on scaberol C derivatives, and there are no reports of scaberol C derivatives being marketed as tumor treatment drugs. Summary of the invention

[0004] The present invention is based on the principle of drug splicing, and splices the dithiocarbamate fragment into the pharmacophore of sesquiterpene lactone, which can not only protect the pharmacophore, but also release the prototype compound and dithiocarbamate under the high oxidation state environment of tumor cells, thereby synergistically exerting anti-tumor effects.

[0005] 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 dithiocarbamate derivatives with better anti-tumor activity, and provide a preparation method of these dithiocarbamate derivatives. The present invention also provides the use of sesquiterpene lactone scaberol C dithiocarbamate derivatives in the preparation of tumor treatment drugs.

[0006] The purpose of the invention is achieved through the following specific technical solutions:

[0007] A sesquiterpene lactone scaberol C dithiocarbamate derivative or a pharmaceutically acceptable salt thereof, the general structural formula of which is shown in general formula I:

[0008]

[0009]

[0010] In the general formula I,

[0011] R is selected from cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, unsubstituted or substituted benzyl, C1-8alkanoyl, unsubstituted or substituted benzoyl, unsubstituted or substituted cinnamoyl, biphenylcarbonyl, 1-naphthoyl, 2-naphthoyl, unsubstituted or substituted 4-pyridoyl, unsubstituted or substituted-3-pyridoyl, unsubstituted or substituted-2-furoyl, unsubstituted or substituted-2-thienylcarbonyl, unsubstituted or substituted 2-furylacryl, unsubstituted or substituted-2-thienyllacryl, unsubstituted or substituted 4-pyridyllacryl, unsubstituted or substituted-3-pyridyllacryl, -CO(CH2) n COOH, -CO(CH2) m P + (Ph)3Br - , wherein n and m are respectively an integer between 2 and 10, N-unsubstituted or substituted carbamoyl and unsubstituted or substituted oxyacyl;

[0012] R1 or R2 is hydrogen, C 1-8 straight-chain or branched alkyl, cyclopentyl, cyclopropyl, cyclohexyl, unsubstituted or substituted piperidinyl, morpholinyl, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, unsubstituted or substituted pyrimidinyl;

[0013] Further, in the general formula I, when R is selected from -CO(CH2) n COOH, -CO(CH2) m P + (Ph)3Br - When n is selected from 2-6, m is selected from 3-7.

[0014] Furthermore, in the general formula I:

[0015] R is selected from 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, cyclopropanecarbonyl, cyclohexanecarbonyl, 4,4-difluorocyclohexanecarbonyl, isovaleryl, hexanoyl, 5-bromovaleryl, unsubstituted or substituted 4-pyridinyl, 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-furylhydroxymethylcarbamoyl and hexylthiocarbamoyl;

[0016] R1 or R2 is each independently selected from hydrogen, methyl, ethyl, isopropyl, benzyl, isobutyl, n-propyl, p-methoxybenzyl, p-fluorobenzyl, p-bromobenzyl, p-trifluoromethylbenzyl, 3-pyridylmethyl, piperidinyl, morpholinyl, 2-thienyl and 2-furylmethyl.

[0017] 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.

[0018] The sesquiterpene lactone scaberol C dithiocarbamate derivatives of the present invention are specifically selected from the following compounds:

[0019]

[0020]

[0021] The present invention provides a synthesis method having a structure as shown in Formula I, comprising the following steps:

[0022] Using sesquiterpene lactone scaberol C as a raw material and a dichloromethane-methanol mixed solvent as a reaction solvent, under ice bath conditions, carbon disulfide, a corresponding amine reaction reagent and triethylamine are first added, and then scaberol C is added, and finally an acylating agent or a halogenated hydrocarbon is reacted to generate a final product;

[0023] The route looks like this:

[0024]

[0025] The present invention provides application of the sesquiterpene lactone scaberol C dithiocarbamate derivative or a pharmaceutically acceptable salt thereof in preparing a drug for treating tumors.

[0026] The present invention provides a pharmaceutical composition, comprising the above-mentioned sesquiterpene lactone scaberol C dithiocarbamate derivative or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant.

[0027] The present invention provides application of the above-mentioned pharmaceutical composition in preparing drugs for treating tumors.

[0028] The sesquiterpene lactone scaberol C dithiocarbamate derivative or its pharmaceutically acceptable salt described in the present invention includes not only a single compound form, but also a mixture of compounds whose structures meet the requirements of the general formula shown. The pharmaceutically acceptable salt refers to 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.

[0029] The dosage form of the pharmaceutical composition of the present invention is capsule tablet, solution, suspension, granule or injection.

[0030] As used in the present invention, the term "pharmaceutically acceptable excipient" refers to one or more of a diluent, a lubricant, a binder, a disintegrant, a stabilizer or a solvent.

[0031] Beneficial effects of the present invention:

[0032] The present invention provides a sesquiterpene lactone scaberol C dithiocarbamate derivative based on the drug splicing principle and tumor microenvironment theory. The sesquiterpene lactone scaberol C dithiocarbamate derivative can not only overcome the off-target disadvantages of covalent compounds, but also exert the dual anti-tumor effects of sesquiterpene lactone and dithiocarbamate. DETAILED DESCRIPTION

[0033] 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:

[0034] Example 1: Preparation of Compound 1

[0035]

[0036] (a) The synthesis method of SC refers to the literature (J.Nat.Prod.2022,85,352-364). At 0°C, carbon disulfide (21.0μL, 0.35mmol), dimethylamine (17.4μL, 0.26mmol), triethylamine (36.2μL, 0.26mmol), and 4mL of anhydrous methanol were added to a 10mL round-bottom flask in sequence. After stirring at 0°C for 0.5-1h, compound SC (24mg, 0.087mmol) was added and stirred at room temperature for 72h. 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 (40:60, v / v) to obtain intermediate 1, and the structural identification data are as follows: m / z: [M+H] + =398.1087, 1 H NMR (400MHz, CDCl3) δ6.90 (s, 1H), 5.28 (d, J = 4.4Hz, 1H), 4.88 (d, J = 9.9Hz, 1H), 4.30 (dd,J=14.8,5.3Hz,1H),4.16(q,J=10.3Hz,1H),3.87–3.81(m,1H),3.78(dd,J=14.8, 2.2Hz,1H),3.66(s,3H),3.52(s,3H),3.32–3.26(m,1H),2.88–2.80(m,2H),2.60(t,J =11.9Hz,1H),2.49–2.41(m,1H),2.19(dd,J=14.6,4.8Hz,1H),1.56(d,J=1.2Hz,3H);

