Lasiokaurine-sulfonamide derivatives, methods for their preparation and use

Abstract

The application discloses a kind of two-faced needle alkali-sulfonamide derivatives, the derivative has as general formula A or general formula B structure: The application provides a kind of two-faced needle alkali-sulfonamide derivatives, its structure is novel, and substrate applicability is wide, easy to operate, byproduct is less, it is convenient to separate and purify, can be applicable to larger scale preparation, has considerable application prospect.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology. More specifically, this invention relates to a sulphurine-like alkaloid-sulfonamide derivative, its preparation method, and its applications. Background Technology

[0002] Cancer is a genetic disease, referring to the abnormal proliferation of cells caused by gene alterations resulting from tumorigenic factors, which disrupt the normal regulation of cell growth. Currently used anticancer drugs have drawbacks to varying degrees, including low targeting, significant toxic side effects, and a tendency to induce drug resistance. Traditional Chinese medicine (TCM), on the other hand, offers advantages such as multi-faceted, multi-target, and multi-functional anticancer effects, and is less prone to inducing drug resistance. Furthermore, its multi-target nature plays a unique role in reversing tumor drug resistance.

[0003] Zanthoxylum nitidum is rich in various alkaloids, flavonoids, steroids, esters, and other active ingredients, possessing anti-inflammatory, antioxidant, anticancer, and cardiovascular protective effects. Nitidine Chloride (NC) is a phenanthreneidine alkaloid extracted and isolated from the plant Zanthoxylum nitidum, exhibiting broad-spectrum antitumor activity. However, most nitidine alkaloid analogs have been found to have poor water solubility and low oral bioavailability, limiting their pharmaceutical applications. Therefore, improving the water solubility, activity, and cytotoxicity of nitidine alkaloid analogs remain primary challenges that need to be addressed.

[0004] A growing body of research indicates that introducing sulfonamide groups to develop next-generation antitumor drugs holds promise. For instance, some sulfonamide derivatives exhibit significant cytotoxicity against human breast cancer cells, human malignant melanoma cells, human liver cancer cells, and human kidney cancer cells, with inhibitory effects superior to sorafenib. Furthermore, the cytotoxicity of some sulfonamide derivatives against human breast cancer cells and human cervical cancer cells is comparable to that of the control drug pentafluorouracil. Therefore, if water-soluble chemical structure modification strategies, such as reducing lipophilic groups and introducing polar groups, can be employed, combined with the principle of active splicing, to design and synthesize water-soluble, highly efficient, and low-toxicity *Zanthoxylum bungeanum*-sulfonamide derivatives, this would not only be of significant value in expanding the *Zanthoxylum bungeanum* analogue library but also lay the foundation for the discovery of novel antitumor compounds and promote the further development and utilization of *Zanthoxylum bungeanum*. Summary of the Invention

[0005] One object of the present invention is to solve at least the above-mentioned problems and to provide at least the advantages that will be described later.

[0006] To achieve these and other advantages according to the invention, a pyrenoid-sulfonamide derivative is provided having a structure of general formula A or general formula B:

[0007]

[0008] In the formula, when R1 is methyl and R2 is hydrogen, R3, R4, R5, and R6 are all hydrogen, or R3, R5, and R6 are hydrogen and R4 is methyl, or R3, R4, and R6 are methoxy and R5 is hydrogen, or R3, R6 are hydrogen, R4, and R5 are chlorine, or R3, R4, and R6 are hydrogen and R5 is fluorine.

[0009] When R1 is hydrogen and R2 is methyl, R3, R4, R5, and R6 are all hydrogen, or R3, R5, and R6 are hydrogen and R4 is methyl, or R3, R4, and R6 are methoxy and R5 is hydrogen, or R3, R6 are hydrogen, R4, and R5 are chlorine, or R3, R4, and R6 are hydrogen and R5 is fluorine.

[0010] When R1 and R2 are methoxy groups, R3, R4, R5, and R6 are all hydrogen, or R3, R5, and R6 are hydrogen and R4 is methyl, or R3, R4, and R6 are methoxy groups and R5 is hydrogen, or R3, R6 are hydrogen, R4, and R5 are chlorine, or R3, R4, and R6 are hydrogen and R5 is fluorine.

[0011] This invention also provides a method for preparing a type of neem alkaloid-sulfonamide derivative, which includes the following steps:

[0012] Step 1: Using acyl chloride compound 1 as shown in Formula 1 and methoxyamine hydrochloride as raw materials, compound 2 as shown in Formula 2 is synthesized in the presence of potassium carbonate and in the solvent of ethyl acetate.

[0013]

[0014] Step 2: Compound 2, iodobenzene, palladium acetate, and silver oxide are dissolved in acetic acid and reacted under nitrogen protection to synthesize compound 3 as shown in Formula 3.

[0015]

[0016] Step 3: Dissolve compound 3 in anhydrous methanol and react under ultraviolet light to obtain compound 4 as shown in Formula 4;

[0017]

[0018] Step 4: Using compound 4 and 1,4-dibromobutane or 1,6-dibromohexane as raw materials, in the presence of sodium hydride and in DMF solvent, compound 5 as shown in Formula 5 or compound 6 as shown in Formula 6 are synthesized.

[0019]

[0020] Step 5: Compound 5 or Compound 6 is combined with phthalimide, potassium iodide and potassium carbonate in acetonitrile solvent to synthesize compound 7 as shown in Formula 7 or compound 8 as shown in Formula 8.

[0021]

[0022] Step 6: Dissolve compound 7 or compound 8 in an aqueous solution of methylamine, stir magnetically, and react to obtain compound 9 as shown in formula 9 or compound 10 as shown in formula 10;

[0023]

[0024] Step 7: React compound 9 or compound 10 with compound 11 as shown in formula 11 under the action of triethylamine and dichloromethane to obtain compound 12 as shown in formula A, or compound 13 as shown in formula B.

[0025]

[0026] Where R1 is methyl and R2 is hydrogen, R3, R4, R5, and R6 are all hydrogen, or R3, R5, and R6 are hydrogen and R4 is methyl, or R3, R4, and R6 are methoxy and R5 is hydrogen, or R3, R6 are hydrogen, R4, and R5 are chlorine, or R3, R4, and R6 are hydrogen and R5 is fluorine.

[0027] When R1 is hydrogen and R2 is methyl, R3, R4, R5, and R6 are all hydrogen, or R3, R5, and R6 are hydrogen and R4 is methyl, or R3, R4, and R6 are methoxy and R5 is hydrogen, or R3, R6 are hydrogen, R4, and R5 are chlorine, or R3, R4, and R6 are hydrogen and R5 is fluorine.

[0028] When R1 and R2 are methoxy groups, R3, R4, R5, and R6 are all hydrogen, or R3, R5, and R6 are hydrogen and R4 is methyl, or R3, R4, and R6 are methoxy groups and R5 is hydrogen, or R3, R6 are hydrogen, R4, and R5 are chlorine, or R3, R4, and R6 are hydrogen and R5 is fluorine.

[0029] Preferably, in the preparation method of the alkaloid-sulfonamide derivative, in step one, the molar ratio of methoxyamine hydrochloride, potassium carbonate, and compound 1 is 1:2:1.

[0030] Preferably, in the preparation method of the alkali-sulfonamide derivative, in step two, the molar ratio of compound 2, iodobenzene, palladium acetate, and silver oxide is 1:2:0.05:2.

[0031] Preferably, in the preparation method of the alkaloid-sulfonamide derivative, in step three, a 175W ultraviolet high-pressure mercury lamp is selected as the ultraviolet lamp.

[0032] Preferably, in the preparation method of the succinate-sulfonamide derivative, in step four, the molar ratio of compound 4, sodium hydride, 1,4-dibromobutane or 1,6-dibromohexane is 1:3.14:5.

[0033] Preferably, in the preparation method of the alkali-sulfonamide derivative, in step five, the molar ratio of compound 5 or compound 6, phthalimide, potassium iodide, and potassium carbonate is 1:1:0.1:3.

[0034] Preferably, in the preparation method of the succinate-sulfonamide derivative, in step six, the molar ratio of compound 9 or compound 10, triethylamine, and compound 11 is 1:7.2:1.

