A β-carboline derivative containing a benzenesulfonamide structure, its preparation method and application

Abstract

This invention discloses a β-carboline derivative containing a benzenesulfonamide structure, its preparation method, and its applications, belonging to the field of medicinal chemistry. The β-carboline derivative containing a benzenesulfonamide structure of this invention has the structure shown in the following formula: where R represents a substituted or unsubstituted aryl group, and the substitution is optional. This invention designs and synthesizes a series of β-carboline compounds containing a benzenesulfonamide structure. These β-carboline derivatives containing a benzenesulfonamide structure exhibit strong α-glucosidase inhibitory activity, with an IC50 value of [missing information]. 50 The highest value is 2.12±0.33 μM, which can be used to treat and / or prevent diabetes. This invention also provides a method for preparing and applying β-carboline derivatives containing a benzenesulfonamide structure.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to a β-carboline derivative containing a benzenesulfonamide structure, its preparation method, and its application. Background Technology

[0002] Diabetes mellitus (DM) is a chronic metabolic disease characterized by glucose homeostasis disturbances such as hyperglycemia, abnormal protein and lipid metabolism, and the development of complications. Currently, clinically used hypoglycemic drugs mainly include sulfonylureas, biguanides, alpha-glucosidase inhibitors, thiazolidinediones, and non-sulfonylurea insulin secretagogues. Among them, alpha-glucosidase inhibitors are oral hypoglycemic drugs that treat diabetes by reducing the rate of carbohydrate digestion and inhibiting postprandial hyperglycemia. Alpha-glucosidase inhibitors competitively or reversibly inhibit the activity of alpha-glucosidase on the brush border of the small intestine, thereby delaying the conversion of polysaccharides to monosaccharides, thus delaying carbohydrate absorption and slowing the rise in postprandial blood glucose. Alpha-glucosidase is mainly located on the brush border of small intestinal mucosal cells and is distributed throughout the small intestine, playing an important role in the catabolism and metabolism of carbohydrates in the body.

[0003] However, currently known α-glucosidase inhibitors on the market have some limitations. For example, existing α-glucosidase inhibitors may cause a series of side effects during treatment; some drugs do not have strong enough α-glucosidase inhibitory activity, requiring higher doses to achieve the desired therapeutic effect, while high doses may increase the toxic side effects of the drugs; long-term use of the same class of drugs may lead to drug resistance in patients, gradually weakening the efficacy of the drugs and requiring a change in treatment regimen; the known structural types of α-glucosidase inhibitors are relatively limited, which cannot meet the needs of different patient groups and also limits the diversity and innovation of drug development.

[0004] Therefore, developing new derivatives with α-glucosidase inhibitory activity remains of great significance. Summary of the Invention

[0005] The present invention aims to at least solve one of the technical problems existing in the prior art. To this end, the present invention proposes a β-carboline derivative containing a benzenesulfonamide structure, which has good α-glucosidase inhibitory activity, thereby being used for the treatment and / or prevention of diabetes.

[0006] The present invention also proposes a method for preparing the above-mentioned β-carboline derivatives containing benzenesulfonamide structures.

[0007] The present invention also proposes applications of the above-mentioned β-carboline derivatives containing benzenesulfonamide structures.

[0008] According to one aspect of the present invention, a β-carboline derivative containing a benzenesulfonamide structure is provided, said β-carboline derivative having the structure shown in the following formula:

[0009]

[0010] In the formula, R represents a substituted or unsubstituted phenyl group, wherein the substitution is optional.

[0011] According to a preferred embodiment of the present invention, at least the following beneficial effects are achieved:

[0012] This invention designs and synthesizes a series of β-carboline derivatives containing benzenesulfonamide structures. The benzenesulfonamide structure contains a special sp3 hybridized sulfur atom and sulfonamide group, which not only provides flexible conformation and more hydrogen bonding, but also extends the π-part. These derivatives exhibit good α-glucosidase inhibitory activity through the splicing of β-carboline and benzenesulfonamide. They are highly efficient and low in toxicity, and can be used as α-glucosidase inhibitors for the treatment or prevention of diabetes.

[0013] The IC of the β-carboline derivatives containing the benzenesulfonamide structure of this invention 50 The highest value was 2.12 ± 0.33 μM; followed by IC. 50 The values ​​were 2.18±0.37 μM and 2.19±0.26 μM, which are 29 to 273 times higher than those of acarbose. Kinetic studies showed that f27, a β-carboline derivative containing a benzenesulfonamide structure, is a reversible, non-competitive inhibitor that can be used as an α-glucosidase inhibitor for the treatment or prevention of diabetes.

[0014] According to some embodiments of the present invention, the substitution is a single substitution or multiple substitutions.

[0015] According to some embodiments of the present invention, the substituents include C 1～6 At least one of alkyl, halogen, methoxy, hydroxy, nitro, cyano, biphenyl, trifluoromethyl or trifluoromethoxy.

[0016] According to some embodiments of the present invention, the R is selected from the following groups:

[0017]

[0018] According to another aspect of the present invention, a method for preparing the above-mentioned β-carboline derivative containing a benzenesulfonamide structure is provided, comprising the following steps:

[0019] The compound e was reacted with a benzenesulfonyl chloride solution containing an R group to obtain a β-carboline derivative containing a benzenesulfonamide structure.

[0020] According to some embodiments of the present invention, in step S5, the molar ratio of compound e to benzenesulfonyl chloride is 1:1 to 2, for example, it can be 1:1, 1:1.2, 1:1.5, 1:1.8, or 1:2.

[0021] According to some embodiments of the present invention, the temperature of the reaction is 20–30°C.

[0022] Preferably, the reaction temperature is 25°C.

[0023] According to some embodiments of the present invention, the reaction time is 1 to 3 hours.

[0024] Preferably, the reaction time is 1 hour.

[0025] According to some embodiments of the present invention, the solvent of the benzenesulfonyl chloride solution containing the R group is a pyridine solution.

[0026] According to some embodiments of the present invention, the post-reaction processing step includes: cooling to room temperature, filtration, and recrystallization with ethanol to obtain a β-carboline derivative containing a benzenesulfonamide structure.

[0027] According to some embodiments of the present invention, the preparation method of compound e includes the following steps:

[0028] S1. Compound b was prepared by reacting L-tryptophan solution and thionyl chloride as raw materials;

[0029] S2. Compound b is prepared by reacting an acid solution with a benzaldehyde solution;

[0030] S3. Compound c is reacted with potassium permanganate to prepare compound d;

[0031] S4. Compound d is reacted with hydrazine hydrate to prepare compound e;

[0032] The structural formulas corresponding to compounds b, c, d, and e are as follows:

[0033]

[0034] According to some embodiments of the present invention, in step S1, the preparation process of compound b includes the following steps:

[0035] Thionyl chloride was slowly added to an L-tryptophan solution, and after the reaction, compound b was obtained.

[0036] According to some embodiments of the present invention, in step S1, the molar ratio of L-tryptophan to thionyl chloride is 1:5 to 8, for example, it can be 1:5, 1:5.1, 1:6, 1:7, or 1:8.

[0037] According to some embodiments of the present invention, in step S1, the temperature of the reaction is 15 to 40°C.

[0038] According to some embodiments of the present invention, in step S1, the reaction time is 6 to 8 hours.

[0039] Preferably, in step S1, the reaction time is 6 hours.

[0040] According to some embodiments of the present invention, the solvent of the L-tryptophan solution is a methanol solution.

[0041] According to some embodiments of the present invention, step S1 further includes a separation and purification step after the reaction.

[0042] According to some embodiments of the present invention, the specific steps of the separation and purification include: evaporating the solvent, adding sodium bicarbonate, adjusting the pH to 7, then extracting with ethyl acetate, washing with saturated brine, drying with anhydrous sodium sulfate, concentrating, and evaporating the solvent to obtain crude compound b.

[0043] According to some embodiments of the present invention, in step S2, the preparation process of compound c includes the following steps:

[0044] Compound c was prepared by reacting a solution of compound b with a solution of benzaldehyde in an acidic environment.

[0045] According to some embodiments of the present invention, in step S2, the molar ratio of compound b to benzaldehyde is 10 to 13:1.

[0046] According to some embodiments of the present invention, in step S2, the temperature of the reaction is 0 to 2°C.

[0047] According to some embodiments of the present invention, in step S2, the reaction time is 6 to 8 hours.

[0048] Preferably, in step S2, the reaction time is 6 hours.

[0049] According to some embodiments of the present invention, in step S2, the acid is trifluoroacetic acid.

[0050] According to some embodiments of the present invention, in step S2, the solvent of the benzaldehyde solution is dichloromethane.