[0037] (b) Add the intermediate 1 (15 mg, 0.038 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 to a 10 mL round-bottom flask, and stir 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. The product was then prepared by reverse phase semi-preparative liquid phase, with the mobile phase being MeCN-H2O (50:50, v / v), to obtain the monomer compound 1 (15.8 mg, yield 89.8%), and the structural identification data are as follows: m / z: [M+Na] + =488.1174, 1 HNMR (600MHz, CDCl3) δ6.93 (s, 1H), 5.33–5.27 (m, 2H), 4.84 (d, J = 9.8Hz, 1H), 4.26 (dd, J = 13. 9,5.2Hz,1H),3.89–3.84(m,1H),3.81(dd,J=13.9,3.4Hz,1H),3.62(s,3H),3.48(s,3H),3.0 4–3.00(m,1H),2.91–2.85(m,2H),2.75(t,J=12.0Hz,1H),2.72–2.67(m,1H),2.22(dd,J=14. 8,4.6Hz,1H),1.75–1.70(m,1H),1.68(d,J=1.3Hz,3H),1.08–1.01(m,2H),0.94–0.86(m,2H).

[0038] Example 2: Preparation of Compound 2

[0039]

[0040] The operation was the same as in Example 1, except that cyclobutyric 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 2 was 56.8%, and the structural identification data were as follows: m / z: [M+Na] + =502.1739, 1H NMR (600MHz, CDCl3) δ6.93(s,1H),5.33–5.27(m,2H),4.84(d,J=9.8Hz,1H),4.26(dd,J=13.9,5.2 Hz,1H),3.89–3.84(m,1H),3.81(dd,J=13.9,3.4Hz,1H),3.62(s,3H),3.48(s,3H),3.14–3.08(m, 1H),3.04–3.00(m,1H),2.91–2.85(m,2H),2.75(t,J=12.0Hz,1H),2.72–2.67(m,1H),2.26(dd,J= 14.8,4.6Hz,1H),2.23–2.17(m,4H),2.01–1.95(m,1H),1.90–1.84(m,1H),1.68(d,J=1.3Hz,3H).

[0041] Example 3: Preparation of Compound 3

[0042]

[0043] The operation was the same as in Example 1, except that cyclopentanoic 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 3 was 66.2%, and the structural identification data were as follows: m / z: [M+Na] + =516.4577, 1 H NMR (600MHz, CDCl3) δ6.93 (s, 1H), 5.33–5.27 (m, 2H), 4.84 (d, J = 9.8Hz, 1H), 4.26 (dd, J =13.9,5.2Hz,1H),3.89–3.84(m,1H),3.81(dd,J=13.9,3.4Hz,1H),3.62(s,3H),3.48( s,3H),3.04–3.00(m,1H),2.91–2.85(m,2H),2.75(t,J=12.0Hz,1H),2.72–2.67(m,2H) ,2.26(dd,J=14.8,4.6Hz,1H),1.91–1.84(m,2H),1.74–1.65(m,7H),1.60–1.54(m,2H).

[0044] Example 4: Preparation of Compound 4

[0045]

[0046] The operation was the same as in Example 1, except that cyclohexanoic acid was used in the second step of the synthesis, and the mobile phase was MeCN-H2O (65:35, v / v). The yield of monomer compound 4 was 60.3%, and the structural identification data were as follows: m / z: [M+Na] + =530.1431, 1 H NMR(600MHz, CDCl3)δ6.93(s,1H),5.33–5.27(m,2H),4.84(d,J=9.8Hz,1H),4.26(dd,J=13.9,5.2Hz,1H),3.8 9–3.84(m,1H),3.81(dd,J=13.9,3.4Hz,1H),3.62(s,3H),3.48(s,3H),3.04–3.00(m,1H),2.91–2.85(m,2H),2 .75(t,J=12.0Hz,1H),2.75(t,J=12.1Hz,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),1.70(d,J=1.4Hz,3H),1.66–1.62(m,1H),1.41–1.35(m,2H),1.30–1.24(m,2H),1.23–1.17(m,1H).

[0047] Example 5: Preparation of Compound 5

[0048]

[0049] The operation was the same as in Example 1, except that the second step synthesis method was as follows: the intermediate 1 (15 mg, 0.038 mmol), 1,1'-Carbonyl-di-(1,2,4-triazole) (12.5 mg, 0.076 mmol), n-propylamine (9.4 μL, 0.11 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 5. The product was then prepared by reverse phase semi-preparative liquid phase, with the mobile phase being MeCN-H2O (50:50, v / v), to obtain a monomer compound 5 with a yield of 75.4%, and the structural identification data are as follows: m / z: [M+H] + =483.1613, 1HNMR (400MHz, CDCl3) δ6.94 (s, 1H), 5.31 (d, J = 4.1Hz, 1H), 5.20 (t, J = 10.2Hz, 1H), 5.15 (t, J=5.9Hz,1H),4.86(d,J=9.8Hz,1H),4.03(dd,J=13.9,6.3Hz,1H),3.95–3.87(m,2H),3.59( s,3H),3.47(s,3H),3.11–3.01(m,3H),2.93–2.83(m,2H),2.73–2.60(m,2H),2.21(dd,J=1 4.8, 4.6Hz, 1H), 1.68 (d, J = 1.4Hz, 3H), 1.48 (dd, J = 14.6, 7.3Hz, 2H), 0.88 (t, J = 7.4Hz, 3H).

[0050] Example 6: Preparation of Compound 6

[0051]

[0052] The operation was the same as in Example 1, except that diethylamine was used in the first step of the synthesis and benzoic acid was used in the second step of the synthesis. The mobile phase was MeCN-H2O (55:45, v / v). The yield of monomer compound 6 was 75.6%. The structural identification data are as follows: m / z: [M+Na] + =552.1993, 1 HNMR (600MHz, CDCl3) δ8.02(d,J=7.5Hz,2H),7.59(t,J=7.5Hz,1H),7.47(t,J=7.7Hz,2H),7.07(s,1H),5.33–5. 27(m,2H),4.84(d,J=9.8Hz,1H),4.26(dd,J=13.9,5.2Hz,1H),3.89–3.84(m,1H),3.81(dd,J=13.9,3.4Hz,1H), 3.62(s,3H),3.48(s,3H),3.04–3.00(m,1H),2.91–2.85(m,2H),2.75(t,J=12.0Hz,1H),2.72–2.67(m,1H),2.33 –2.30(m,4H),2.26(dd,J=14.8,4.6Hz,1H),1.68(d,J=1.3Hz,3H),1.23(t,J=7.6Hz,3H),1.11(t,J=7.6Hz,3H).