[0035] This invention also provides the application of a type of schizophyllum commune-sulfonamide derivative in the preparation of a tumor-treating drug, the derivative having a structure of general formula A or general formula B:

[0036]

[0037] In the formula, when R1 is methyl and R2 is hydrogen, R3, R4, R5, and R6 are all hydrogen, or R3, R5, and R6 are hydrogen and R4 is methyl, or R3, R4, and R6 are methoxy and R5 is hydrogen, or R3, R6 are hydrogen, R4, and R5 are chlorine, or R3, R4, and R6 are hydrogen and R5 is fluorine.

[0038] When R1 is hydrogen and R2 is methyl, R3, R4, R5, and R6 are all hydrogen, or R3, R5, and R6 are hydrogen and R4 is methyl, or R3, R4, and R6 are methoxy and R5 is hydrogen, or R3, R6 are hydrogen, R4, and R5 are chlorine, or R3, R4, and R6 are hydrogen and R5 is fluorine.

[0039] When R1 and R2 are methoxy groups, R3, R4, R5, and R6 are all hydrogen, or R3, R5, and R6 are hydrogen and R4 is methyl, or R3, R4, and R6 are methoxy groups and R5 is hydrogen, or R3, R6 are hydrogen, R4, and R5 are chlorine, or R3, R4, and R6 are hydrogen and R5 is fluorine.

[0040] The present invention has at least the following beneficial effects:

[0041] 1. This invention provides a sulphurine-based derivative with a novel structure, broad substrate applicability, simple operation, few byproducts, easy separation and purification, and is suitable for large-scale preparation, showing promising application prospects.

[0042] 2. The succinate-sulfonamide derivatives provided by this invention have excellent antitumor activity. Compounds 12h and 12n have significant inhibitory activity against the proliferation of Hepg2, H460 and HeLa cells. At a concentration of 40 μmol / L, the inhibition rate against these cells is greater than 50%. The inhibition rates of compounds 12h, 12n and 13h against H460 cells are 82.39%, 86.62% and 88.98%, respectively, which are not only superior to the positive control 5-fluorouracil (45.08%), but also comparable to its parent nucleus structure, succinate chloride (86.68%).

[0043] Other advantages, objectives and features of the present invention will become apparent in part from the following description, and in part from those skilled in the art through study and practice of the invention. Attached Figure Description

[0044] Figure 1 The structural formula of the succinate-sulfonamide derivative described in one embodiment of the present invention is shown below.

[0045] Figure 2 This is a flowchart of a method for preparing a succinate-sulfonamide derivative according to another embodiment of the present invention. Detailed Implementation

[0046] The present invention will now be described in further detail with reference to the accompanying drawings and embodiments, so that those skilled in the art can implement it based on the description.

[0047] It should be understood that terms such as “having,” “comprising,” and “including” as used herein do not exclude the presence or addition of one or more other elements or combinations thereof.

[0048] It should be noted that, unless otherwise specified, the experimental methods described in the following implementation plan are all conventional methods, and the reagents and materials described are all commercially available unless otherwise specified.

[0049] In the description of this invention, the terms "lateral", "longitudinal", "up", "down", "front", "back", "left", "right", "vertical", "horizontal", "top", "bottom", "inner", and "outer" indicate the orientation or positional relationship based on the orientation or positional relationship shown in the accompanying drawings. They are used only for the convenience of describing this invention and simplifying the description, and do not indicate or imply that the device or element referred to must have a specific orientation, or be constructed and operated in a specific orientation. Therefore, they should not be construed as limitations on this invention.

[0050] <Example 1>

[0051] like Figure 1 As shown, the present invention provides a type of neem alkaloid-sulfonamide derivative, which has the following properties: Figure 1The structural formulas of general formula A and general formula B;

[0052] Figure 1 When R1 is methyl and R2 is hydrogen, R3, R4, R5, and R6 are all hydrogen, or R3, R5, and R6 are hydrogen and R4 is methyl, or R3, R4, and R6 are methoxy and R5 is hydrogen, or R3, R6 are hydrogen, R4, and R5 are chlorine, or R3, R4, and R6 are hydrogen and R5 is fluorine.

[0053] When R1 is hydrogen and R2 is methyl, R3, R4, R5, and R6 are all hydrogen, or R3, R5, and R6 are hydrogen and R4 is methyl, or R3, R4, and R6 are methoxy and R5 is hydrogen, or R3, R6 are hydrogen, R4, and R5 are chlorine, or R3, R4, and R6 are hydrogen and R5 is fluorine.

[0054] When R1 and R2 are methoxy groups, R3, R4, R5, and R6 are all hydrogen, or R3, R5, and R6 are hydrogen and R4 is methyl, or R3, R4, and R6 are methoxy groups and R5 is hydrogen, or R3, R6 are hydrogen, R4, and R5 are chlorine, or R3, R4, and R6 are hydrogen and R5 is fluorine.

[0055] <Example 2>

[0056] like Figure 2 As shown, this invention provides a method for preparing a type of schizophyllum commune-sulfonamide derivative, specifically including the following steps:

[0057] Step 1: Take a 150 mL round-bottom flask, weigh and add methoxyamine hydrochloride (CH3ONH2·HCl) (0.835 g, 10 mmol) and K2CO3 (2.76 g, 20 mmol), dissolve in 60 mL of ethyl acetate, place in a 0 °C cold well and stir, slowly add 15 mL of water, then add 15 mL of ethyl acetate solution containing compound 1 (e.g., compounds 1a-1c: m-methylbenzoyl chloride, p-methylbenzoyl chloride, 3,4-dimethoxybenzoyl chloride) (10 mmol), stir for 5 min, then transfer to room temperature and stir for 5 h, monitor the reaction by TLC (petroleum ether: ethyl acetate = 1:1), after the reaction is complete, collect the ethyl acetate layer, extract the aqueous layer with ethyl acetate (3 × 20 mL), combine the organic layers and dry with anhydrous Na2SO4, distill under reduced pressure to obtain compound 2 (e.g., compounds 2a-2c);

[0058]

[0059] Step 2: Under N2 protection, add compound 2 (2a-2c) (8 mmol), iodobenzene (1.79 mL, 16 mmol), palladium acetate (0.334 g, 0.4 mmol), and silver oxide (3.708 g, 16 mmol) to a 100 mL round-bottom flask. Dissolve the compound in 60 mL of acetic acid and reflux at 120 °C for 26 h. Monitor the reaction by TLC (petroleum ether: ethyl acetate = 2:1). After the reaction is complete, add 100 mL of ethyl acetate solution. Filter to remove the brown insoluble matter. Wash the resulting brown-black filtrate with an appropriate amount of saturated NaHCO3 until the pH is about 7, then wash with water. Extract by separation. Dry the organic phase with anhydrous Na2SO4 and concentrate. Separate and purify the residue by column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain compound 3 (3a-3c).

[0060]

[0061] Step 3: Take a 50 mL vial, add compound 3 (3a-3c) (1.4 mmol), dissolve it in 45 mL of anhydrous methanol, and irradiate it under a 175 W ultraviolet high-pressure mercury lamp for 8 h. Monitor the reaction by TLC (petroleum ether: ethyl acetate = 1:1). After the reaction is complete, directly distill under reduced pressure to obtain compound 4 (4a-4c).

[0062]

[0063] Step 4: Take a 50 mL round-bottom flask, add compound 4 (4a-4c) (0.86 mmol) and sodium hydride (60%, 0.105 g, 2.7 mmol), dissolve in 20 mL LDM, stir at room temperature for 1 h, then add 1,4-dibromobutane (0.516 mL, 4.3 mmol) or 1,6-dibromohexane (0.696 mL, 4.3 mmol), stir at room temperature for 6 h, monitor the reaction by TLC (petroleum ether: ethyl acetate = 2:1), after the reaction is complete, quench with ice water, extract with ethyl acetate (3 × 10 mL), combine the organic phases and wash with saturated sodium chloride solution, dry with anhydrous Na2SO4 and concentrate, the residue is separated and purified by column chromatography (eluent: petroleum ether: ethyl acetate = 5:1) to compound 5 (5a-5c) or 6 (6a-6c);

[0064]

[0065] Step 5: Under electromagnetic stirring, compound 5 (5a-5c) or 6 (6a-6c) (2 mmol) was dissolved in 20 mL of acetonitrile, and phthalimide (0.294 g, 2 mmol), potassium iodide (0.0332 g, 0.2 mmol), and potassium carbonate (0.829 g, 6 mmol) were added. The mixture was refluxed and stirred at 80 °C for 6 h, and the reaction was monitored by TLC (petroleum ether: ethyl acetate = 2:1). After the reaction was completed, 30 mL of saturated NaHCO3 solution was added, and then extracted with ethyl acetate (3 × 10 mL). The combined organic phases were acidified with 2N HCl and washed with water. The pH was adjusted to 12 with 4N NaOH solution, and then extracted with dichloromethane. The mixture was dried over anhydrous sodium sulfate and concentrated to obtain compound 7 (7a-7c) or 8 (8a-8c).