[0051] According to some embodiments of the present invention, in step S2, the post-reaction treatment step includes: adding sodium bicarbonate, adjusting the pH value to 7, then extracting with dichloromethane, washing with saturated brine, drying with anhydrous sodium sulfate, concentrating, and evaporating the solvent to obtain crude compound c.

[0052] According to some embodiments of the present invention, in step S3, the preparation process of compound d includes the following steps:

[0053] Compound d was prepared by reacting a solution of compound c with potassium permanganate through an oxidation reaction.

[0054] According to some embodiments of the present invention, in step S3, the molar ratio of compound c to potassium permanganate is 1:1 to 5, for example, it can be 1:1, 1:2, 1:3, 1:4, or 1:5.

[0055] According to some embodiments of the present invention, in step S3, the reaction time is 8 to 14 hours.

[0056] Preferably, in step S3, the reaction time is 12 hours.

[0057] According to some embodiments of the present invention, in step S3, the solvent of the compound c solution is dimethylformamide (DMF).

[0058] According to some embodiments of the present invention, in step S3, the post-reaction treatment step includes: extraction with ethyl acetate, washing with saturated sodium bicarbonate solution and saturated brine respectively, drying with anhydrous sodium sulfate, and rotary evaporation to obtain compound d.

[0059] According to some embodiments of the present invention, in step S4, the preparation process of compound e includes the following steps:

[0060] Hydrazine hydrate was added to a solution of compound d, and the reaction yielded compound e.

[0061] According to some embodiments of the present invention, in step S4, the molar ratio of compound e to hydrazine hydrate is 1:8 to 12, for example, it can be 1:8, 1:9, 1:10, 1:11, or 1:12.

[0062] According to some embodiments of the present invention, in step S4, the temperature of the reaction is 65-75°C.

[0063] Preferably, in step S4, the reaction temperature is 70°C.

[0064] According to some embodiments of the present invention, in step S4, the reaction time is 8 to 14 hours.

[0065] Preferably, in step S4, the reaction time is 8 hours.

[0066] According to some embodiments of the present invention, in step S4, the solvent of the compound d solution is ethanol.

[0067] According to some embodiments of the present invention, in step S4, the post-reaction processing step includes: cooling to room temperature and then filtering to obtain compound e.

[0068] According to a third aspect of the present invention, an α-glucosidase inhibitor is provided, comprising the above-mentioned β-carboline derivatives containing a benzenesulfonamide structure.

[0069] According to a fourth aspect of the present invention, the use of the above-mentioned β-carboline derivatives containing a benzenesulfonamide structure in the preparation of products for the prevention and / or treatment of diabetes is proposed.

[0070] The application of the preferred embodiments of the present invention has at least the following beneficial effects: The present invention uses computer-aided drug design methods, combined with in vitro pharmacological activity evaluation experiments, to conduct in-depth research on the related biological activities and structure-activity relationships of α-glucosidase as the target protein, providing a solid theoretical basis for finding and discovering lead compounds of highly effective and low-toxicity α-glucosidase inhibitors.

[0071] According to some embodiments of the present invention, the product includes a drug.

[0072] According to some embodiments of the present invention, the dosage form of the pharmaceutical composition is a tablet, capsule, oral liquid or injection.

[0073] According to some embodiments of the present invention, the product includes health supplements.

[0074] According to a fifth aspect of the invention, a pharmaceutical composition is provided comprising the above-described β-carboline derivatives containing a benzenesulfonamide structure and / or a pharmaceutically acceptable salt thereof.

[0075] The structural formula appears in this invention Indicates the linking site of a functional group.

[0076] The term "pharmaceutically acceptable" as used in this invention refers to a substance that is acceptable from a toxicological point of view for pharmaceutical use and will not adversely interact with the active ingredient.

[0077] As used in this article, "optional substitution" means that a group may or may not be further substituted by one or more groups.

[0078] Other features and advantages of the invention will be set forth in the description which follows, and will be apparent in part from the description, or may be learned by practicing the invention. Attached Figure Description

[0079] The above and / or additional aspects and advantages of the present invention will become apparent and readily understood from the description of the embodiments taken in conjunction with the following drawings, in which:

[0080] Figure 1 This is a graph showing the half-maximal inhibitory concentration (IC50) of the β-carboline derivative f27 containing a benzenesulfonamide structure against α-glucosidase in vitro, as described in Example 2 of this invention.

[0081] Figure 2 This is an in vitro enzyme kinetic diagram of α-glucosidase on β-carboline derivative f27 containing a benzenesulfonamide structure, as shown in Example 3 of the present invention.

[0082] Figure 3 This is a substrate kinetic diagram of β-carboline derivative f27 containing a benzenesulfonamide structure on α-glucosidase in vitro, as shown in Example 4 of the present invention.

[0083] Figure 4 This is a graph showing the in vitro cytotoxicity of the β-carboline derivative f27 containing a benzenesulfonamide structure to α-glucosidase in Example 5 of the present invention. Detailed Implementation

[0084] The following will describe the concept and technical effects of the present invention clearly and completely with reference to embodiments, so as to fully understand the purpose, features and effects of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are all within the scope of protection of the present invention.

[0085] In the description of this invention, the use of terms such as "first," "second," etc., is for the purpose of distinguishing technical features only and should not be construed as indicating or implying relative importance, or implicitly indicating the number of technical features indicated, or implicitly indicating the order of the technical features indicated.

[0086] When a numerical range is disclosed herein, the range is considered continuous and includes the minimum and maximum values ​​of the range, as well as every value between the minimum and maximum values. Furthermore, when the range refers to integers, it includes every integer between the minimum and maximum values ​​of the range. Additionally, when multiple ranges are provided to describe a feature or characteristic, the ranges may be combined. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges to which they are incorporated.

[0087] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of the present invention.

[0088] Unless otherwise specified, the reagents, methods and equipment used in this invention are all conventional reagents, methods and equipment in this technical field.

[0089] Reagents used in the embodiments of this invention:

[0090] L-Tryptophan CAS No.: 73-22-3;

[0091] CAS No.: 7719-09-7;

[0092] Benzaldehyde CAS No.: 100-52-7;

[0093] Trifluoroacetic acid CAS number: 76-05-1;

[0094] Potassium permanganate CAS number: 7722-64-7;

[0095] CAS No.: 7803-57-8.

[0096] Example 1

[0097] This embodiment prepared a series of β-carboline derivatives containing benzenesulfonamide structures, and the synthetic route is as follows:

[0098]

[0099] The specific steps are as follows:

[0100] L-tryptophan (compound a, 1 mmol) was slowly added to a methanol (6 mL) solution with thionyl chloride (5.1 mmol) and stirred at room temperature for 6 hours. The solvent was then evaporated, sodium bicarbonate was added, the pH was adjusted to 7, and the mixture was subsequently extracted with ethyl acetate and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to give crude compound b.

[0101] Compound b (11.45 mmol) was dissolved in anhydrous dichloromethane with benzaldehyde (1.12 mmol), and the mixture was ventilated. Trifluoroacetic acid (2.15 mmol) was slowly added under ice bath conditions, and the reaction was carried out for 6 hours. Sodium bicarbonate was then added to adjust the pH to 7. Subsequently, the mixture was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the solvent was evaporated to obtain crude compound c.

[0102] Compound c (1 mmol) was dissolved in DMF, and potassium permanganate (3 mmol) was slowly added under ice bath conditions. The ice bath was then removed, and the reaction was carried out at room temperature for 12 hours. After extraction with ethyl acetate, the mixture was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and rotary evaporated to obtain compound d.

[0103] Hydrazine hydrate (10 mmol) was added to an ethanol (100 mL) solution of compound d (1 mmol), and the mixture was refluxed at 70 °C for 8 h. After cooling to room temperature, the mixture was filtered to obtain intermediate e.

[0104] Compound e (0.5 mmol) and a series of pyridine solutions containing benzenesulfonyl chloride (0.6 mmol) with R groups were stirred at room temperature for 1 hour. After quenching the reaction with ice water, the mixture was filtered and recrystallized from ethanol to give the corresponding β-carboline derivatives f1–f32 containing benzenesulfonamide structures.

