Indoline-fused 2H-1,4-oxathiine compounds, preparation methods thereof and applications

Abstract

The present invention discloses a kind of indoline-fused 2H -1,4-oxathiine compounds, belonging to the field of organic chemical synthesis; the preparation method is to dissolve 3-halooxindole (I) and pyridinium 1,4-zwitterionic thiolate (II) in an organic solvent, then add a base, and stir and react at room temperature for 3-72 h. After the reaction is completed, the product can be obtained by direct separation and purification; the present invention realizes the construction of indoline-fused 2H -1,4-oxathiine tricyclic compounds with one chiral center through the (3+3) cycloaddition reaction of 3-halooxindole as a three-atom synthon and pyridinium 1,4-zwitterionic sulfur / nitrogen salts; the preparation method of the present invention has the advantages of novelty, simplicity, simple operation, mild reaction conditions, good substrate generality, etc.; and these compounds show application prospects in anti-tumor aspects.

Description

Technical Field

[0001] The present invention relates to the field of organic synthesis, and in particular to indoline-fused 2H-1,4-oxathiine compounds, a preparation method thereof, and applications thereof. Background Art

[0002] Diverse heterocyclic skeletons widely exist in pharmaceutical agents, fluorescent dyes, and functional material molecules and have a wide range of biological activities. Among them, the indoline ring, as an important nitrogen-containing heterocycle, is an important part of many bioactive molecules. Therefore, developing simple and efficient methods for synthesizing heterocyclic compounds with novel indoline-fused heterocyclic skeletons is of great significance in organic chemistry and medicinal chemistry.

[0003] 3-Halooxindoles, as a class of good electrophiles, are often used to construct potentially bioactive oxindole derivatives. However, through literature research, the inventors found that all current reactions construct 3,3-disubstituted oxindoles through a one-step addition reaction. Therefore, it is extremely challenging to use 3-halooxindoles to achieve cycloaddition reactions to construct indoline-fused heterocyclic compounds.

[0004] In view of the importance of compounds containing indoline-fused heterocyclic skeletons, it is of great significance to develop a simple and efficient synthesis method with mild conditions, easy operation, readily available and stable substrates, and a wide application range for constructing a series of novel indoline-fused 2H-1,4-oxathiine compounds. Summary of the Invention

[0005] One object of the present invention is to provide a class of novel indoline-fused 2H-1,4-oxathiine compounds to solve the above problems.

[0006] To achieve the above object, the technical solution adopted by the present invention is as follows: A class of novel indoline-fused 2H-1,4-oxathiine compounds having the structure shown in the following structural formula (Ⅲ):

[0007]

[0008] In the above structural formula, R 1 is selected from a monosubstituted electron-donating group or an electron-withdrawing group aryl; R 2 is selected from an ester group; R 3 is selected from an ester group; R 4 is selected from an aryl group, a benzyl group, or a linear alkyl group.

[0009] The present invention provides a class of novel indoline-fused 2H-1,4-oxathiine compounds, which have an indoline ring skeleton and a six-membered ring structural unit containing a sulfur heteroatom.

[0010] The second object of the present invention is to provide a method for preparing the above indolinocyclo-fused 2H-1,4-oxathiine compounds, and the technical solution adopted is as follows:

[0011] Dissolve 3-halooxindole (I) and pyridinium 1,4-zwitterionic sulfur / nitrogen salt (II) in a reaction solvent, then add a base, and stir the reaction at room temperature for 3-72 h. After the reaction is completed, directly separate and purify to obtain indolinocyclo-fused 2H-1,4-oxathiine compounds (III);

[0012] Among them, the 3-halooxindole (I) has the following structure:

[0013]

[0014] The pyridinium 1,4-zwitterionic sulfur / nitrogen salt (II) has the following structure:

[0015]

[0016] The synthesis route is as follows:

[0017]

[0018] The present invention adopts the above synthesis method to synthesize a series of indolinocyclo-fused 2H-1,4-oxathiine compounds with novel structures.

[0019] As a preferred technical solution: the reaction solvent is selected from at least one of dichloromethane, chloroform, toluene, mesitylene, tetrahydrofuran, ethyl acetate, acetonitrile, methyl tert-butyl ether, 1,4-dioxane, and chlorobenzene.

[0020] As a preferred technical solution: the base is an organic base or an inorganic base.

[0021] As a preferred technical solution: the dosage of the base is 1.0-3.0 molar equivalents.

[0022] As a preferred technical solution: the separation and purification method is flash column chromatography.

[0023] The third object of the present invention is to provide the application of the above indolinocyclo-fused 2H-1,4-oxathiine compounds in the preparation of anti-tumor drugs.

[0024] As a preferred technical solution: the tumor is lung cancer, cervical cancer or liver cancer.

[0025] In addition, the application value of the compounds of the present invention also lies in that: existing indolinobenzheterocyclic derivatives generally have good biological activities. Therefore, a large class of novel-structured indoline ring-fused 2H-1,4-oxathiin compounds provided by the present invention have great potential application value, providing a sufficient source of compounds for the discovery and screening of drug candidate molecules, especially high-throughput screening, and enriching the library of such lead compounds. In addition, the method of the present invention can successfully construct a series of indoline ring-fused 2H-1,4-oxathiin compounds in moderate to excellent yields, and has developed a synthetic route for such compounds with mild conditions and simple operation.

[0026] The advantages of the present invention are as follows: The present invention realizes the construction of indoline ring-fused 2H-1,4-oxathiin compounds in moderate to excellent yields by using 3-halooxindole and pyridinium 1,4-zwitterionic sulfur / nitrogen salts to carry out a (3+3) cycloaddition reaction. In addition, the present invention for the first time uses 3-halooxindole as a C-C-O synthon to participate in organic chemical reactions; the compounds prepared by this method enrich the types of indoline ring-fused heterocyclic compounds, thus providing a sufficient source of compounds for the screening of lead compounds and drug candidate molecules; meanwhile, through cell experiments, it is shown that the synthesized indoline ring-fused 2H-1,4-oxathiin compounds have antitumor activities. The preparation method of the present invention has the advantages of novelty, simplicity, simple operation, mild reaction conditions, good substrate generality, etc. Brief Description of the Drawings

[0027] Figure 1 1H NMR spectrum of Ⅲ-b prepared in Example 2;

[0028] Figure 2 13C NMR spectrum of Ⅲ-b prepared in Example 2;

[0029] Figure 3 Single crystal diagram of Ⅲ-b prepared in Example 2. Detailed Description of the Invention

[0030] The present invention will be further described below in conjunction with the drawings.