[0066]

[0067] Step 6: Under electromagnetic stirring, compound 7 (7a-7c) or 8 (8a-8c) (3 mmol) was dissolved in 30 mL of 40% methylamine aqueous solution and stirred at room temperature for 36 h. The reaction was monitored by TLC (dichloromethane:methanol = 90:1). After the reaction was completed, 20 mL of 20% (w / v) NaOH solution was added and stirred at room temperature for 1.5 h. Then 4 g of sodium chloride was added, and the solution was extracted with dichloromethane (3 × 10 mL). The organic phases were combined and washed with water, dried over anhydrous sodium sulfate, and concentrated to obtain compound 9 (9a-9c) or 10 (10a-10c).

[0068]

[0069] Step 7: Dissolve compound 9 (9a-9c) or 10 (10a-10c) (0.5 mmol) and triethylamine (0.5 mL, 3.6 mmol) in 15 mL of dichloromethane. Add benzenesulfonyl chloride compound 11 (11a-11e) (benzenesulfonyl chloride or p-toluenesulfonyl chloride or 2,4,6-trimethoxybenzenesulfonyl chloride or 3,4-dichlorobenzenesulfonyl chloride or 3-fluorobenzenesulfonyl chloride) (0.5 mmol) at 0 °C. Stir at room temperature for 3 h and monitor with TLC. The reaction (dichloromethane:methanol = 90:1) was carried out. After the reaction was completed, the solvent and triethylamine were removed by vacuum distillation. The resulting precipitate was then dissolved in 10 mL of dichloromethane and washed with 10 mL of 5% (mass concentration) NaHCO3 solution and water. The organic aqueous layer was dried over anhydrous sodium sulfate and the filtrate was concentrated. Recrystallization from dichloromethane / methanol yielded compound 12 (12a-12o) of general formula A or compound (13a-13o) of general formula B.

[0070] The specific structural formulas and characterizations of compounds 12a-12o and 13a-13o are shown below:

[0071]

[0072] 12a: White needle-like crystals, yield 68%, mp 150.1-151.6℃; HRMS(ESI) m / z: calcd for C 24 H 24 N₂O₃S[M+H] + :421.1587,found:421.1586. 1 H NMR (500MHz, CDCl3) δ8.31(s,1H),8.26(d,J=7.8Hz,1H),8.17(d,J=8.3Hz,1H),7.88(d ,J=7.3Hz,2H),7.58(d,J=7.3Hz,1H),7.54–7.50(m,2H),7.47(t,J=7.4Hz,2H),7.36(d, J=8.4Hz,1H),7.31(t,J=7.5Hz,1H),5.13(t,J=6.0Hz,1H,-NH),4.37(t,J=7.2Hz,2H,- NCH2),3.09(q,J=6.6Hz,2H,-SCH2),2.52(s,3H),1.86–1.80(m,2H),1.69–1.64(m,2H). 13 C NMR (126MHz, CDCl3) δ161.78,140.12,138.33,136.55,134.08,132.66,131.26,129.35,129.20,12 8.67,127.15,125.23,123.42,122.64,121.77,119.81,115.08,42.95,41.84,26.67,24.77,21.52.

[0073]

[0074] 12b: White needle-like crystals, yield 63%, mp 161.5-163.8℃; HRMS(ESI) m / z: calcd for C 25 H 26 N₂O₃S[M+H] + :435.1747,found:435.1742. 1HNMR(500MHz, CDCl3)δ8.33(d,J=10.6Hz,1H),8.30–8.25(m,1H),8.18(dd,J=11.1,8.4Hz,1H),7. 77(dd,J=11.2,8.3Hz,2H),7.59(t,J=9.2Hz,1H),7.53(dd,J=18.1,7.9Hz,1H),7.41–7.35(m,1H) ,7.35–7.27(m,3H),5.09–4.94(m,1H,-NH),4.38(d,J=6.9Hz,2H,-NCH2),3.07(dq,J=13.0,6.6Hz ,2H,-SCH2),2.53(d,J=11.3Hz,3H),2.40(d,J=11.3Hz,3H),1.89–1.80(m,2H),1.68–1.64(m,2H). 13 CNMR (126MHz, CDCl3) δ161.76,143.42,138.31,137.10,136.58,134.06,131.26,129.81,129.35,128.6 7,127.23,125.26,123.42,122.62,121.77,119.80,115.09,42.92,41.89,26.73,24.76,21.63,21.52.

[0075]

[0076] 12c: White needle-like crystals, yield 60%, mp 160.1-161.1℃; HRMS(ESI) m / z: calcd for C 27 H 30 N₂O₃S[M+Na] + :485.1881,found:485.1875. 1H NMR(500MHz, CDCl3)δ8.31(s,1H),8.27(d,J=7.4Hz,1H),8.17(d,J=8.3Hz,1H),7.60–7 .56(m,1H),7.52(dd,J=11.5,4.2Hz,1H),7.35(d,J=8.4Hz,1H),7.31(t,J=7.5Hz,1H),6 .91(s,2H),4.96(t,J=6.2Hz,1H,-NH),4.37(t,J=7.2Hz,2H,-NCH2),3.01(q,J=6.7Hz,2 H,-SCH2),2.63(s,6H),2.52(s,3H),2.25(s,3H),1.84–1.78(m,2H),1.67–1.62(m,2H). 13 C NMR (126MHz, CDCl3) δ161.74,142.19,139.12,138.31,136.59,134.05,132.08,131.25,129.33,128.6 7,125.28,123.43,122.60,121.77,119.81,115.07,42.35,41.90,26.82,24.88,23.14,21.53,21.03.

[0077]

[0078] 12d: White needle-like crystals, yield 66%, mp 167.8-168.8℃; HRMS(ESI) m / z: calcd for C 24 H 22 Cl2N2O3S[M+H] + :489.0810,found:489.0806. 1H NMR (500MHz, CDCl3) δ8.32(s,1H),8.27(d,J=8.0Hz,1H),8.17(d,J=8.3Hz,1H),8.02(d,J=1.7Hz, 1H),7.73(dd,J=8.4,1.8Hz,1H),7.59(d,J=8.3Hz,1H),7.55(d,J=8.4Hz,1H),7.52(t,J=7.8Hz,1H ),7.37(d,J=8.4Hz,1H),7.32(t,J=7.6Hz,1H),5.77(t,J=5.9Hz,1H,-NH),4.38(t,J=6.9Hz,2H,- NCH2),3.12(q,J=6.3Hz,2H,-SCH2),2.52(s,3H),1.91–1.84(m,2H),1.68(dt,J=13.9,6.9Hz,2H). 13 C NMR (126MHz, CDCl3) δ161.96,140.27,138.42,137.35,136.49,134.19,133.79,131.30,131.23,129.36,12 9.26,128.68,126.32,125.15,123.50,122.77,121.81,119.90,115.04,43.04,41.79,26.34,24.91,21.51.

[0079]

[0080] 12e: White needle-like crystals, yield 64%, mp 147.6-148.5℃; HRMS(ESI) m / z: calcd for C 24 H 23 FN2O3S[M+H] + :439.1498,found:439.1492. 1H NMR (500MHz, CDCl3) δ8.31(s,1H),8.26(d,J=7.9Hz,1H),8.16(d,J=8.3Hz,1H),7.68(d,J=7.8Hz,1 H),7.60(dd,J=16.7,7.8Hz,2H),7.52(t,J=7.6Hz,1H),7.46(td,J=8.0,5.4Hz,1H),7.36(d,J=8.4 Hz,1H),7.31(t,J=7.5Hz,1H),7.22(td,J=8.3,2.1Hz,1H),5.49(t,J=5.9Hz,1H,-NH),4.38(t,J=7 .2Hz,2H,-NCH2),3.12(q,J=6.5Hz,2H,-SCH2),2.52(s,3H),1.89–1.82(m,2H),1.71–1.65(m,2H). 13 C NMR (126MHz, CDCl3) δ163.56,161.87,161.56,142.35,138.38,136.48,134.14,131.26,131.02,130.95,129.35,128.67,125.16 ,123.45,122.93,122.91,122.71,121.78,119.91,119.84,119.74,115.05,114.69,114.50,43.01,41.79,26.47,24.83,21.51.