[0105] In the formula, R in f1 to f32 is shown in Table 1 below:

[0106] Table 1. Structural formulas of the R group

[0107]

[0108]

[0109] The structures of derivatives f1–f32 were characterized by NMR, MS, and melting point analysis. The following are the characterization results of each compound, including its properties, yield, NMR, and mass spectrometry:

[0110] N'-(1-phenyl-9H-pyrido[3,4-b]indole-3-carbonyl)benzenesulfonylhydrazide(f1).Yield 63%; White solid; mp245.6-246.3℃; 1 H NMR (500MHz, DMSO-d6) δ11.93(s,1H),10.39(s,1H),10.08(s,1H),8.70(s,1H),8.40(d,J=10.0Hz,1H),8.18(d,J=10.0Hz,2H),7.90(d,J=5.0Hz,2H ),7.70(s,1H),7.68(s,1H),7.67(d,J=5.0Hz,1H),7.65(d,J=5.0Hz,1H), 7.59(s,1H),7.58(s,1H),7.57(s,1H),7.55(s,1H),7.30(t,J=5.0Hz,1H); 13C NMR(126MHz,DMSO-d6)δ163.79,141.52,140.90,139.22,138.12,137.22,134.45,133.05,129.71,129.10,128.94,128.92,128.84,128.76,127.68,122.15,121.11,120.36,113.88,112.74;HRMS(ESI-MS)m / z:[M+H] + calcd for C 24 H 18 N4O3S:443.1177,found:443.1163.

[0111] 4-Methyl-N'-(1-phenyl-9H-pyrido[3,4-b]indole-3-carbonyl)benzenesulfonyl hydrazide(f2).Yield 66%;White solid;m.p.283.1-284.3℃; 1 H NMR(500 MHz,DMSO-d6)δ11.93(s,1H),10.32(s,1H),9.97(s,1H),8.71(s,1H),8.40(d,J=10.0 Hz,1H),8.17(d,J=10.0 Hz,2H),7.78(d,J=10.0 Hz,2H),7.69(d,J=10.0 Hz,1H),7.66(s,1H),7.64(d,J=10.0 Hz,1H),7.60(d,J=5.0 Hz,1H),7.58(d,J=5.0 Hz,1H),7.37(s,1H),7.35(s,1H),7.30(t,J=5.0 Hz,1H),2.38(s,3H); 13 C NMR(126 MHz,DMSO-d6)δ163.71,149.63,143.29,141.52,140.91,138.14,137.23,136.27,134.45,129.70,129.40,129.11,128.90,128.76,127.76,123.93,122.15,121.11,120.35,113.89,112.74,21.11;HRMS(ESI-MS)m / z:[M+H] + calcd for C 25 H 20 N4O3S:457.1334,found:457.1317.

[0112] 3-Methyl-N'-(1-phenyl-9H-pyrido[3,4-b]indole-3-carbonyl)benzenesulfonyl hydrazide(f3).Yield 69%;White solid;m.p.321.4-322.6℃; 1 H NMR(500 MHz,DMSO-d6)δ11.93(s,1H),10.32(s,1H),10.01(s,1H),8.71(s,1H),8.41(d,J=10.0 Hz,1H),8.16(d,J=5.0 Hz,2H),7.70(d,J=5.0 Hz,1H),7.68(s,1H),7.66(d,J=5.0 Hz,1H),7.64(s,1H),7.62(d,J=10.0 Hz,1H),7.60(s,1H),7.57(d,J=10.0 Hz,1H),7.49(d,J=5.0 Hz,1H),7.44(t,J=10.0 Hz,1H),7.31(t,J=5.0 Hz,1H),2.33(s,3H); 13 CNMR(126 MHz,DMSO-d6)δ163.77,141.52,140.88,139.06,138.53,138.19,137.23,134.43,133.66,129.72,129.10,128.86,128.81,128.76,127.84,124.83,122.15,121.12,120.36,113.86,112.73,20.78;HRMS(ESI-MS)m / z:[M+H] + calcd forC 25 H 20 N4O3S:457.1334,found:457.1318.

[0113] 4-Fluoro-N'-(1-phenyl-9H-pyrido[3,4-b]indole-3-carbonyl)benzenesulfonyl hydrazide(f4).Yield 71%;White solid;m.p.326.4-327.9 oC; 1HNMR(500 MHz,DMSO-d6)δ11.93(s,1H),10.49(s,1H),10.15(s,1H),8.69(s,1H),8.41(d,J=10.0 Hz,1H),8.20(d,J=10.0 Hz,2H),7.94(dd,J=10.0,5.0 Hz,2H),7.69(d,J=10.0Hz,1H),7.66(d,J=5.0 Hz,1H),7.63(s,1H),7.60(d,J=5.0 Hz,1H),7.58(d,J=5.0 Hz,1H),7.40(t,J=10.0 Hz,2H),7.30(t,J=10.0 Hz,1H); 13 C NMR(126 MHz,DMSO-d6)δ165.60,163.93,163.61,149.63,141.51,140.95,138.09,137.23,135.73,134.47,130.81(d,J=25.2 Hz),129.70,129.10,128.97,128.74,123.93(d,J=12.6 Hz),122.17,121.12,120.35(d,J=12.6 Hz),116.17,115.99,113.93,112.74;HRMS(ESI-MS)m / z:[M+H] + calcd for C 24 H 17 FN4O3S:461.1083,found:461.1066.

[0114] 3-Fluoro-N'-(1-phenyl-9H-pyrido[3,4-b]indole-3-carbonyl)benzenesulfonyl hydrazide(f5).Yield 68%;White solid;m.p.375.2-376.0℃; 1H NMR(500 MHz,DMSO-d6)δ11.93(s,1H),10.56(s,1H),10.30(s,1H),8.71(s,1H),8.41(d,J=10.0 Hz,1H),8.21(d,J=5.0 Hz,2H),7.73(d,J=5.0 Hz,1H),7.71(s,1H),7.70(d,J=5.0 Hz,1H),7.67(d,J=10.0 Hz,1H),7.64(s,1H),7.62(d,J=5.0 Hz,1H),7.59(s,1H),7.58(s,1H),7.56(d,J=5.0 Hz,1H),7.32-7.29(m,1H); 13 C NMR(126 MHz,DMSO-d6)δ164.09,162.57,160.60,141.61(d,J=10.0 Hz),141.52,140.96,138.09,137.23,134.47,131.20(d,J=25.2 Hz),129.70,129.10,128.96,128.75,123.94(d,J=12.6 Hz),122.18,121.13,120.31(d,J=12.6 Hz),120.10,114.75,114.56,113.99,112.74;HRMS(ESI-MS)m / z:[M+H] + calcd for C 24 H 17 FN4O3S:461.1083,found:461.1068.

[0115] 2-Fluoro-N'-(1-phenyl-9H-pyrido[3,4-b]indole-3-carbonyl)benzenesulfonyl hydrazide(f6).Yield 78%;White solid;m.p.363.2-364.7℃; 1H NMR(500 MHz,DMSO-d6)δ11.92(s,1H),10.59(s,1H),10.33(s,1H),8.69(s,1H),8.40(d,J=10.0 Hz,1H),8.21(d,J=5.0 Hz,2H),7.84-7.80(m,1H),7.70(s,1H),7.67(d,J=10.0Hz,1H),7.65(s,1H),7.63(s,1H),7.59(s,1H),7.58(s,1H),7.44(t,J=10.0 Hz,1H),7.31(d,J=5.0 Hz,1H),7.28(d,J=5.0 Hz,1H); 13 C NMR(126 MHz,DMSO-d6)δ164.20,141.50,140.92,138.09,137.20,135.68(d,J=12.6 Hz),134.44,130.32,129.68,129.09,128.98,128.84,128.74,127.92(d,J=25.2 Hz),124.29,122.15,121.11,120.35,117.25,117.08,113.96,112.74;HRMS(ESI-MS)m / z:[M+H] + calcd for C 24 H 17 FN4O3S:461.1083,found:461.1068.

[0116] 4-Bromo-N'-(1-phenyl-9H-pyrido[3,4-b]indole-3-carbonyl)benzenesulfonyl hydrazide(f7).Yield 71%;White solid;m.p.288.2-289.6℃; 1 H NMR(500 MHz,DMSO-d6)δ11.94(s,1H),10.54(s,1H),10.24(s,1H),8.71(s,1H),8.41(d,J=10.0 Hz,1H),8.21(d,J=10.0 Hz,2H),7.89(d,J=10.0 Hz,2H),7.69(d,J=10.0 Hz,1H),7.67(s,1H),7.65(s,1H),7.64(s,1H),7.61(s,1H),7.59(s,1H),7.58(s,1H),7.30(s,1H); 13C NMR(126 MHz,DMSO-d6)δ164.02,141.51,140.96,138.44,138.07,137.84,137.23,134.47,129.70,129.66,129.10,129.05,128.99,128.74,122.18,121.12,120.36,113.99,112.74;HRMS(ESI-MS)m / z:[M+H] + calcd for C 24 H 17 ClN4O3S:477.0788,found:477.0773.