[0031] The structures of the compounds prepared in the following Examples 1-28 are as follows in sequence:

[0032]

[0033] Example 1: Synthesis of compound (Ⅲ-a)

[0034] Add 3-halooxindole Ⅰ-a (0.1 mmol), pyridinium 1,4-zwitterionic sulfide salt Ⅱ-a (0.12 mmol), and an inorganic base into a dry reaction test tube, and then add 2.0 mL of a solvent. After the reaction is complete, the crude product is separated and purified by column chromatography to obtain compound Ⅲ-a. Different reaction conditions are shown in Table 1, and the specific reaction process is as follows:

[0035]

[0036] Table 1 Different reaction conditions

[0037]

[0038] The above reaction was carried out with Ⅰ-a (0.1 mmol), Ⅱ-a (0.12 mmol), base (0.15 mmol), and solvent (x mL) at room temperature; the yield refers to the yield after separation and purification.

[0039] As can be seen from Table 1, through the investigation of common solvents and common bases, finally, using 1.5 molar equivalents of inorganic base potassium carbonate, 2 mL of dichloromethane as the solvent, and the reaction temperature at room temperature is a more preferred scheme.

[0040] Under the optimal conditions, the obtained Ⅲ-a is as follows:

[0041] Colorless oil; 76.8 mg was obtained, with a yield of 97%;

[0042] Structure identification: 1 H NMR (400 MHz, DMSO-d6) δ 7.73 (d, J = 6.9 Hz, 1H), 7.42 - 7.38 (m, 1H), 7.37 - 7.27 (m, 2H), 7.16 - 7.05 (m, 3H), 6.82 - 6.74 (m, 2H), 3.94 (s, 3H), 3.85 (s, 3H), 3.58 (d, J = 13.6 Hz, 1H), 3.15 (d, J = 13.6 Hz, 1H); 13 C NMR (101 MHz, DMSO-d6) δ 168.1, 163.1, 159.7, 150.1, 142.2, 133.4, 133.2, 130.3 (2C), 129.4 (2C), 128.0, 127.4, 125.8, 124.0, 120.2, 108.8, 53.8, 53.7, 48.4, 37.7; HRMS (ESI-TOF) calcd. for C 21 H 18 NO5S [M + H]+ 396.0900; found: 396.0904.

[0043] Example 2: Synthesis of Compound Ⅲ-b

[0044] Add 3-halooxindole Ⅰ-b (0.2 mmol), pyridinium 1,4-zwitterionic sulfide salt Ⅱ-a (0.24 mmol), and inorganic base K2CO3 (0.3 mmol) into a dry reaction tube, then add 4.0 mL of dichloromethane, and stir the reaction mixture at room temperature; after the reaction is complete, the crude product is separated and purified by column chromatography to obtain Compound Ⅲ-b;

[0045] White solid; 66.4 mg was obtained, with a yield of 81%; m.p. 138.8 - 139.7 °C;

[0046] Structure identification: 1 H NMR (400 MHz, DMSO-d6) δ 7.49 (d, J = 7.4 Hz, 1H), 7.45 - 7.37 (m, 2H), 7.29 - 7.25 (m, 1H), 7.09 - 7.03 (m, 1H), 6.97 (dd, J = 15.0, 7.4 Hz, 2H), 6.84 (d, J = 7.4 Hz, 1H), 3.91 (s, 3H), 3.85 (s, 3H), 3.52 (d, J = 14.3 Hz, 1H), 3.19 (d, J = 14.3 Hz, 1H), 1.95 (s, 3H); 13 C NMR (101 MHz, DMSO-d6) δ 168.3, 163.1, 159.5, 149.9, 142.0, 136.7, 133.7, 131.7, 130.4, 130.3, 130.2, 127.5, 125.6, 125.5, 124.0, 120.2, 109.3, 53.8, 53.7, 48.3, 34.4, 19.0; HRMS (ESI-TOF) calcd. for C 22 H 20 NO5S [M + H]+ 410.1057; found: 410.1062.

[0047] Example 3: Synthesis of Compound Ⅲ-c

[0048] Add 3-halooxindole Ⅰ-c (0.2 mmol), pyridinium 1,4-zwitterionic sulfide salt Ⅱ-a (0.24 mmol), and inorganic base K2CO3 (0.3 mmol) into a dry reaction tube, then add 4.0 mL of dichloromethane, and stir the reaction mixture at room temperature; after the reaction is complete, the crude product is separated and purified by column chromatography to obtain Compound Ⅲ-c;

[0049] Colorless oil; 69.0 mg was obtained, with a yield of 84%;

[0050] Structure identification:1 1H NMR (400 MHz, DMSO-d6) δ 7.71 (d, J = 7.3 Hz, 1H), 7.43 - 7.39 (m, 1H), 7.38 - 7.29 (m, 2H), 6.99 - 6.92 (m, 2H), 6.63 - 6.53 (m, 2H), 3.94 (s, 3H), 3.85 (s, 3H), 3.52 (d, J = 13.6 Hz, 1H), 3.09 (d, J = 13.6 Hz, 1H), 2.09 (s, 3H); 13 13C NMR (101 MHz, DMSO-d6) δ 168.2, 163.1, 159.6, 150.2, 142.2, 137.0, 133.6, 133.0, 130.3 (2C), 128.0, 127.8, 126.4, 125.7, 124.0, 120.1, 108.8, 53.8, 53.7, 48.3, 37.7, 20.8; HRMS (ESI-TOF) calcd. for C 22 H 20 NO5S [M + H] + 410.1057; found: 410.1062.

[0051] Example 4: Synthesis of Compound Ⅲ-d

[0052] Add 3-halooxindole Ⅰ-d (0.2 mmol), pyridinium 1,4-zwitterionic sulfide salt Ⅱ-a (0.24 mmol), and inorganic base K2CO3 (0.3 mmol) to a dry reaction tube, then add 4.0 mL of dichloromethane, and stir the reaction mixture at room temperature; after the reaction is complete, purify the crude product by column chromatography to obtain Compound Ⅲ-d;

[0053] White solid; 76.3 mg was obtained, with a yield of 93%; m.p. 125.6 - 126.4 °C;

[0054] Structure identification: 1 1H NMR (400 MHz, DMSO-d6) δ 7.73 (d, J = 7.3 Hz, 1H), 7.42 - 7.38 (m, 1H), 7.37 - 7.28 (m, 2H), 6.89 (d, J = 7.9 Hz, 2H), 6.66 (d, J = 8.0 Hz, 2H), 3.94 (s, 3H), 3.85 (s, 3H), 3.53 (d, J = 13.7 Hz, 1H), 3.09 (d, J = 13.7 Hz, 1H), 2.14 (s, 3H); 1313C NMR (101 MHz, DMSO-d6) δ 168.2, 163.1, 159.7, 150.2, 142.2, 136.5, 133.5, 130.3, 130.0, 129.3 (2C), 128.6 (2C), 125.7, 124.0, 120.2, 108.7, 53.8, 53.7, 48.4, 37.3, 20.5; HRMS (ESI-TOF) calcd. for C 22 H 20 NO5S [M+H]+ 410.1057; found: 410.1066.