[0081]

[0082] 12f: White solid, yield 69%, mp 179.3-182.2℃; HRMS(ESI) m / z: calcd for C 24 H 24 N₂O₃S[M+H] + :421.1590,found:421.1586. 1H NMR (500MHz, CDCl3) δ8.40(d,J=8.1Hz,1H),8.29(d,J=8.0Hz,1H),8.06(s,1H),7.88(d,J=7.8H z,2H),7.52(dd,J=14.3,6.9Hz,2H),7.47(t,J=7.4Hz,2H),7.40(d,J=8.1Hz,1H),7.36(d,J=8.3 Hz,1H),7.31(t,J=7.6Hz,1H),5.17(d,J=5.5Hz,1H,-NH),4.35(t,J=7.1Hz,2H,-NCH2),3.08(dd ,J=13.0,6.5Hz,2H,-SCH2),2.57(s,3H),1.86–1.79(m,2H),1.66(s,1H),1.40(t,J=7.3Hz,1H). 13 CNMR (126MHz, CDCl3) δ161.74,143.22,140.19,137.08,133.70,132.63,129.71,129.58,129.19,128.9 4,127.15,123.61,123.16,122.54,121.77,119.64,115.13,46.06,42.97,41.81,26.73,24.80,22.32.

[0083]

[0084] 12g: White solid, yield 63%, mp 133.3-136.5℃; HRMS(ESI) m / z: calcd for C 25 H 26 N₂O₃S[M+H] + :435.1740,found:435.1742. 1H NMR (500MHz, CDCl3) δ8.39(d,J=8.1Hz,1H),8.29(d,J=7.4Hz,1H),8.06(s,1H),7.75(d,J=8. 2Hz,2H),7.56–7.51(m,1H),7.38(dd,J=17.1,8.2Hz,2H),7.31(t,J=7.5Hz,1H),7.27(s,1H), 5.05(t,J=6.2Hz,1H,-NH),4.35(t,J=7.3Hz,2H,-NCH2),3.05(q,J=6.6Hz,2H,-SCH2),2.57(s ,3H),2.38(s,3H),1.83(dt,J=15.1,7.4Hz,2H),1.68(d,J=7.0Hz,1H),1.63(d,J=6.9Hz,1H). 13 C NMR (126MHz, CDCl3) δ161.60,143.29,143.08,137.01,136.98,133.58,129.69,129.59,129.46,128.8 2,127.11,123.49,123.06,122.41,121.66,119.52,115.01,42.81,41.73,26.65,24.67,22.20,21.50.

[0085]

[0086] 12h: White solid, yield 64%, mp 200.1-203.3℃; HRMS(ESI) m / z: calcd for C 27 H 30 N₂O₃S[M+H] + :463.2056,found:463.2055. 1H NMR (500MHz, CDCl3) δ8.39(d,J=8.1Hz,1H),8.30(d,J=7.3Hz,1H),8.06(s,1H),7.53(t,J=7.2H z,1H),7.45–7.37(m,2H),7.35(d,J=8.4Hz,1H),7.31(t,J=7.7Hz,1H),6.91(s,1H),5.01(t,J= 6.3Hz,1H,-NH),4.36(t,J=7.2Hz,2H,-NCH2),3.01(q,J=6.7Hz,2H,-SCH2),2.63(s,6H),2.57( s,3H),2.25(s,3H),1.81(dt,J=15.1,7.5Hz,2H),1.65(d,J=7.2Hz,1H),1.61(d,J=7.1Hz,1H). 13 C NMR (126MHz, CDCl3) δ161.58,143.08,142.04,139.01,137.00,133.58,131.95,129.56,129.46,128.8 3,123.50,123.08,122.39,121.65,119.53,114.98,42.24,41.73,26.72,24.78,23.00,22.20,20.90.

[0087]

[0088] 12i: White solid, yield 68%, mp 150.4-153.2℃; HRMS(ESI) m / z: calcd for C 24 H 22 Cl2N2O3S[M+H] + :489.0810,found:489.0806. 1H NMR(500MHz, CDCl3)δ8.39(d,J=8.1Hz,1H),8.31–8.27(m,1H),8.06(s,1H),8.01(d,J=2.1Hz,1H ),7.72(dd,J=8.4,2.1Hz,1H),7.56–7.54(m,1H),7.53(dd,J=8.5,1.3Hz,1H),7.40(d,J=7.5Hz,1 H),7.37(d,J=8.4Hz,1H),7.32(t,J=7.6Hz,1H),5.82(t,J=6.0Hz,1H,-NH),4.37(t,J=7.2Hz,2H ,-NCH2),3.11(dd,J=12.8,6.5Hz,2H,-SCH2),2.57(s,3H),1.90–1.84(m,2H),1.73–1.67(m,2H). 13 C NMR (126MHz, CDCl3) δ161.90,143.36,140.22,137.33,136.97,133.76,133.71,131.23,129.72,129.65,12 9.24,128.94,126.31,123.67,123.02,122.67,121.81,119.70,115.09,43.02,41.74,26.37,24.89,22.34.

[0089]

[0090] 12j: Off-white solid, yield 70%, mp 173.2-175.6℃; HRMS(ESI) m / z: calcd for C 24 H 23 FN2O3S[M+H] + :439.1510,found:439.1508.. 1H NMR (500MHz, CDCl3) δ8.40(d,J=9.1Hz,1H),8.29(d,J=8.1Hz,1H),8.06(s,1H),7.68(d,J=7.8Hz,1H) ,7.61(dd,J=8.2,1.5Hz,1H),7.53(t,J=7.8Hz,1H),7.46(dd,J=13.8,6.2Hz,1H),7.40(d,J=8.1Hz,1H ),7.36(d,J=8.5Hz,1H),7.31(t,J=7.6Hz,1H),7.22(t,J=8.3Hz,1H),5.47(t,J=5.5Hz,1H,-NH),4.36 (t,J=7.0Hz,2H,-NCH2),3.13–3.09(m,2H,-SCH2),2.57(s,3H),1.88–1.82(m,2H),1.68–1.64(m,2H). 13 C NMR (126MHz, CDCl3) δ163.57,161.84,143.31,142.36,137.04,133.71,131.02,130.96,129.72,129.63,128.96,123.66,12 3.11,122.94,122.91,122.62,121.79,119.90,119.73,119.69,115.10,114.70,114.51,43.02,41.75,26.54,24.85,22.34.

[0091]

[0092] 12K: White solid, 70% yield, mp 186.6-188.4℃; HRMS(ESI) m / z: calcd for C 25 H 26 N₂O₅S[M+H] + :467.1643,found:467.1641. 11H NMR (500 MHz, CDCl3) δ 8.16 (d, J = 7.7 Hz, 1H), 7.89 (d, J = 3.6 Hz, 2H), 7.87 (s, 1H), 7.59 (s, 1H), 7.55–7.50 (m, 2H), 7.47 (t, J = 7.4 Hz, 2H), 7.37 (d, J = 8.4 Hz, 1H), 7.31 (t, J = 7.5 Hz, 1H), 5.15 (t, J = 6.1 Hz, 1H, -NH), 4.37 (t, J = 7.2 Hz, 2H, -NCH2), 4.09 (s, 3H, -OCH3), 4.03 (s, 3H, -OCH3), 3.09 (q, J = 6.6 Hz, 2H, -SCH2), 1.87–1.80 (m, 2H), 1.66 (dd, J = 14.3, 7.0 Hz, 2H). 13 13C NMR (126 MHz, CDCl3) δ 161.20, 153.55, 150.02, 140.22, 136.46, 132.63, 129.19, 128.97, 128.52, 127.15, 123.08, 122.47, 119.52, 119.45, 115.18, 109.05, 102.64, 56.34, 56.28, 43.02, 41.92, 26.76, 24.93.