[0117] 3-Bromo-N'-(1-phenyl-9H-pyrido[3,4-b]indole-3-carbonyl)benzenesulfonyl hydrazide(f8).Yield 75%;White solid;m.p.356.2-357.9℃; 1 H NMR(500 MHz,DMSO-d6)δ11.93(s,1H),10.59(s,1H),10.32(s,1H),8.70(s,1H),8.41(d,J=10.0 Hz,1H),8.21(d,J=5.0 Hz,2H),8.03(t,J=5.0 Hz,1H),7.88(d,J=10.0 Hz,1H),7.85(d,J=10.0 Hz,1H),7.69(d,J=10.0 Hz,1H),7.67(s,1H),7.65(s,1H),7.60(d,J=5.0 Hz,1H),7.58(s,1H),7.51(t,J=10.0 Hz,1H),7.31(t,J=10.0Hz,1H); 13 C NMR(126MHz,DMSO-d6)δ164.13,141.51,140.97,138.09,137.23,134.47,133.48,132.93,130.90,129.69,129.10,128.98,128.85,128.75,127.26,126.34,122.18,121.13,120.36,114.00,112.74;HRMS(ESI-MS)m / z:[M+H] + calcd for C 24 H 17 ClN4O3S:477.0788,found:477.0773.

[0118] 2-Bromo-N'-(1-phenyl-9H-pyrido[3,4-b]indole-3-carbonyl)benzenesulfonyl hydrazide(f9).Yield 75%;White solid;m.p.364.2-365.4℃; 1 H NMR(500 MHz,DMSO-d6)δ11.91(s,1H),10.55(s,1H),10.17(s,1H),8.70(s,1H),8.39(d,J=10.0 Hz,1H),8.19(d,J=10.0 Hz,2H),8.00(d,J=10.0 Hz,1H),7.69(s,1H),7.68(s,1H),7.65(s,1H),7.64(s,1H),7.62(s,1H),7.60(d,J=10.0Hz,1H),7.56(d,J=10.0 Hz,1H),7.44(t,J=5.0 Hz,1H),7.29(d,J=10.0 Hz,1H); 13 C NMR(126 MHz,DMSO-d6)δ164.28,141.49,140.89,138.09,137.58,137.20,134.43,134.24,132.11,131.73,131.06,129.69,129.08,128.95,128.84,128.74,127.14,122.13,121.12,120.34,114.02,112.73;HRMS(ESI-MS)m / z:[M+H] + calcd for C 24 H 17 ClN4O3S:477.0788,found:477.0773.

[0119] 4-Chloro-N'-(1-phenyl-9H-pyrido[3,4-b]indole-3-carbonyl)benzenesulfonyl hydrazide(f10).Yield 72%;White solid;m.p.383.4-384.2℃; 1HNMR(500 MHz,DMSO-d6)δ11.93(s,1H),10.52(s,1H),10.23(s,1H),8.71(s,1H),8.41(d,J=10.0 Hz,1H),8.20(d,J=5.0 Hz,2H),7.82(s,1H),7.80(s,1H),7.79(s,1H),7.77(s,1H),7.68(s,1H),7.67(s,1H),7.65(s,1H),7.60(s,1H),7.58(s,1H),7.30(s,1H); 13 C NMR(126 MHz,DMSO-d6)δ164.01,141.50,140.95,138.87,138.07,137.22,134.46,131.98,129.72,129.69,128.97,128.73,126.88,122.16,121.11,120.35,113.97,112.73;HRMS(ESI-MS)m / z:[M+H] + calcd for C 24 H 17 BrN4O3S:523.0260,found:523.0244.

[0120] 3-Chloro-N'-(1-phenyl-9H-pyrido[3,4-b]indole-3-carbonyl)benzenesulfonyl hydrazide(f11).Yield 76%;White solid;m.p.298.0-299.8℃; 1 HNMR(500 MHz,DMSO-d6)δ11.93(s,1H),10.59(s,1H),10.32(s,1H),8.70(s,1H),8.41(d,J=10.0 Hz,1H),8.21(d,J=5.0 Hz,2H),8.03(t,J=5.0 Hz,1H),7.88(d,J=10.0 Hz,1H),7.85(d,J=5.0 Hz,1H),7.70(s,1H),7.65(t,J=15.0 Hz,3H),7.59(d,J=5.0 Hz,1H),7.51(t,J=10.0 Hz,1H),7.30(d,J=10.0 Hz,1H); 13C NMR(126MHz,DMSO-d6)δ164.12,141.60,141.50,140.97,138.09,137.22,135.77,134.46,131.11,130.01,129.68,129.08,128.96,128.74,126.64,122.16,121.76,121.12,120.35,113.99,112.73;HRMS(ESI-MS)m / z:[M+H] + calcd for C 24 H 17 BrN4O3S:523.0260,found:523.0248.

[0121] 2-Chloro-N'-(1-phenyl-9H-pyrido[3,4-b]indole-3-carbonyl)benzenesulfonyl hydrazide(f12).Yield 75%;White solid;m.p.274.5-275.8℃; 1 HNMR(500 MHz,DMSO-d6)δ11.91(s,1H),10.53(s,1H),10.10(s,1H),8.72(s,1H),8.39(d,J=10.0 Hz,1H),8.19(d,J=5.0 Hz,2H),8.07(d,J=10.0 Hz,1H),7.87(d,J=5.0 Hz,1H),7.68(d,J=10.0 Hz,1H),7.64(d,J=10.0 Hz,1H),7.62(d,J=10.0 Hz,1H),7.59(s,1H),7.57(s,1H),7.53(d,J=10.0 Hz,1H),7.50(d,J=10.0 Hz,1H),7.30(t,J=5.0 Hz,1H); 13 C NMR(126 MHz,DMSO-d6)δ164.28,141.50,140.90,139.21,138.10,137.21,135.27,134.44,134.18,131.33,129.69,129.07,128.95,128.74,127.71,122.13,121.12,120.56,120.35,114.04,112.73;HRMS(ESI-MS)m / z:[M+H] + calcd for C 24 H 17BrN4O3S:523.0260,found:523.0245.

[0122] 4-Iodo-N'-(1-phenyl-9H-pyrido[3,4-b]indole-3-carbonyl)benzenesulfonylhydrazide(f13).Yield 60%;White solid;m.p.371.0-372.5℃; 1 H NMR(500 MHz,DMSO-d6)δ11.93(s,1H),10.49(s,1H),10.20(s,1H),8.71(s,1H),8.41(d,J=10.0 Hz,1H),8.20(d,J=10.0 Hz,2H),7.96(d,J=10.0 Hz,2H),7.69(d,J=10.0 Hz,1H),7.67(s,1H),7.65(d,J=5.0 Hz,1H),7.64(s,1H),7.63(s,1H),7.60(d,J=5.0 Hz,1H),7.58(d,J=10.0Hz,1H),7.31(t,J=10.0 Hz,1H); 13 C NMR(126MHz,DMSO-d6)δ163.99,149.61,141.51,140.94,139.19,138.08,137.80,137.22,134.46,129.69,129.38,129.09,128.97,128.75,123.93,122.17,121.12,120.36,113.98,112.73,101.32;HRMS(ESI-MS)m / z:[M+H] + calcdfor C 24 H 17 IN4O3S:569.0144,found:569.0131.

[0123] 4-Cyano-N'-(1-phenyl-9H-pyrido[3,4-b]indole-3-carbonyl)benzenesulfonyl hydrazide(f14).Yield 67%;White solid;m.p.343.7-344.3℃; 1HNMR(500 MHz,DMSO-d6)δ11.93(s,1H),10.67(s,1H),10.47(s,1H),8.68(s,1H),8.40(d,J=10.0 Hz,1H),8.22(d,J=10.0 Hz,2H),8.07(s,1H),8.06(s,1H),8.05(s,1H),8.04(s,1H),7.69(d,J=10.0 Hz,1H),7.66(d,J=10.0 Hz,1H),7.64(s,1H),7.60(d,J=5.0 Hz,1H),7.57(d,J=10.0 Hz,1H),7.30(t,J=10.0 Hz,1H); 13 C NMR(126 MHz,DMSO-d6)δ164.24,144.10,141.50,140.99,138.00,137.21,134.49,133.02,129.68,129.10,129.01,128.75,128.73,128.42,122.18,121.11,120.37,117.89,115.16,114.04,112.74;HRMS(ESI-MS)m / z:[M+H] + calcd for C 25 H 17 N5O3S:468.1115,found:468.1131.