[0055] Example 5: Synthesis of Compound Ⅲ-e

[0056] 3-Halooxindole Ⅰ-e (0.2 mmol), pyridinium 1,4-zwitterionic sulfide salt Ⅱ-a (0.24 mmol), and inorganic base K2CO3 (0.3 mmol) were added to a dry reaction tube, and then 4.0 mL of dichloromethane was added. The reaction mixture was stirred at room temperature. After the reaction was complete, the crude product was separated and purified by column chromatography to obtain Compound Ⅲ-e;

[0057] Colorless oil; 74.9 mg was obtained, with a yield of 88%;

[0058] Structure identification: 1 1H NMR (400 MHz, CDCl3) δ 7.48 - 7.30 (m, 2H), 7.28 - 7.21 (m, 2H), 6.78 (d, J = 8.5 Hz, 2H), 6.65 (d, J = 8.5 Hz, 2H), 3.98 (s, 3H), 3.90 (s, 3H), 3.71 (s, 3H), 3.27 (d, J = 13.9 Hz, 1H), 3.06 (d, J = 13.9 Hz, 1H); 13 13C NMR (101 MHz, CDCl3) δ 168.8, 163.9, 160.3, 159.0, 151.0, 143.1, 133.8, 131.1 (2C), 130.2, 125.5, 124.9, 123.4, 120.9, 113.6 (2C), 109.1, 55.2, 53.7, 53.6, 48.7, 38.0;

[0059] HRMS (ESI-TOF) calcd. for C 22 H 20 NO6S [M+H] + 426.1006; found: 426.1006.

[0060] Example 6: Synthesis of Compound Ⅲ-f

[0061] In a dry reaction tube, add 3-halooxindole I-f (0.2 mmol), pyridinium 1,4-zwitterionic sulfide salt II-a (0.24 mmol), and inorganic base K2CO3 (0.3 mmol), then add 4.0 mL of dichloromethane, and stir the reaction mixture at room temperature; after the reaction is complete, the crude product is separated and purified by column chromatography to obtain compound III-f;

[0062] Colorless oil; 75.6 mg was obtained, with a yield of 91%;

[0063] Structure identification: 1 H NMR (400 MHz, CDCl3) δ 7.43 - 7.30 (m, 3H), 7.26 - 7.21 (m, 1H), 7.17 - 7.08 (m, 1H), 6.94 - 6.79 (m, 3H), 3.97 (s, 3H), 3.90 (s, 3H), 3.42 (d, J = 14.0 Hz, 1H), 3.29 (d, J = 14.0 Hz, 1H); 13 C NMR (101 MHz, CDCl3) δ 168.4, 163.8, 160.9 (d, J = 248.5 Hz, 1C), 160.2, 150.7, 143.2, 133.4, 131.7 (d, J = 3.6 Hz, 1C), 130.3, 129.7 (d, J = 8.3 Hz, 1C), 125.5, 123.9 (d, J = 3.7 Hz, 1C), 123.3 (d, J = 1.7 Hz, 1C), 120.7, 120.3 (d, J = 15.3 Hz, 1C), 115.4 (d, J = 22.5 Hz, 1C), 109.0, 53.7, 53.5, 48.2, 31.5 (d, J = 2.4 Hz, 1C); HRMS (ESI-TOF) calcd. for C 21 H 17 FNO5S [M + H] + 414.0806; found: 414.0809.

[0064] Example 7: Synthesis of compound III-g

[0065] In a dry reaction tube, add 3-halooxindole I-g (0.2 mmol), pyridinium 1,4-zwitterionic sulfide salt II-a (0.24 mmol), and inorganic base K2CO3 (0.3 mmol), then add 4.0 mL of dichloromethane, and stir the reaction mixture at room temperature; after the reaction is complete, the crude product is separated and purified by column chromatography to obtain compound III-g;

[0066] Yellow solid; 71.7 mg obtained, yield 83%; m.p. 112.7 - 113.5 °C;

[0067] Structure identification: 1 H NMR (400 MHz, DMSO-d6) δ 7.71 (d, J = 7.4 Hz, 1H), 7.47 - 7.40 (m, 1H), 7.38 - 7.26 (m, 3H), 7.18 - 7.14 (m, 1H), 7.04 - 7.01 (m, 1H), 6.82 - 6.73 (m, 1H), 3.89 (s, 3H), 3.84 (s, 3H), 3.69 (d, J = 14.1 Hz, 1H), 3.49 (d, J = 14.1 Hz, 1H); 13 C NMR (101 MHz, DMSO-d6) δ 167.8, 163.1, 159.4, 150.0, 142.0, 133.6, 133.3, 131.5, 130.8, 130.5, 129.5, 129.4, 126.7, 125.7, 124.2, 120.1, 109.2, 53.8, 53.6, 48.0, 34.9; HRMS (ESI-TOF) calcd. for C 21 H 17 ClNO5S [M + H] + 430.0510; found: 430.0492.

[0068] Example 8: Synthesis of compound Ⅲ-h

[0069] Add 3-halooxindole Ⅰ-h (0.2 mmol), pyridinium 1,4-zwitterionic sulfide Ⅱ-a (0.24 mmol), and inorganic base K2CO3 (0.3 mmol) to a dry reaction tube, then add 4.0 mL of dichloromethane, and stir the reaction mixture at room temperature; after the reaction is complete, the crude product is separated and purified by column chromatography to obtain compound Ⅲ-h;

[0070] Colorless oil; 75.6 mg obtained, yield 91%;

[0071] Structure identification: 1 H NMR (400 MHz, DMSO-d6) δ 7.79 - 7.67 (m, 1H), 7.44 - 7.40 (m, 1H), 7.35 (dd, J = 7.5, 5.4 Hz, 2H), 7.20 - 7.12 (m, 2H), 6.86 (s, 1H), 6.78 (d, J = 7.5 Hz, 1H), 3.93 (s, 3H), 3.84 (s, 3H), 3.58 (d, J = 13.6 Hz, 1H), 3.19 (d, J = 13.6 Hz, 1H); 1313C NMR(101MHz, DMSO-d6) δ 167.9, 163.1, 159.5, 150.0, 141.9, 135.6, 133.2, 132.5, 130.5, 129.8, 129.5, 128.1, 127.4, 125.8, 124.0, 120.3, 108.9, 53.8, 53.7, 48.1, 37.1; HRMS(ESI-TOF) calcd. for C 21 H 17 ClNO5S [M+H] + 430.0510; found: 430.0497.