[0053] Example 7: Preparation of Compound 7

[0054]

[0055] The operation was the same as in Example 1, except that diethylamine was used in the first step of the synthesis and 4-methylbenzoic 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 75.3%. The structural identification data are as follows: m / z: [M+Na] + =566.1749, 1 H NMR (600MHz, CDCl3) δ7.90(d,J=8.2Hz,2H),7.27(d,J=7.1Hz,2H),7.06(s,1H),5.33–5.27(m,2H),4.84(d,J =9.8Hz,1H),4.26(dd,J=13.9,5.2Hz,1H),3.89–3.84(m,1H),3.81(dd,J=13.9,3.4Hz,1H),3.62(s,3H),3.48 (s,3H),3.04–3.00(m,1H),2.91–2.85(m,2H),2.75(t,J=12.0Hz,1H),2.72–2.67(m,1H),2.42(s,3H),2.33–2 .30(m,4H),2.26(dd,J=14.8,4.6Hz,1H),1.68(d,J=1.3Hz,3H),1.23(t,J=7.6Hz,3H),1.11(t,J=7.6Hz,3H).

[0056] Example 8: Preparation of Compound 8

[0057]

[0058] The operation was the same as in Example 1, except that diethylamine was used in the first step of the synthesis and 4-fluorobenzoic acid was used in the second step of the synthesis. The mobile phase was MeCN-H2O (55:45, v / v). The yield of monomer compound 8 was 68.9%. The structural identification data are as follows: m / z: [M+Na] + =570.4509, 1H NMR (600MHz, CDCl3) δ7.98(d,J=8.2Hz,2H),7.34(d,J=7.3Hz,2H),7.07(s,1H),5.33–5.27(m,2H),4.84(d ,J=9.8Hz,1H),4.26(dd,J=13.9,5.2Hz,1H),3.89–3.84(m,1H),3.81(dd,J=13.9,3.4Hz,1H),3.62(s,3H) ,3.48(s,3H),3.04–3.00(m,1H),2.91–2.85(m,2H),2.75(t,J=12.0Hz,1H),2.72–2.67(m,1H),2.33–2.30 (m, 4H), 2.26 (dd, J = 14.8, 4.6 Hz, 1H), 1.68 ( d, J = 1.3 Hz, 3H), 1.23 ( t, J = 7.6 Hz, 3H), 1.11 ( t, J = 7.6 Hz, 3H).

[0059] Example 9: Preparation of Compound 9

[0060]

[0061] The operation was the same as in Example 1, except that diethylamine was used in the first step of the synthesis and 4-pyridinecarboxylic acid was used in the second step of the synthesis. The mobile phase was MeCN-H2O (45:55, v / v). The monomer compound 8 was obtained with a yield of 45.3%. The structural identification data are as follows: m / z: [M+Na] + =553.5632, 1 H NMR (600MHz, CDCl3) δ8.84(s,2H),7.84(d,J=2.9Hz,2H),7.07(s,1H),5.33–5.27(m,2H),4.84(d,J=9.8 Hz,1H),4.26(dd,J=13.9,5.2Hz,1H),3.89–3.84(m,1H),3.81(dd,J=13.9,3.4Hz,1H),3.62(s,3H),3.4 8(s,3H),3.04–3.00(m,1H),2.91–2.85(m,2H),2.75(t,J=12.0Hz,1H),2.72–2.67(m,1H),2.33–2.30(m ,4H), 2.26(dd,J=14.8,4.6Hz,1H), 1.68(d,J=1.3Hz,3H), 1.23(t,J=7.6Hz,3H), 1.11(t,J=7.6Hz,3H).

[0062] Example 10: Preparation of Compound 10

[0063]

[0064] The operation was the same as in Example 1, except that diethylamine 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 (55:45, v / v). The monomer compound 8 was obtained with a yield of 76.3%. The structural identification data are as follows: m / z: [M+Na] + =620.8970, 1 H NMR (600MHz, CDCl3) δ8.12(d,J=8.2Hz,2H),7.41(d,J=7.3Hz,2H),7.09(s,1H),5.33–5.27(m,2H),4.84(d ,J=9.8Hz,1H),4.26(dd,J=13.9,5.2Hz,1H),3.89–3.84(m,1H),3.81(dd,J=13.9,3.4Hz,1H),3.62(s,3H) ,3.48(s,3H),3.04–3.00(m,1H),2.91–2.85(m,2H),2.75(t,J=12.0Hz,1H),2.72–2.67(m,1H),2.33–2.30 (m, 4H), 2.26 (dd, J = 14.8, 4.6 Hz, 1H), 1.68 ( d, J = 1.3 Hz, 3H), 1.23 ( t, J = 7.6 Hz, 3H), 1.11 ( t, J = 7.6 Hz, 3H).

[0065] Example 11: Preparation of Compound 11

[0066]

[0067] The operation was the same as in Example 1, except that 3-pyridinemethylamine 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 (55:45, v / v). The yield of monomer compound 11 was 85.4%, and the structural identification data were as follows: m / z: [M+Na] + =577.5640, 1H NMR (400MHz, CDCl3) δ8.61(d,J=1.4Hz,1H),8.49(d,J=4.3Hz,1H),8.29(t,J=4.3Hz,1H),8.05(d,J=4.9Hz,1H),7.78(dt,J= 7.8,1.4Hz,1H),7.66(d,J=4.4Hz,1H),7.29–7.25(m,1H),6.95(s,1H),6.79(m,1H),5.35–5.29(m,2H),5.06(dd,J=14.8,4.8 Hz,1H),4.95(dd,J=14.8,4.8Hz,1H),4.82(d,J=9.7Hz,1H),4.07(dd,J=14.1,5.1Hz,1H),3.91–3.85(m,1H),3.81(dd,J=14 .1,3.3Hz,1H),3.04–2.99(m,1H),2.91–2.85(m,2H),2.76–2.67(m,2H),2.23(dd,J=14.8,4.6Hz,1H),1.68(d,J=1.3Hz,3H).