[0124] 3-Cyano-N'-(1-phenyl-9H-pyrido[3,4-b]indole-3-carbonyl)benzenesulfonyl hydrazide(f15).Yield 73%;White solid;m.p.322.9-323.5℃; 1 HNMR(500 MHz,DMSO-d6)δ11.93(s,1H),10.67(s,1H),10.44(s,1H),8.68(s,1H),8.41(d,J=7.9 Hz,1H),8.30(s,1H),8.21(d,J=10.0 Hz,2H),8.16(d,J=10.0 Hz,2H),7.77(t,J=10.0 Hz,1H),7.69(d,J=10.0 Hz,1H),7.67(s,1H),7.65(s,1H),7.59(s,1H),7.57(d,J=5.0 Hz,1H),7.30(t,J=10.0 Hz,1H); 13C NMR(126 MHz,DMSO-d6)δ164.30,141.50,141.11,141.01,138.01,137.21,136.45,134.49,132.10,131.30,130.36,129.67,129.09,129.00,128.85,128.74,122.19,121.12,120.36,117.67,114.03,112.74,112.07;HRMS(ESI-MS)m / z:[M+H] + calcd for C 25 H 17 N5O3S:468.1115,found:468.1131.

[0125] 2-Cyano-N'-(1-phenyl-9H-pyrido[3,4-b]indole-3-carbonyl)benzenesulfonyl hydrazide(f16).Yield 77%;White solid;m.p.299.9-300.5℃; 1 HNMR(500 MHz,DMSO-d6)δ11.93(s,1H),10.69(s,1H),10.45(s,1H),8.68(s,1H),8.41(d,J=10.0 Hz,1H),8.31(s,1H),8.22(s,1H),8.21(s,1H),8.18(s,1H),8.16(d,J=5.0 Hz,1H),7.77(t,J=10.0 Hz,1H),7.69(d,J=10.0 Hz,1H),7.66(d,J=10.0 Hz,1H),7.64(s,1H),7.60(d,J=5.0 Hz,1H),7.58(s,1H),7.30(t,J=10.0 Hz,1H); 13 C NMR(126 MHz,DMSO-d6)δ164.45,149.63,141.50,140.96,138.01,137.22,135.61,134.47,133.34,130.09,129.63,129.07,129.02,128.72,123.93,122.13,121.11,120.35,116.34,114.01,112.74,110.53;HRMS(ESI-MS)m / z:[M+H] + calcd for C 25 H 17N5O3S:468.1117,found:468.1131.

[0126] 3-Methoxy-N'-(1-phenyl-9H-pyrido[3,4-b]indole-3-carbonyl)benzenesulfonyl hydrazide(f17).Yield 71%;White solid;m.p.345.2-346.8℃; 1 HNMR(500 MHz,DMSO-d6)δ11.93(s,1H),10.37(s,1H),10.07(s,1H),8.72(s,1H),8.41(d,J=10.0 Hz,1H),8.16(d,J=10.0 Hz,2H),7.69(d,J=10.0 Hz,1H),7.65(d,J=10.0 Hz,1H),7.64(d,J=5.0 Hz,1H),7.60(d,J=10.0 Hz,1H),7.57(d,J=10.0 Hz,1H),7.47(d,J=10.0 Hz,1H),7.45(d,J=5.0 Hz,1H),7.40(s,1H),7.31(t,J=10.0 Hz,1H),7.24(d,J=10.0 Hz,1H),3.74(s,3H); 13 C NMR(126 MHz,DMSO-d6)δ163.81,159.20,141.52,140.90,140.39,138.16,137.22,134.44,130.11,129.72,129.10,128.88,128.76,122.16,121.12,120.36,119.79,119.13,113.91,112.74,112.41,55.46;HRMS(ESI-MS)m / z:[M+H] + calcdfor C 25 H 20 N4O4S:473.1269,found:473.1284.

[0127] 2-Methoxy-N'-(1-phenyl-9H-pyrido[3,4-b]indole-3-carbonyl)benzenesulfonyl hydrazide(f18).Yield 75%;White solid;m.p.372.2-373.4℃; 1HNMR(500 MHz,DMSO-d6)δ11.93(s,1H),10.32(s,1H),9.57(s,1H),8.74(s,1H),8.41(d,J=10.0 Hz,1H),8.13(s,2H),7.75(d,J=10.0 Hz,1H),7.69(d,J=10.0 Hz,1H),7.66(s,1H),7.64(s,1H),7.63(s,1H),7.61(s,1H),7.58(s,1H),7.30(t,J=10.0 Hz,1H),7.26(d,J=10.0 Hz,1H),7.01(t,J=10.0 Hz,1H),3.94(s,3H); 13 C NMR(126 MHz,DMSO-d6)δ163.73,157.30,149.64,141.51,140.91,138.05,137.19,136.16,135.08,134.44,129.77,129.72,129.12,128.87,128.78,127.12,123.93,122.19,121.13,120.36,119.75,113.92,112.99,112.73,56.39;HRMS(ESI-MS)m / z:[M+H] + calcd for C 25 H 20 N4O4S:473.1271,found:473.1284.

[0128] 4-Methoxy-N'-(1-phenyl-9H-pyrido[3,4-b]indole-3-carbonyl)benzenesulfonyl hydrazide(f19).Yield 76%;White solid;m.p.383.6-384.4℃; 1HNMR(500 MHz,DMSO-d6)δ11.93(s,1H),10.29(s,1H),9.88(s,1H),8.71(s,1H),8.40(d,J=10.0 Hz,1H),8.17(d,J=5.0 Hz,2H),7.82(d,J=10.0 Hz,2H),7.69(d,J=10.0 Hz,1H),7.66(s,1H),7.64(d,J=5.0 Hz,1H),7.60(d,J=10.0Hz,1H),7.57(d,J=10.0 Hz,1H),7.30(t,J=10.0 Hz,1H),7.08(d,J=10.0 Hz,2H),3.82(s,3H); 13 C NMR(126 MHz,DMSO-d6)δ163.65,162.70,141.52,140.90,138.15,137.23,134.45,130.55,129.98,129.72,129.12,128.91,128.76,122.16,121.12,120.36,114.14,113.87,112.74,55.66;HRMS(ESI-MS)m / z:[M+H] + calcd for C 25 H 20 N4O4S:473.1270,found:473.1284.

[0129] 4-Nitro-N'-(1-phenyl-9H-pyrido[3,4-b]indole-3-carbonyl)benzenesulfonyl hydrazide(f20).Yield 73%;White solid;m.p.312.2-313.9℃; 1 HNMR(500 MHz,DMSO-d6)δ11.93(s,1H),10.70(s,1H),10.54(s,1H),8.67(s,1H),8.40(s,1H),8.39(s,1H),8.38(s,1H),8.23(s,1H),8.21(s,1H),8.14(s,1H),8.13(s,1H),7.69(d,J=10.0 Hz,1H),7.66(s,1H),7.65(s,1H),7.59(s,1H),7.58(d,J=5.0 Hz,1H),7.30(t,J=5.0 Hz,1H); 13C NMR(126 MHz,DMSO-d6)δ164.30,149.81,145.67,141.51,141.00,138.03,137.21,134.48,129.67,129.31,129.10,129.02,128.75,128.72,124.15,122.14,121.10,120.36,114.03,112.75;HRMS(ESI-MS)m / z:[M+H] + calcd for C 24 H 17 N5O5S:488.1015,found:488.1028.

[0130] 3-Nitro-N'-(1-phenyl-9H-pyrido[3,4-b]indole-3-carbonyl)benzenesulfonyl hydrazide(f21).Yield 79%;White solid;m.p.396.2-397.8℃; 1 HNMR(500 MHz,DMSO-d6)δ11.92(s,1H),10.72(s,1H),10.52(s,1H),8.66(s,2H),8.52(d,J=10.0 Hz,1H),8.39(d,J=10.0 Hz,1H),8.28(d,J=10.0 Hz,1H),8.21(d,J=10.0 Hz,2H),7.86(t,J=10.0 Hz,1H),7.69(d,J=10.0 Hz,1H),7.65(d,J=10.0 Hz,1H),7.63(s,1H),7.59(s,1H),7.57(d,J=5.0 Hz,1H),7.29(t,J=10.0 Hz,1H); 13 C NMR(126 MHz,DMSO-d6)δ164.33,147.61,141.51,140.99,138.00,137.19,134.47,133.73,130.92,129.65,129.08,128.99,128.84,128.72,127.50,122.58,122.16,121.10,120.35,114.00,112.72;HRMS(ESI-MS)m / z:[M+H] + calcd for C 24 H 17 N5O5S:488.1016,found:488.1028.