[0093]

[0094] 12l: White solid, yield 73%, m.p. 189.3 - 192.4 °C; HRMS (ESI) m / z: calcd for C 26 H 28 N2O5S [M + H] + : 481.1802, found: 481.1797. 1 1H NMR (500 MHz, CDCl3) δ 8.16 (d, J = 7.6 Hz, 1H), 7.89 (s, 1H), 7.75 (d, J = 8.2 Hz, 2H), 7.59 (s, 1H), 7.51 (dd, J = 11.4, 4.1 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.31 (t, J = 7.6 Hz, 1H), 7.27 (s, 1H), 5.04 (t, J = 6.1 Hz, 1H, -NH), 4.37 (t, J = 7.3 Hz, 2H, -NCH2), 4.09 (s, 3H, -OCH3), 4.03 (s, 3H, -OCH3), 3.06 (q, J = 6.6 Hz, 2H, -SCH2), 2.39 (s, 3H), 1.86–1.80 (m, 2H), 1.70–1.65 (m, 2H).13 C NMR (126MHz, CDCl3) δ161.19,153.53,150.00,143.42,137.15,136.47,129.81,128.97,128.52,127.23,1 23.08,122.47,119.51,119.46,115.19,109.04,102.63,56.34,56.28,42.97,41.96,26.79,24.91,21.62.

[0095]

[0096] 12m: White solid, yield 69%, mp 169.2-171.3℃; HRMS(ESI) m / z: calcd for C 28 H 32 N₂O₅S[M+H] + :509.2115,found:509.2110. 1 H NMR(500MHz, CDCl3)δ8.17(d,J=7.4Hz,1H),7.89(s,1H),7.60(s,1H),7.53–7.49(m, 1H),7.36(d,J=8.4Hz,1H),7.32(t,J=7.6Hz,1H),6.91(s,2H),5.00(t,J=6.2Hz,1H, -NH),4.38(t,J=7.2Hz,2H,-NCH2),4.09(s,3H,-OCH3),4.03(s,3H,-OCH3),3.01(q, J=6.6Hz,2H,-SCH2),2.63(s,6H),2.26(s,3H),1.85–1.78(m,2H),1.68–1.63(m,2H). 13 C NMR (126MHz, CDCl3) δ161.19,153.54,150.00,142.18,139.13,136.49,133.85,132.07,128.95,128.52,123. 10,122.45,119.52,119.48,115.17,109.05,102.64,56.31,56.29,42.38,41.95,26.87,25.02,23.13,21.02.

[0097]

[0098] 12n: White solid, yield 72%, mp 172.8-174.6℃; HRMS(ESI) m / z: calcd for C 25 H 24 Cl2N2O5S[M+H] + :535.0864,found:535.0861. 1 H NMR (500MHz, CDCl3) δ8.08 (d, J=7.9Hz, 1H), 7.91 (s, 1H), 7.79 (s, 1H), 7.62 (d, J= 8.4Hz,1H),7.49(s,1H),7.44(dd,J=20.5,8.3Hz,2H),7.29(d,J=8.4Hz,1H),7.23 (t,J=7.5Hz,1H),5.70(s,1H,-NH),4.29(s,2H,-NCH2),4.01(s,3H,-OCH3),3.94( s,3H,-OCH3),3.03(d,J=6.0Hz,2H,-SCH2),1.83–1.73(m,2H),1.63–1.57(m,2H). 13 C NMR (126MHz, CDCl3) δ161.35,153.62,150.05,140.22,137.35,136.35,133.78,131.21,129.22,128.98,128.5 6,126.30,123.15,122.61,119.57,119.31,115.13,108.98,102.63,56.36,56.29,43.08,41.85,26.37,25.02.

[0099]

[0100] 12°C: White solid, yield 75%, mp 178.6-181.8°C; HRMS(ESI) m / z: calcd for C 25 H 25 FN2O5S[M+H] + :485.1544,found:485.1546. 1H NMR (500MHz, CDCl3) δ8.16(d,J=7.9Hz,1H),7.88(s,1H),7.68(d,J=7.8Hz,1H),7.61(dd,J=8.2,2.1Hz ,1H),7.58(s,1H),7.51(t,J=7.8Hz,1H),7.46(td,J=8.1,5.3Hz,1H),7.37(d,J=8.5Hz,1H),7.32(t,J= 7.6Hz,1H),7.23(td,J=8.3,2.1Hz,1H),5.53(t,J=6.0Hz,1H,-NH),4.38(t,J=7.1Hz,2H,-NCH2),4.09 (s,3H,-OCH3),4.03(s,3H,-OCH3),3.11(q,J=6.5Hz,2H,-SCH2),1.89–1.83(m,2H),1.69–1.65(m,2H). 13 C NMR (126MHz, CDCl3) δ163.57,161.57,161.29,153.58,150.02,142.41,142.36,136.38,130.99,130.93,128.97,128.53,123.11,122.9 3,122.90,122.55,119.89,119.72,119.54,119.36,115.15,114.68,114.49,109.00,102.61,56.34,56.28,43.09,41.88,26.52,25.00.

[0101]

[0102] 13a: White solid, yield 71%, mp 163.3-164.5℃; HRMS(ESI) m / z: calcd for C 26 H 28 N₂O₃S[M+H] + :449.1900,found:449.1899. 1H NMR (500MHz, CDCl3) δ8.36(s,1H),8.28(d,J=7.4Hz,1H),8.18(d,J=8.3Hz,1H),7.91–7.84( m,2H),7.58(dd,J=8.2,1.4Hz,1H),7.56–7.51(m,2H),7.51–7.47(m,2H),7.37(d,J=8.4Hz, 1H),7.31(t,J=7.5Hz,1H),4.86(t,J=5.9Hz,1H,-NH),4.37(t,J=7.1Hz,2H,-NCH2),2.97(q ,J=6.6Hz,2H,-SCH2),2.52(s,3H),1.80–1.73(m,2H),1.52–1.46(m,2H),1.44–1.38(m,4H). 13 C NMR (126MHz, CDCl3) δ161.75,140.33,138.35,136.70,134.00,132.62,131.23,129.22,129.19,128.77,1 27.14,125.37,123.40,122.49,121.74,119.84,115.18,42.97,42.22,29.41,27.32,26.14,25.94,21.53.

[0103]

[0104] 13b: White solid, yield 66%, mp 105.3-107.2℃; HRMS(ESI) m / z: calcd for C 27 H 30 N₂O₃S[M+H] + :463.2060,found:463.2055. 1H NMR (500MHz, CDCl3) δ8.36(s,1H),8.28(d,J=7.9Hz,1H),8.18(d,J=8.3Hz,1H),7.75(d,J=8. 1Hz,2H),7.58(d,J=7.9Hz,1H),7.52(t,J=7.6Hz,1H),7.37(d,J=8.4Hz,1H),7.29(t,J=7.5H z,3H),4.77(t,J=5.9Hz,1H,-NH),4.38(d,J=6.8Hz,2H,-NCH2),2.94(dd,J=13.1,6.6Hz,2H, -SCH2),2.52(s,3H),2.40(s,3H),1.76(s,2H),1.48(d,J=5.5Hz,2H),1.41(d,J=7.0Hz,4H). 13 C NMR (126MHz, CDCl3) δ161.71,143.35,138.32,137.29,136.72,133.98,131.23,129.79,129.22,128.75,127.21, 125.38,123.39,122.48,121.74,119.83,115.17,45.98,42.99,42.29,29.44,27.33,26.22,26.04,21.63,21.52.

[0105]

[0106] 13c: White solid, yield 72%, mp 122.3-124.5℃; HRMS(ESI) m / z: calcd for C 29 H 34 N₂O₃S[M+H] + :491.2362,found:491.2368. 1H NMR (500MHz, CDCl3) δ8.35(d,J=8.4Hz,1H),8.28(t,J=8.5Hz,1H),8.18(t,J=8.7Hz,1H),7.59(t,J=8.2Hz,1 H),7.52(dd,J=16.0,7.7Hz,1H),7.37(t,J=8.7Hz,1H),7.31(dd,J=16.6,8.5Hz,1H),6.95(d,J=9.0Hz,2H),4 .69(d,J=7.8Hz,1H,-NH),4.37(d,J=6.7Hz,2H,-NCH2),3.00–2.83(m,2H,-SCH2),2.65(d,J=9.1Hz,6H),2.5 3(d,J=9.1Hz,3H),2.28(d,J=9.1Hz,3H),1.76(d,J=6.8Hz,2H),1.48(d,J=6.0Hz,2H),1.40(d,J=5.0Hz,4H). 13 C NMR (126MHz, CDCl3) δ161.54,142.08,139.06,138.19,136.63,133.85,133.75,131.96,131.11,129.09,128.62,125 .29,123.28,122.34,121.63,119.71,115.02,45.92,42.31,42.22,29.38,27.22,26.20,26.11,23.03,21.41,20.93.