[0068] Example 12: Preparation of Compound 12

[0069]

[0070] The operation was the same as in Example 1, except that 3-pyridinemethylamine was used in the first step of the synthesis, 2-thiophenecarboxylic acid was used in the second step of the synthesis, and MeCN-H2O (55:45, v / v) was used as the mobile phase. The monomer compound 12 was obtained with a yield of 77.4%. The structural identification data are as follows: m / z: [M+Na] + =593.7843, 1H NMR (400MHz, CDCl3) δ8.61(d,J=1.4Hz,1H),8.49(d,J=4.3Hz,1H),8.29(t,J=4.3Hz,1H),8.07(d,J=4.9Hz,1H),7.78(dt,J= 7.8,1.4Hz,1H),7.64(d,J=4.4Hz,1H),7.29–7.25(m,1H),6.95(s,1H),6.78(m,1H),5.35–5.29(m,2H),5.06(dd,J=14.8,4.8 Hz,1H),4.95(dd,J=14.8,4.8Hz,1H),4.82(d,J=9.7Hz,1H),4.07(dd,J=14.1,5.1Hz,1H),3.91–3.85(m,1H),3.81(dd,J=14 .1,3.3Hz,1H),3.04–2.99(m,1H),2.91–2.85(m,2H),2.76–2.67(m,2H),2.23(dd,J=14.8,4.6Hz,1H),1.68(d,J=1.3Hz,3H).

[0071] Example 13: Preparation of Compound 13

[0072]

[0073] The operation was the same as in Example 1, except that 3-pyridinemethylamine was used in the first step of the synthesis, 4-methoxybenzoic 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 13 was obtained with a yield of 82.4%. The structural identification data are as follows: m / z: [M+Na] + =617.3409, 1H NMR (400MHz, CDCl3) δ8.61(d,J=1.4Hz,1H),8.49(d,J=4.3Hz,1H),8.29(t,J=4.3Hz,1H),7.97(d,J=8.9Hz,2H),7.78(dt ,J=7.8,1.4Hz,1H),7.29–7.25(m,1H),6.95(d,J=8.9Hz,2H),6.95(s,1H),5.35–5.29(m,2H),5.06(dd,J=14.8,4.8Hz,1H ),4.95(dd,J=14.8,4.8Hz,1H),4.82(d,J=9.7Hz,1H),4.07(dd,J=14.1,5.1Hz,1H),3.91–3.85(m,4H),3.81(dd,J=14.1, 3.3Hz, 1H), 3.04–2.99 (m, 1H), 2.91–2.85 (m, 2H), 2.76–2.67 (m, 2H), 2.23 (dd, J = 14.8, 4.6Hz, 1H), 1.68 (d, J = 1.3Hz, 3H).

[0074] Example 14: Preparation of Compound 14

[0075]

[0076] The operation was the same as in Example 1, except that 3-pyridinemethylamine was used in the first step of the synthesis, trans-cinnamic acid was used in the second step of the synthesis, and the mobile phase was MeCN-H2O (70:30, v / v). The yield of monomer compound 14 was 86.7%, and the structural identification data were as follows: m / z: [M+Na] + =613.1473, 1H NMR (400MHz, CDCl3) δ8.61(d,J=1.4Hz,1H),8.49(d,J=4.3Hz,1H),8.29(t,J=4.3Hz,1H),7.78(dt,J=7.8,1.4Hz,1H),7.69(d,J=16.0 Hz,1H),7.53(dd,J=6.5,2.9Hz,2H),7.44–7.38(m,3H),7.29–7.25(m,1H),6.95(s,1H),6.40(d,J=16.0Hz,1H),5.35–5.29(m,2H),5. 06(dd,J=14.8,4.8Hz,1H),4.95(dd,J=14.8,4.8Hz,1H),4.82(d,J=9.7Hz,1H),4.07(dd,J=14.1,5.1Hz,1H),3.91–3.85(m,1H),3.81 (dd,J=14.1,3.3Hz,1H),3.04–2.99(m,1H),2.91–2.85(m,2H),2.76–2.67(m,2H),2.23(dd,J=14.8,4.6Hz,1H),1.68(d,J=1.3Hz,3H).

[0077] Example 15: Preparation of Compound 15

[0078]

[0079] The operation was the same as in Example 1, except that cyclopentylamine 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 (65:35, v / v). The yield of monomer compound 15 was 86.5%, and the structural identification data were as follows: m / z: [M+Na] + =620.1160, 1H NMR (400MHz, CDCl3) δ7.64(d,J=15.9Hz,1H),7.48(d,J=8.7Hz,2H),6.94(s,1H),6.91(d,J=8.7H z,2H),6.26(d,J=15.9Hz,1H),5.36–5.28(m,2H),4.86(d,J=9.5Hz,1H),4.79(dd,J=12.8,6.2Hz ,1H),3.95–3.85(m,2H),3.84(s,3H),3.81(dd,J=14.0,3.6Hz,1H),3.05–2.97(m,1H),2.96–2.8 6(m,2H),2.82–2.72(m,2H),2.23(dd,J=14.8,4.6Hz,1H),2.17–2.07(m,2H),1.76–1.60(m,10H);

[0080] Example 16: Preparation of Compound 16

[0081]

[0082] The operation was the same as in Example 1, except that cyclopentylamine was used in the first step of the synthesis and 4-methoxy trans-cinnamic acid was used in the second step of the synthesis. The mobile phase was MeCN-H2O (70:30, v / v). The yield of monomer compound 16 was 88.3%. The structural identification data are as follows: m / z: [M+Na] + =608.9043, 1 H NMR (400MHz, CDCl3) δ7.65(d,J=16.0Hz,1H),7.52(dd,J=8.6,5.4Hz,2H),7.09(t,J=8.6Hz,2H ),6.96(s,1H),6.32(d,J=16.0Hz,1H),5.36–5.28(m,2H),4.86(d,J=9.5Hz,1H),4.79(dd,J=12 .8,6.2Hz,1H),3.95–3.85(m,2H),3.81(dd,J=14.0,3.6Hz,1H),3.05–2.97(m,1H),2.96–2.86( m,2H),2.82–2.72(m,2H),2.23(dd,J=14.8,4.6Hz,1H),2.17–2.07(m,2H),1.76–1.60(m,10H);

[0083] Example 17: Preparation of Compound 17

[0084]

[0085] The operation was the same as in Example 1, except that cyclopentylamine was used in the first step of the synthesis and 4-methyl trans-cinnamic acid was used in the second step of the synthesis. The mobile phase was MeCN-H2O (70:30, v / v). The monomer compound 17 was obtained with a yield of 91.5%. The structural identification data are as follows: m / z: [M+Na] + =604.2286, 1 H NMR (400MHz, CDCl3) δ7.64(d,J=15.9Hz,1H),7.45(d,J=8.7Hz,2H),6.98(s,1H),6.89(d,J=8 .7Hz,2H),6.28(d,J=15.9Hz,1H),5.36–5.28(m,2H),4.86(d,J=9.5Hz,1H),4.79(dd,J=12.8, 6.2Hz,1H),3.95–3.85(m,2H),3.81(dd,J=14.0,3.6Hz,1H),3.05–2.97(m,1H),2.96–2.86(m ,2H),2.82–2.72(m,5H),2.23(dd,J=14.8,4.6Hz,1H),2.17–2.07(m,2H),1.76–1.60(m,10H);