[0131] 2-Nitro-N'-(1-phenyl-9H-pyrido[3,4-b]indole-3-carbonyl)benzenesulfonyl hydrazide(f22).Yield 66%;White solid;m.p.279.2-280.6℃; 1 HNMR(500 MHz,DMSO-d6)δ11.92(s,1H),10.56(s,1H),10.18(s,1H),8.71(s,1H),8.39(d,J=10.0 Hz,1H),8.20(d,J=10.0 Hz,2H),8.01(d,J=10.0 Hz,1H),7.70(s,1H),7.68(s,1H),7.65(s,1H),7.64(s,1H),7.62(s,1H),7.60(d,J=10.0Hz,1H),7.56(d,J=10.0 Hz,1H),7.44(t,J=10.0 Hz,1H),7.31(d,J=10.0 Hz,1H); 13 C NMR(126 MHz,DMSO-d6)δ164.47,147.62,141.51,140.96,138.14,137.23,134.48,132.70,132.55,130.94,129.69,129.09,129.01,128.84,128.75,124.48,122.14,121.13,120.36,114.07,112.76;HRMS(ESI-MS)m / z:[M+H] + calcd for C 24 H 17 N5O5S:488.1014,found:488.1028.

[0132] 4-Hydroxy-N'-(1-phenyl-9H-pyrido[3,4-b]indole-3-carbonyl)benzenesulfonyl hydrazide(f23).Yield 64%;White solid;m.p.333.9-334.7℃; 1HNMR(500 MHz,DMSO-d6)δ11.93(s,1H),10.48(s,1H),10.18(s,1H),9.78–9.66(m,1H),8.72(s,1H),8.41(d,J=10.0 Hz,1H),8.15(d,J=5.0 Hz,2H),7.71(s,1H),7.69(s,1H),7.67(d,J=10.0 Hz,1H),7.65(s,1H),7.64(s,1H),7.60(d,J=10.0 Hz,1H),7.57(d,J=5.0Hz,1H),7.31(t,J=5.0 Hz,1H),6.87(d,J=10.0 Hz,2H); 13 C NMR(126 MHz,DMSO-d6)δ164.47,147.62,141.51,140.96,138.14,137.23,134.48,132.70,132.55,130.94,129.69,129.09,129.01,128.84,128.75,124.48,122.14,121.13,120.36,114.07,112.76;HRMS(ESI-MS)m / z:[M+H] + calcd for C 24 H 18 N4O4S:459.1127,found:459.1113.

[0133] N'-(1-phenyl-9H-pyrido[3,4-b]indole-3-carbonyl)-4-(trifluoromethyl)benzenesulfonyl hydrazide(f24).Yield 69%;White solid;m.p.294.8-295.1℃; 1 HNMR(500 MHz,DMSO-d6)δ11.94(s,1H),10.63(s,1H),10.41(s,1H),8.69(s,1H),8.39(d,J=10.0 Hz,1H),8.22(d,J=10.0 Hz,2H),8.10(d,J=10.0 Hz,2H),7.97(d,J=10.0 Hz,2H),7.69(d,J=10.0 Hz,1H),7.65(d,J=10.0 Hz,1H),7.63(s,1H),7.60(d,J=5.0 Hz,1H),7.58(s,1H),7.30(t,J=10.0 Hz,1H);13 C NMR(126MHz,DMSO-d6)δ164.23,143.80,141.51,140.99,138.09,137.24,134.48,132.58,132.33,129.68,129.10,129.00,178.75,128.71,128.65,126.09,126.06,122.54,122.15,121.12,120.36,114.00,112.74;HRMS(ESI-MS)m / z:[M+H] + calcd for C 25 H 17 F3N4O3S:511.1052,found:511.1039.

[0134] N'-(1-phenyl-9H-pyrido[3,4-b]indole-3-carbonyl)-4-(trifluoromethoxy)benzenesulfonyl hydrazide(f25).Yield 69%;White solid;m.p.376.4-377.2℃; 1 HNMR(500 MHz,DMSO-d6)δ11.93(s,1H),10.56(s,1H),10.25(s,1H),8.68(s,1H),8.39(d,J=10.0 Hz,1H),8.21(d,J=10.0 Hz,2H),8.02(d,J=10.0 Hz,2H),7.70(d,J=10.0 Hz,1H),7.65(d,J=10.0 Hz,1H),7.63(s,1H),7.59(s,1H),7.58(s,1H),7.57(s,1H),7.56(s,1H),7.31(s,1H); 13 C NMR(126 MHz,DMSO-d6)δ164.11,151.24,141.51,140.97,138.50,138.14,137.23,134.47,130.34,129.67,129.08,128.97,128.74,128.71,122.09,121.10,121.00,120.92,120.36,113.89,112.74;HRMS(ESI-MS)m / z:[M+H] + calcd forC 25 H 17 F3N4O4S:527.1001,found:527.0986.

[0135] 4-(Tert-butyl)-N'-(1-phenyl-9H-pyrido[3,4-b]indole-3-carbonyl)benzenesulfonyl hydrazide(f26).Yield 71%;White solid;m.p.326.4-327.9 oC; 1 HNMR(500 MHz,DMSO-d6)δ11.93(s,1H),10.28(s,1H),9.93(s,1H),8.72(s,1H),8.39(d,J=10.0 Hz,1H),8.16(d,J=5.0 Hz,2H),7.83(d,J=10.0 Hz,2H),7.69(d,J=10.0 Hz,1H),7.65(d,J=5.0 Hz,1H),7.62(s,1H),7.61(s,1H),7.60(s,1H),7.58(s,1H),7.57(d,J=5.0 Hz,1H),7.31(t,J=5.0 Hz,1H),1.29(s,9H); 13 C NMR(126 MHz,DMSO-d6)δ163.90,155.96,141.53,140.94,138.27,137.26,136.40,134.47,129.69,129.07,128.88,128.76,127.54,125.80,122.10,121.11,120.37,113.86,112.76,34.90,30.84;HRMS(ESI-MS)m / z:[M+H] + calcd for C 28 H 26 N4O3S:499.1805,found:499.1786.

[0136] N'-(1-phenyl-9H-pyrido[3,4-b]indole-3-carbonyl)-[1,1'-biphenyl]-4-sulfonohydrazide(f27).Yield 70%;White solid;m.p.274.9-275.8℃; 1H NMR(500MHz,DMSO-d6)δ11.93(s,1H),10.44(s,1H),10.12(s,1H),8.71(s,1H),8.38(d,J=10.0Hz,1H),8.18(d,J=5.0 Hz,2H),7.97(d,J=10.0 Hz,2H),7.88(d,J=10.0 Hz,2H),7.75(d,J=5.0 Hz,2H),7.69(d,J=10.0 Hz,1H),7.62(s,1H),7.61(s,1H),7.59(d,J=5.0Hz,1H),7.55(d,J=10.0 Hz,1H),7.53(s,1H),7.51(s,1H),7.44(t,J=10.0 Hz,1H),7.31-7.27(m,1H); 13 C NMR(126 MHz,DMSO-d6)δ163.92,144.23,141.51,140.94,138.40,138.18,137.24,134.46,129.69,129.18,129.06,128.93,128.73,128.60,128.38,127.05,127.00,122.14,121.11,120.34,113.92,112.73;HRMS(ESI-MS)m / z:[M+H] + calcdforC 30 H 22 N4O3S:519.1493,found:519.1476.

[0137] 3,4,5-Trifluoro-N'-(1-phenyl-9H-pyrido[3,4-b]indole-3-carbonyl)benzenesulfonyl hydrazide(f28).Yield 64%;White solid;m.p.354.9-355.5℃; 1 HNMR(500 MHz,DMSO-d6)δ11.93(s,1H),10.68(s,1H),10.49(s,1H),8.74(s,1H),8.42(d,J=10.0 Hz,1H),8.22(d,J=5.0 Hz,2H),7.85(t,J=5.0 Hz,2H),7.69(d,J=10.0 Hz,1H),7.66(s,1H),7.64(s,1H),7.59(s,1H),7.58(s,1H),7.31(t,J=10.0 Hz,1H);13 C NMR(126 MHz,DMSO-d6)δ164.48,150.94,149.00,148.92,141.52,141.00,138.05,137.23,136.47,134.51,129.72,129.11,129.01,128.75,128.71,122.21,121.14,120.37,114.12,113.57,113.08,112.75;HRMS(ESI-MS)m / z:[M+H] + calcd for C 24 H 15 F3N4O3S:497.0895,found:497.0880.