[0072] Example 9: Synthesis of Compound Ⅲ-i

[0073] Add 3-halooxindole Ⅰ-i (0.2 mmol), pyridinium 1,4-zwitterionic sulfide salt Ⅱ-a (0.24 mmol), and inorganic base K2CO3 (0.3 mmol) to a dry reaction tube, then add 4.0 mL of dichloromethane. The reaction mixture is stirred at room temperature. After the reaction is complete, the crude product is separated and purified by column chromatography to obtain Compound Ⅲ-i;

[0074] White solid; 86.2 mg was obtained, with a yield of 91%;

[0075] Structure identification: 1 1H NMR(400MHz, DMSO-d6) δ 7.78 - 7.69(m, 1H), 7.45 - 7.38(m, 1H), 7.37 - 7.25(m, 4H), 6.75(d, J = 8.4Hz, 2H), 3.93(s, 3H), 3.84(s, 3H), 3.55(d, J = 13.6Hz, 1H), 3.16(d, J = 13.6Hz, 1H); 13 13C NMR(101MHz, DMSO-d6) δ 167.9, 163.1, 159.5, 150.0, 142.0, 133.2, 132.6, 131.6(2C), 130.9(2C), 130.4, 125.9, 124.0, 120.8, 120.2, 108.9, 53.8, 53.7, 48.1, 36.9; HRMS(ESI-TOF) calcd. for C 21 H 17 BrNO5S [M+H]+ 474.0005; found: 474.0013.

[0076] Example 10: Synthesis of Compound Ⅲ-j

[0077] Add 3-halooxindole Ⅰ-j (0.2 mmol), pyridinium 1,4-zwitterionic sulfide salt Ⅱ-a (0.24 mmol), and inorganic base K2CO3 (0.3 mmol) to a dry reaction tube, then add 4.0 mL of dichloromethane, and stir the reaction mixture at room temperature; after the reaction is complete, the crude product is separated and purified by column chromatography to obtain compound Ⅲ-j;

[0078] Yellow oil; 75.1 mg was obtained, with a yield of 89%;

[0079] Structure identification: 1 H NMR (400 MHz, CDCl3) δ 7.37 (d, J = 3.3 Hz, 2H), 7.25 (q, J = 5.4, 3.7 Hz, 2H), 6.87 (d, J = 7.6 Hz, 1H), 6.63 (s, 1H), 6.56 (d, J = 7.6 Hz, 1H), 3.98 (s, 3H), 3.90 (s, 3H), 3.27 (d, J = 13.7 Hz, 1H), 3.04 (d, J = 13.7 Hz, 1H), 2.13 (s, 3H), 2.09 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ 168.8, 163.9, 160.3, 151.0, 143.0, 136.3, 135.9, 133.9, 131.4, 130.2, 130.1, 129.4, 127.2, 125.3, 123.4, 120.8, 109.2, 53.7, 53.5, 48.6, 38.4, 19.7, 19.5; HRMS (ESI-TOF) calcd. for C 23 H 22 NO5S [M + H]+ 424.1213; found: 424.1214.

[0080] Example 11: Synthesis of compound Ⅲ-k

[0081] Add 3-halooxindole Ⅰ-k (0.2 mmol), pyridinium 1,4-zwitterionic sulfide salt Ⅱ-a (0.24 mmol), and inorganic base K2CO3 (0.3 mmol) to a dry reaction tube, then add 4.0 mL of dichloromethane, and stir the reaction mixture at room temperature; after the reaction is complete, the crude product is separated and purified by column chromatography to obtain compound Ⅲ-k;

[0082] Yellow solid; 90.6 mg was obtained, with a yield of 99%; m.p. 163.1 - 163.9 °C;

[0083] Structure identification: 11H NMR (400 MHz, DMSO-d6) δ 7.82 - 7.74 (m, 2H), 7.68 - 7.60 (m, 2H), 7.45 - 7.41 (m, 2H), 7.39 - 7.33 (m, 3H), 7.29 - 7.22 (m, 1H), 6.90 (dd, J = 8.4, 1.4 Hz, 1H), 3.96 (s, 3H), 3.87 (s, 3H), 3.74 (d, J = 13.6 Hz, 1H), 3.34 (d, J = 13.6 Hz, 1H); 13 13C NMR (101 MHz, DMSO-d6) δ 168.6, 163.6, 160.1, 150.6, 142.7, 134.0, 132.9, 132.5, 131.3, 130.8, 129.0, 127.9, 127.8, 127.7, 127.6, 126.7, 126.5, 126.3, 124.5, 120.6, 109.4, 54.3, 54.2, 48.9, 38.4; HRMS (ESI-TOF) calcd. for C 25 H 20 NO5S [M + H] + 446.1057; found: 446.1062.

[0084] Example 12: Synthesis of Compound III-l

[0085] Add 3-halooxindole I-l (0.2 mmol), pyridinium 1,4-zwitterionic sulfide salt II-a (0.24 mmol), and inorganic base K2CO3 (0.3 mmol) to a dry reaction tube, then add 4.0 mL of dichloromethane. The reaction mixture is stirred at room temperature; after the reaction is complete, the crude product is separated and purified by column chromatography to obtain Compound III-l;

[0086] Colorless oil; 76.8 mg was obtained, with a yield of 96%;

[0087] Structure identification: 1 1H NMR (400 MHz, CDCl3) δ 7.42 (s, 2H), 7.25 (s, 2H), 7.04 (d, J = 5.1 Hz, 1H), 6.86 - 6.78 (m, 1H), 6.64 (d, J = 2.8 Hz, 1H), 3.97 (s, 3H), 3.90 (s, 3H), 3.54 (d, J = 14.9 Hz, 1H), 3.39 (d, J = 14.9 Hz, 1H); 1313C NMR (101 MHz, DMSO-d6) δ 168.0, 163.1, 159.6, 150.6, 142.3, 134.4, 133.5, 130.6, 127.9, 126.6, 126.1, 126.0, 123.9, 120.3, 108.6, 53.8, 53.7, 48.1, 32.1; HRMS (ESI-TOF) calcd. for C 19 H 16 NO5S2 [M+H] + 402.0464; found: 402.0470.