[0086] Example 18: Preparation of Compound 18

[0087]

[0088] The operation was the same as in Example 1, except that cyclopentylamine 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 (70:30, v / v). The monomer compound 18 was obtained with a yield of 87.2%. The structural identification data are as follows: m / z: [M+Na] + =658.8044, 1 H NMR (400MHz, CDCl3) δ7.69–7.62(m,5H),6.94(s,1H),5.36–5.28(m,2H),6.47(d, J=16.0Hz,1H),4.86(d,J=9.5Hz,1H),4.79(dd,J=12.8,6.2Hz,1H),3.95–3.85(m ,2H),3.81(dd,J=14.0,3.6Hz,1H),3.05–2.97(m,1H),2.96–2.86(m,2H),2.82–2 .72(m,2H),2.23(dd,J=14.8,4.6Hz,1H),2.17–2.07(m,2H),1.76–1.60(m,10H);

[0089] Example 19: Preparation of Compound 19

[0090]

[0091] The operation was the same as in Example 5, except that 4-fluorobenzylamine was used in the first step of the synthesis and cyclopropylamine was used in the second step of the synthesis. The mobile phase was MeCN-H2O (50:50, v / v). The monomer compound 19 was obtained with a yield of 78.2%. The structural identification data are as follows: m / z: [M+Na] + =583.3900, 1 H NMR (400MHz, CDCl3) δ7.52(s,1H),7.37(dd,J=8.5,5.4Hz,2H),7.03(t,J=8.5Hz,2H),6.95(s,1H),5.3 7–5.29(m,2H),4.99(dd,J=14.6,5.4Hz,1H),4.92–4.81(m,2H),4.08(dd,J=14.1,5.2Hz,1H),3.94–3.8 5(m,1H),3.82(dd,J=14.1,3.3Hz,1H),3.05–2.99(m,1H),2.93–2.87(m,2H),2.79–2.70(m,2H),2.23( dd,J=14.7,4.8Hz,1H),1.76–1.70(m,1H),1.69(d,J=1.2Hz,3H),1.08–0.99(m,2H),0.96–0.88(m,2H);

[0092] Example 20: Preparation of Compound 20

[0093]

[0094] The operation was the same as in Example 5, except that 4-fluorobenzylamine was used in the first step of the synthesis and cyclopentylamine was used in the second step of the synthesis. The mobile phase was MeCN-H2O (55:45, v / v). The monomer compound 20 was obtained with a yield of 75.3%. The structural identification data are as follows: m / z: [M+Na] + =611.6396, 1H NMR (400MHz, CDCl3) δ7.52 (s, 1H), 7.37 (dd, J = 8.5, 5.4Hz, 2H), 7.03 (t, J = 8.5Hz, 2H), 6.95 (s, 1H), 5. 37–5.29(m,2H),4.99(dd,J=14.6,5.4Hz,1H),4.92–4.81(m,2H),4.08(dd,J=14.1,5.2Hz,1H),3.94–3 .85(m,1H),3.82(dd,J=14.1,3.3Hz,1H),3.05–2.99(m,1H),2.93–2.87(m,2H),2.79–2.70(m,2H),2.7 1–2.66(m,1H),2.26(dd,J=14.7,4.8Hz,1H),1.91–1.84(m,2H),1.74–1.65(m,7H),1.60–1.54(m,2H).

[0095] Example 21: Preparation of Compound 21

[0096]

[0097] The operation was the same as in Example 5, except that 4-fluorobenzylamine was used in the first step of the synthesis and n-propylamine was used in the second step of the synthesis. The mobile phase was MeCN-H2O (55:45, v / v). The yield of monomer compound 21 was 75.3%. The structural identification data are as follows: m / z: [M+Na] + =585.8523, 1 H NMR (400MHz, CDCl3) δ7.52 (s, 1H), 7.37 (dd, J = 8.5, 5.4Hz, 2H), 7.03 (t, J = 8.5Hz, 2H), 6.95 (s, 1H), 5. 37–5.29(m,2H),4.99(dd,J=14.6,5.4Hz,1H),4.92–4.81(m,2H),4.08(dd,J=14.1,5.2Hz,1H),3.94–3 .85(m,1H),3.82(dd,J=14.1,3.3Hz,1H),3.11–3.01(m,3H),2.93–2.87(m,2H),2.79–2.70(m,2H),2. 23(dd,J=14.7,4.8Hz,1H), 1.69(d,J=1.2Hz,3H), 1.48(dd,J=14.6,7.3Hz,2H), 0.88(t,J=7.4Hz,3H).

[0098] Example 22: Preparation of Compound 22

[0099]

[0100] The operation was the same as in Example 5, except that morpholine was used in the first step of the synthesis and n-propylamine was used in the second step of the synthesis. The mobile phase was MeCN-H2O (55:45, v / v). The monomer compound 22 was obtained with a yield of 76.8%. The structural identification data are as follows: m / z: [M+Na] + =601.8842, 1 H NMR (400MHz, CDCl3) δ7.20 (dd, J=4.7, 1.4Hz, 1H), 6.96–6.91 (m, 3H), 5.30 (d, J=4. 4Hz,1H),4.91(d,J=9.9Hz,1H),4.42(dd,J=14.9,5.1Hz,2H),4.26–4.12(m,2H),4 .04(s,2H),3.94–3.70(m,7H),3.39–3.29(m,2H),2.91–2.83(m,2H),2.61(t,J=11 .9Hz,1H),2.57–2.49(m,1H),2.20(dd,J=14.8,4.6Hz,1H),1.58(d,J=1.2Hz,3H);

[0101] Example 23: Preparation of Compound 23

[0102]