[0138] 2,5-Dichloro-N'-(1-phenyl-9H-pyrido[3,4-b]indole-3-carbonyl)benzenesulfonyl hydrazide(f29).Yield 70%;White solid;m.p.348.7-349.8℃; 1 HNMR(500 MHz,DMSO-d6)δ11.93(s,1H),10.71(s,1H),10.44(s,1H),8.75(s,1H),8.40(d,J=10.0 Hz,1H),8.22(d,J=10.0 Hz,2H),8.02(s,1H),7.73(s,2H),7.70(d,J=5.0 Hz,1H),7.66(s,1H),7.63(s,1H),7.60(d,J=10.0 Hz,1H),7.56(d,J=10.0 Hz,1H),7.30(t,J=10.0 Hz,1H); 13 C NMR(126 MHz,DMSO-d6)δ164.63,141.52,140.99,139.65,138.10,137.22,134.50,133.83,133.49,131.52,130.96,130.05,129.73,129.09,129.00,128.84,128.74,122.16,121.15,120.37,114.15,112.76;HRMS(ESI-MS)m / z:[M+H] + calcd forC 24 H 16 Cl2N4O3S:511.0398,found:511.0382.

[0139] 3,4-Dichloro-N'-(1-phenyl-9H-pyrido[3,4-b]indole-3-carbonyl)benzenesulfonyl hydrazide(f30).Yield 66%;White solid;m.p.363.4-364.8℃; 1 HNMR(500 MHz,DMSO-d6)δ11.93(s,1H),10.64(s,1H),8.72(s,1H),8.41(d,J=10.0 Hz,1H),8.21(d,J=10.0 Hz,2H),8.07(s,1H),7.84(d,J=10.0 Hz,1H),7.81(d,J=10.0 Hz,1H),7.69(d,J=10.0 Hz,1H),7.66(s,1H),7.65(s,1H),7.63(s,1H),7.59(s,1H),7.58(s,1H),7.31(d,J=10.0 Hz,1H); 13 C NMR(126 MHz,DMSO-d6)δ164.18,141.50,140.98,140.37,138.12,137.23,135.79,134.47,131.71,131.23,129.70,129.37,129.09,128.99,128.84,128.73,127.74,122.12,121.13,120.35,114.03,112.73;HRMS(ESI-MS)m / z:[M+H] + calcd for C 24 H 16 Cl2N4O3S:511.0398,found:511.0381.

[0140] 2,4,6-Trichloro-N'-(1-phenyl-9H-pyrido[3,4-b]indole-3-carbonyl)benzenesulfonyl hydrazide(f31).Yield 75%;White solid;m.p.343.7-344.1℃; 1HNMR(500 MHz,DMSO-d6)δ11.93(s,1H),10.75(s,1H),10.44(s,1H),8.74(d,J=5.0 Hz,1H),8.40(d,J=10.0 Hz,1H),8.22(d,J=5.0Hz,2H),7.85(s,2H),7.69(d,J=10.0 Hz,1H),7.65(d,J=10.0 Hz,1H),7.63(s,1H),7.60(d,J=10.0 Hz,1H),7.57(d,J=5.0 Hz,1H),7.30(t,J=10.0 Hz,1H); 13 C NMR(126 MHz,DMSO-d6)δ164.73,141.50,140.95,137.98,137.19,137.08,135.85,135.31,134.47,130.79,129.70,129.08,129.02,128.73,122.16,121.13,120.36,114.18,112.74;HRMS(ESI-MS)m / z:[M+H] + calcdforC 24 H 15 Cl3N4O3S:546.9977,found:546.9957.

[0141] 2,5-Dibromo-N'-(1-phenyl-9H-pyrido[3,4-b]indole-3-carbonyl)benzenesulfonyl hydrazide(f32).Yield 69%;White solid;m.p.377.9-378.0℃; 1 HNMR(500 MHz,DMSO-d6)δ11.93(s,1H),10.65(s,1H),10.38(s,1H),8.76(s,1H),8.41(d,J=10.0 Hz,1H),8.21(s,1H),8.20(s,2H),7.80(d,J=10.0 Hz,1H),7.74(d,J=5.0 Hz,1H),7.69(d,J=10.0 Hz,1H),7.65(s,1H),7.63(s,1H),7.60(d,J=10.0 Hz,1H),7.57(s,1H),7.31(t,J=10.0 Hz,1H); 13C NMR(126 MHz, DMSO-d6)δ164.43,141.50,140.95,138.19,137.22,137.16,136.58,134.46,133.00,129.71,129. 07,128.97,128.75,122.17,121.14,120.35,120.30,119.66,114.08,112.74; HRMS(ESI-MS)m / z:[M+H] + cal cd forC 24 H 16 Br2N4O3S:600.9364,found:600.9350.

[0142] The results above show that a series of β-carboline derivatives containing benzenesulfonamide structures can be successfully prepared by the above synthetic route, and the preparation method has the advantages of high yield and simple operation.

[0143] Example 2

[0144] This embodiment provides a test for the α-glucosidase inhibitory activity of β-carboline derivatives containing a benzenesulfonamide structure. 1. Preparation of reagents and standard solutions

[0145] (1) 100mM phosphate buffer (PBS, pH 6.8): Weigh a certain amount of potassium dihydrogen phosphate and disodium hydrogen phosphate, dissolve them in ultrapure water, and use them to dissolve and dilute the reagent.

[0146] (2) Preparation of α-glucosidase solution: Add an appropriate amount of 100mM PBS to the enzyme with an activity of 100U to prepare a working concentration of 0.05U / mL, and then dispense and freeze.

[0147] (3) Substrate preparation: Accurately weigh an appropriate amount of 4-nitrophenyl-D-pyranoside (PNPG), add 100mM PBS solution to dissolve, prepare a substrate working solution with a concentration of 0.25mM, vortex mix well, and prepare fresh before each experiment.

[0148] Preparation of test drug: Accurately weigh an appropriate amount of the test drug, dissolve it in DMSO to prepare a 10 mM stock solution, and store it at -20℃ protected from light. Before the experiment, dilute with DMSO to different required concentrations (0–200 μM), with the DMSO content equal to 5%.

[0149] 2. Experimental Procedure

[0150] (1) Add 10 μL of α-glucosidase with a working concentration of 0.05 U / mL, 130 μL of phosphate buffer (pH 6.8) with a concentration of 100 mM, and 10 μL of compounds of different concentrations (β-carboline derivatives f1 to f32 containing benzenesulfonamide structure prepared in Example 1) to a 96-well plate in sequence. Replace 10 μL of the compound with 10 μL of DMSO with a content of 5% in the blank control group. Use acarbose as a positive control. Set up 4 replicates for each group. Incubate the enzyme reaction system on a microplate reader at 37°C for 10 min.

[0151] (2) Subsequently, 50 μL of substrate PNPG was added to the enzyme reaction system to start the enzyme reaction. The microplate was placed on the microplate reader and incubated at 37°C for 15 min. During the incubation, the time was evenly distributed 3 times, and the reading was taken once at a wavelength of 405 nm for each time period. The readings were recorded as OD1, OD2, and OD3.

[0152] (3) The α-glucosidase inhibitory activity of the test compound is calculated according to the following formula:

[0153] Inhibition rate (%) = [(OD3-OD)-(OD1-OD)] / OD3-OD × 100%

[0154] Where OD represents the absorbance value of the blank control group. Data processing: Data were analyzed and processed using MS Excel, and the half-maximal inhibitory concentration (IC50) was calculated using Origin 9.1. 50 IC 50 This represents the concentration of the test compound required to inhibit α-glucosidase activity by 50% under the experimental conditions stated.

[0155] 3. Results Analysis

[0156] The α-glucosidase inhibitory activity of the synthesized compounds was evaluated using in vitro enzymatic experiments, and the results are shown in Table 2.

[0157] Table 2. Results of in vitro inhibitory activity of compounds f1–f32 against α-glucosidase.

[0158]

[0159] The positive control drug, acarbose, had an IC50 value of [missing information]. 50 The concentration was 579.67 μM. Previous literature has reported that β-carboline alone has an IC50 concentration of 579.67 μM. 50 The concentration was 180 ± 3.2 μM. Table 2 shows that compounds f1–f32 all exhibited inhibitory activity against α-glucosidase, with the strongest being bio-f27, exhibiting an inhibition rate of 2.12 ± 0.33 μM, which is 273 times that of acarbose. The half-maximal inhibitory concentration (IC50) of bio-f27 is shown in the figure. Figure 1 As shown. The results indicate that these derivatives exhibit strong binding affinity when interacting with α-glucosidase. Therefore, it can be inferred that the β-carboline derivatives containing the benzenesulfonamide structure of this invention have good α-glucosidase inhibitory activity, and compounds f1 to f32 can all be used as α-glucosidase inhibitors for the treatment or prevention of diabetes.

