WO2007036131A1 - Carzole sulphamide derivatives and their preparation method - Google Patents

Abstract

The present application has disclosed carzole sulphamide derivatives and their pharmaceutically acceptable salts of formula (I). The compounds can be used as small molecular anti-mitotic agent. The compounds not only can inhibit tumor cell in the first mitosis, but also have remarkable antitumor activity. They have the advantage of small molecular and simple synthesis without drug resistance problems. The present application also provides pharmaceutical composition containing the carzole sulphamide derivatives as active ingredient.

Description

 Oxazole sulfonamide derivative and preparation method thereof

Technical field

 The present invention relates to a novel carbazole sulfonamide derivative and a process for the preparation thereof, and to a pharmaceutical composition containing the carbazole sulfonamide derivative as an active ingredient. Background technique

 Anti-mitotic agents are a class of potent anti-tumor drugs that block tumor cells in mitosis (M) and induce apoptosis, causing tumor atrophy or necrosis. Traditional anti-mitotic agents, mainly tubulin inhibitors, such as paclitaxel and vinblastine antitumor drugs, can inhibit the polymerization or depolymerization of microtubules and mitosis of tumor cells by combining with specific sites of tubulin. In the process, the spindle is difficult to form, the cell cycle is blocked in the M phase, and the apoptosis of the tumor cells is further induced (Li Jianong, Jiang Jiandong, Journal of Pharmaceutical Sciences, (2003), 38 (4), 311-315). Currently, acting on microtubules. The paclitaxel and vinblastine anti-mitotic agents of the protein have been widely used in the clinical treatment of various malignant tumors. However, the application and preparation of these tubulin inhibitors have the following problems: As a natural product of a macromolecule, the synthesis is difficult, the bioavailability is poor, and there are neurotoxic side effects, in particular, The emergence of multi-drug resistant glycoproteins (P-gP) has severely challenged the effectiveness of their treatment (Li, Jian-Nong; Song, Dan-Qing Lin, Yi-He; et al. Biochemical Pharmacology (2003) ), 65 (10), 1691-1699), to some extent limits the development and application of paclitaxel and vinblastine tubulin inhibitors. Therefore, it is necessary to synthesize a small molecule anti-mitotic agent which has a novel mechanism of action, good pharmacological properties, and is effective for various tumor cells. Summary of the invention

 The main object of the present invention is to screen and synthesize a new class of small molecule anti-mitotic agents by studying the structure-activity of heterocyclic sulfonamide derivatives: carbazole sulfonamide derivatives and pharmaceutically acceptable salts, which can not only tumors The cell is blocked in the mitosis (M) phase, and also has significant antitumor activity, and has the advantages of small molecular weight, simple synthesis, and small toxic side effects.

 The invention also provides a process for the preparation of the oxazole sulfonamide derivative.

 The present invention also provides a pharmaceutical composition containing such an oxazole sulfonamide derivative as an active ingredient.

A further object of the present invention is to provide an anti-tumor application of the carbazole sulfonamide derivative and a pharmaceutically acceptable salt thereof, which can be used as an anti-mitotic agent, especially in the treatment of solid tumors, including with other anti-tumor Chemotherapy drugs Combined with radiotherapy and the like.

 The present invention first provides an oxazole sulfonamide derivative having the following general formula (I) and a pharmaceutically acceptable salt -

 among them:

 Representative: hydrogen, one or more nitro, halogen, cyano, ester, amide, hydroxy, decyl, substituted or unsubstituted lower alkyl, lower alkoxy or aryloxy, attached to the phenyl ring, Lower alkylthio or arylthio, amino, substituted amino, etc.;

R ₂ represents: hydrogen, lower sulfhydryl;

X represents: S0 ₂ NR ₃ or NR ₃ S0 ₂ , or a salt thereof, wherein R ₃ represents:

Hydrogen, lower sulfhydryl, or an acyl group represented by the formula (II);

R ¹ represents a lower sulfhydryl group, or a different amine-substituted lower alkyl group represented by the formula (III) or a salt thereof;

n in the above formula (III) is 1-6; R ² and R ³ respectively represent the same or different groups: hydrogen, lower fluorenyl, hydroxyalkyl, aminoalkyl; or R ² , R ³ Linked together by nitrogen to form a 5-7 membered cyclic amine group, such as pyrrolyl, piperidinyl, piperazinyl, morpholinyl, etc., or a salt thereof;

 Ar stands for:

 Substituted phenyl, the substituent may be one or more lower alkyl, lower cyclodecyl, lower decyloxy, lower sulfonylthio, hydroxy, decyl, amino, substituted amino (eg, mono- or di-substituted) a substituent such as an amide group, an ester group, a nitro group, a cyano group, a halogen or a halogenated alkyl group;

 Pyridyl or substituted pyridyl, the substituent of which may be one or more lower alkyl, lower cyclodecyl, lower decyloxy, lower sulfonylthio, hydroxy, decyl, amino, substituted amino (eg, monosubstituted or Disubstituted), amide group, ester group, nitro group, cyano group, halogen, etc.;

a pyrimidinyl or substituted pyrimidinyl group, the substituent of which may be one or more lower alkyl, lower cycloalkyl, lower alkoxy, lower alkylthio, hydroxy, decyl, amino, substituted amino (eg, monosubstituted or Disubstituted), amide Base, ester group, nitro group, cyano group, halogen, etc.; or,

 Thiophene, bicyclic or tricyclic aromatic heterocycle.

 As stated in the above definition:

 "Lower sulfhydryl" especially refers to a straight or branched fluorenyl or cycloalkyl group having from 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, allyl, ring Propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, cyclopentyl, n-hexyl, isohexyl, cyclohexyl and the like. Among the compounds of the present invention, a methyl group, an ethyl group, a n-propyl group, an isopropyl group or the like is preferable.

 "Lower decyloxy" means a methoxy group having from 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec. Butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, n-hexyloxy, isohexyloxy and the like.

 "Aryloxy" means phenyloxy, tolyloxy, xylyloxy and the like.

 "Lower alkylthio" refers to an alkylthio group having from 1 to 6 carbon atoms, such as methylthio, ethylthio, n-propylthio, isopropylthio, cyclopropylthio, n-butylthio, Isobutylthio, sec-butylthio, tert-butylthio, n-pentylthio, isopentylthio, n-hexylthio, isohexylthio, etc.;

 "Arylthio" means phenylthio, tolylthio, xylylthio and the like.

 "Amido" may be methyl amide, ethyl amide, n-propyl amide, isopropyl amide, allyl amide, cyclopropyl amide, n-butyl amide, isobutyl amide A group, a n-pentylamide group, a n-hexylamide group, a phenylamide group, a tolylamide group and the like.

 Preferred compounds according to the invention are selected from the group consisting of hydrogen, nitro, amino or amide groups, lower fluorenyl groups or lower decyloxy groups.

 Preferred compounds according to the invention may be lower sulfhydryl groups, especially methyl, ethyl, propyl or isopropyl groups and the like.

The carbazole sulfonamide derivative (I) proposed by the present invention comprises an oxazole sulfonamide and a carbazole-substituted aromatic heterocyclic sulfonamide and derivatives thereof, and X in the general structure is preferably 30 _{2 3} or ^0 ₂ Or a hydrochloride salt thereof, wherein R ₃ may be hydrogen or a lower alkanoyl group or a lower amino group substituted lower decanoyl group, and specific examples of X may be: S0 ₂ NH, NHS0 ₂ , S0 ₂ NC0CH ₂ NMe ₂ , S0 ₂ NCOCH ₂ NHMe, S0 ₂ NC0CH ₂ CH ₂ NMe ₂ , S0 ₂ NCOCH ₂ CH ₂ NHMe, S0 ₂ NC0CH ₂ NEt ₂ , S0 ₂ NCOCH ₂ NHEt , or a hydrochloride thereof.

When Ar is a substituted phenyl, pyridyl or pyrimidinyl group in the compound, the substituent may be a lower alkyl group, a lower cycloalkyl group, a lower alkoxy group, a lower alkylthio group, a hydroxyl group, a decyl group, an amino group, a mono- or di- or di- a substituent such as a substituted amino group, an amide group, an ester group, a nitro group, a cyano group, a halogen or a trifluoroalkyl group; wherein Ar is a pyridyl group or a substituted pyridyl group, It is preferably 3-pyridyl. Ar may also be another aromatic heterocyclic ring such as thiophene, benzothiophene, benzothiazole, naphthalene or carbazole. Preferably, when Ar in the compound may be a substituted phenyl, pyridyl or pyrimidinyl group, the substituent is selected from the group consisting of lower alkyl, lower cyclodecyl, lower alkoxy, hydroxy, amino, monosubstituted or disubstituted amino , amide group, ester group, nitro group, cyano group, halogen or trifluoromethyl group. More preferably, Ar may be 3-alkyloxyphenyl, 5-alkoxyphenyl, di- or tri-methoxyphenyl, chloro-alkoxyphenyl, cyanophenyl or alkoxypyridyl Wait.

 Specific examples of Ar may be a phenylthio group, a tolylthio group, a chlorophenyl group, a fluorophenyl group, an aminophenyl group, a cyanophenyl group, a carbamoylphenyl group, a dimethoxyphenyl group, Trimethoxyphenyl, monoethoxyphenyl, diethoxyphenyl, triethoxyphenyl, 4-isopropoxyphenyl, 4-butoxyphenyl, 4-phenoxybenzene , 3, 4-methylenedioxyphenyl, trifluoromethylphenyl, aminomethoxyphenyl, methoxychlorophenyl, naphthyl, 2-pyridyl, 3-pyridyl, 4 -pyridyl, 2-methoxy-3-pyridyl, 4-methoxy-3-pyridyl, 2,4-dimethoxy-3-pyridyl, 4-chloro-2-pyridyl, 5-chloro-3-pyridyl, 6-chloro-2-pyridyl, 6-chloro-3-pyridyl, 4-nitro-2-pyridyl, 5-nitro-3-pyridyl, 5 -carboxamido-3-pyridyl, 5-hexamido-3-pyridyl, 5-aminoformyl-3-pyridyl, 4-amino-2-pyridyl, 5-amino-3-pyridine , 6-amino-4-pyridyl, 4-fluoro-2-pyridyl, 5-fluoro-3-pyridyl, 6-fluoro-2-pyridyl, 3-fluoro-4-pyridyl ,two Methoxypyrimidinyl, diethoxypyrimidinyl, thienyl, benzothienyl, benzothiazolyl, methoxybenzothiazolyl, and the like.

 More preferably, Ar is a dimethoxyphenyl group, a trimethoxyphenyl group, a methoxychlorophenyl group, a methoxypyridyl group, a halogenated pyridyl group or the like.

 The carbazole sulfonamide derivative of the formula (I) according to the invention as defined above also includes a product which undergoes a salt-forming reaction with an acid. Examples of the salt of the compound (I) with an acid may be inorganic acids such as hydrochloride, hydrobromide and sulfate; and organic acid salts such as acetate, lactate, succinate, and fumarate. , maleate, citrate, benzoate, methanesulfonate and p-benzoate.