[0103] The operation was the same as in Example 5, except that morpholine was used in the first step of the synthesis and 2-furanmethylamine was used in the second step of the synthesis. The mobile phase was MeCN-H2O (55:45, v / v). The monomer compound 23 was obtained with a yield of 76.8%. The structural identification data are as follows: m / z: [M+Na] + =585.9022, 1 H NMR (400MHz, CDCl3) δ7.19 (dd, J=4.7, 1.4Hz, 1H), 6.96–6.91 (m, 3H), 5.30 (d, J=4. 4Hz,1H),4.91(d,J=9.9Hz,1H),4.42(dd,J=14.9,5.1Hz,2H),4.26–4.12(m,2H),4 .04(s,2H),3.94–3.70(m,9H),3.39–3.29(m,2H),2.91–2.83(m,2H),2.61(t,J=11 .9Hz,1H),2.57–2.49(m,1H),2.20(dd,J=14.8,4.6Hz,1H),1.58(d,J=1.2Hz,3H);

[0104] Example 24: Preparation of Compound 24

[0105]

[0106] The operation was the same as in Example 5, except that morpholine was used in the first step of the synthesis and 4-pyridinemethylamine was used in the second step of the synthesis. The mobile phase was MeCN-H2O (60:40, v / v). The monomer compound 24 was obtained with a yield of 85.3%. The structural identification data are as follows: m / z: [M+Na] + =596.5490, 1 H NMR (400MHz, CDCl3) δ8.94(d,J=1.4Hz,2H),8.45(d,J=1.4Hz,2H),6.90(s,1H),5.30 (d,J=4.4Hz,1H),4.91(d,J=9.9Hz,1H),4.42(dd,J=14.9,5.1Hz,2H),4.26–4.12(m, 2H),4.04(s,2H),3.94–3.70(m,7H),3.39–3.29(m,2H),2.91–2.83(m,2H),2.61(t,J =11.9Hz,1H),2.57–2.49(m,1H),2.20(dd,J=14.8,4.6Hz,1H),1.58(d,J=1.2Hz,3H);

[0107] Example 25: Preparation of Compound 25

[0108]

[0109] The operation was the same as in Example 5, except that morpholine was used in the first step of the synthesis and benzylamine was used in the second step of the synthesis. The mobile phase was MeCN-H2O (70:30, v / v). The yield of monomer compound 25 was 88.2%. The structural identification data are as follows: m / z: [M+Na] + =595.4733, 1H NMR(400MHz, CDCl3) δ7.98(d,J=7.5Hz,2H),7.46(t,J=7.5Hz,1H),7.41(t,J=7.7Hz,2H),6 .90(s,1H),5.30(d,J=4.4Hz,1H),4.91(d,J=9.9Hz,1H),4.42(dd,J=14.9,5.1Hz,2H),4.2 6–4.12(m,2H),4.04(s,2H),3.94–3.70(m,7H),3.39–3.29(m,2H),2.91–2.83(m,2H),2.61 (t,J=11.9Hz,1H),2.57–2.49(m,1H),2.20(dd,J=14.8,4.6Hz,1H),1.58(d,J=1.2Hz,3H);

[0110] Example 26: Preparation of Compound 26

[0111]

[0112] The operation was the same as in Example 5, except that morpholine 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 (70:30, v / v). The monomer compound 26 was obtained with a yield of 89.2%. The structural identification data are as follows: m / z: [M+Na] + =613.7410, 1 H NMR (400MHz, CDCl3) δ7.37 (dd, J=8.5, 5.4Hz, 2H), 7.03 (t, J=8.5Hz, 2H), 6.90 (s, 1H), 5.30(d,J=4.4Hz,1H),4.91(d,J=9.9Hz,1H),4.42(dd,J=14.9,5.1Hz,2H),4.26–4.12( m,2H),4.04(s,2H),3.94–3.70(m,7H),3.39–3.29(m,2H),2.91–2.83(m,2H),2.61(t, J=11.9Hz,1H),2.57–2.49(m,1H),2.20(dd,J=14.8,4.6Hz,1H),1.58(d,J=1.2Hz,3H);

[0113] Example 27: Preparation of Compound 27

[0114]

[0115] The operation was the same as in Example 5, except that morpholine was used in the first step of the synthesis and 4-trifluoromethylbenzylamine was used in the second step of the synthesis. The mobile phase was MeCN-H2O (70:30, v / v). The monomer compound 27 was obtained with a yield of 78.3%. The structural identification data are as follows: m / z: [M+Na] + =663.6403, 1 H NMR (400MHz, CDCl3) δ8.06–8.01(m,2H),7.15(t,J=8.6Hz,2H),6.90(s,1H),5.30(d ,J=4.4Hz,1H),4.91(d,J=9.9Hz,1H),4.42(dd,J=14.9,5.1Hz,2H),4.26–4.12(m,2H ),4.04(s,2H),3.94–3.70(m,7H),3.39–3.29(m,2H),2.91–2.83(m,2H),2.61(t,J= 11.9Hz,1H),2.57–2.49(m,1H),2.20(dd,J=14.8,4.6Hz,1H),1.58(d,J=1.2Hz,3H);

[0116] Example 28: Preparation of Compound 28

[0117]

[0118] The operation was the same as in Example 5, except that morpholine 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 (70:30, v / v). The monomer compound 28 was obtained with a yield of 75.6%. The structural identification data are as follows: m / z: [M+Na] + =625.6824, 1 H NMR(400MHz, CDCl3)δ7.48(d,J=8.7Hz,2H),6.91–6.90(m,3H),5.30(d,J=4.4Hz,1H ),4.91(d,J=9.9Hz,1H),4.42(dd,J=14.9,5.1Hz,2H),4.26–4.12(m,2H),4.04(s,2H ),3.94–3.70(m,7H),3.84(s,3H),3.39–3.29(m,2H),2.91–2.83(m,2H),2.61(t,J= 11.9Hz,1H),2.57–2.49(m,1H),2.20(dd,J=14.8,4.6Hz,1H),1.58(d,J=1.2Hz,3H);

[0119] Example 29: Preparation of Compound 29

[0120]

[0121] The operation was the same as in Example 5, except that cyclopropylamine 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 (60:40, v / v). The monomer compound 29 was obtained with a yield of 83.7%. The structural identification data are as follows: m / z: [M+Na] + =517.4317, 1 H NMR(400MHz, CDCl3) δ6.93(s,1H),5.33–5.27(m,2H),4.84(d,J=9.8Hz,1H),4.26(dd,J=13.9,5.2 Hz,1H),3.89–3.84(m,1H),3.81(dd,J=13.9,3.4Hz,1H),3.04–3.00(m,1H),2.91–2.85(m,2H),2. 75(t,J=12.0Hz,1H),2.72–2.67(m,1H),2.22(dd,J=14.8,4.6Hz,1H),1.75–1.70(m,2H),1.68(d, J=1.3Hz,3H),1.34(d,J=6.5Hz,3H),1.29(d,J=6.5Hz,3H),1.08–1.01(m,2H),0.94–0.86(m,2H).