[0107]

[0108] 13d: White solid, 70% yield, mp 156.5-157.3℃; HRMS(ESI) m / z: calcd for C 26 H 26 Cl2N2O3S[M+H] + :517.1122,found:517.1119. 1H NMR (500MHz, CDCl3) δ8.38(s,1H),8.29(d,J=7.8Hz,1H),8.19(d,J=8.3Hz,1H),7.99(d,J=2.0Hz,1H ),7.72(dd,J=8.4,2.0Hz,1H),7.58(dd,J=11.7,8.4Hz,2H),7.52(t,J=7.4Hz,1H),7.39(d,J=8.4Hz ,1H),7.32(t,J=7.5Hz,1H),5.36(t,J=5.9Hz,1H,-NH),4.41(t,J=6.6Hz,2H,-NCH2),3.00(q,J=6.2 Hz,2H,-SCH2),2.53(s,3H),1.81(p,J=7.0Hz,2H),1.53–1.46(m,4H),1.40(dd,J=13.7,6.7Hz,2H). 13 C NMR (126MHz, CDCl3) δ161.96,140.56,138.47,137.26,136.61,134.12,133.74,131.27,131.21,129.24,129.16,1 28.80,126.27,125.26,123.43,122.60,121.77,119.91,115.23,42.81,41.96,29.20,27.26,25.73,25.52,21.54.

[0109]

[0110] 13e: White solid, yield 74%, mp 158.6-160.3℃; HRMS(ESI) m / z: calcd for C 26 H 27 FN2O3S[M+H] + :467.1811,found:467.1805. 1H NMR (500MHz, CDCl3) δ8.38(d,J=6.8Hz,1H),8.29(t,J=7.6Hz,1H),8.19(t,J=7.8Hz,1H),7.69(t,J= 7.3Hz,1H),7.63–7.58(m,2H),7.54–7.46(m,2H),7.38(t,J=7.9Hz,1H),7.32(dd,J=15.2,7.8Hz,1H ),7.27(s,1H),5.15(d,J=6.0Hz,1H,-NH),4.40(d,J=6.4Hz,2H,-NCH2),3.00(dd,J=13.2,6.6Hz,2H ,-SCH2),2.53(d,J=7.4Hz,3H),1.79(dd,J=14.1,7.1Hz,2H),1.54–1.49(m,2H),1.48–1.39(m,4H). 13 C NMR (126MHz, CDCl3) δ163.56,161.86,161.57,142.60,139.07,138.41,136.65,134.05,131.25,131.00,130.94,129.23,128.79,125.3 2,123.41,122.90,122.55,121.75,119.88,119.69,119.08,115.20,114.64,114.45,42.90,42.07,29.31,27.28,25.92,25.70,21.52.

[0111]

[0112] 13f: White solid, yield 72%, mp 156.5-157.3℃; HRMS(ESI) m / z: calcd for C 26 H 28 N₂O₃S[M+H] + :449.1898,found:449.1899. 1H NMR(500MHz, CDCl3)δ8.43(d,J=8.1Hz,1H),8.30(d,J=8.0Hz,1H),8.07(s,1H),7.91–7.86(m ,2H),7.54(d,J=7.3Hz,2H),7.50(d,J=7.6Hz,2H),7.40(d,J=8.2Hz,1H),7.36(d,J=8.5Hz,1H ),7.31(t,J=7.6Hz,1H),4.87(d,J=5.6Hz,1H,-NH),4.37(d,J=6.5Hz,2H,-NCH2),2.97(dd,J =12.6,6.1Hz,2H,-SCH2),2.57(s,3H),1.79–1.73(m,2H),1.48(d,J=6.3Hz,2H),1.40(s,4H). 13 C NMR (126MHz, CDCl3) δ161.72,143.12,140.43,137.25,133.69,132.61,129.61,129.58,129.19,129.05,1 27.16,123.60,123.31,122.41,121.75,119.70,115.21,42.97,42.15,29.44,27.34,26.14,25.93,22.32.

[0113]

[0114] 13g: white solid, yield 70%, mp 150.1-152.2℃; HRMS(ESI) m / z: calcd for C 27 H 30 N₂O₃S[M+H] + :463.2053,found:463.2055. 1H NMR (500MHz, CDCl3) δ8.43(d,J=8.1Hz,1H),8.30(d,J=8.1Hz,1H),8.07(s,1H),7.75(d,J =7.9Hz,2H),7.53(t,J=7.8Hz,1H),7.40(d,J=8.2Hz,1H),7.36(d,J=8.5Hz,1H),7.29(t,J =7.2Hz,3H),4.74(t,J=6.0Hz,1H,-NH),4.36(t,J=7.0Hz,2H,-NCH2),2.95(q,J=6.5Hz,2H ,-SCH2),2.57(s,3H),2.40(s,3H),1.79–1.73(m,2H),1.48(d,J=5.9Hz,2H),1.40(s,4H). 13 C NMR (126MHz, CDCl3) δ161.69,143.37,143.10,137.27,133.69,129.80,129.59,129.04,127.23,123. 60,123.33,122.39,121.75,119.69,115.20,42.99,42.21,29.47,27.36,26.23,26.03,22.31,21.63.

[0115]

[0116] 13h: White solid, yield 77%, mp 163.2-164.6℃; HRMS(ESI) m / z: calcd for C 29 H 34 N₂O₃S[M+H] + :491.2368,found:491.2368. 1H NMR (500MHz, CDCl3) δ8.42(d,J=8.1Hz,1H),8.30(d,J=8.0Hz,1H),8.07(s,1H),7.53(t,J= 7.7Hz,1H),7.40(d,J=8.1Hz,1H),7.36(d,J=8.5Hz,1H),7.31(t,J=7.5Hz,1H),6.94(s,2H) ,4.66(s,1H,-NH),4.40–4.29(m,2H,-NCH2),2.90(dd,J=12.8,6.3Hz,2H,-SCH2),2.64(s, 6H),2.57(s,3H),2.27(s,3H),1.79–1.71(m,2H),1.49–1.45(m,2H),1.39(d,J=3.2Hz,4H). 13 C NMR (126MHz, CDCl3) δ161.62,143.07,142.18,139.19,137.30,133.68,132.07,129.58,129.02,123. 60,122.36,121.75,119.68,115.17,42.45,42.27,29.52,27.35,26.34,26.23,23.12,22.31,21.03.

[0117]

[0118] 13i: White solid, yield 66%, mp 128.6-129.3℃; HRMS(ESI) m / z: calcd for C 26 H 26 Cl2N2O3S[M+H] + :517.1124,found:517.1119. 1H NMR (500MHz, CDCl3) δ8.44(d,J=8.1Hz,1H),8.31(d,J=7.3Hz,1H),8.08(s,1H),8.00(d,J=2.0Hz,1H), 7.72(dd,J=8.4,2.1Hz,1H),7.57(d,J=8.4Hz,1H),7.55–7.52(m,1H),7.41(d,J=8.1Hz,1H),7.39(d,J= 8.4Hz,1H),7.32(t,J=7.5Hz,1H),5.44(t,J=6.0Hz,1H,-NH),4.40(t,J=6.5Hz,2H,-NCH2),3.00(q,J= 6.2Hz,2H,-SCH2),2.57(s,3H),1.80(p,J=7.0Hz,2H),1.54–1.46(m,4H),1.39(dd,J=14.1,7.0Hz,2H). 13 C NMR (126MHz, CDCl3) δ161.94,143.27,140.66,137.24,137.14,133.73,131.21,129.71,129.60,129.17,129.0 5,126.29,123.63,123.18,122.52,121.78,119.76,115.28,42.77,41.85,29.25,27.27,25.68,25.47,22.33.