[0088] Example 13: Synthesis of Compound Ⅲ-m

[0089] 3-Halooxindole Ⅰ-m (0.2 mmol), pyridinium 1,4-zwitterionic sulfide Ⅱ-a (0.24 mmol), and inorganic base K2CO3 (0.3 mmol) were added to a dry reaction tube, and then 4.0 mL of dichloromethane was added. The reaction mixture was stirred at room temperature. After the reaction was complete, the crude product was separated and purified by column chromatography to obtain Compound Ⅲ-m;

[0090] Colorless oil; 54.7 mg was obtained, with a yield of 76%;

[0091] Structure identification: 1 1H NMR (400 MHz, DMSO-d6) δ 7.69 (d, J = 7.2 Hz, 1H), 7.55 (d, J = 7.7 Hz, 1H), 7.51 - 7.47 (m, 1H), 7.36 - 7.33 (m, 1H), 3.89 (s, 3H), 3.81 (s, 3H), 2.30 (dd, J = 14.2, 7.3 Hz, 1H), 1.85 (dd, J = 14.2, 7.3 Hz, 1H), 1.04 (m, 1H), 0.64 (d, J = 6.6 Hz, 3H), 0.56 (d, J = 6.6 Hz, 3H); 13 13C NMR (101 MHz, DMSO-d6) δ 169.5, 163.1, 159.5, 150.4, 142.0, 134.0, 130.4, 126.0, 123.6, 120.5, 109.0, 53.8, 53.7, 47.5, 41.0, 25.1, 23.5, 22.3; HRMS (ESI-TOF) calcd. for C 18 H 20 NO5S [M+H] + 362.1057; found: 362.1058.

[0092] Example 14: Synthesis of Compound Ⅲ-n

[0093] Add 3-halooxindole Ⅰ-n (0.2 mmol), pyridinium 1,4-zwitterionic sulfide salt Ⅱ-a (0.24 mmol), and inorganic base K2CO3 (0.3 mmol) into a dry reaction tube, then add 4.0 mL of dichloromethane, and stir the reaction mixture at room temperature; after the reaction is complete, the crude product is separated and purified by column chromatography to obtain Compound Ⅲ-n;

[0094] Colorless oil; 54.6 mg was obtained, with a yield of 79%;

[0095] Structure identification: 1 H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 7.8 Hz, 1H), 7.48 - 7.36 (m, 2H), 7.30 - 7.23 (m, 1H), 5.46 - 5.36 (m, 1H), 5.14 - 5.01 (m, 2H), 3.94 (s, 3H), 3.88 (s, 3H), 2.80 (dd, J = 13.9, 6.4 Hz, 1H), 2.58 (dd, J = 13.9, 6.4 Hz, 1H); 13 C NMR (101 MHz, CDCl3) δ 168.8, 163.8, 160.2, 150.8, 143.0, 134.0, 130.3, 129.1, 125.7, 123.0, 121.6, 121.0, 108.9, 53.7, 53.5, 47.5, 36.8; HRMS (ESI-TOF) calcd. for C 17 H 16 NO5S [M+H] + 346.0744; found: 346.0749.

[0096] Example 15: Synthesis of Compound Ⅲ-o

[0097] Add 3-halooxindole Ⅰ-o (0.2 mmol), pyridinium 1,4-zwitterionic sulfide salt Ⅱ-a (0.24 mmol), and inorganic base K2CO3 (0.3 mmol) into a dry reaction tube, then add 4.0 mL of dichloromethane, and stir the reaction mixture at room temperature; after the reaction is complete, the crude product is separated and purified by column chromatography to obtain Compound Ⅲ-o;

[0098] Yellow solid; 66.6 mg was obtained, with a yield of 85%; m.p. 103.8 - 104.6 °C;

[0099] Structure identification: 11H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 7.9 Hz, 2H), 7.47 - 7.43 (m, 1H), 7.29 - 7.26 (m, 1H), 4.04 - 3.90 (m, 5H), 3.86 (s, 3H), 3.14 (d, J = 16.0 Hz, 1H), 2.98 (d, J = 16.0 Hz, 1H), 1.03 (t, J = 7.1 Hz, 3H); 13 13C NMR (101 MHz, CDCl3) δ 168.0, 167.2, 163.4, 160.0, 151.0, 143.4, 133.4, 130.6, 125.9, 123.4, 121.1, 108.2, 61.3, 53.6, 53.5, 44.7, 37.5, 13.7; HRMS (ESI-TOF) calcd. for C 18 H 18 NO7S [M + H] + 392.0798; found: 392.0801.

[0100] Example 16: Synthesis of Compound Ⅲ-p

[0101] Add 3-halooxindole Ⅰ-o (0.2 mmol), pyridinium 1,4-zwitterionic sulfide salt Ⅱ-a (0.24 mmol), and inorganic base K2CO3 (0.3 mmol) to a dry reaction tube, then add 4.0 mL of dichloromethane, and stir the reaction mixture at room temperature; after the reaction is complete, purify the crude product by column chromatography to obtain Compound Ⅲ-o;

[0102] White solid; 82.9 mg was obtained, with a yield of 82%; m.p. 75.6 - 76.1 °C;

[0103] Structure identification: 1 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 7.9 Hz, 1H), 7.47 - 7.34 (m, 2H), 7.26 (q, J = 7.5, 6.1 Hz, 1H), 3.91 (s, 3H), 3.86 (s, 3H), 3.52 - 3.47 (m, 1H), 3.33 - 3.27 (m, 1H), 2.49 - 2.41 (m, 1H), 2.34 - 2.28 (m, 1H), 0.97 - 0.89 (m, 21H); 1313C NMR (101 MHz, DMSO-d6) δ 169.8, 163.1, 159.8, 151.1, 142.9, 133.1, 130.3, 125.6, 123.6, 120.3, 107.9, 59.0, 53.7, 53.5, 46.5, 35.8, 17.6 (3C), 17.5 (3C), 11.2 (3C); HRMS (ESI-TOF) calcd. for C 25 H 36 NO6SSi [M + H] + 506.2027; found: 506.2031.

[0104] Example 17: Synthesis of Compound Ⅲ-q

[0105] In a dry reaction tube, 3-halooxindole Ⅰ-q (0.2 mmol), pyridinium 1,4-zwitterionic sulfide salt Ⅱ-a (0.24 mmol), and inorganic base K2CO3 (0.3 mmol) were added, and then 4.0 mL of dichloromethane was added. The reaction mixture was stirred at room temperature. After the reaction was complete, the crude product was separated and purified by column chromatography to obtain Compound Ⅲ-q;

[0106] Colorless oil; 68.6 mg was obtained, with a yield of 92%;

[0107] Structure identification: 1 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 7.8 Hz, 1H), 7.49 - 7.46 (m, 1H), 7.41 (d, J = 7.4 Hz, 1H), 7.32 - 7.29 (m, 1H), 3.94 (s, 3H), 3.87 (s, 3H), 3.16 - 3.10 (m, 1H), 3.03 - 2.93 (m, 1H), 2.40 - 2.27 (m, 2H); 13 13C NMR (101 MHz, CDCl3) δ 168.5, 163.5, 160.0, 151.0, 143.1, 133.0, 130.7, 126.1, 122.7, 121.4, 108.6, 53.7, 53.5, 46.7, 46.3, 32.6; HRMS (ESI-TOF) calcd. for C 16 H 15 N4O5S [M + H] + 375.0758; found: 375.0763.