 The present invention is a carbazole sulfonamide derivative as defined in the screening of a large number of candidate compounds, non-limiting examples of which may be -

N-(3,4-dimethoxyphenyl)-9-ethylcarbazole-3-sulfonamide (42);

 N-(3,5-Dimethoxyphenyl)-9-ethylcarbazole-3-sulfonamide (66);

 9-ethyl-N-(3,4,5-trimethoxyphenyl)-oxazole -3-sulfonamide (43);

 9-methyl-N-(3,4,5-trimethoxyphenyl)-oxazole -3-sulfonamide (88);

 N-(3,4,5-trimethoxyphenyl)-9H-carbazole-3-sulfonamide (89);

 N-(2,4-dimethoxyphenyl)-9-ethylcarbazole-3-sulfonamide (116);

N-(2,5-Dimethoxyphenyl)-9-ethylcarbazole-3-sulfonamide (117); N-(3-chloro-4-methoxyphenyl)-9-ethylcarbazole-3-sulfonamide (114);

 N-(5-chloro-2,4-dimethoxyphenyl)-9-ethylcarbazole-3-sulfonamide (113);

 N-(5-chloro-2,4-dimethoxyphenyl)-9-methylcarbazole-3-sulfonamide (129);

 N-(4-chloro-2, 5-dimethoxyphenyl)-9-ethylcarbazole-3-sulfonamide (115);

 N-(4-chloro-2,5-dimethoxyphenyl)-9-methylcarbazole-3-sulfonamide (130);

 9-methyl N-(2,4,6-trimethoxyphenyl)-oxazole -3-sulfonamide (131);

 9-ethyl-6-nitro-N-(3,4,5-trimethoxyphenyl)-oxazole- 3-sulfonamide (118);

 6-amino-9-ethyl-N-(3,4,5-trimethoxyphenyl)-oxazole -3-sulfonamide (119);

 9-ethyl-N-(4-fluorophenyl)-carbazole-3-sulfonamide (44);

 9-ethyl-N-(2-methoxypyridine-5-substituted)-indazole -3-sulfonamide (75);

 N_(2,6-dimethoxypyridine-3-substituted)-9-ethylcarbazole-3-sulfonamide (76);

 N-(2,6-dimethoxypyridine-3-substituted)-9-methylcarbazole-3-sulfonamide (105);

 9-ethyl-N-(2-methoxypyridine-3-buty)-carbazole-3-sulfonamide (106);

 N-[(Dimethylamino)acetyl]-9-ethyl-N-(3,4,5-trimethoxyphenyl)-carbazole-3-sulfonamide hydrochloride (133); N- (2,6-dimethoxypyridine-3-substituted)-N-[(dimethylamino)acetyl]-9-methylcarbazole-3-sulfonamide hydrochloride (134);

 N-[(Dimethylamino)acetyl]-9-methyl-N-(3,4,5-trimethoxyphenyl)-carbazole-3-sulfonamide hydrochloride (144); N- (4-Chloro-2, 5-dimethoxyphenyl)-N-[(dimethylamino)acetyl]-9-methylcarbazole-3-sulfonamide hydrochloride (146);

 N-[(Dimethylamino)acetyl]-9-methyl-N-(2,4,6-trimethoxyphenyl)-oxazole-3-sulfonamide hydrochloride (145);

N-(9-ethylcarbazole-3-substituted)-3-methoxybenzenesulfonamide (95);

 N-(9-ethylcarbazole-3-substituted)-2,5-dimethoxybenzenesulfonamide (96).

 As a new class of small molecule anti-mitotic agents, pharmacological experiments have shown that these compounds not only block tumor cells in mitosis (M) phase, but also have strong ability to kill various tumor cells; In vivo studies of animal models of breast cancer and liver cancer have been shown to significantly inhibit the growth of malignant tumors without significant toxic side effects. Particularly preferred compounds may include -

9-ethyl-N-(3,4,5-trimethoxyphenyl)-oxazole -3-sulfonamide (43);

 9-Methyl-N-(3,4,5-trimethoxyphenyl)-oxazole- 3-sulfonamide (88);

 N-(2,4-dimethoxyphenyl)-9-ethylcarbazole-3-sulfonamide (116);

N-(2,5-dimethoxyphenyl)-9-ethylcarbazole-3-sulfonamide (117); N-(3-chloro-4-methoxyphenyl)-9-ethylcarbazole-3-sulfonamide (114);

 N-(5-chloro-2,4-dimethoxyphenyl)-9-ethylcarbazole-3-sulfonamide (113);

 N-(5-chloro-2,4-dimethoxyphenyl)-9-methylcarbazole-3-sulfonamide (129);

 N-(4-chloro-2, 5-dimethoxyphenyl)-9-ethylcarbazole-3-sulfonamide (115);

 N-(4-chloro-2,5-dimethoxyphenyl)-9-methylcarbazole-3-sulfonamide (130);

 9-methyl N-(2, 4, 6-trimethoxyphenyl)-carbazole-3-sulfonamide (131);

 9-ethyl-6-nitro-N-(3,4,5-trimethoxyphenyl)-indazole- 3-sulfonamide (118);

 6-Amino-9-ethyl-N-(3,4,5-trimethoxyphenyl)-indazole-3-sulfonamide (119);

 9-ethyl-N-(2-methoxypyridine-5-substituted)-carbazole-3-sulfonamide (75);

 N-(2,6-dimethoxypyridine-3-substituted)-9-ethylcarbazole-3-sulfonamide (76);

 N-(2,6-dimethoxypyridine-3-substituted)-9-methylcarbazole-3-sulfonamide (105);

 9-ethyl-N-(2-methoxypyridine-3-substituted)-indazole -3-sulfonamide (106);

 N-[(Dimethylamino)acetyl]-9-ethyl-N-(3,4,5-trimethoxyphenyl)-carbazole-3-sulfonamide hydrochloride (133); N - (2,6-Dimethoxypyridine-3-substituted)-N-[(Dimethylamino)acetyl]-9-methylcarbazole-3-sulfonamide hydrochloride (1.34). The present invention further provides the use of the carbazole sulfonamide derivative or a salt thereof as an anti-mitotic agent, and in the preparation of an antitumor drug.

 Another aspect of the present invention provides an antitumor pharmaceutical composition comprising a therapeutically effective amount of the above-mentioned carbazole sulfonamide derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable pharmaceutical excipient, which may be the compound itself or Mixtures with pharmaceutically acceptable excipients, diluents and the like are administered orally in the form of tablets, capsules, granules, powders or syrups or parenterally in the form of injections.

The above formulations can be prepared by conventional pharmaceutical methods. Examples of useful pharmaceutical adjuvants include excipients (e.g., saccharide derivatives such as lactose, sucrose, glucose, mannitol, and sorbitol; starch derivatives such as corn starch, potato starch, dextrin, and carboxymethyl starch; Cellulose derivatives such as crystalline cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose; gum arabic; dextran; silicate derivatives such as magnesium metasilicate Aluminum; phosphate derivatives such as calcium phosphate; carbonate derivatives such as calcium carbonate; sulfate derivatives such as calcium sulfate, etc., binders (eg gelatin, polyvinylpyrrolidone and polyethylene glycol), disintegration Agents (such as cellulose derivatives such as sodium carboxymethylcellulose, polyvinylpyrrolidone), lubricants (such as talc, calcium stearate, magnesium stearate, cetyl, boric acid, sodium benzoate, leucine) , stabilizers (methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, etc.), flavoring agents (such as commonly used sweeteners, sour agents and perfumes), diluents and solvents for injections (eg water, ethanol) And glycerin, etc.) . The amount of the compound of the present invention to be administered varies depending on the age, sex, race, condition, and the like of the patient. A typical adult dosage is from about 50 to 5000 mg, preferably from 100 to 3000 mg.

 The carbazole sulfonamide compound of the present invention or a derivative thereof and a pharmaceutically acceptable salt can be obtained by any known method, but it is preferably obtained by reacting a sulfonyl chloride compound of a suitable structure with an amino compound. In the specific synthesis, the starting materials and reactants can be determined according to the structural design of X in the target compound, for example, the carbazole sulfonamide is prepared by sulfonamidation reaction between various substituted carbazole sulfonamides and arylamines. (Method 1 below), or a sulfonamidation reaction between various substituted aminocarbazoles and an aromatic ring sulfonyl chloride to prepare a carbazole-substituted aromatic cyclic sulfonamide (Method 2 below). The specific process can be:

 1. Preparation of carbazole sulfonamide (IV) or its pharmaceutically acceptable salt (V)

 The reaction process is shown below, and the different substituted oxazole sulfonyl chloride (III) can be referred to by the literature (M sumori,

The method of Susumu; Tsuri, Tatsuo; Honma, Tsunetoshi; et al. Journal of Medicinal Chemistry (2003), 46 (12), 2436-2445) or other related reported methods. Then, in the organic solvent, oxazole sulfonyl chloride (ΙΠ) is reacted with various arylamines (Ar-NH ₂ ) to obtain carbazole sulfonamide (IV). The reaction conditions in the process (temperature, time, catalyst, etc.) The choice is based on conventional knowledge, for example, the solvent is dimethylformamide (DMF), catalyzed by a basic substance such as triethylamine (NEt ₃ ), pyridine (Py), carbonate, etc. (without adding a catalyst) The reaction, the reaction time is generally 1-2 hours, and the end of the reaction can be detected by chromatography (simple point plate method).

The obtained carbazole sulfonamide (IV) can be used as it is, or in a tetrahydrofuran (THF) solvent, and in a basic substance such as dimethylaminopyridine (DMAP), diisopropylethylamine (i- The pharmaceutically acceptable salt (V) is further prepared by reacting with a suitable decanoyl chloride (R'COCl) under the catalysis of Pr ₂ NEt).

(V) 2. Preparation of a carbazole-substituted aromatic heterocyclic sulfonamide (VII) or a pharmaceutically acceptable salt thereof (VIII)

 The reaction process can be illustrated by the following process:

 ( VIII )

 In the above process, the preparation of the carbazole-substituted aromatic heterocyclic sulfonamide (VII) can be carried out by reacting various substituted 9-aminocarbazoles (VI) prepared by various known methods with various suitable aromatic heterocyclic sulfonyl chlorides. The specific preparation conditions were the same as those of the aforementioned carbazole sulfonamide.

 Similarly, a pharmaceutically acceptable salt of the sulfonamide (VIII) can be obtained by the same method as the above compound (V).

The selection principles of the substituents R, R ₂ , R ¹ and Ar referred to in the above description are the same as defined above. Antitumor activity and pharmacological experiment of the compound of the present invention

 Using the partial carbazole sulfonamide compound prepared by the present invention, the inventors have simultaneously provided the following experimental results, which are intended to illustrate the medicinal efficacy of the compound of the present invention. I. Determination of antitumor activity in vitro

Human leukemia CEM cells in the exponential growth phase were inoculated into 96-well culture plates, and different concentrations of compounds were added. At the same time, solvent control wells were set up, cultured in C0 ₂ incubator at 37 °C for 48 hours, and stained with MTT for 4 hours, 50% DMF- The 20% SDS was decolorized overnight, and the absorbance at a wavelength of 570 nm (A ₅₇ .) was measured on an enzyme analyzer.

The results are given by the formula (solvent control A ₅₇ - dosing cell A ₅₇ .) / solvent control VIII ₅₇ . Calculate the cell death rate (°/.) and calculate the effective tumoricidal concentration IC ₅ by the Reed-Muench method. . See Table 1 for the results. Second, cell morphology changes experiment

Human leukemia CEM cells were collected after treatment for 24 hours, and cell samples of slides were used with Cytospin. The centrifuge (LTP-C, Experimental Apparatus Factory, CAMMS) was prepared at room temperature, 700 g, for 5 minutes. The slides were air dried, fixed in methanol, and stained with Giemsa for 15 minutes at room temperature. The tumor cells arrested in the mitosis (M) phase were observed with a microscope, and the chromosomal scatter was distributed in the cytoplasm and the nuclear membrane disappeared. This experimental determination was performed on some of the compounds to evaluate the anti-mitotic effect of the compounds.

 The results of the above assays are shown in Table 1, and the structure of the compounds is as follows:

 Table 1

/900ZN3/X3d TC19C0/.00Z OAV

 Note: The "+" under the column "Blocking mitosis" in the table indicates that the compound has anti-mitotic effects. III. Compounds 43, 76, 88, 115, 116, 117 In vitro against the activity assay of various types of tumor cells. The measurement was carried out in the same manner as in Experimental Example 1, and the results are shown in Table 2 below.

Table 2. In vitro anti-tumor activity tumor cell compound IC ₅ . ( g/ml)

 Human cell

 Model 43 76 88 115 116 117

CEM T cell lymphoma 0. 04 0. 05 0. 02 0. 025 0. 025 0. 03

Molt-3 Τ cell lymphoma 0. 008 0. 009 0. 008 0. 03 0. 02 0. 02

Bel - 7402 Liver cancer 0. 09 0. 37 0. 05 0. 06 0. 04 0. 09

MCF-7 breast cancer 0. 04 0. 09 0. 03 0. 03 0. 02 0. 04

DU-145 Prostate cancer 0. 27 0. 27 0. 1 0. 075 0. 06 0. 15

PC-3 prostate cancer 0. 09 0. 25 0. 05 0. 04 0. 06 0. 32

DND-1 Skin cancer 0. 04 0. 08 0. 03 0. 04 0. 05 0. 08

CRL-2049 Lung cancer 0. 85 2. 0 0. 90 1 1 1 IV. Determination of antitumor activity in vivo

Anti-human breast cancer in nude mice (female, 4-8 weeks old, weight 15-20 g), subcutaneous transplantation 24 hours after estrogen administration > 10 ⁶ MCF-7 breast cancer cells / only, 7 days later, randomly divided into controls There were 5 rats in each group and the treatment group, and the control group was given a solvent (5-10% PBS solution for dimethyl sulfoxide (DMS0) for injection), and the treatment group was administered every other day (ip).

Ten human nude mice (male, 6-7 weeks old, weighing 16-20 g) were treated with liver cancer BEL-7402, subcutaneous subcutaneous transplantation 4 mm ³ /only, and were randomly divided into control group and treatment group after 7 days. Each of the 5 rats was given a solvent every other day, and the treatment group was administered every other day (ip).