[0160] Example 3 Enzyme kinetics experiment

[0161] In this embodiment, in vitro enzyme kinetics experiments were used to evaluate the α-glucosidase inhibitory activity of the synthesized compound f27.

[0162] 1. Preparation of reagents and standard solutions

[0163] (1) 100mM phosphate buffer (PBS, pH 6.8): Weigh a certain amount of potassium dihydrogen phosphate and disodium hydrogen phosphate, dissolve them in ultrapure water, and use them to dissolve and dilute the reagent.

[0164] (2) Preparation of α-glucosidase solution: Add an appropriate amount of 100mM PBS to the enzyme with an activity of 100U to prepare working concentrations of 0.0375U / mL, 0.05U / mL, 0.0625U / mL and 0.075U / mL, and then dispense and freeze.

[0165] (3) Substrate preparation: Accurately weigh an appropriate amount of 4-nitrophenyl-D-pyranoside (PNPG), add 100mM PBS solution to dissolve, prepare a substrate working solution with a concentration of 0.25mM, vortex mix well, and prepare fresh before each experiment.

[0166] Preparation of test drug: Accurately weigh an appropriate amount of the test drug, dissolve it in DMSO to prepare a 10 mM stock solution, and store it at -20℃ protected from light. Before the experiment, dilute with DMSO to different required concentrations (0–200 μM), with the DMSO content equal to 5%.

[0167] 2. Experimental Procedure

[0168] (1) 10 μL of α-glucosidase with concentrations of 0.0375 U / mL, 0.05 U / mL, 0.0625 U / mL and 0.075 U / mL, respectively, 130 μL of 100 mM phosphate buffer (pH 6.8), and 10 μL of compound (compound f27 prepared in Example 1) with different concentrations (0 μM, 1 μM, 2 μM and 4 μM) were added to a 96-well plate. The blank control group was replaced with 10 μL of DMSO with a content of 5%. Acarbose was used as a positive control. Four replicates were set up for each group. The enzyme reaction system was incubated at 37°C for 10 min on a microplate reader.

[0169] (2) Subsequently, 50 μL of substrate PNPG with a concentration of 0.25 mM was added to the enzyme reaction system to start the enzyme reaction. The microplate was placed on the microplate reader and incubated at 37°C for 15 min. During the incubation process, the time was evenly divided into 3 times, and the reading was taken once at a wavelength of 405 nm for each time period. The readings were recorded as OD1, OD2, and OD3.

[0170] (3) Data processing: MS Excel was used to analyze and process the data. The reaction rate of the enzyme reaction system was ΔOD / min.

[0171] 3. Results Analysis

[0172] The results of the enzyme kinetic inhibition type evaluation experiment of β-carboline derivative f27 containing benzenesulfonamide structure are as follows: Figure 2 As shown. The results indicate that the inhibitor binds to the enzyme via non-covalent bonds, repressing its activity in a reversible manner. Results for other compounds are similar; to avoid redundancy, they are not shown individually.

[0173] Example 4: Substrate Dynamics Experiment

[0174] In this embodiment, in vitro substrate kinetics experiments were used to evaluate the α-glucosidase inhibitory activity kinetics of the synthesized active compound:

[0175] 1. Preparation of reagents and standard solutions

[0176] (1) 100mM phosphate buffer (PBS, pH 6.8): Weigh a certain amount of potassium dihydrogen phosphate and disodium hydrogen phosphate, dissolve them in ultrapure water, and use them to dissolve and dilute the reagent.

[0177] (2) Preparation of α-glucosidase solution: Add an appropriate amount of 100mM PBS to the enzyme with an activity of 100U to prepare a working concentration of 0.05U / mL, and then dispense and freeze.

[0178] (3) Substrate preparation: Accurately weigh an appropriate amount of 4-nitrophenyl-D-pyranoside (PNPG), add 100mM PBS solution to dissolve, and prepare substrate working solutions with concentrations of (0.25mM, 0.5mM, 0.75mM, 1mM). Vortex mix well and prepare fresh before each experiment.

[0179] Preparation of test drug: Accurately weigh an appropriate amount of the test drug, dissolve it in DMSO to prepare a 10 mM stock solution, and store it at -20℃ protected from light. Before the experiment, dilute with DMSO to different required concentrations (0–200 μM), with the DMSO content equal to 5%.

[0180] 2. Experimental Procedure

[0181] (1) Add 10 μL of 0.5 U / mL α-glucosidase, 130 μL of 100 mM phosphate buffer (pH 6.8), and 10 μL of different concentrations (0 μM, 1 μM, 2 μM, 4 μM) of compound (compound f27 prepared in Example 1) to a 96-well plate in sequence. Replace 10 μL of compound with 10 μL of 5% DMSO for the blank control group. Use acarbose as a positive control. Set up 4 replicates for each group. Incubate the enzyme reaction system on a microplate reader at 37°C for 10 min.

[0182] (2) Subsequently, 50 μL of substrate PNPG of different concentrations was added to the enzyme reaction system to start the enzyme reaction. The microplate was placed on the microplate reader and incubated at 37°C for 15 min. During the incubation, the time was evenly distributed 3 times, and the reading was taken once at a wavelength of 405 nm for each time period. The readings were recorded as OD1, OD2, and OD3.

[0183] (3) Data processing: MS Excel was used to analyze and process the data. The reaction rate of the enzyme reaction system was ΔOD / min.

[0184] 3. Results Analysis

[0185] The experimental results for evaluating the substrate kinetic inhibition type of β-carboline derivatives f27 containing benzenesulfonamide structures are as follows: Figure 3 The figures show the substrate kinetics of β-carboline derivative f27 containing benzenesulfonamide structure in vitro on α-glucosidase, corresponding to different concentrations. Figure 3 The substrate kinetics were plotted using the double reciprocal plot method. The results show that the screened inhibitors are non-competitive inhibitors, indicating that they can bind not only to α-glucosidase but also to the α-glucosidase-substrate complex. Results for other compounds were similar; to avoid redundancy, they are not shown individually.

[0186] Example 5 Cytotoxicity Experiment

[0187] In this embodiment, the MTT assay was used to evaluate the cytotoxicity of the synthesized active compound f27.

[0188] 1. Experimental Procedure

[0189] (1) Place the DMEM medium in an incubator (37°C, containing 5% CO2) for cell culture.

[0190] (2) Human normal liver cells (LO2 cells) were seeded in 96-well plates and cultured for 24 hours.

[0191] (3) After that, add solutions containing different concentrations of F27 compounds and continue culturing. Two days later, add culture medium and MTT solution and continue culturing for 4 hours.

[0192] (4) Incubate and add formazan, measure the absorbance of the solution at 490 nm using an ELISA reader, and calculate the survival rate.

[0193] 2. Results Analysis

[0194] The experimental results of β-carboline derivative f27 containing a benzenesulfonamide structure are as follows: Figure 4 As shown in the figure. The results indicate that compound f27, at concentrations ranging from 0 to 32 μM, had no significant effect on LO2 cell viability, verifying the good safety profile of f27. Results for other compounds were similar; to avoid redundancy, they are not all shown.

[0195] In summary, this invention prepared a series of β-carboline derivatives f1–f32 containing benzenesulfonamide structures and determined their activities against α-glucosidase. The results showed that all synthesized derivatives exhibited significant inhibitory activity against α-glucosidase, with compound f27 exhibiting the strongest inhibitory effect (IC50, 10⁻⁶). 50 The values ​​were 2.12 μM, which is 273 times that of acarbose, and it can be used as an α-glucosidase inhibitor for the treatment or prevention of diabetes.

[0196] The embodiments of the present invention have been described in detail above, but the present invention is not limited to the above embodiments. Within the scope of knowledge possessed by those skilled in the art, various changes can be made without departing from the spirit of the present invention.

Claims

1. A β-carboline derivative containing a benzenesulfonamide structure, characterized in that, The β-carboline derivative containing a benzenesulfonamide structure has one of the structures shown in the following formula: 。 2. An α-glucosidase inhibitor, characterized in that, Including β-carboline derivatives containing a benzenesulfonamide structure as described in claim 1.

3. The use of a β-carboline derivative containing a benzenesulfonamide structure as described in claim 1 in the preparation of products for the prevention and / or treatment of diabetes.

4. A pharmaceutical composition, characterized in that, It includes β-carboline derivatives containing a benzenesulfonamide structure as described in claim 1 and / or their pharmaceutically acceptable salts.

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