[0108] Example 18: Synthesis of Compound Ⅲ-r

[0109] Add 3-halooxindole Ⅰ-r (0.2 mmol), pyridinium 1,4-zwitterionic sulfide salt Ⅱ-a (0.24 mmol), and inorganic base K2CO3 (0.3 mmol) into a dry reaction tube, then add 4.0 mL of dichloromethane, and stir the reaction mixture at room temperature; after the reaction is complete, purify the crude product by column chromatography to obtain compound Ⅲ-r;

[0110] White solid; 39.0 mg was obtained; yield 41%; m.p. 177.9 - 178.4 °C;

[0111] Structure identification: 1 H NMR (400 MHz, CDCl3) δ 7.78 - 7.74 (m, 2H), 7.71 - 7.68 (m, 2H), 7.56 - 7.47 (m, 2H), 7.39 - 7.35 (m, 1H), 7.23 - 7.19 (m, 1H), 3.92 (s, 3H), 3.81 (s, 3H), 3.55 - 3.40 (m, 2H), 2.66 (dt, J = 14.2, 7.1 Hz, 1H), 2.47 (dt, J = 14.2, 7.1 Hz, 1H); 13 C NMR (101 MHz, DMSO-d6) δ 168.1, 167.4 (2C), 163.0, 159.0, 150.5, 141.3, 134.4 (2C), 132.9, 131.4 (2C), 130.5, 126.0, 123.5, 123.0 (2C), 120.7, 109.8, 53.8, 53.5, 46.4, 33.4, 29.6; HRMS (ESI-TOF) calcd. for C 24 H 19 N2O7S [M + H] + 479.0907; found: 479.0914.

[0112] Example 19: Synthesis of compound Ⅲ-s

[0113] Add 3-halooxindole Ⅰ-s (0.2 mmol), pyridinium 1,4-zwitterionic sulfide salt Ⅱ-a (0.24 mmol), and inorganic base K2CO3 (0.3 mmol) into a dry reaction tube, then add 4.0 mL of dichloromethane, and stir the reaction mixture at room temperature; after the reaction is complete, purify the crude product by column chromatography to obtain compound Ⅲ-s;

[0114] Yellow oil; 76.6 mg was obtained, yield 94%;

[0115] Structure identification: 11H NMR (400 MHz, DMSO-d6) δ 7.54 (s, 1H), 7.19 (d, J = 3.3 Hz, 2H), 7.11 (q, J = 5.0, 4.6 Hz, 3H), 6.79 (dd, J = 7.2, 2.0 Hz, 2H), 3.94 (s, 3H), 3.85 (s, 3H), 3.55 (d, J = 13.6 Hz, 1H), 3.12 (d, J = 13.6 Hz, 1H), 2.38 (s, 3H); 13 13C NMR (101 MHz, DMSO-d6) δ 167.4, 163.2, 159.7, 147.7, 142.4, 135.3, 133.5, 133.2, 130.7, 129.4 (2C), 128.0 (2C), 127.4, 124.4, 119.8, 108.6, 53.8, 53.7, 48.3, 37.9, 21.1; HRMS (ESI-TOF) calcd. for C 22 H 20 NO5S [M + H] + 410.1057; found: 410.1064.

[0116] Example 20: Synthesis of Compound Ⅲ-t

[0117] Add 3-halooxindole Ⅰ-t (0.2 mmol), pyridinium 1,4-zwitterionic sulfide salt Ⅱ-a (0.24 mmol), and inorganic base K2CO3 (0.3 mmol) to a dry reaction tube, then add 4.0 mL of dichloromethane, and stir the reaction mixture at room temperature; after the reaction is complete, purify the crude product by column chromatography to obtain Compound Ⅲ-t;

[0118] Colorless oil; 95.6 mg was obtained, with a yield of 99%;

[0119] Structure identification: 1 1H NMR (400 MHz, DMSO-d6) δ 8.07 (d, J = 1.9 Hz, 1H), 7.57 (dd, J = 8.3, 1.9 Hz, 1H), 7.25 (d, J = 8.3 Hz, 1H), 7.17 - 7.06 (m, 3H), 6.81 (dd, J = 6.4, 2.7 Hz, 2H), 3.94 (s, 3H), 3.85 (s, 3H), 3.64 (d, J = 13.6 Hz, 1H), 3.16 (d, J = 13.6 Hz, 1H); 1313C NMR(101MHz, DMSO-d6) δ 168.2, 162.9, 159.5, 149.3, 141.9, 135.6, 133.2, 133.0, 129.4 (2C), 128.1 (2C), 127.5, 127.3, 121.9, 118.1, 108.9, 53.8, 53.7, 48.6, 37.5; HRMS(ESI-TOF) calcd. for C 21 H 17 BrNO5S [M+H] + 474.0005; found: 474.0013.

[0120] Example 21: Synthesis of Compound Ⅲ-u

[0121] Add 3-halooxindole Ⅰ-u (0.2 mmol), pyridinium 1,4-zwitterionic sulfide salt Ⅱ-a (0.24 mmol), and inorganic base K2CO3 (0.3 mmol) to a dry reaction tube, then add 4.0 mL of dichloromethane. The reaction mixture is stirred at room temperature. After the reaction is complete, the crude product is separated and purified by column chromatography to obtain Compound Ⅲ-u;

[0122] Colorless oil; 76.9 mg was obtained, with a yield of 89%;

[0123] Structure identification: 1 1H NMR(400MHz, DMSO-d6) δ 7.78 (d, J = 8.8 Hz, 1H), 7.40 (d, J = 7.0 Hz, 2H), 7.12 (dd, J = 5.1, 1.6 Hz, 3H), 6.81 (dd, J = 6.5, 2.6 Hz, 2H), 3.94 (s, 3H), 3.85 (s, 3H), 3.59 (d, J = 13.6 Hz, 1H), 3.16 (d, J = 13.6 Hz, 1H); 13 13C NMR(101MHz, DMSO-d6) δ 169.3, 163.0, 159.5, 151.6, 141.9, 134.7, 132.9, 132.2, 129.5 (2C), 128.1 (2C), 127.5, 125.6, 125.5, 120.3, 109.2, 53.8, 53.7, 48.3, 37.4; HRMS(ESI-TOF) calcd. for C 21 H 17 ClNO5S [M+H] + 430.0510; found: 430.0509.