[0119]

[0120] 13j: White solid, yield 71%, mp 120.3-121.9℃; HRMS(ESI) m / z: calcd for C 26 H 27 FN2O3S[M+H] + :467.1802,found:467.1805. 1H NMR (500MHz, CDCl3) δ8.44(d,J=8.1Hz,1H),8.30(d,J=8.0Hz,1H),8.07(s,1H),7.68(d,J=7.8Hz,1H),7.61(d,J =8.2Hz,1H),7.53(t,J=7.8Hz,1H),7.48(td,J=8.0,5.5Hz,1H),7.41(d,J=8.2Hz,1H),7.37(d,J=8.5Hz,1H),7.3 1(t,J=7.6Hz,1H),7.24(dd,J=8.3,1.7Hz,1H),5.16(t,J=5.9Hz,1H,-NH),4.39(d,J=6.6Hz,2H,-NCH2),3.00(q, J=6.3Hz,2H,-SCH2),2.57(s,3H),1.78(dt,J=13.9,7.1Hz,2H),1.50(dd,J=13.3,6.8Hz,2H),1.47–1.37(m,4H). 13 C NMR (126MHz, CDCl3) δ163.58,161.83,161.59,143.20,137.19,133.71,131.00,130.94,129.66,129.59,129.06,123.62,123.2 5,122.92,122.46,121.76,119.85,119.73,119.68,115.25,114.66,114.47,42.88,41.98,29.35,27.30,25.89,25.68,22.33.

[0121]

[0122] 13K: White solid, yield 75%, mp 144.4-146.5℃; HRMS(ESI) m / z: calcd for C 27 H 30 N₂O₅S[M+H] + :495.1951,found:495.1954. 1H NMR(500MHz, CDCl3)δ8.19(d,J=7.5Hz,1H),8.00(s,1H),7.91–7.87(m,2H),7.61(s,1H),7 .56–7.51(m,2H),7.49(d,J=7.8Hz,2H),7.39(d,J=8.4Hz,1H),7.32(t,J=7.5Hz,1H),5.12( t,J=6.1Hz,1H,-NH),4.40(t,J=6.8Hz,2H,-NCH2),4.10(s,3H,-OCH3),4.04(s,3H,-OCH3) ,2.98(q,J=6.2Hz,2H,-SCH2),1.82–1.75(m,2H),1.50–1.42(m,4H),1.38(d,J=6.7Hz,2H). 13 C NMR (126MHz, CDCl3) δ161.36,153.56,150.13,140.52,136.59,132.57,129.17,128.83,128.48,127.15,1 23.08,122.38,119.62,115.30,109.30,102.61,56.47,56.29,42.78,42.12,29.23,27.46,25.93,25.73.

[0123]

[0124] 13L: White solid, yield 81%, mp 150.1-152.2℃; HRMS(ESI) m / z: calcd for C 28 H 32 N₂O₅S[M+H] + :509.2114,found:509.2110. 1H NMR (500MHz, CDCl3) δ8.19(d,J=7.9Hz,1H),8.00(s,1H),7.76(d,J=8.2Hz,2H),7.61(s,1H),7. 51(t,J=7.8Hz,1H),7.39(d,J=8.4Hz,1H),7.32(t,J=7.6Hz,1H),7.28(d,J=8.1Hz,2H),4.96(t ,J=6.1Hz,1H,-NH),4.40(t,J=6.9Hz,2H,-NCH2),4.10(s,3H,-OCH3),4.04(s,3H,-OCH3),2.95 (q,J=6.3Hz,2H,-SCH2),2.40(s,3H),1.81–1.75(m,2H),1.50–1.43(m,4H),1.42–1.38(m,2H). 13 C NMR (126MHz, CDCl3) δ161.31,153.53,150.10,143.31,137.44,136.60,129.78,128.83,128.47,127.21,123. 07,122.36,119.60,115.28,109.27,102.61,56.45,56.29,42.81,42.18,29.28,27.47,26.02,25.84,21.63.

[0125]

[0126] 13m: White solid, yield 80%, mp 162.3-163.4℃; HRMS(ESI) m / z: calcd for C 30 H 36 N₂O₅S[M+H] + :537.2422,found:537.2423. 1H NMR(500MHz, CDCl3)δ8.18(d,J=7.6Hz,1H),7.96(s,1H),7.61(s,1H),7.51(t,J=7 .3Hz,1H),7.37(d,J=8.4Hz,1H),7.31(t,J=7.5Hz,1H),6.94(s,2H),4.38(t,J=7.1 Hz,2H,-NCH2),4.10(s,3H,-OCH3),4.05(s,3H,-OCH3),2.90(t,J=6.5Hz,2H,-SCH2 ),2.64(s,6H),2.27(s,3H),1.79–1.74(m,2H),1.46(d,J=6.3Hz,2H),1.40(s,4H). 13 C NMR (126MHz, CDCl3) δ161.19,153.50,150.06,142.15,139.19,136.62,133.96,132.06,128.81,128.46,123.07, 122.33,119.58,115.25,109.21,102.61,56.41,56.28,42.31,42.28,29.43,27.45,26.20,26.12,23.12,21.03.

[0127]

[0128] 13n: White solid, yield 76%, mp 141.2-143.3℃; HRMS(ESI) m / z: calcd for C 27 H 28 Cl2N2O5S[M+H] + :563.1172,found:563.1174. 11H NMR (500 MHz, CDCl3) δ 8.20 (d, J = 8.0 Hz, 1H), 8.04 (s, 1H), 8.00 (d, J = 2.1 Hz, 1H), 7.74 (dd, J = 8.4, 2.1 Hz, 1H), 7.62 (s, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.52 (t, J = 7.8 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.33 (t, J = 7.5 Hz, 1H), 5.72 (t, J = 6.1 Hz, 1H, -NH), 4.44 (s, 2H, -NCH2), 4.10 (s, 3H, -OCH3), 4.05 (s, 3H, -OCH3), 3.01 (q, J = 5.9 Hz, 2H, -SCH2), 1.86–1.80 (m, 2H), 1.52–1.47 (m, 4H), 1.39–1.33 (m, 2H). 13 13C NMR (126 MHz, CDCl3) δ 161.62, 153.68, 150.25, 140.80, 137.20, 136.48, 133.71, 131.19, 129.20, 128.84, 128.55, 126.28, 123.12, 122.51, 119.71, 119.49, 115.37, 109.36, 102.62, 56.55, 56.31, 42.56, 41.81, 28.92, 27.41, 25.44, 25.25.

[0129]

[0130] 13o: White solid, yield 79%, m.p. 152.6 - 153.8 °C; HRMS (ESI) m / z: calcd for C 27 H 29 1FN2O5S8.02 (s, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.63–7.60 (m, 2H), 7.51 (t, J = 7.8 Hz, 1H), 7.47 (td, J = 8.1, 5.3 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.32 (t, J = 7.6 Hz, 1H), 7.23 (dd, J = 8.0, 2.1 Hz, 1H), 5.43 (t, J = 6.0 Hz, 1H, -NH), 4.42 (t, J = 6.5 Hz, 2H, -NCH2), 4.10 (s, 3H, -OCH3), 4.05 (s, 3H, -OCH3), 3.00 (q, J = 5.9 Hz, 2H, -SCH2), <1.81 (p, J = 7.0 Hz, 2H), 1.48 (s, 4H), 1.41–1.36 (m, 2H).13 C NMR (126MHz, CDCl3) δ163.56,161.56,161.46,153.60,150.17,142.80,136.52,130.97,130.91,128.83,128.50,123.09,122.90,122.88,1 22.44,119.79,119.65,119.62,119.53,115.33,114.65,114.46,109 .30,102.60,56.49,56.29,42.70,41.96,29.07,27.41,25.68,25.48.

[0131] <Example 3>

[0132] Experiment on the antitumor activity of nemesis-sulfonamide derivatives

[0133] The inhibition rate of nemesis-sulfonamide derivatives against human hepatocellular carcinoma cells (Hep G2), human cervical cancer cells (HeLa), human lung cancer cells (H460), and normal human hepatocytes (LO2) at a concentration of 40 μmol / L was studied using the CCK-8 assay, with 5-fluorouracil and nemesis chloride as positive control groups.