The tumor volume was measured weekly until it exceeded 2000 mm ³ and the experiment was terminated. Tumor volume = length and width ² X 0. 52. The tumor growth inhibition rate of the drug-administered group and the control group was calculated according to the following formula:

 Growth inhibition rate (%) = ( C - T ) / C X 100

 T : mean tumor volume in the drug-administered group - mean tumor volume before administration

 C : mean tumor volume in the control group - mean tumor volume before administration

 See Table 3 for the results:

 ..., indicates the survival rate (%) of the nude mice in the treatment group at the end of the experiment. The above results have preliminarily verified the role of the small molecule carbazole sulfonamide compound or its pharmaceutically acceptable salt of the present invention in anti-tumor and anti-mitosis, and should have a good application prospect. detailed description

 The invention is further illustrated by the following examples, but the practice of the invention is not limited to the examples. Example 1: N-(3,4-Dimethoxyphenyl)-9-ethylcarbazole-3-sulfonamide (42)

 9-Ethylcarbazole-3-sulfonyl chloride was synthesized according to the method of Mitsumori, Susumu; Tsuri, Tatsuo; Honma, Tsunetoshi et al, Journal of Medicinal Chemistry (2003), 46 (12), 2436-2445.

3 ml of DMF and 3,4-dimethoxyaniline (80 mg, 0.52 诵ol) were added to the reaction flask, and self-made 9-ethylcarbazole-3-sulfonyl chloride (150 mg, 0. 51 mmol) was added at room temperature with stirring. After 5 minutes, triethylamine (0.11 ml, 0.77 ol) was added and the reaction was continued for 2 hours. Then, ice water was added, and the mixture was stirred for a while, and the precipitate was filtered, washed three times with water, dried, and evaporated to give a pale brown solid (160 mg, 76%), s 175-177 s. 'H匪R (DMSO-ΰΟ; δ 1.30 (t, J=7.2Hz, 3H), 3.59 (s, 6H), 4.46 (q, J=7.2Hz, 2H), 6.56 (dd, J=8.7, 2.1 Hz, IH), 6.71—6.74 (m, 2H), 7.27 (dd, J=7.5, 7.2Hz' IH),

7.53 (dd, ]=7.8, 7.5Hz, IH), 7.68 (d, J-8.1Hz, IH), 7.74 (d, J=8.7Hz, IH), 7.78 (d, J=8.7Hz, IH), 8.24 (d, ]=7.8Hz, IH), 8.56 (s, IH), 9.82 (s, IH).

' ³ C NMR (DMS0 - cO; δ 148.7, 145.7, 141.2, 140.3, 131.1, 129.4, 126.9, 124.1, 121.7,

121.4, 120.2, 120.0, 113.0, 112.0, 109.8, 109.4, Ϊ06.1, 55.5, 55.3, 37.3, 13.7.

Elemental analysis for C ₂₂ H ₂₂ N ₂ 0 ₄ S - 0.3 H ₂ 0, Calculated: C, 63.53; H, 5.49; N, 6.73. Found: C, 63.54; H, 5.33; N, 7.11. The following compound was obtained in the same manner as in Example 1 from the corresponding arylamine and carbazolesulfonyl chloride. Example 2: N-(3,5-Dimethoxyphenyl)-9-ethylcarbazole-3-sulfonamide (66)

 The product was obtained as a light brown solid, yield: 63%; mp 171-173.

 NMR NMR (DMS0-o0; δ 1.30 (t, J-6.9Hz, 3H), 3.60 (s, 6H), 4.46 (q, J=6.9Hz, 2H), 6.07 (d, J=2.1Hz, IH) , 6.32 (d, J=2.1Hz, 2H), 7.28 (dd, J=7.5, 7.2Hz, IH),

7.54 (dd, J=7.8, 7.5Hz, IH), 7.68 (d, J=8. lHz, IH), 7.77 (d, J=8.7Hz, IH), 7.85 (d, J=8.7Hz, 1H) , 8.28 (d, J=7.5Hz, IH), 8.66 (s, IH), 10.20 (s, IH).

¹³ C NMR (DMS0-d); δ 160.6, 141.2, 140.2, 140.0, 129.3, 126.9, 124.0, 121.6, 121.4, 120.8, 120.3, 120.0, 109.7, 109.6, 97.4, 94.8, 55.0, 37.3, 13.6.

Elemental analysis for C ₂₂ H ₂₂ N ₂ 0 ₄ S, calc.: C, 64.37; H, 5.41; N, 6.83. Found: C, 64.70; H, 5.67; N, 6.90. Example 3: N-(3,4-Methylenedioxyphenyl)-9-ethylcarbazole-3-sulfonamide (65)

 The product was obtained as a light brown solid. Yield: 74%; mp 182 - 184.

 NMR NMR (DMS0-o0; δ 1.30 (t, J=6.9Hz, 3H), 4.46 (q, J=6.9Hz, 2H), 5.89 (s, 2H), 6.50 (d, J=8.4Hz, IH) , 6.68—6.71 (m, 2H), 7.27 (dd, J=7.5, 7.2Hz, IH), 7.53 (dd, J=7.8, 7.5Hz, IH), 7.68 (d, J-8.4Hz, IH), 7.72-7,79 (m, 2H), 8.25 (d, J=7.8Hz, IH), 8.55 (s, IH), 9.89 (s, IH).

' ³ C NMR (DMS0- o ; δ 147.3, 144.1, 141.2, 140.3, 132.0, 129.2, 126.9, 124.0, 121.7: 121.5, 120.9, 120.1, 120.0, 114.2, 109.8, 109.5, 108.2, 103.1, 101.2, 37.3, 13.7.

Elemental analysis for C ₂₁ H ₁₈ N ₂ 0 ₄ S - 0.3 H ₂ 0, Calculated: C, 63.07; H, 4.70; N, 7.01. Found: C, 62.99; H, 4.33; N, 6.83. Example 4: 9-Ethyl-N-(3,4,5-trimethoxyphenyl)-oxazole- 3-sulfonamide (43) The product was obtained as a white solid, yield: 56%; mp 201 - 203 °C.

 NMR NMR (DMSO-oQ; δ 1.30 (t, J = 7.2 Hz, 3H), 3.48 (s, 3H), 3.61 (s, 6H), 4.56 (q, J = 7.2 Hz, 2H), 6.42 (s, 2H), 7.28 (dd, J=7.5, 7.2Hz, 1H), 7.53 (dd, J=8.1, 7.2Hz, 1H), 7.69 (d, J=8.4Hz, 1H), 7.77 (d, J=8.7 Hz, 1H), 7.84 (d, J=8.7Hz, 1H), 8.28 (d, J=8.4Hz, 1H), 8.65 (s, 1H), 10.02 (s, 1H).

l ³ C should be 靡SO- c ₆ ) ; δ 152.9, 141.3, 140.3, 134.2, 133, 8, 129.3, 127.0, 124.2, 121.7, 121.5, 120.8, 120.5, 120.0, 109.8, 109.6, 97.4, 60.0, 55.7, 37.3, 13.6.

Elemental analysis for C ₂₃ H ₂₄ N ₂ 0 ₅ S · 0.43⁄40, Calculated: C, 61.70; H, 5.58; N, 6.26. Found: C, 61.73; H, 5.43; N, 6.22. Example 5: 9-Methyl-N-(3,4,5-trimethoxyphenyl)-oxazole- 3-sulfonamide (88)

 This compound was obtained in the same manner as in Example 1 from 3,4,5-trimethoxyaniline and previously synthesized 9-methylcarbazole-3-sulfonyl chloride. The synthesis of 9-methylcarbazole-3-sulfonyl chloride is described in Mitsumori, Susumu; Tsuri, Tatsuo; Honma, Tsunetoshi; et al, Journal of Medicinal Chemistry (2003), 46(12), 2436-2445.

 The product was a white solid, yield: 65%; mp 206 - 208.

 NMR (DMSO-t/e); δ 3.41 (s, 3H), 3.61 (s, 6H), 3.89 (s, 3H), 6.42 (s, 2H), 7.28 (dd, J=6.9, 7.2 Hz, 1H ), 7.54 (dd, J=8.1, 7.2Hz, 1H), 7.66 (d, J=7.8Hz, 1H), 7.73 (d, J-9.0Hz, 1H), 7.85 (d, J=8.7Hz, 1H ), 8.26 (d, J=8.4Hz, 1H), 8.64 (s, 1H), 10.03(s, 1H).

' ³ C NMR (DMS0- oQ; δ 152.9, 142.3, 141.4, 134.2, 133.7, 129.1, 126.9, 124.1,

121.5, 121.3, 120.7, 120.3, 120.0, 109.9, 109.7, 97.3, 60.0, 55.7, 29.3.

Elemental analysis for C ₂₂ H ₂₂ N ₂ 0 ₅ S · 0.25 Η ₂ 0, Calculated: C, 61.30; Η, 5.27; Ν, 6.50. Found: C, 61.30; Η, 5.04; Ν, 6.33. Example 6: Ν-(3,4,5-trimethoxyphenyl)-9Η-carbazole- 3-sulfonamide (89)

 The compound of interest is prepared from 3,4,5-trimethoxyaniline and previously prepared 9-oxazole-3-sulfonyl chloride. The synthesis of 9Η-carbazole-3-sulfonyl chloride is referred to Mitsumori, Susumu; Tsuri, Tatsuo; Honma, Tsunetoshi; et al, Journal of Medicinal Chemistry (2003), 46(12), 2436-2445.

 The product was obtained as a white solid. Yield: 57%; mp 205-206.

lH NMR (DMSO-oO; δ 3.47 (s, 3H), 3.60 (s, 6H), 6.41 (s, 2H), 7.28 (dd, J=7.2, 7.8 Hz, 1H), 7.45 (dd, J=8.1 , 7.2Hz, 1H), 7.53 (d, J=8.4Hz, 1H), 7.59 (d, J=8.1Hz, IH), 7.77 (d, J=7.8Hz, IH), 8.22 (d, ]=7.5Hz, IH), 8.61 (s, IH), 9.99 (s, IH), 11.79 (s, 1H).

¹³ C NMR (DMSO-oO; δ 152.9, 141.6, 140.5, 134.2, 133.8, 129.1, 126.8, 124.1, 121.9, 121.7, 120.6, 120.4, 119.8, 111.6, 111.3, 97.4, 60.0, 55.7.

Elemental analysis of C _2l H ₂ . N ₂ 0 ₅ S, calculated: C, 61.15; H, 4.89; N, 6.79. Found: C, 61.06;

H, 4.81; N, 6.69.

HR-MS C ₂₁ H ₂₁ NAS, calcd: 413.1171. Found: 413.1182. Example 7: N-(2,4-Dimethoxyphenyl)-9-ethylcarbazole-3-sulfonamide (116)

 The product was a brown solid, yield: 75%; mp 185-187.

 3⁄4 NMR (DMSO - cO; δ 1.30 (t, J = 7.2 Hz, 3H), 3.43 (s, 3H), 3.60 (s, 3H), 4.78

(q, J=7.2Hz, 2H), 6.56 (dd, J=9.0, 2.7Hz, IH), 6.76 (d, J=9.0Hz, IH), 6.86 (d, J=2.7Hz, IH), 7.23 (dd, J-7.5, 7.8Hz, IH), 7.53 (dd, J=8.4, 7.5Hz, IH), 7.68 (d, J=8.4Hz, 1H), 7.74 (d, J=8.7Hz, 1H) , 7.84 (dd, J=8.7, 1.5Hz, IH), 8.24 (d, J=8.1Hz, IH), 8.60 (d, J=l.5Hz, IH), 9.32 (s, IH).

' ³ C Li R (DMS0- o ; δ 153.4, 145.9, 141.7, 140.8, 130.7, 127.4, 127.3, 124.7,

122, 3, 121.8, 121.3, 120.5, 120.4, 113.1, 110.3, 110.0, 109.9, 109.7, 56.6, 55.8, 37.8, 14.1.

Elemental analysis for C ₂₂ H ₂₂ N ₂ 0 ₄ S · 0. Calculated: C, 63.25; H, 5.51; N, 6.70. Found: C, 63.38; H, 5.51; N, 6.37. Example 8: N-(2,5-Dimethoxyphenyl)-9-ethylcarbazole-3-sulfonamide (117)

 The product was a brown solid, yield: 70%; mp 164-166. C.

 'H NMR (DMSO-o0; δΐ.30 (t, J=6.9Hz, 3H), 3.33 (s, 3H), 3.65 (s, 3H), 4.48 (q, J=6.9Hz, 2H), 6.34 ( d, J=2.1Hz, 1H), 6.41 (dd, J=9.0, 2.1Hz, IH), 7.10 (d, J=9. OHz, 1H), 7.26 (dd, J=7.5, 7.8Hz' IH) , 7.52 (dd, J=7.8, 7.5Hz, 1H), 7.68 (d, J-7.8Hz, IH), 7.68-7.72 (m, 2H), 8.21 (d, J=7.8Hz, IH), 8.45 ( s, 1H), 9.07 (s, IH;).