[0124] Example 22: Synthesis of Compound Ⅲ-v

[0125] In a dry reaction tube, add 3-halooxindole I-a (0.2 mmol), pyridinium 1,4-zwitterionic sulfide salt II-b (0.24 mmol), inorganic base K2CO3 (0.3 mmol), and then add 4.0 mL of dichloromethane. The reaction mixture is stirred at room temperature. After the reaction is complete, the crude product is separated and purified by column chromatography to obtain compound III-v;

[0126] White solid; 76.6 mg was obtained, yield 90%; m.p. 123.9 - 124.7 °C;

[0127] Structure identification: 1 H NMR (400 MHz, DMSO-d6) δ 7.74 (d, J = 7.2 Hz, 1H), 7.42 - 7.38 (m, 1H), 7.38 - 7.27 (m, 2H), 7.18 - 7.03 (m, 3H), 6.84 - 6.74 (m, 2H), 4.40 (q, J = 7.1 Hz, 2H), 4.30 (q, J = 7.1 Hz, 2H), 3.58 (d, J = 13.6 Hz, 1H), 3.13 (d, J = 13.6 Hz, 1H), 1.35 (t, J = 7.1 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, DMSO-d6) δ 168.2, 162.6, 159.1, 150.2, 142.7, 133.5, 133.2, 130.3, 129.4 (2C), 128.0 (2C), 127.4, 125.7, 124.0, 120.1, 108.4, 62.9, 62.8, 48.4, 37.7, 13.7, 13.6; HRMS (ESI-TOF) calcd. for C 23 H 22 NO5S [M + H] + 424.1213; found: 424.1221.

[0128] Example 23: Synthesis of compound III-w

[0129] In a dry reaction tube, add 3-halooxindole I-a (0.2 mmol), pyridinium 1,4-zwitterionic sulfide salt II-c (0.24 mmol), inorganic base K2CO3 (0.3 mmol), and then add 4.0 mL of dichloromethane. The reaction mixture is stirred at room temperature. After the reaction is complete, the crude product is separated and purified by column chromatography to obtain compound III-w;

[0130] White solid; 39.4 mg was obtained, yield 43%; m.p. 62.7 - 63.3 °C;

[0131] Structural identification: 1 H NMR(400MHz,DMSO-d6)δ8.03(d,J=7.6Hz,2H),7.76-7.72(m,1H),7.69(d,J=7.4Hz,1H),7.62-7.59(m,2H),7.40-7.36(m,1H),7.30(d,J=8.0Hz,2H),7.11(d,J=5.5Hz,3H),6.88(dd,J=5.9,3.2Hz,2H),4.14(q,J=7.1Hz,2H),3.65(d,J=13.4Hz,1H),3.44(d,J=13.4Hz,1H),1.02(t,J=7.1Hz,3H); 13 C NMR(101MHz,DMSO-d6)δ188.6,168.5,158.0,150.3,136.5,134.7,134.6,133.4,133.3,130.3,129.8(2C),129.3(2C),129.2(2C),127.9(2C),127.4,125.5,124.1,120.0,118.6,62.5,48.9,37.8,13.4;HRMS(ESI-TOF)calcd.for C 27 H 22 NO4S[M+H] + 456.1264;found:456.1272。

[0132] Example 24:Synthesis of compound Ⅲ-x

[0133] Add 3-halooxindole Ⅰ-a(0.2mmol),pyridinium 1,4-zwitterionic sulfide Ⅱ-d(0.24mmol),inorganic base K2CO3(0.3mmol)to a dry reaction tube,and then add 4.0mL of dichloromethane.The reaction mixture is stirred at room temperature.After the reaction is complete,the crude product is separated and purified by column chromatography to obtain compound Ⅲ-x;

[0134] White solid;39.0mg was obtained in a yield of 40%,m.p.127.8-128.3℃;

[0135] Structural identification: 11H NMR (400 MHz, DMSO-d6) δ 8.03 (d, J = 7.3 Hz, 2H), 7.78 - 7.74 (m, 1H), 7.71 - 7.59 (m, 3H), 7.42 - 7.34 (m, 1H), 7.35 - 7.25 (m, 2H), 7.13 (dd, J = 5.0, 1.7 Hz, 3H), 6.87 (dd, J = 6.9, 2.3 Hz, 2H), 3.64 (d, J = 13.5 Hz, 1H), 3.39 (d, J = 13.5 Hz, 1H), 1.21 (s, 9H); 13 13C NMR (101 MHz, DMSO-d6) δ 188.6, 168.6, 156.7, 150.3, 137.6, 134.9, 134.6, 133.4, 133.3, 130.3, 129.7 (2C), 129.5 (2C) 129.4 (2C), 127.9 (2C), 127.4, 125.4, 124.1, 120.0, 117.0, 84.7, 48.8, 37.9, 27.1 (3C); HRMS (ESI-TOF) calcd. for C 29 H 26 NO4S [M + H] + 484.1577; found: 484.1576.

[0136] Example 25: Synthesis of Compound Ⅲ-y

[0137] Add 3-halooxindole Ⅰ-a (0.2 mmol), pyridinium 1,4-zwitterionic sulfide salt Ⅱ-e (0.24 mmol), and inorganic base K2CO3 (0.3 mmol) to a dry reaction tube, then add 4.0 mL of dichloromethane. The reaction mixture is stirred at room temperature; after the reaction is complete, the crude product is separated and purified by column chromatography to obtain Compound Ⅲ-y;

[0138] White solid; 36.8 mg was obtained, with a yield of 39%; m.p. 163.1 - 163.9 °C;

[0139] Structure identification: 11H NMR (400 MHz, DMSO-d6) δ 7.91 (d, J = 8.2 Hz, 2H), 7.66 (d, J = 7.4 Hz, 1H), 7.39 (dd, J = 13.1, 7.9 Hz, 3H), 7.33 - 7.26 (m, 2H), 7.17 - 7.07 (m, 3H), 6.88 (dd, J = 7.2, 2.1 Hz, 2H), 4.14 (q, J = 7.1 Hz, 2H), 3.64 (d, J = 13.4 Hz, 1H), 3.41 (d, J = 13.4 Hz, 1H), 2.40 (s, 3H), 1.04 (t, J = 7.1 Hz, 3H); 13 13C NMR (101 MHz, DMSO-d6) δ 188.0, 168.5, 158.0, 150.3, 145.5, 136.3, 133.3, 133.2, 132.3, 130.3, 129.8 (2C), 129.7 (2C), 129.4 (2C), 127.9 (2C), 127.3, 125.4, 124.1, 120.0, 118.7, 62.4, 48.8, 37.8, 21.3, 13.4; HRMS (ESI-TOF) calcd. for C 28 H 24 NO4S [M + H] + 470.1421; found: 470.1426.