[0134] (1) Cell culture: Take out the frozen cells, thaw them completely in a 37℃ water bath, disinfect them with alcohol and place them in a clean bench. Take a clean centrifuge tube, add the thawed cells and an appropriate amount of culture medium containing 10% fetal bovine serum, centrifuge, add an appropriate amount of 10% culture medium to resuspend the cells into a cell suspension and transfer it into a culture flask for culture. Observe the cell status after 12 hours.

[0135] (2) Seeding: When cells have grown densely at the bottom of the flask (approximately 80%), remove the culture medium and wash 1-2 times with PBS buffer. Digest with 0.25% trypsin for 1-2 min, add culture medium to stop digestion, centrifuge, remove the supernatant, and add culture medium to prepare a cell suspension. Count cells using a cell counting chamber, seeding 100 μL per well in a 96-well plate at a cell count of 50,000 / mL.

[0136] (3) Drug addition: The synthesized compounds 12a-12o, 13a-13o, the positive control drug (5-fluorouracil-5-Fu), and nifedipine chloride (NC) were dissolved in DMSO to prepare samples with a concentration of 40 μmol / L. Each concentration was tested in triplicate, with 100 μL per well. The blank control group was prepared with 100 μL of 1% DMEM medium per well. Cells were cultured for another 24 h.

[0137] (4) Test: Take out the 96-well plate after 24 hours of drug-treated culture, add 10 μL of LCK-8 reagent to each well, incubate in the dark for 2 hours, and then measure the inhibition rate at 450 nm using a microplate reader. The inhibition rate formula is as follows:

[0138] Cell growth inhibition rate (%) = [(Ac-As)] / (Ac-Ab)] × 100%

[0139] As: Absorbance of experimental wells; Ac: Absorbance of control wells; Ab: Absorbance of blank wells.

[0140] The calculated inhibitory rates of the succinate-sulfonamide derivatives on cells are shown in Table 1.

[0141] Table 1. Inhibition rate of cells by nemesis alkaloid-sulfonamide derivatives at a concentration of 40 μmol / L.

[0142]

[0143]

[0144] The antitumor experiments conducted on the succinate-sulfonamide derivatives provided by this invention yielded the data shown in Table 1. It can be seen that the succinate-sulfonamide derivatives possess certain antitumor effects. Specifically, compounds 12h and 12n exhibited significant inhibitory activity against the proliferation of Hepg2, H460, and HeLa cells, with inhibition rates exceeding 50% at a concentration of 40 μmol / L. Furthermore, compounds 12h, 12n, and 13h showed inhibition rates of 82.39%, 86.62%, and 88.98% against H460 cells, respectively. These rates were not only superior to the positive control 5-fluorouracil (45.08%) but also comparable to succinate chloride (NC) (86.68%).

[0145] The number of devices and processing scale described herein are for the purpose of simplifying the description of the invention. Applications, modifications, and variations of the invention will be readily apparent to those skilled in the art.

[0146] Although embodiments of the present invention have been disclosed above, they are not limited to the applications listed in the specification and embodiments. They can be applied to various fields suitable for the present invention. For those skilled in the art, other modifications can be easily made. Therefore, without departing from the general concept defined by the claims and their equivalents, the present invention is not limited to the specific details and illustrations shown and described herein.

Claims

1. A sulfonamide-based derivative of the alkaloid genus, characterized in that, The derivative has a structure of general formula A or general formula B: In the formula, R1 is methyl, R2 is hydrogen, R3, R4, R5, and R6 are all hydrogen, or R3, R5, and R6 are hydrogen and R4 is methyl, or R3, R4, and R6 are methoxy and R5 is hydrogen, or R3, R6 are hydrogen, R4, and R5 are chlorine, or R3, R4, and R6 are hydrogen and R5 is fluorine. Or R1 is hydrogen, R2 is methyl, and R3, R4, R5, and R6 are all hydrogen, or R3, R5, and R6 are hydrogen and R4 is methyl, or R3, R4, and R6 are methoxy and R5 is hydrogen, or R3, R6 are hydrogen, R4, and R5 are chlorine, or R3, R4, and R6 are hydrogen and R5 is fluorine. Alternatively, R1 and R2 may be methoxy groups, and R3, R4, R5, and R6 may all be hydrogen, or R3, R5, and R6 may be hydrogen and R4 may be methyl, or R3, R4, and R6 may be methoxy groups and R5 may be hydrogen, or R3, R6 may be hydrogen, R4, and R5 may be chlorine, or R3, R4, and R6 may be hydrogen and R5 may be fluorine.

2. The method for preparing the succinate-sulfonamide derivative as described in claim 1, characterized in that, Includes the following steps: Step 1: Using acyl chloride compound 1 as shown in Formula 1 and methoxyamine hydrochloride as raw materials, compound 2 as shown in Formula 2 is synthesized in the presence of potassium carbonate and in the solvent of ethyl acetate. Step 2: Compound 2, iodobenzene, palladium acetate, and silver oxide are dissolved in acetic acid and reacted under nitrogen protection to synthesize compound 3 as shown in Formula 3. Step 3: Dissolve compound 3 in anhydrous methanol and react under ultraviolet light to obtain compound 4 as shown in Formula 4; Step 4: Using compound 4 and 1,4-dibromobutane or 1,6-dibromohexane as raw materials, in the presence of sodium hydride and in DMF solvent, compound 5 as shown in Formula 5 or compound 6 as shown in Formula 6 are synthesized. Step 5: Compound 5 or Compound 6 is combined with phthalimide, potassium iodide and potassium carbonate in acetonitrile solvent to synthesize compound 7 as shown in Formula 7 or compound 8 as shown in Formula 8. Step 6: Dissolve compound 7 or compound 8 in an aqueous solution of methylamine, stir magnetically, and react to obtain compound 9 as shown in formula 9 or compound 10 as shown in formula 10; Step 7: React compound 9 or compound 10 with compound 11 as shown in formula 11 under the action of triethylamine and dichloromethane to obtain compound 12 as shown in formula A, or compound 13 as shown in formula B. Wherein, R1 is methyl, R2 is hydrogen, R3, R4, R5, and R6 are all hydrogen or R3, R5, and R6 are hydrogen and R4 is methyl or R3, R4, and R6 are methoxy and R5 is hydrogen or R3, R6 are hydrogen and R4, R5 is chlorine or R3, R4, and R6 are hydrogen and R5 is fluorine. Or R1 is hydrogen, R2 is methyl, and R3, R4, R5, and R6 are all hydrogen, or R3, R5, and R6 are hydrogen and R4 is methyl, or R3, R4, and R6 are methoxy and R5 is hydrogen, or R3, R6 are hydrogen, R4, and R5 are chlorine, or R3, R4, and R6 are hydrogen and R5 is fluorine. Alternatively, R1 and R2 may be methoxy groups, and R3, R4, R5, and R6 may all be hydrogen, or R3, R5, and R6 may be hydrogen and R4 may be methyl, or R3, R4, and R6 may be methoxy groups and R5 may be hydrogen, or R3, R6 may be hydrogen, R4, and R5 may be chlorine, or R3, R4, and R6 may be hydrogen and R5 may be fluorine.

3. The method for preparing the schizophyllum commune-sulfonamide derivative as described in claim 2, characterized in that, In step one, the molar ratio of methoxyamine hydrochloride, potassium carbonate, and compound 1 is 1:2:

1.

4. The method for preparing the schizophyllum commune-sulfonamide derivative as described in claim 2, characterized in that, In step two, the molar ratio of compound 2, iodobenzene, palladium acetate, and silver oxide is 1:2:0.05:

2.

5. The method for preparing the succinate-sulfonamide derivative as described in claim 2, characterized in that, In step three, a 175 W high-pressure ultraviolet lamp is selected as the ultraviolet lamp.

6. The method for preparing the schizophyllum commune-sulfonamide derivative as described in claim 2, characterized in that, In step four, the molar ratio of compound 4, sodium hydride, and 1,4-dibromobutane or 1,6-dibromohexane is 1:3.14:

5.

7. The method for preparing the succinate-sulfonamide derivative as described in claim 2, characterized in that, In step five, the molar ratio of compound 5 or compound 6, phthalimide, potassium iodide, and potassium carbonate is 1:1:0.1:

3.

8. The method for preparing the succinate-sulfonamide derivative as described in claim 2, characterized in that, In step seven, the molar ratio of compound 9 or compound 10, triethylamine, and compound 11 is 1:7.2:1.

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