¹³ C NMR (DMSO-oQ; δ 158.5, 154.2, 141.1, 140.2, 130.7, 127.6, 126.7, 124.4, 121.8, 121.2, 120.7, 119.9, 118.3, 109.7, 108.9, 104.5, 98.9, 55.2, 37.3, 13.6.

Elemental analysis for C ₂₂ H ₂₂ N ₂ 0 ₄ S, calc.: C, 64.37; H, 5.41; N, 6.83. Found: C, 64.39; H, 5.50; N, 6.64. Example 9: N-(3-chloro-4-methoxyphenyl)-9-ethylcarbazole- 3-sulfonamide (114)

 The product was a brown solid, yield: 72%; mp 222 - 224.

 NMR NMR (DMSO-ί/β); δ 1.33 (t, J=7.2Hz, 3H), 3.72 (s, 3H), 4.49 (q, J=7.2Hz, 2H), 6.99 (dd, J=9.0Hz , IH), 7.05 (dd, J=8.7, 2.4Hz, IH), 7.16 (d, J=2.4Hz, IH), 7.30 (dd, J=7.5, 7.2Hz, IH), 7.56 (dd, J= 7.2, 7.2Hz, IH), 7.71 (d, J=8.4Hz, IH), 7.78-7.79 (m, 2H), 8.28 (d, J=8.1Hz, IH), 8.59 (s, IH), 10.07 ( s, IH).

Elemental analysis for C ₂₁ H ₁₉ ClN ₂ 0 _: s. Found: C, 61.03; H, 4.64; N, 6.44. Example 10: N-(5-Chloro-2,4-dimethoxyphenyl)-9-ethylcarbazole-3-sulfonamide (113) The product was obtained as a brown solid, yield: 76%; mp 194 - 196 ° C.

 lH NMR (DMSO - οθ; δ 1.30 (t, J=6.9Hz, 3H), 3.34 (s, 3H), 3.75 (s, 3H), 4.48 (q, J=6.9Hz, 2H), 6.57 (s, 1H), 7.19 (s, IH), 7.27 (dd, J=7.5, 7.2Hz, IH), 7.52 (dd, J=7.2, 8.1Hz, IH), 7.68 (d, J=8.1Hz, IH), 7.70—7.75 (m, 2H), 8.23 (d, J=7.5Hz, IH), 8.48 (s, IH), 9.33 (s, IH).

1C NMR (DMS0-c/ ₆ ); 5153.4, 153.2, 141.2, 140.3, 130.3, 127.4, 126.8, 124.4, 121.8

121.3, 120.8, 121.0, 118.5, 111.1, 109.8, 109.1, 98.0, 56.3, 55.9, 37.3, 13.7.

Elemental analysis for C ₂₂ H ₂₁ C1N ₂ 0 ₄ calc.: C, 59.38; H, 4.77; N, 6.29. Found: C, 59.58; H, 4.54; N, 5.98. Example 11: N-(5-Chloro-2,4-dimethoxyphenyl)-9-methylcarbazole- 3-sulfonamide (129)

 The product was a white solid, yield: 45%.

 'HNMR (DMSO-oD; δ 3.40 (s, 3H), 3.71 (s, 3H), 3.92 (s, 3H), 6.28 (d, J=8.4Hz, IH), 7.27 (dd, J-7.8, 7.2 Hz, IH), 7.42 (d, J=8.4Hz, IH), 7.54 (dd, J=7.2, 8.1Hz, 1H), 7.67 (d, J=7.8Hz, IH), 7.61 (s, IH), 7.73 (s, IH), 7.70—7.75 (m, 2H), 8.23 (d, J=7.2Hz, IH), 8.47 (s, IH), 9.32 (s, IH). Example 12: N-(4 -Chloro-2,5-dimethoxyphenyl)-9-ethylcarbazole-3-sulfonamide (115)

 The product was a brown solid, yield: 56%; mp 188 - 190.

NMR NMR (DMSO-oO; δ 1.30 (t, J = 7.2 Hz, 3H), 3.39 (s, 3H), 3.70 (s, 3H), 4.47 (q, J = 7.5 Hz, IH), 6.95 (s, IH), 7.06 (s, IH), 7.27 (dd, J=7.8, 7.2Hz, 1H), 7.53 (dd, J=8.1, 7.5Hz, IH), 7.69 (d, J=8.1Hz, 1H), 7.75 (d, J=8.7Hz, IH), 7.82 (dd, J=8.7, 1.5Hz' 1H), 8.25 (d, J-7.8Hz, 1H), 8.60 (d, J=1.5Hz, 1H), 9.49 (s, 1H). Elemental analysis ( ₂₂ Η ₂₁ (: ΐΝ ₂ 0^, calculated: C, 59.38; Η, 4.77; Ν, 6.30. Found: C, 59.25; Η, 4.85; Ν, 6.04. Example 13: Ν- ( 4-Chloro-2,5-dimethoxyphenyl)-9-methylcarbazole-3-sulfonamide (130)

 The product was a pale white solid, yield: 67%; mp 218 - 220.

 NMR NMR (DMSO-c/e); δ 3.41 (s, 3H), 3.70 (s, 3H), 3.90 (s, 3H), 6.95 (s, 1H), 7.07 (s, 1H), 7.28 (dd, J=7.2, 7.8Hz, 1H), 7.54 (dd, J=8.4, 7.2Hz, 1H), 7.66 (d, J=8.4Hz, 1H), 7.71 (d, J=8.7Hz, 1H), 7.83 ( d, J = 8.7 Hz, 1H), 8.25 (d, J = 7.8 Hz, 1H), 8.62 (s, 1H), 9.48 (s, 1H).

1 ³ C NMR (DMSO - ; δ 148.1, 145.7, 142.3, 141.4, 129.8, 126.8, 125.6, 124.3, 121.5:

121.2, 120.6, 120.1, 120.0, 117.0, 113.9, 109.8, 109.3, 108.7, 56.4, 56.3, 29.3.

Elemental analysis (: ₂₁ (1 0 ₄ 5, calculated: C, 58.53; Η, 4.45; Ν, 6.50. Found: C, 58.51; Η, 4.41; Ν, 6.32ο Example 14: 9-methyl oxime - (2, 4, 6--trimethoxyphenyl)-carbazole-3-sulfonamide (131)

 The product was a white solid, yield: 70%; mp 209 - 21 Γ〇.

 'Η NMR (DMSO- οθ; δ 3.29 (s, 6H), 3.71 (s, 3H), 3.93 (s, 3H), 6.09 (s, 2H), 7.26 (dd, J=8.1, 7.5Hz, 1H) , 7.53 (dd, J=8.4, 8.1Hz, 1H), 7.66 (d, J=8.4Hz, 1H), 7.70 (d, J=8.7Hz, 1H), 7.78 (dd, J=8.7, 1.8Hz, 1H), 8.22 (d, J = 7.5 Hz, 1H), 8.22 (d, J = 7.5 Hz, 1H), 8.44 (d, J = 1.8 Hz, 1H), 8.52 (s, 1H).

, ^{; ,} C NMR (DMS0-c ₆ ) _; δ 160.3, 158.5, 142.6, 141.9, 133.1, 127.4, 125.2, 122.3,

121.5, 121.0, 120.5, 120.1, 110.3, 109.2, 106.7, 91.4, 55.9, 55.9, 29, 8.

Elemental analysis for C ₂₂ H ₂₂ N ₂ 0 ₅ S, calc.: C, 61.95; H, 5.21. Found: C, 61.59; H, 5.25; N, 6.26. Example 15: 9-Ethyl-6-nitro-N-(3,4,5-trimethoxyphenyl)-oxazole- 3-sulfonamide (118) 66-nitrogen prepared by a similar method - 9-ethylcarbazole - 3-sulfonyl chloride replaces 9-ethylcarbazole in Example 1

- 3 -sulfonyl chloride, the product was obtained as a yellow solid, yield: 74%; mp 263-265. .

lH陋R (DMS0 - c/ ₆ ); δ 1.32 (t, J=6.9Hz, 3H), 3.42 (s, 3H), 3.61 (s, 6H), 4.54 (q, J=6.9Hz, 2H), 6.44 (s, 2H), 7.88 (d, J=9.0Hz, 1H), 7.94 (d, J=9.0Hz, 1H), 7.96 (dd, J=9.0, 1.5Hz, 1H), 8.39 (dd, J =9.0, 2.4Hz, 1H), 8.99 (d, J=l.5Hz, 1H), 9.40 (d, J=2.4Hz, 1H).

Elemental analysis for C ₂₃ H ₂₃ N ₃ 0 ₇ S: C, 56.89; H, 4.78; N, 8.66. Found: C, 56.64; H, 4.92; N, 8.42. Example 16: 6-Amino- 9-ethyl-N-(3,4,5-trimethoxyphenyl)-oxazole- 3-sulfonamide (119) in 5 ml of dimethylformamide (DMF) Add the above compound (II ⁸ ) (^Omg, 1.0 for ol), add 1.13 g of tin dichloride (SnCl ₂ · 2H ₂ 0) with stirring, then react at 90 ° for 4 hours, reduce to room temperature, add 20 ml of water. The pH was adjusted to 7-8 with a 10% K ₂ C0 ₃ solution, and the precipitate was filtered and washed three times with water. The precipitate was dissolved in 100 ml of acetone, filtered, washed three times with acetone, and the filtrate was evaporated under reduced pressure to give the product as a brown solid, yield: 40%; mp 203 - 205 °C.

 'Η NMR(DMS0 - oQ; δ 1.25(t, J=7.2Hz, 3H), 3.49(s, 3H), 3.61 (s, 6H), 4.34 (q, J=7.2Hz, 2H), 4.88 (s , 2H), 6.41 (s, 2H), 6.88 (d, J=8.7, 1.5Hz, IH), 7.28 (d, J=1.5Hz, IH), 7.37 (d, J=8.7Hz, IH), 7.60 (d, J=9. OHz, IH), 7.73 (d, J=9. OHz, 1H), 8.36 (s, IH).

l ³ C NMR (DMS0-c/ ₆ ); δ 152.9, 142.8, 141.3, 134.3, 133.7, 133.2, 127.8, 123.5, 122.4, 121.0, 119.9, 116.3, 110.2, 109.1, 103.6, 97.3, 60.0, 55.7, 37.2 , 13.7. Example 17: 9-Ethyl-N-(4-fluorophenyl)-oxazole- 3-sulfonamide (44)

 The 3,4-dimethoxyaniline of Example 1 was replaced with 4-fluoroaniline as a light brown solid. Yield: 95%; mp 158 - 160.

 NMR NMR (DMS0—oQ; δ 1.24 (t, J=6.6Hz, 3H), 4.46 (q, J=6.6Hz, 2H), 7.00-7.06 (m, 1H), 7.16-7.26 (m, IH), 7.24 (d, J=7.5Hz, IH), 7.48 (dd, J=8.1, 7.2Hz, IH), 7.57 (d, J=7.5Hz, 1H), 7.69 (d, J=8.1Hz, IH), 7.69 (d, J=8.7 Hz, 1H), 7.83 (d, J=8.7 Hz, IH), 8.22 (d, ]=7.5 Hz, IH), 8.62 (s, 1H), 10.20 (s, IH).

¹ C NMR (DMS0-c/e); δ 158.9 (d, J = 856.7 Hz), 141.3, 140.3, 134.5 (d, . 11.4 Hz), 129.2, 127.0, 124.0, 122.4 (d, J = 32.1 Hz) , 121.7, 121.6, 120.9, 120.2, 115.8 (d, J = 91.8 Hz), 109.7, 109.5, 37.3, 13.6.

Elemental analysis of C ₂ . _Hl7 FN ₂ 0 ₂ S - 0.2H ₂ 0, Calcd.: C, 64.56; H, 4.72; N, 7.53. Found: C, 64.91; H, 4.85; N' 7.13. Example 18: 9-Ethyl-N-(2-methoxypyridine-5-substituted)-carbazole-3-sulfonamide (75)

 Substituting 5-amino-2-methoxypyridine for the 3,4-dimethoxyaniline of Example 1, the product was obtained as a white solid, yield: 72%; mp 167 - 169 °C.

NMR NMR (DMS0-o0; δ 1.30 (t, J=6.9Hz, 3H), 3.69 (s, 3H), 4.47 (q, J=6.9Hz, 2H), 6.68 (d, J=8.7Hz, 1H), 7.27 (dd, J=7.5, 7.2Hz, 1H), 7.40 (dd, J=ll.7, 2.1Hz, 1H), 7.53 (dd, J =7.8, 7.5Hz, 1H), 7.68 (d, J=8.1Hz, 1H), 7.76-7.81 (m, 3H), 8.25 (d, J=7.8Hz, 1H), 8.53 (s, 1H), 9.96 (s, 1H).