[0140] Example 26: Synthesis of Compound V-a

[0141]

[0142] Add 3-halooxindole IV-a (0.2 mmol), pyridinium 1,4-zwitterionic sulfide II-a (0.24 mmol), and inorganic base K2CO3 (0.3 mmol) to a dry reaction tube, then add 4.0 mL of dichloromethane. The reaction mixture is stirred at room temperature. After the reaction is complete, the crude product is separated and purified by column chromatography to obtain Compound V-a;

[0143] Colorless oil; 34.7 mg was obtained, with a yield of 45%;

[0144] Structure identification: 1 1H NMR (400 MHz, DMSO-d6) δ 7.59 (d, J = 8.0 Hz, 2H), 7.55 - 7.44 (m, 3H), 7.39 (d, J = 6.9 Hz, 3H), 7.29 - 7.25 (m, 1H), 3.78 (s, 3H), 3.75 (s, 3H); 1313C NMR (101 MHz, DMSO-d6) δ 168.3, 162.8, 159.3, 149.5, 143.0, 136.3, 133.1, 130.4, 129.5, 129.4 (2C), 126.4, 125.6 (2C), 123.9, 120.8, 109.0, 53.8, 53.7, 51.5; HRMS (ESI-TOF) calcd. for C 20 H 16 NO5S [M+H] + 382.0744; found: 382.0753.

[0145] Example 27: Synthesis of Compound V-b

[0146] 3-Halooxindole IV-b (0.2 mmol), pyridinium 1,4-dipolar sulfide II-a (0.24 mmol), and inorganic base K2CO3 (0.3 mmol) were added to a dry reaction tube, and then 4.0 mL of dichloromethane was added. The reaction mixture was stirred at room temperature. After the reaction was complete, the crude product was separated and purified by column chromatography to obtain Compound V-b;

[0147] Colorless oil; 40.2 mg was obtained, with a yield of 50%;

[0148] Structure identification: 1 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 7.8 Hz, 1H), 7.51 - 7.36 (m, 3H), 7.26 (s, 1H), 7.22 - 7.19 (m, 1H), 7.04 - 7.00 (m, 2H), 3.84 (s, 6H); 13 13C NMR (101 MHz, CDCl3) δ 168.8, 163.5, 163.0 (d, J = 250.1 Hz, 1C), 159.6, 150.2, 143.3, 136.6, 130.2, 128.9 (d, J = 3.3 Hz, 1C), 127.9 (d, J = 8.5 Hz, 1C), 126.2, 123.2, 121.2, 116.4 (d, J = 22.1 Hz, 1C), 109.4, 53.6, 53.4, 51.5; HRMS (ESI-TOF) calcd. for C 20 H 15 FNO5S [M+H] + 400.0649; found: 400.0653.

[0149] Example 28: Synthesis of Compound V-c

[0150] In a dry reaction tube, add 3-halooxindole Ⅳ-c (0.2 mmol), pyridinium 1,4-zwitterionic sulfide salt Ⅱ-a (0.24 mmol), and inorganic base K2CO3 (0.3 mmol). Then add 4.0 mL of dichloromethane, and stir the reaction mixture at room temperature. After the reaction is complete, the crude product is separated and purified by column chromatography to obtain compound Ⅴ-c;

[0151] Colorless oil; 26.8 mg was obtained, with a yield of 34%;

[0152] Structure identification: 1 H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 7.8 Hz, 1H), 7.37 (dd, J = 19.3, 7.7 Hz, 3H), 7.29 (d, J = 7.5 Hz, 1H), 7.16 (dd, J = 26.3, 7.6 Hz, 3H), 3.83 (s, 6H), 2.30 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ 169.1, 163.7, 159.8, 150.3, 143.2, 139.2, 136.9, 130.0, 129.9 (3C), 126.0, 125.7 (2C), 123.2, 121.1, 109.7, 53.6, 53.3, 51.8, 21.2; HRMS (ESI-TOF) calcd. for C 21 H 18 NO5S [M + H] + 396.0900; found: 396.0902.

[0153] Example 29 Biological activity test

[0154] Using three cancer cell lines, namely lung cancer cell line A549, cervical cancer cell line Hela, and liver cancer cell line HepG2, the anti-cancer activity of indolenine-fused 2H-1,4-oxathiine compounds was evaluated by CCK-8 assay. Briefly, cells were seeded at 5,000 cells / well in a 96-well plate and grown overnight to adhere. The synthesized compounds were added in triplicate at concentrations of 0.74, 2.22, 6.67, 20.01, 60.03, and 100.00 μM and co-cultured with the cells for 48 hours. Then, the supernatant was removed, and the cells were washed twice with PBS to remove residual compounds. 100 μL of medium containing 10% CCK8 was added to each well. After incubation for 2 hours, the absorbance at 450 nm was measured using a PerkinElmer Victor Nivo microplate reader (Waltham, MA, USA). The IC 50 values of various compounds against different cells are as follows (cisplatin IC 50(A549) = 20.3 uM; IC 50 (Hela) = 15.2 uM; IC 50 (HepG2) = 23.3 uM):

[0155] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, and improvements made within the spirit and principles of the present invention shall be included within the protection scope of the present invention.

Claims

1. Indolenine-fused 2H -1,4-oxathiins, characterized in that It has the structure shown in the following structural formula: 。 2. The preparation method of the indoline ring-fused 2H -1,4-oxathiine compounds as claimed in claim 1, characterized in that It includes the following steps: Dissolve 3-halooxindole (I) and pyridinium 1,4-zwitterionic sulfur / nitrogen salt (II) in a reaction solvent, then add a base and stir the reaction at room temperature for 3 - 72 h. After the reaction is completed, directly separate and purify to obtain indoline ring-fused 2H -1,4-oxathiophene compounds (III); Among them, the 3-halooxindole (I) has the following structure: ； The pyridinium 1,4-zwitterionic sulfur / nitrogen salt (II) has the following structure: ， Among them, the above R 1 , R 2 , R 3 and R 4 , selected from the substituents corresponding to the structural formulas III-f, III-i, III-k, III-p, III-r, III-s, III-t, III-u, and V-a.

3. The preparation method according to claim 2, characterized in that: The reaction solvent is selected from at least one of dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, acetonitrile, ethyl acetate, methyl tert-butyl ether, toluene, mesitylene, and chlorobenzene.

4. The preparation method according to claim 3, characterized in that: The reaction solvent is dichloromethane.

5. The preparation method according to claim 2, characterized in that: The base is at least one of the inorganic bases potassium carbonate, sodium carbonate, potassium phosphate and the organic bases triethylamine, diisopropylethylamine.

6. The preparation method according to claim 2, characterized in that: The dosage of the base is 1.0 - 3.0 molar equivalents.

7. The preparation method according to claim 2, wherein: The method for separation and purification is column chromatography.

8. Use of the indoline ring-fused 2H 2H -1,4-oxathiine compound in the preparation of an anti-tumor drug, wherein the tumor is lung cancer, cervical cancer or liver cancer.

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