[0122] Example 30: Preparation of Compound 30

[0123]

[0124] The operation was the same as in Example 5, except that cyclopropylamine was used in the first step of the synthesis and cyclopropyl alcohol was used in the second step of the synthesis. The mobile phase was MeCN-H2O (60:40, v / v). The monomer compound 30 was obtained with a yield of 79.5%. The structural identification data are as follows: m / z: [M+Na] + =516.6890, 1H NMR (400MHz, CDCl3) δ6.93 (s, 1H), 5.33–5.27 (m, 2H), 4.84 (d, J = 9.8Hz, 1H), 4.26 (dd,J=13.9,5.2Hz,1H),3.89–3.84(m,1H),3.81(dd,J=13.9,3.4Hz,1H),3.04–3. 00(m,1H),2.91–2.85(m,2H),2.75(t,J=12.0Hz,1H),2.72–2.67(m,1H),2.22(dd ,J=14.8,4.6Hz,1H),1.75–1.70(m,2H),1.68(d,J=1.3Hz,3H),1.08–0.86(m,8H).

[0125] Example 31: Preparation of Compound 31

[0126]

[0127] The operation was the same as in Example 5, except that cyclopropylamine 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 (65:35, v / v). The yield of monomer compound 31 was 74.6%. The structural identification data are as follows: m / z: [M+Na] + =544.7522, 1 H NMR(400MHz, CDCl3) δ6.93(s,1H),5.33–5.27(m,2H),4.84(d,J=9.8Hz,1H),4.26(dd,J=13.9,5 .2Hz,1H),3.89–3.84(m,1H),3.81(dd,J=13.9,3.4Hz,1H),3.04–3.00(m,1H),2.91–2.85(m,2H) ,2.75(t,J=12.0Hz,1H),2.71–2.66(m,2H),2.26(dd,J=14.7,4.8Hz,1H),1.91–1.84(m,2H),1. 74–1.65(m,8H),1.68(d,J=1.3Hz,3H),1.60–1.54(m,2H),1.08–1.01(m,2H),0.94–0.86(m,2H).

[0128] Example 32: Preparation of Compound 32

[0129]

[0130] The operation was the same as in Example 5, except that cyclopropylamine was used in the first step of the synthesis and benzyl alcohol was used in the second step of the synthesis. The mobile phase was MeCN-H2O (75:25, v / v). The monomer compound 32 was obtained with a yield of 86.9%. The structural identification data are as follows: m / z: [M+Na] + =566.8500, 1 HNMR(400MHz, CDCl3)δ8.01(d,J=7.5Hz,2H),7.58(t,J=7.5Hz,1H),7.45(t,J=7.7Hz,2H),6.93(s,1H), 5.33–5.27(m,2H),4.84(d,J=9.8Hz,1H),4.26(dd,J=13.9,5.2Hz,1H),3.89–3.84(m,3H),3.81(dd,J=1 3.9,3.4Hz,1H),3.04–3.00(m,1H),2.91–2.85(m,2H),2.75(t,J=12.0Hz,1H),2.72–2.67(m,1H),2.22( dd,J=14.8,4.6Hz,1H),1.75–1.70(m,1H),1.68(d,J=1.3Hz,3H),1.08–1.01(m,2H),0.94–0.86(m,2H).

[0131] Example 33: Preparation of Compound 33

[0132]

[0133] The operation was the same as in Example 5, except that isopropylamine was used in the first step of the synthesis and benzyl alcohol was used in the second step of the synthesis. The mobile phase was MeCN-H2O (65:35, v / v). The yield of monomer compound 33 was 76.2%. The structural identification data are as follows: m / z: [M+Na] + =515.3396, 1H NMR (400MHz, CDCl3) δ6.95 (s, 1H), 5.35–5.28 (m, 2H), 4.85 (d, J = 9.7Hz, 1H), 4.76–4.67 ( m,1H),4.07(d,J=4.8Hz,2H),3.96–3.86(m,2H),3.84–3.77(m,1H),3.04–2.98(m,1H),2 .95–2.86(m,2H),2.81–2.72(m,2H),2.48(t,J=2.5Hz,1H),2.23(dd,J=14.8,4.6Hz,1H) ,1.76–1.69(m,1H),1.68(d,J=1.2Hz,3H),1.34(d,J=6.5Hz,3H),1.29(d,J=6.5Hz,3H);

[0134] Example 34: Preparation of Compound 34

[0135]

[0136] The operation was the same as in Example 5, except that isopropylamine 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 (75:25, v / v). The monomer compound 34 was obtained with a yield of 88.4%. The structural identification data are as follows: m / z: [M+Na] + =586.4458, 1 H NMR (400MHz, CDCl3) δ7.36 (dd, J=8.5, 5.4Hz, 2H), 7.04 (t, J=8.5Hz, 2H), 6.95 (s, 1H), 5.3 5–5.28(m,2H),4.85(d,J=9.7Hz,1H),4.76–4.67(m,1H),3.96–3.86(m,4H),3.84–3.77(m ,1H),3.04–2.98(m,3H),2.95–2.86(m,2H),2.81–2.72(m,2H),2.23(dd,J=14.8,4.6Hz,1 H),1.76–1.69(m,1H),1.68(d,J=1.2Hz,3H),1.34(d,J=6.5Hz,3H),1.29(d,J=6.5Hz,3H);

[0137] Example 35: Preparation of Compound 35

[0138]

[0139] The operation was the same as in Example 5, except that isopropylamine was used in the first step of the synthesis and 2-furanmethanol was used in the second step of the synthesis. The mobile phase was MeCN-H2O (60:40, v / v). The monomer compound 35 was obtained with a yield of 76.8%. The structural identification data are as follows: m / z: [M+Na] + =558.7723, 1 H NMR(400MHz, CDCl3)δ7.19(dd,J=4.7,1.4Hz,1H),6.96–6.91(m,3H),5.35–5.28(m,2 H),4.85(d,J=9.7Hz,1H),4.76–4.67(m,1H),3.96–3.86(m,2H),3.84–3.77(m,3H),3. 04–2.98(m,1H),2.95–2.86(m,2H),2.81–2.72(m,2H),2.23(dd,J=14.8,4.6Hz,1H),1 .76–1.69(m,1H),1.68(d,J=1.2Hz,3H),1.34(d,J=6.5Hz,3H),1.29(d,J=6.5Hz,3H);