_{^{13 C NMR (DMS0-c 6}} ); δ 160.8, 141.3, 140.3, 140.3, 134.1, 128.9, 128.5, 127.0, 124.0, 120.7, 121.6, 120.9, 120.2, 120.0, 110.6, 109.8, 109.6, 53.2, 37.4, 13.7 .

Elemental analysis of C ₂ . H ₁₉ N ₃ 0 ₃ S .0.2H ₂ 0, calcd for C, 62.38; H, 5.09; N, 10.92. Found: C, 62.42; H, 4.69; N, 10.52. Example 19: N-(2,4-dimethoxypyridin-3-substituted)-9-ethylcarbazole-3-sulfonamide (76)

 The same procedure as in Example 18 gave m.

 Ή NMR (DMSO-oO; δ 1.30 (t, J=6.9Hz, 3H), 3.36 (s, 3H), 3.70 (s, 3H), 4.48

(q, J=6.9Hz, 2H), 6.29 (d, J=8.1Hz, 1H), 7.26 (dd, J=7.5, 7.5Hz, 1H), 7.44 (d, J=8.1Hz, 1H), 7.52 (dd, J=7.8, 7.5Hz, 1H), 7.68 (d, J=7.8Hz, 1H), 7.70-7.76 (m, 2H), 8.22 (d, J=7.8Hz, 1H), 8.46 (s, 1H), 9.31 (s, 1H).

¹³ C NMR (DMS0- oQ; δ 153.8, 153.7, 141.7, 140.8, 130.8, 127.8, 127.3, 124.8, 122.3, 121.8, 121.1, 120.4, 119.0, 111.6, 110.2, 109.5, 98.5, 56.8, 56.3, 37.8, 14.1.

Elemental analysis for C ₂₁ H ₂₁ N ₃ 0 ₄ S, calc.: C, 61.29; H, 5.15; N, 10.21. Found: C, 60.94; H, 5.27; N, 9.93. Example 20: N-(2,4-dimethoxypyridin-3-substituted)-9-methylcarbazole-3-sulfonamide (105) The procedure was the same as Example 18 : 80%; rap 170- 172 °C.

NMR NMR (DMS0-c ₆ ); δ 3.40 (s, 3H), 3.71 (s, 3H), 3.92 (s, 3H), 6.28 (d, J = 8.4 Hz, 1H),

7.27(dd, J=7.5, 7.5Hz, 1H), 7.42 (d, J=8.4Hz, 1H), 7.54 (dd, J=8.1, 7.8Hz, 1H), 7.66 (d, J=8.4Hz, 1H ), 7.72-7.74 (m, 2H), 8.23 (d, J = 8.4 Hz, lH), 8.47 (s, 1H), 9.32 (s, lH).

1 ³ C NMR (DMS0-c ₆ ); δ 160, 2, 156.7, 142.2, 141.3, 139.3, 130.3, 126.7, 124.3, 121.6, 121.1, 120.6, 119.9, 119.8, 112.2, 109.8, 109.1, 100.6, 53.4, 52.9, 29.3.

Elemental analysis with 0 ₄ S, calculated: C, 60.44; H, 4.82; N, 10.57. Found: C, 60.56;

H, 4.85; N, 10.44. Example 21: 9-Ethyl-N-(2-methoxypyridine-3-substituted)-indazole -3-sulfonamide (106)

 The procedure was the same as in Example 18, mp. mp.

NMR (DMS0-ca); δ 1.29 (t, J=7, 2Hz, 3H), 3.55 (s, 3H), 4.47 (q, J = 7.2 Hz, 2H), 6.89 (dd, J=7.5, 7.8Hz' IH), 7.27 (dd, J=7.8, 6.9Hz, IH), 7.53 (t, J=7.8, 7.5Hz, 1H), 7.60 (dd, J =7.5, 1.5Hz, 1H), 7.68 (d, J=8.1Hz, IH), 7.75 (d, J=9. OHz, IH), 7.81 (dd, J=2.1, 1.5Hz, IH), 7.83 ( Dd, J=l.5, 1.2Hz, IH), 8.24 (d, J-7.8Hz, IH), 8.58 (d, J=l.5Hz, IH), 9.65 (s, IH).

, ³ C NMR (DMSO-d); δ 156.2, 142.4, 141.3, 140.3, 131.2, 130.0, 126.9, 124.2,

121.8, 121.4, 121.2, 120.8, 120.0, 120.0, 117.0, 109, 8, 109.3, 53.1, 37.3, 13.6.

Elemental analysis for C ₁₉ H ₁₈ N ₃ 0 ₃ S, calc.: C, 62.97; Found: C, 62.83; H, 5.02; N, 10.80.

_{HR-MS C 20 H 2O N} 3 O 3 S, Calculated: 382.1225. Found: 382.1212. Example 22: 9-Ethyl-N-(6-methoxypyrimidin-4-substituted)-carbazole-3-sulfonamide (107)

 The product was a white solid, yield: 65%; mp 201 - 203.

 lH NMR (DMSO-oO; δ 1.31 (t, J = 7.2 Hz, 3H), 3.79 (s, 3H), 4.48 (q, ] = 7.2 Hz, 2H), 6.41 (d, J = 0.9 Hz, IH) , 7.29 (dd, J=7.8, 7.2Hz, IH), 7.54 (dd, J=8.1, 7.2Hz, IH), 7.69 (d, J=8.4Hz, IH), 7.79 (d, J=8.7Hz, IH), 7.96 (dd, J=8.7, 1.8Hz, IH), 8.34 (d, J=7.8Hz, IH), 8.37 (d, J=0.9Hz, 1H), 8.79 (d, J=l.8Hz , IH), 11.80 (s, IH).

, ³ C NMR (DMS0-d); δ 169.9, 158.7, 157.0, 141.4, 140.3, 129.8, 127.0, 124.3, 121.8, 121.5, 121.1, 120.5, 120.0, 109.8, 109.6, 90.8, 54.0, 37.4, 13.7.

Elemental analysis for C ₁₉ H ₁₈ N ₄ 0 ₃ S, calc. C, 59.77; H, 4.75; N, 14.39c Example 23: N-(2,6-dimethoxypyrimidine-4-substituted)-9-ethylcarbazole-3-sulfonamide (108 The product was a yellow solid, yield: 32%; mp 179-181.

'Η NMR (DMS0-£ ₆ ); δ 1.31 (t, J=7.2Hz, 3H), 3.74 (s, 3H), 3.74 (s, 3H), 4.47 (q, J=7.2Hz, 2H), 6.00 (s, IH), 7.29 (dd, J=7.8, 7.2Hz, IH), 7.54 (dd, J-7.5, 7.2Hz, IH), 7.69 (d, J=8.4Hz, IH), 7.80 (d, J=8.7Hz, IH), 7.97 (dd, J=8.7, 1.8Hz, 1H), 8.31 (d, J=7.8Hz, IH), 8.81 (d, J= 1.8Hz, IH), 11.46 (s, IH).

^{1: i} C NMR (DMS0-d _h ); δ 171.6, 164.3, 160.0, 141.5, 140.4, 129.5, 127.0, 124.4, 121.7, 121.4, 121.0, 120.9, 120.1, 109.8, 109.6, 84.4, 54.4, 53.7, 37.4 , 13.7.

Elemental analysis of C ₂ . H _2Q N ₄ 0 ₄ S, calculated: C, 58.24; H, 4.89; N, 13.58. Found: C, 58.36; H, 4.98; N, 13.54.

HR- MS C ₂ . H ₂₁ N ₄ 0 ₄ S, calculated: 413.1284. Found: 413.1287. Example 24: N-(4,6-Dimethoxypyrimidine-2-substituted)-9-ethylcarbazole-3-sulfonamide (109) The product was obtained as a yellow solid, yield: 54%; mp 144- 147 ° C.

 NMR NMR (DMSO-d); δ 1.32 (t, J = 7.2 Hz, 3H), 3.76 (s, 3H), 3.76 (s, 6H), 4, 49 (q, J = 7.2 Hz, 2H), 5.70 (s, 1H), 7.29 (dd, J=7.5, 7.5Hz, 1H), 7.55 (dd, J=7.5, 7.5Hz' 1H), 7.70 (d, J=8.4Hz, 1H), 7.80 (d, J=8, 7Hz, 1H), 8.01 (dd, J=8.7, 1.5Hz, 1H), 8.27 (d, J=7.5Hz, 1H), 8.85 (d, J=l.5Hz, 1H), 11.51 ( s, 1H).

¹³ C NMR (DMS0-d ₆ ); δ 171.3, 156.1, 141.4, 140.3, 130.0, 126.9, 124.7, 121,7, 121.6, 121.1, 120.7, 120.1, 109.8, 109.3, 83.3, 54.1, 37.3, 13.7.

Elemental analysis of C ₂ . H ₂ . NAS ·0· 1Η ₂ 0, Calculated: C, 57.98; Η, 4.92; Ν, 13.53. Found: C, 58.13; Η, 4.93; Ν, 13.17. Example 25: Ν-(9-ethylcarbazole-3-substituted)-9-ethylcarbazole-3-sulfonamide (67)

 The product was obtained as a white solid. Yield: 82%; mp 230-232.

 3⁄4 NMR (DMSO— ); δ 1.20 (t, J=6.6Hz, 3H), 1.26 (t, J=6.6Hz, 3H), 4.29 (q, J=6.6Hz, 2H), 4.42 (q, J= 6.6Hz, 2H), 7.12-7.14 (m, 2H), 7.23 (dd, J=7.5, 7.2Hz, 1H), 7.38-7.41 (m, 2H), 7.47-7.52 (m, 2H), 7.64 (d , ]=7.5Hz, 1H), 7.70 (d, J=8.4Hz, 1H), 7.79 (d, J=8.7Hz, 1H), 7.86 (s, 1H), 7.99 (d, ]=7.5Hz, 1H ), 8.19 (d, ] = 7.2 Hz, 1H), 8.57 (s, 1H), 9.93 (s, 1H).

 lC NMR (DMS0- ά)·, δ 141.6, 140.7, 140.4, 137.4, 130.1, 129.9, 127.3, 126.4, 124.7, 122.6, 122.2, 122.2, 121.9, 121.6, 121.2, 120.7, 120.6, 120.4, 119.1, 114, 6 110.2, 109.8, 109.7, 109.6, 37.7, 37.4, 14.1.

Elemental analysis for _{C 2S H 25 N 3 0 2} S · 0.2H 2 0, Calcd: C, 71.36; H, 5.49 ; N, 8.92. Found: C, 71.42; H, 5.25; N, 8.79. Example 26: N-(3-Amino-4-methoxyphenyl)-9-ethylcarbazole-3-sulfonamide hydrochloride (112) a) . N-(4-methoxy-3 -nitrophenyl)-9-ethylcarbazole-3-sulfonamide

 This compound was prepared from 4-methoxy-3-nitroaniline (see Rubenstein, Steven M.; Baichwal,

Vijay _; Beckmann, Holger; et al. Journal of Medicinal Chemistry (2001), 44 (22), 3599-3605.) was prepared in the same manner as in Example 1 with 9-ethylcarbazole-3-sulfonyl chloride.

 The product was a yellow solid, yield: 71%; mp 218 - 220.

lH wake up R (DMSO-oQ; δ 1.29 (t, J=6.9Hz, 3H), 3.77 (s, 3H), 4.46 (q, J-6.9Hz, 2H), 7.21 (d, J=8. Hz, 1H), 7.28 (dd, J=7.2, 7.8Hz, 1H), 7.36 (d, J=9.0Hz, 1H), 7.53 (dd, J=7.2, 7.8Hz, 1H), 7.60 (s, 1H), 7.68 (d, J=8.4Hz, 1H), 7.52-7.83 (m, 2H), 8.26 (d, J=7.8Hz , 1H), 8.60 (s, 1H), 10.06 (s, 1H).

 b) . N-(3-Amino-4-methoxyphenyl)-9-ethylcarbazole-3-sulfonamide

The above compound a) (180 mg, 0.42 mmol) was added to 1⁄21 anhydrous ethanol, and tin dichloride (SnCl ₂ · 2H ₂ 0) (520 mg, 2.31 draw 1) was added with stirring, followed by reflux for 2 hours. At room temperature, 20 ml of water was added, and pH 7-8 was adjusted with a 10% K ₂ CO ₃ solution, and the precipitate was filtered and washed three times with water. The precipitate was dissolved in 100 ml of acetone, washed three times with acetone, and the filtrate was evaporated under reduced pressure to give a precipitate.

 c). The above precipitate was dissolved in 10 ml of anhydrous ethyl acetate, and hydrogen chloride gas was introduced into an ice water bath to make it saturated. After stirring at room temperature for 3 hours, the precipitate was filtered to give (112), m. C.

 NMR NMR (DMSO- oQ; δ 1.30 (t, J=7: 2Hz, 3H), 3.52 (s, 3H), 3.71 (s, 3H), 4.46

(q, J=7.2Hz, 2H), 6.86 (dd, J=9.0, 2.1Hz, 1H), 6.92 (d, J=9.0Hz, 1H), 7.13 (d, J=2.1Hz, 1H), 7.28 (dd, J=7.5, 7.5Hz, 1H), 7.53 (dd, J=7.8, 7.5Hz, 1H), 7.68 (d, J=7.8Hz, 1H), 7.74 (d, J=8.7Hz, 1H) , 7.79 (dd, J=8.7, 1.5Hz' 1H), 8.24 (d, J=7.8Hz, 1H), 8.59 (d, J=l.5Hz, 1H), 10.06 (s, 1H).

lC NMR (DMS0-c/ ₆ ); δ 147.3, 141.2, 140.2, 131.1, 129.3, 126.9, 125.3, 124.0, 121.7,

121.4, 120.9, 120.1, 120.0, 117.8, 114.1, 112.2, 109.8, 109.5, 55.9, 37.3, 13.7.

Elemental analysis for C ₂₁ H ₂₂ C1 N ₃ 0 ₃ S. 1.25. Found: C, 55.50; H, 5.44; N, 9.25. Found: C, 55.73; H, 5.14; N, 8.88. Example 27: N-(3,5-bis(trifluoromethyl)phenyl)-9-ethylcarbazole- 3-sulfonamide (111)

 In a reaction flask, 5 ml of pyridine and 3,5-bis(trifluoromethyl)aniline (0.31 ml, 2. Ommol) were added, and 9-ethylcarbazole-3-sulfonyl chloride prepared in advance was added thereto with stirring at room temperature. (600 mg, 2.05 ol), the reaction was continued for 1.5 hours, then pyridine was evaporated under reduced pressure, and then purified to afford white crystals (852 mg, 88%). C.

 'Η NMR (DMS0—oQ; δ 1.32 (t, J-7.2Hz, 3H), 4.49 (q, J=7.2Hz, 2H), 7.32 (dd, J=7.2, 7.8Hz, 1H), 7.57 (dd , J=7.8, 7.2Hz, 1H), 7.70-7.74 (m, 4H), 7.84 (d, J=8.7Hz, 1H), 7.88 (d, J=8.7Hz, 1H), 8.32 (d, J= 7.5 Hz, 1H), 8.74 (s, 1H), 11.14 (s, 1H).

' ³ C陋R(DMS0- oD; δ 142.0, 140.9, 140.8, 131.6( q, 132.0Hz), 128.6, 127.5, 124.2, 123.3 (q, J=1084.0Hz), 122.2, 122.1, 121.3, 120.8, 120.6 , 118.7, 116.6, 110.4, 110.3, 37.8, 14.0.

Elemental analysis for _{C 22 H 16 F 6 N 2} 0 2 S Calcd: C, 54.32; H, 3.32 ; N, 5.76. Found: C, 54.31; H, 3.33; N, 5.47. The following compounds (68) and (69) were prepared in the same manner as in Example 27. Example 28: N-(benzothiazole-2-substituted)-9-ethylcarbazole-3-sulfonamide (68)

 The product was a brown solid, yield: 76%; mp 255-257.

NMR NMR (DMS0-c ₆ ); δ 1.28 (t, J = 6.6 Hz, 3H), 4.46 (q, J = 6.6 Hz, 2H), 7.20 - 7.26 (m, 3H), 7.33 (d, J = 7.2 Hz, 1H), 7.49-7.54 (m, 1H), 7.66 (d, J=8.4Hz, 1H), 7.73-7.78 (m, 2H), 7.92 (d, J=7.8Hz, 1H), 8.31 (d , J=7.2Hz, 1H), 8.68 (s, 1H), 13.04 (s, 1H).

¹³ C匪R(DMS0-o; 5166.4, 141.1, 140.3, 136.3, 132.1, 127,1, 126.8, 124.7, 123.5, 123.4, 122.7, 121.9, 121.6, 121.0, 119.8, 119.1, 112.6, 109.7, 109.3, 37.3 , 13.6.

Elemental analysis for _{C 2l H 17 N 3 0 2} S 2 · 0.2H 2 0, Calcd: C, 61.35; H, 4.27 ; N, 10.22. Found: C,

61.42; H, 3.95; N, 10.06. Example 29: 9-Ethyl-N-(6-methoxybenzothiazole-2-substituted)-carbazole-3-sulfonamide (69) The product was obtained as a brown solid, yield: 56%; mp 292 294 C.

NMR NMR (DMSO- c ₆ ); δ 1.29 (t, J = 7.2 Hz, 3H), 3.73 (s, 3H), 4.46 (q, J = 7.2 Hz, 2H), 6.94 (d, J = 8.7 Hz, 1H), 7.16 (d, J=8.4Hz, 1H), 7.26 (dd, J=7.5, 7.2Hz, 1H), 7.43 (s, 1H), 7.52 (dd, J=8.1, 7.2Hz, 1H), 7.67 (d, J=8.1Hz, 1H), 7.74 (d, J=8.7Hz, 1H), 7.91 (d, J=8.4Hz, 1H), 8.31 (d, J=8. ΙΗζ'ΙΗ), 8.67 (s, 1H), 12.89 (s, 1H).

1 ³ C NMR (DMS0-c ₆ ); δ 165.9, 156.0, 141.1, 140.3, 132.2, 130.0, 126.8, 126.0, 123.5, 121.9, 121.5, 121.0, 119.8, 119.1, 114.6, 113.4, 109.7, 109.4, 107.0, 55.7, 37.3, 13.7.

Elemental analysis for C ₂₂ H ₁₉ N ₃ 0 ₃ S ₂ · 1.25 Η ₂ 0, Calculated: C, 57.43; H, 4.72; N, 9.13. Found: C, 57.44; H, 4.48; N, 8.84. Example 30: N-[(Dimethylamino)acetyl]-9-ethyl-N-(3,4,5-trimethoxyphenyl)-oxazole- 3-sulfonamide hydrochloride (133 )

10 ml of THF and the compound of Example 4 (43) (850 mg, 2. Ommol) were added to the reaction flask, and dimethylaminoacetyl chloride hydrochloride (460 mg, 2.9 mmol) was added thereto at room temperature, and after 5 minutes, it was added. Dimethylaminopyridine (DMAP) (30 mg, 0.2 诵ol), diisopropylethylamine (1.25 ml, 7.2 mmol). Then, most of the solvent was distilled off under reduced pressure, diluted with 100ml ethyl acetate and washed with 5% aqueous solution _103, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to give a white solid. Dissolve it in 15 ml of anhydrous ethyl acetate and introduce hydrogen chloride into the ice water bath. The mixture was stirred, and then stirred at room temperature for 2 hr. and then filtered to give a white solid (133), yield: 71%; mp 218 - 220 °C.

 NMR NMR (DMSO-d); δ 1.35 (t, J = 6.9 Hz, 3H), 2.65 (s, 6H), 3.75 (s, 3H), 3.83 (s, 6H), 3.92 (s, 2H), 4.55 (q, J=6.9Hz, 2H), 6.79 (s, 2H), 7.33 (dd, J=7.5, 7.5Hz, 1H), 7.59 (dd, J=8.4, 7.5Hz, 1H), 7.76 (d, J=8.4Hz, 1H), 7.91 (d, J=9.0Hz, 1H), 8.11 (d, J=9.0Hz, 1H), 8.43 (d, J=7.5Hz, 1H), 8.92 (s, 1H) , 9.68 (s, 1H).

¹³ C NMR (DMS0- oD; δ 165.1, 153.2, 142.3, 140.5, 138.7, 129.0, 127.3, 127.1, 126.4, 122.9, 121.8, 121.3, 120.5, 110.0, 109, 4, 108.0, 97.4, 60.1, 58.0, 56.1 , 43.4, 37.5, 13.8.

Elemental analysis for _{C 27 H 31 N 3 0 6} S - HC1 · 0.25 0, Calcd: C, 57.23; H, 5.79 ; N, 7.42. Found: C, 57.18; H, 5.75; N, 7.25. The following compounds (134), (144), (146) and (145) were prepared from the corresponding carbazole sulfonamides (105), (88), (130) and (131) in the same manner as in Example 30. Example 31: N-(2,6-Dimethoxypyridine-3-substituted)-N-[(dimethylamino)acetyl]-9-methylcarbazole-3-sulfonamide hydrochloride ( 134)

 The product was a white solid, yield: 80%; mp 216 - 218.

 NMR NMR (DMSO-GO; δ 2.64 (s, 6H), 3.77 (d, J = 17.1 Hz, 1H), 3.85 (s, 3H), 3.97 (s, 3H), 3.98 (s, 3H), 4.08 ( d, J=17.1Hz, 1H), 6.61 (d, J=8.1Hz, 1H), 7.34 (dd, J-7.8, 7.5Hz, 1H), 7.60 (dd, J=8.4, 7.5Hz' 1H), 7.74 (d, J=8.1Hz, 1H), 7.84 (d, J=8.4Hz, 1H), 7.85 (d, J=8.7Hz, 1H), 8.06 (dd, J=8.7, 1.8Hz, 1H), 8.40 (d, J = 7.8 Hz, 1H), 8.84 (d, J = 1.8 Hz, 1H), 9.89 (s, 1H;).

¹³ C NMR (DMS0- o0; δ 165.5, 163.6, 158.8, 143.9, 143.4, 141.6, 127.2, 126.9, 126.5, 122.9, 121.6, 121.4, 121.0, 120.5, 110.1, 109.2, 108.8, 102.4, 57.6, 54.1, 53.9 , 43.2, 29.5.

Elemental analysis for _{C 24 H 2e N 4 0 5} S 'HC1, Calcd: C, 55.53; H, 5.25 ; N, 10.80. Found: C,

55.35; H, 5.23; N, 10.58. Example 32: N-[(Dimethylamino)acetyl]-9-methyl-N-(3,4,5-trimethoxyphenyl)-oxazole- 3-sulfonamide hydrochloride (144 )

The product was a white solid, yield: 68%; mp 225-227 "Co 'H just R (DMSO-oO; δ 2.65 (s, 6H), 3.75 (s, 3H), 3.83 (s, 6H), 3.91 (s, 2H),

4.00 (s, 3H), 6.78 (s, 2H), 7.34 (m, IH), 7.60 (m, IH), 7.74 (d, J=9.0Hz, IH),

7.88 (d, J=9.0Hz, IH), 8.12 (dd, J=9.0, 1.8Hz, IH), 8.43 (d, J=8.1Hz, IH), 8.92 (d, J=l,8Hz, IH) , 9.63 (s, IH). Example 33: N-(4-Chloro-2,5-dimethoxyphenyl)-N-[(dimethylamino)acetyl]-9-methylcarbazole-3-sulfonamide hydrochloride (146)

 The product was obtained as a white solid. Yield: 67%; mp 178 - 180.

 NMR NMR (DMS0- οθ; δ 2.62 (s, 6H), 3.62 (d, J=17.1Hz, IH), 3.72 (s, 3H), 3.89 (s, 3H), 3.99 (s, 3H), 4.02 ( d, J=17.1Hz), 7.27 (s'lH), 7.60 (dd, J=8.1, 7.2Hz, 1H), 7.74 (d, J=8.1Hz, IH), 7.85 (d, J=9.0Hz, 1H), 8.10 (dd, J=9.0, 0.9Hz, IH), 8.40 (d, J=8.1Hz, IH), 8.64 (d, J=0, 9Hz, IH), 8.72 (s, IH). Example 34: N-[(Dimethylamino)acetyl]-9-methyl-N-(2,4,6-trimethoxyphenyl)-indazole- 3 -sulfonamide hydrochloride (145)

 The product was obtained as a white solid. Yield: 67%; mp 223 - 225.

 lH NMR (DMSO-oO; δ 2.61 (s, 6H), 3.71 (s, 2H), 3.82 (s, 6H), 3.89 (s, 3H),

3.97 (s, 3H), 6.44 (s, 2H), 7.33 (dd, J=7.2, 7.8Hz, 1H), 7.59 (dd, J=7.2, 7.8Hz, IH), 7.73 (d, J=8.4Hz , 1H), 7.83 (d, J=9.0Hz, IH), 8.07 (dd, J=9.0, 1.5Hz, IH), 8.35 (d, J=7.8Hz, IH), 8.80 (s, 1H), 9.70 (s, IH).