[0140] Example 36: Preparation of Compound 36

[0141]

[0142] The operation was the same as in Example 5, except that isopropylamine was used in the first step of the synthesis and n-pentanethiol was used in the second step of the synthesis. The mobile phase was MeCN-H2O (70:30, v / v). The monomer compound 36 was obtained with a yield of 43.2%. The structural identification data are as follows: m / z: [M+Na] + =564.4813, 1 H NMR (400MHz, CDCl3) δ6.93 (s, 1H), 5.36 (t, J = 10.3Hz, 1H), 5.32 (d, J = 4.4Hz, 1H), 4.91 (d, J = 9. 8Hz,1H),4.20(dd,J=14.0,5.1Hz,1H),3.88–3.81(m,1H),3.75(dd,J=14.0,4.2Hz,1H),3.61(s ,3H),3.47(s,3H),3.11–3.05(m,1H),2.93–2.85(m,3H),2.84–2.68(m,3H),2.24(dd,J=14.7, 4.8Hz,1H),1.76–1.69(m,1H),1.70(d,J=1.1Hz,3H),1.38–1.28(m,8H),0.89(t,J=7.0Hz,3H).

[0143] Example 37: Preparation of Compound 37

[0144]

[0145] The operation was the same as in Example 5, except that n-propylamine was used in the first step of the synthesis and phenol was used in the second step of the synthesis. The mobile phase was MeCN-H2O (70:30, v / v). The monomer compound 37 was obtained with a yield of 23.7%. The structural identification data are as follows: m / z: [M+Na] + =554.7902, 1 HNMR(400MHz, CDCl3)δ8.02(d,J=7.4Hz,2H),7.60(t,J=7.4Hz,1H),7.45(t,J=7.7 Hz,2H),6.95(s,1H),5.36–5.29(m,2H),4.85(d,J=9.8Hz,1H),4.00–3.86(m,2H),3 .83–3.71(m,2H),3.04–2.98(m,1H),2.95–2.85(m,2H),2.80–2.70(m,2H),2.23(d d,J=14.8,4.6Hz,1H),1.78–1.69(m,4H),1.68(d,J=1.1Hz,3H),1.04–0.96(m,3H);

[0146] Example 38: Preparation of Compound 38

[0147]

[0148] The operation was the same as in Example 5, except that n-propylamine was used in the first step of the synthesis and 2-thiophene methanol was used in the second step of the synthesis. The mobile phase was MeCN-H2O (65:35, v / v). The monomer compound 38 was obtained with a yield of 85.7%. The structural identification data are as follows: m / z: [M+Na] + =574.9045, 1 H NMR (400MHz, CDCl3) δ7.20 (dd, J=4.7, 1.4Hz, 1H), 6.95–6.91 (m, 3H), 6.95 (s, 1H),5.36–5.29(m,2H),4.85(d,J=9.8Hz,1H),4.00–3.86(m,2H),3.83–3.71( m,4H),3.04–2.98(m,1H),2.95–2.85(m,2H),2.80–2.70(m,2H),2.23(dd,J=1 4.8,4.6Hz,1H),1.78–1.69(m,4H),1.68(d,J=1.1Hz,3H),1.04–0.96(m,3H);

[0149] Example 39: Preparation of Compound 39

[0150]

[0151] The operation was the same as in Example 5, except that n-propylamine was used in the first step of the synthesis and thiophenol was used in the second step of the synthesis. The mobile phase was MeCN-H2O (70:30, v / v). The monomer compound 39 was obtained with a yield of 33.5%. The structural identification data are as follows: m / z: [M+Na] + =570.3906, 1 HNMR(400MHz, CDCl3) δ8.03(d,J=7.5Hz,2H),7.59(t,J=7.5Hz,1H),7.44(t,J=7.7 Hz,2H),6.95(s,1H),5.36–5.29(m,2H),4.85(d,J=9.8Hz,1H),4.00–3.86(m,2H),3 .83–3.71(m,2H),3.04–2.98(m,1H),2.95–2.85(m,2H),2.80–2.70(m,2H),2.23(d d,J=14.8,4.6Hz,1H),1.78–1.69(m,4H),1.68(d,J=1.1Hz,3H),1.04–0.96(m,3H);

[0152] Example 40: Anti-tumor activity screening experiment

[0153] The cell proliferation activity was detected by MTT method, and the in vitro antitumor activity of 39 tested compounds (1-39) was screened.

[0154] 1. Experimental materials:

[0155] (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.

[0156] (2) Test drug: sesquiterpene lactone scaberol C dithiocarbamate derivative (1-39) synthesized by the present invention.

[0157] (3) Positive control: cisplatin.

[0158] 2. Experimental methods:

[0159] (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.

[0160] (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.

[0161] 3. The activity results are shown in Table 1

[0162] Table 1 Inhibitory activity of scaberol C dithiocarbamate derivatives on different tumor cells (IC 50 ,μM)

[0163]

[0164]

[0165]

[0166] The activity test results showed that the screened compounds showed good inhibitory activity against a variety of tumor cells and low toxicity to normal cells. Most of the test compounds were more active than 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 dithiocarbamate derivative, characterized in that: The structure is shown in general formula I wherein R is selected from the group consisting of cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, 4,4-difluorocyclohexylcarbonyl, 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-picolinoyl, 3-picolinoyl, 2-furoyl, 2-thienylcarboxyl, 2-furylacryl, 2-thienylacryl, 4-pyridylacryl, 3-pyridylacryl, 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 and hexylthiocarbamoyl; R1 or R2 are each independently selected from hydrogen, C 1-8 Straight-chain or branched alkyl, cyclopentyl, cyclopropyl, cyclohexyl, piperidinyl, morpholinyl, phenyl, benzyl, p-methoxybenzyl, p-fluorobenzyl, p-bromobenzyl, p-trifluoromethylbenzyl, 3-pyridylmethyl, 2-thienylmethyl and 2-furylmethyl, and pyrimidinyl.

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

3. Use of the sesquiterpene lactone scaberol C dithiocarbamate 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 dithiocarbamate 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 dithiocarbamate derivative is specifically 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 dithiocarbamate derivative according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

6. The pharmaceutical composition according to claim 5, characterized in that The dosage form of the pharmaceutical composition is a capsule tablet, solution, suspension, granule or injection; the pharmaceutically acceptable excipient is one or more of a diluent, a lubricant, a binder, a disintegrant, a stabilizer or a solvent.

7. Use of the pharmaceutical composition according to any one of claims 5 to 6 in the preparation of drugs for treating tumors.

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