^{, 3} C NMR (DMS0-c/e); δ 165.7, 162.8, 158.0, 143.3, 141.6, 127.5, 127.1, 126.9, 123.1, 121.6, 121.1, 120.7, 120.4, 110.1, 108.8, 103.7, 91.5, 57.1, 56.2 , 55.9, 43.0, 29.5. The following compound was obtained in the same manner as in Example 1 from the corresponding 3-amino-9-methyl or ethylcarbazole and an aheterocyclic sulfonyl chloride. Example 35: Ν-(9-Methylcarbazole-3-substituted)-4-methoxybenzenesulfonamide (84)

 The product was obtained as a white solid. Yield: 87%; mp 206-208.

Ή NMR (DMSO-oQ; δ 3.73 (s, 3H), 3.79 (s, 3H), 6.85 (d, J = 8.7 Hz, 2H), 7.10 (d, J-8.4 Hz, IH), 7.16 (dd, J=7.5, 7.2Hz, IH), 7.42-7.46 (m, 2H), 7.54 (d, J=8.4Hz, IH), 7.60 (d, J=8.7Hz, 2H), 7.80 (s, 1H), 8.02 (d, J = 7.5 Hz, IH), 8.66 (s, IH) ₀ 1C NMR (DMSO-c/e); 5162.2, 141.0, 138.9, 131.2, 129.1, 129.0, 126.0, 122.0, 121.5, 121.4, 120.2, 118.8, 114.3, 114.2, 109.4, 109.2, 55.5, 29.0.

Elemental analysis of C ₂ . H ₁₈ N ₂ 0 ₃ S, Calculated: C, 65.55; H, 4.96; N, 7.65. Found: C, 65.62; H, 5.00; N, 7.44. Example 36: N-(9-ethylcarbazole-3-substituted)-4-isopropylbenzenesulfonamide (70)

 The product was a brown solid, yield: 64%; mp 154 - 156.

 'Η NMR (DMSO - ο ; δ 1.19 (d, J=6.0Hz, 6H), 1.24 (t, J=6.9Hz, 3H), 4.34 (q, J=6.9Hz, 2H), 4.56-4.64 (m , 1H), 6.95 (d, J-8.7Hz, 2H), 7.11 (dd, J=8.7, 1.2Hz, 1H), 7.14 (dd, J=7.5, 7.2Hz, 1H), 7.42 (dd, J= 8.4, 7.2 Hz, 1H), 7.45 (d, J=8.4 Hz, 1H), 7.54 (d, J=8.4 Hz, 1H), 7.59 (d, J=8.7 Hz, 1H), 7.78 (d, J= L.2 Hz, 1H), 8.00 (d, 7.8 Hz, 1H), 10.06 (s, 1H).

¹³ C NMR (DMS0-i/ ₆ ); δ 160.5, 139.9, 137.1, 130.9, 129.2, 128.7, 126.0, 122.1, 121.7, 121.4, 120.2, 118.7, 115.3, 114.3, 109.3, 109.2, 69.7, 36.9, 21.5, 13.6.

Elemental analysis for C ₂₃ H ₂₄ N ₂ 0 ₃ S: C, 67.62; H, 5.93; N, 6.86. Found: C, 67.83; H, 5.81; N, 6.82. Example 37: N-(9-ethylcarbazole-3-substituted)-4-n-butylbenzenesulfonamide (71)

 The product was a yellow solid, yield: 78%; mp 131 - 133.

3⁄4刚R (DMS0-i _e ); δ 0.87 (t, J=7.5Hz, 3H), 1.25 (t, J=6.9Hz, 3H), 1.32-1.42 (m, 2H), 1.58-1.67 (m, 2H), 3.94 (t, J=6.3Hz, 3H), 4.35 (q, J=6.9Hz, 2H), 6.95 (d, J=9.0Hz, 2H), 7.09-7.17 (m, 2H), 7.40- 7.46 (m, 2H), 7.55 (d, J=8.4Hz, 1H), 7.60 (d, J=9.0Hz, 1H), 7.79 (s, 1H), 8.01 (d, J=7.8Hz, 1H), 9.85 (s, 1H).

¹³ C just R (DMS0- o0; δ 161.7, 139.9, 137.1, 131.1, 129.2, 129.0, 126,0, 122.2, 121.7, 121.3, 120.3, 118.7, 114.5, 14.2, 109.3, 109.1, 67.6, 37.0, 30.4, 18.6, 13.6, 13.5.

Elemental analysis for _{C 24 H 2e N 2 0 3} S Calcd: C, 68.21; H, 6.21 ; N, 6.63. Found: C, 68.36; H, 6.04; N, 6.50. Example 38: N-(9-ethylcarbazole-3-substituted)-4-phenoxybenzenesulfonamide (72)

 The product was a brown foamy solid, yield: 70%.

3⁄4 NMR (DMS0 - οθ; δ 1.25 (t, J = 7.2 Hz, 3H), 4.36 (q, ] = 7.2 Hz, 2H), 6.99-7.04 (m, 4H), 7.11-7.22 (m, 3H), 7.36-7.49 (m, 4H), 7.56 (d, J=8.4Hz, 1H), 7.67 (d, 8.7 Hz, 2H), 7.77 (s, 1H), 8.02 (d, J = 7.5 Hz, 1H), 9, 95 (s, 1H).

 ' NMR (DMS0- o0; δ 160.5, 154.8, 139.9, 137.2, 133.6, 130.3, 129.3, 128.9, 126.0, 124.8, 122.2, 121.7, 120.3, 120.0, 118.8, 117.5, 114.6, 109.4, 109.2, 37.0, 13.7 c

Elemental analysis for _{C 2S H 22 N 2 0 3} S, Calcd: C, 70.56; H, '5.02; N, 6.33. Found: C, 70.65;

H, 4.75; N, 6.29o Example 39 N-(9-ethylcarbazole-3-substituted)-3-methoxybenzenesulfonamide (95)

 Light brown solid, Yield: 71%; mp 176 - 178.

 lH NR (DMSO-o; δ 1.25 (t, J=7.2Hz, 3H), 3.70 (s, 3H), 4.35 (q, J=7.2Hz, 2H), 7.10—7.18 (m, 3H), 7.27— 7.29 (m, 2H), 7.37-7.48 (m, 3H), 7.55 (d, J=8.1Hz, 1H), 7.82 (d, J=l.5Hz, 1H), 8.03 (d, J=7.5Hz, 1H), 10.02 (s, 1H).

¹³ C NMR (DMSO-oO; δ 159.2, 140.8, 139.9' 137.2, 130.3, 128.7, 126.1, 122.1' 121.6, 121.5, 120.3, 118.9, 118.8, 118.4, 114.6, 111.7, 109.4, 109.2, 55.5, 37.0, 13.7.

Elemental analysis of C ₂₁ H ₂ . N ₂ 0 ₃ S, calculated: C, 68.29; H, 5.31; N, 7.36. Found: C, 65.95; H, 5.23; N, 7.21. Example 40: N-(9-ethylcarbazole-3-substituted)-2,5-dimethoxybenzenesulfonamide (96)

 The product was obtained as a white solid. Yield: 84%; mp 237-239.

 NMR NMR (DMSO-oD; δ 1.25 (t, J=6.6Hz, 3H), 3.62 (s, 3H), 3.91 (s, 3H), 4.35 ■ (q, J=6.6Hz, 2H), 7.07—7.17 (m, 5H), 7.39—7.45 (m, 2H), 7.54 (d, J=8.1Hz, 1H), 7.80 (s, 1H), 8.01 (d, J=7.8Hz, 1H), 9.71 (s, 1H).

¹³ C NMR (DMSO-ί/β); δ 152.0, 150.3, 139.9, 137.0, 128.8, 127.1, 125.9, 122.0, 121.6, 121.1, 120.1, 119.5, 118.7, 115.1, 113.9, 113.9, 109.2, 109.1, 55.3, 55.6,

Elemental analysis for _{C 22 H 22 N 2 0 4} S · 0.2H 2 0 Calcd: C, 63.81; H, 5.46 ; N, 6.77. Found: C, 63.78; H, 5.43; N, 6.74. Example 41: N-(9-ethylcarbazole-3-substituted)-3,4-dimethoxybenzenesulfonamide (46)

 The product was obtained as a light brown solid. Yield: 77%; mp 168 169.

lH NMR (DMS0-c/ _fi ); δ 1.24 (t, J=6.6Hz, 3H), 3.68 (s, 3H), 3.73 (s, 3H), 4.35 (q, J=6.6Hz, 2H), 6.98 (d, J=8.7Hz, 1H), 7.11-7.23 (m, 4H), 7.43 (dd, J=7.8' 7.2Hz, 1H), 7.46 (d, J=8.1Hz, 1H), 7.55 (d, J=8.1Hz, 1H), 7.83 (s, 1H), 8.03 (d, J=7.5Hz, 1H), 9.85 (s, 1H).

¹³ C NMR (DMS0-cO; δ 151.9, 148.4, 139.9, 137, 1, 131.1, 129.1, 126.0, 122.1, 121.7, 121.5, 120.6, 120.3, 118.7, 114.5, 110.9, 109.5, 109.3, 109.2, 55.6, 36.9, 13.6.

Elemental analysis for C ₂₂ H ₂ Ju 0 ₄ S · 0.25H ₂ 0, Calcd: C, 63.66; H, 5.42 ; N, 6.75. Found: C,

63.41; H, 5.32; N, 6.68. Example 42: N-(9-ethylcarbazole-3-substituted)-3-cyanobenzenesulfonamide (102)

 The product was obtained as a white solid. Yield: 71%; mp 198-200 s.

 With R (DMS0- οθ; δ 1.25 (t, J=7.2Hz, 3H), 4.36 (q, ]=7.2Hz, 2H), 7.06 (dd, J=8.7, 1.8Hz, 1H), 7.16 (dd, J=7.5, 7.2Hz, 1H), 7.44 (dd, J=7.8, 7.2Hz, 1H), 7.48 (d, J=8.7Hz, 1H), 7.56 (d, J=8.1Hz, 1H), 7.71 ( Dd, J=8.1, 7.8Hz, 1H), 7.82 (d, J=1.8Hz, 1H), 7.94 (d, J=8.1Hz, 1H), 8.05—8.09 (ra, 2H), 10.20 (s, 1H :).

¹³ C NMR (DMS0-c/ _e ); δ 140.8, 140.0, 137.5, 131.2, 130.6, 130.2, 127.9, 126.2, 122.3, 121.9, 121.6, 120.4, 118.8, 117.4, 115.4, 112.3, 109.5, 109.3, 37.0, 13.6.

Elemental analysis for C ₂₁ H _l7 N ₃ 0 ₂ S · 0.2H ₂ 0, calc.: C, 66.54; H, 4.64; N, 11.09. Found: C,

66.52; H, 4.54; N, 10.83. Example 43: N-(9-ethylcarbazole-3-substituted)-6-(morpholine-4-substituted)benzenesulfonamide (103)

 The product was obtained as a white solid. Yield: 68%; mp 172 - 173.

'HNMR(DMS0- ο ; δ 1.26 (t, J=6.9Hz, 3H), 3.43(t, J=4.8Hz, 4H), 3.58 (t, J=4.8Hz _: 4H), 4.36 (q, J= 6.9 Hz, 2H), 6.83 (d, J = 9.0 Hz, 1H), 7.13 - 7.18 (m, 2H), 7.43 (dd, J = 8.1, 7.2 Hz, 1H), 7.48 (d, J = 8.7 Hz, 1H), 7.56 (d, ]=7.8Hz, 1H), 7.69(dd, J=9.0, 2.4Hz, 1H), 7.82(d, J=l.5Hz, 1H), 8.04 (d, J=7.8Hz , 1H), 8.29 (d, J=2.1Hz, 1H), 9.88 (s, 1H).

¹³ C wake up R (DMS0- o0; δ 159.7, 147.2, 139.9, 137.0, 135.9' 129.1, 126.0, 123, 4, 122.1, 121.6, 121.0, 120.3, 118.7, 113.9, 109.4, 109.2, 105.9, 65.7, 44.3, 36.9, 13.7.

HR-MS C ₂₁ H ₂₃ N ₄ 0 ₃ S, Calculated: 437.1647. Found: 437.1630. Example 44: N-(9-ethylcarbazole-3-substituted)-2-naphthalenesulfonamide (47)

 The product was a yellow solid, yield: 82%; mp 162-164. C.

lH NMR (DMS0-c ₆ ); δ 1.20 (t, J=6.9Hz, 3H), 4.30 (q, J=6.9Hz, 2H), 7.08—7.15 (m, 2H), 7.39-7.42 (m, 2H), 7.51-7.64 (m, 3H), 7.78 (d, J=8.4Hz, IH), 7.86 (s, IH), 7.95—8.07 (m, 4H ), 8.34 (s, IH), 10.14 (s, IH).

' ³ C NMR (DMSO - oO ; δ 140.6, 137.9, 137.5, 134.9, 132.3, 129.9, 129.8129.5, 129.4, 128.7, 128.2, 126.8, 123.1, 122.9, 122.4, 122.3, 121.0, 119.5, 115.5, 110.1, 109.9, 37.7, 14.3.

Elemental analysis of C ₂₄ H ₂ . N ₂ 0 ₄ S, calculated: C, 71.97; H, 5.04; N, 7.00. Found: C, 71.78; H, 4.77; N, 6.92. Example 45: N-(9-ethylcarbazole-3-substituted)-2-thiophenesulfonamide (48)

 The product was a brown solid, yield: 87%; mp 186 188.

'Η NMR (DMS0-c ₆ ); δ 1.26 (t, J=6.9Hz, 3H), 4.37 (q, J=6.9Hz, 2H), 7.06 (dd,

J=4.5, 3.9Hz, IH), 7.16 (dd, J=7.2, 7.2Hz, IH), 7.16 (d, J=8.7Hz, IH), 7.41-7.46 (m, 2H), 7.50 (d, J =8.7Hz, IH), 7.56 (d, J=8.4Hz, 1H), 7.82 (d, J=8.7Hz, IH), 7.84 (s, 1H), 8.04 (d, J=8.4Hz' IH), 10.15 (s, IH).

¹³ C NMR (DMSO - oQ ; δ 156.7, 140.0, 137.4, 133.0, 132.1, 128.5, 127.5, 126.1, 122.1, 121.8, 120.3, 118.8, 114.9, 109.4, 109.3, 99.5, 37.0, 13.7.

Elemental analysis C _l8 H ₁₆ N ₂ 0 ₂ S, Calcd.: C, 60.64; H, 4.53; N, 7.86. Found: C, 60.43; H, 4.34; N, 7.73. Example 46: N-(9-ethylcarbazole-3-substituted)-1-benzothiophene-2-sulfonamide (49)

 The product was a brown solid, yield: 58%; mp 186 - 188.

 Ή NMR (DMSO-oQ; δ 1.25 (t, J = 6.9 Hz, 3H), 4.35 (q, J = 6.9 Hz, 2H), 7.15 (dd,

J=7.8, 7.2Hz, IH), 7.18 (dd, J=9.0, 1.5Hz, IH), 7.38-7.50 (m, 4H), 7.56 (d, J=8.1Hz, IH), 7.85 (s, IH) ), 7.92-7.94 (m, 2H), 8.01 (d, J=8.4Hz, 1H), 8.04 (d, J=8.4Hz, 1H), 10.42 (s, 1H).

¹³ C NMR (DMS0- o0 δ 140.9, 140.6, 140.0, 137.5, 137.3, 129.3, 128.2, 127.2, 126.1, 125.8, 125.4, 123.0, 122.2, 121.7, 120.4, 118.8, 115.0, 109.5, 109.3, 37.0, 13.7.

Elemental analysis for C ₂₂ H _l8 N ₂ 0 ₂ S ₂ , calc.: C, 64.99; H, 4.47; N, 6.89. Found: C, 65.07; H, 4.44; N, 7.10.

Claims

 Claim

1. A carbazole sulfonamide derivative or a salt thereof, having the following general formula (I)

(I) wherein - represents: hydrogen, one or more nitro, amino, substituted amino, halogen, cyano, ester, amide, hydroxy, decyl, substituted or unsubstituted lower alkyl attached to the phenyl ring a lower decyloxy or aryloxy group, a lower sulfonylthio group or an arylthio group;

 Representative: hydrogen, lower sulfhydryl;

X represents: S0 ₂ NR ₃ or NR ₃ S0 ₂ , or a salt thereof, wherein R ₃ represents:

a hydrogen, a lower alkyl group, or a substituted acyl group represented by the formula (Π);

R ¹ represents a lower alkyl group, or an amine-substituted lower alkyl group represented by the formula (III) or a salt thereof;

n in the formula (III) is 1-6; R ² and R ³ respectively represent the same or different groups: hydrogen, lower fluorenyl, hydroxyalkyl, amino fluorenyl; or R ² , R ³ Connecting together by nitrogen to form a 5-7 membered cyclic amine group, or a salt thereof;

 Ar stands for:

 Substituted phenyl, the substituent may be one or more lower fluorenyl, lower cyclodecyl, lower alkoxy, lower alkylthio, hydroxy, decyl, amino, substituted amino, amide, ester, nitrate Base, cyano, halogen or haloalkyl;

Pyridyl or substituted pyridyl, the substituent of which may be one or more lower fluorenyl, lower cycloalkyl, lower alkoxy, lower alkylthio, hydroxy, decyl, amino, substituted amino, amide, ester Base, nitro, cyano or halogen; a pyrimidinyl or substituted pyrimidinyl group, the substituent of which may be one or more lower alkyl, lower cyclodecyl, lower decyloxy, lower thiol, hydroxy, decyl, amino, substituted amino, amide, ester Base, nitro, cyano or halogen; or,

 Thiophene, bicyclic or tricyclic aromatic heterocycle.

The carbazole sulfonamide derivative or a salt thereof according to claim 1, wherein R is selected from the group consisting of hydrogen, nitro, amino or amido group, lower alkyl group or lower decyloxy group.

The carbazole sulfonamide derivative or a salt thereof according to claim 1, wherein X is S0 ₂ NR ₃ or NR ₃ S0 ₂ or a hydrochloride thereof, wherein hydrogen or an amine-substituted lower alkane Acyl group.

The carbazole sulfonamide derivative or a salt thereof according to claim 1, wherein, when Ar is a substituted phenyl group, pyridyl group or pyrimidinyl group, the substituent is selected from the group consisting of a lower alkyl group, a lower cycloalkyl group, and a lower alkoxy group. A hydroxy group, an amino group, a monosubstituted or disubstituted amino group, an amide group, an ester group, a nitro group, a cyano group, a halogen or a trifluoromethyl group.

The carbazole sulfonamide derivative or a salt thereof according to claim 4, wherein Ar is a 3-alkoxyphenyl group, a 5-methoxyphenyl group, a di- or tri-methoxyphenyl group, or a chloro-hydrazine. Oxyphenyl, cyanophenyl or decyloxypyridyl.

The carbazole sulfonamide derivative or a salt thereof according to any one of claims 1 to 5, which comprises:

 N-(3,4-dimethoxyphenyl)-9-ethylcarbazole-3-sulfonamide;

 N-(3, 5-Dimethoxyphenyl)-9-ethylcarbazole-3-sulfonamide;

 9-ethyl-N-(3,4,5-trimethoxyphenyl)-oxazole- 3-sulfonamide;

 9-methyl-N-(3,4,5-trimethoxyphenyl)-oxazole- 3-sulfonamide;

 N-(3,4,5-trimethoxyphenyl)-9H-carbazole-3-sulfonamide;

 N-(2,4-dimethoxyphenyl)-9-ethylcarbazole-3-sulfonamide;

 N-(2, 5-Dimethoxyphenyl)-9-ethylcarbazole -3-sulfonamide;

 N-(3-chloro-4-methoxyphenyl)-9-ethylcarbazole -3-sulfonamide;

 N-(5-chloro-2,4-dimethoxyphenyl)-9-ethylcarbazole-3-sulfonamide;

 N-(5-chloro-2,4-dimethoxyphenyl)-9-methylcarbazole-3-sulfonamide;

 N-(4-chloro-2,5-dimethoxyphenyl)-9-ethylcarbazole-3-sulfonamide;

 N-(4-chloro-2,5-dimethoxyphenyl)-9-methylcarbazole-3-sulfonamide;

 9-methyl N-(2, 4, 6-trimethoxyphenyl)-carbazole -3-sulfonamide;

9-ethyl-6-nitro-N-(3,4,5-trimethoxyphenyl)-carbazole-3-sulfonamide; 6-Amino-9-ethyl-N-(3,4,5-trimethoxyphenyl)-oxazole- 3-sulfonamide;

 9-ethyl-N-(4-fluorophenyl)-carbazole-3-sulfonamide;

 9-ethyl-N-(2-methoxypyridine _5_substituted)-carbazole-3-sulfonamide;

 N-(2,6-dimethoxypyridine-3-substituted)-9-ethylcarbazole-3-sulfonamide;

 N - (2,6-dimethoxypyridine -3_substituted) -9-methylcarbazole- 3-sulfonamide;

 9-ethyl-N-(2-methoxypyridine-3-substituted)-indazole- 3-sulfonamide;

 N-[(Dimethylamino)acetyl]-9-ethyl-N-(3,4,5-trimethoxyphenyl)-carbazole-3-sulfonamide hydrochloride; N-(2, 6-Dimethoxypyridine-3-substituted) -N-[(Dimethylamino)acetyl]_9-methylcarbazole- 3-sulfonamide salt

N-[(Dimethylamino)acetyl]-9-methyl-N-(3,4,5-trimethoxyphenyl)-carbazole-3-sulfonamide hydrochloride; N_(4-chloro - 2, 5-dimethoxyphenyl)-N-[(dimethylamino)acetyl]_9-methylcarbazole- 3-sulfonamide hydrochloride

N-[(Dimethylamino)acetyl]-9-methyl-N-(2,4,6-trimethoxyphenyl)-carbazole-3-sulfonamide hydrochloride;

N-(9-ethylcarbazole-3-substituted)-3-methoxybenzenesulfonamide;

 N-(9-ethylcarbazole-3-substituted)-2,5-dimethoxybenzenesulfonamide.

The carbazole sulfonamide derivative or a salt thereof according to claim 6, which comprises:

 9-ethyl-N-(3,4,5-trimethoxyphenyl)-oxazole -3-sulfonamide;

 9-methyl-N-(3,4,5-trimethoxyphenyl)-carbazole-3-sulfonamide;

 N-(2,4-dimethoxyphenyl)-9-ethylcarbazole-3-sulfonamide;

 N-(2,5-dimethoxyphenyl)-9-ethylcarbazole-3-sulfonamide;

 N-(3-chloro-4-methoxyphenyl)-9-ethylcarbazole-3-sulfonamide;

 N-(5-chloro-2,4-dimethoxyphenyl)-9-ethylcarbazole-3-sulfonamide;

 N-(5-chloro-2,4-dimethoxyphenyl)-9-methylcarbazole-3-sulfonamide;

 N - (4-chloro-2, 5-dimethoxyphenyl)-9-ethylcarbazole -3-sulfonamide;

 N-(4-chloro-2,5-dimethoxyphenyl)-9-methylcarbazole-3-sulfonamide;

 9-methyl-N-(2,4,6-trimethoxyphenyl)-oxazole- 3-sulfonamide;

 9-ethyl-6-nitro-N-(3,4,5-trimethoxyphenyl)-oxazole- 3-sulfonamide;

 6-amino-9-ethyl-N-(3,4,5-trimethoxyphenyl)-oxazole -3-sulfonamide;

 9-ethyl-N-(2-methoxypyridine-5-substituted)-indazole- 3-sulfonamide;

N-(2,6-dimethoxypyridin-3-substituted)-9-ethylcarbazole-3-sulfonamide; N - (2,6-dimethoxypyridin-3-substituted)-9-methylcarbazole-3-sulfonamide;

 9-ethyl-N-(2-methoxypyridine-3-substituted)-indazole-3-sulfonamide;

 N-[(Dimethylamino)acetyl] _9-ethyl-N-(3,4,5-trimethoxyphenyl)-carbazole-3-sulfonamide hydrochloride; N - (2, 6 -Dimethoxypyridin-3-substituted)-N-[(Dimethylamino)acetyl]-9-methylcarbazole-3-sulfonamide hydrochloride.

Use of the carbazole sulfonamide derivative or a salt thereof according to any one of claims 1 to 7 as an anti-mitotic agent.

Use of the carbazole sulfonamide derivative or a salt thereof according to any one of claims 1 to 7 for the preparation of an antitumor drug.

An antitumor pharmaceutical composition comprising a therapeutically effective amount of the carbazole sulfonamide derivative or a salt thereof according to any one of claims 1 to 7 and a pharmaceutically acceptable pharmaceutical excipient.

The process for producing a carbazole sulfonamide derivative or a salt thereof according to claim 1, which comprises a process for producing an oxazole sulfonamide or a carbazole-substituted aromatic heterocyclic sulfonamide by a reaction of a sulfonyl chloride with an amino compound.

The process according to claim 11, wherein the reaction of the sulfonyl chloride compound with the amino compound comprises a reaction of using a substituted oxazolesulfonyl chloride with an arylamine or a reaction of an aminocarbazole with an arachidylsulfonyl chloride. .

The process according to claim 11 or 12, which further comprises the step of reacting the product of the reaction with alkanoyl chloride to prepare a pharmaceutically acceptable salt of the carbazole sulfonamide derivative.