Benzoisothiazole compounds and methods of treating schizophrenia

Abstract

Disclosed are benzoisothiazole compounds and a use in the preparation of anti-schizophrenia drugs. The benzoisothiazole compounds of the present invention not only have strong affinity for dopamine D.sub.3 receptor, 5-HT.sub.1A receptor and 5-HT.sub.2A receptor, but also can observably improve the symptoms of schizophrenia relevant to apomorphine model and MK-801 model mice, with oral absorption being good, safety being high and side-effect being less, and having developmental value as new anti-neurotic disease drugs. The present invention is the compounds having a structure of general formula (I), or geometric isomers, free alkalies, salts, hydrates or solvates thereof. ##STR00001##

Claims

1. The benzoisothiazole compound, characterized in that it is the compound having the structure of general formula (I) or the geometric isomers, free alkalies, salts, hydrates or solvates thereof: ##STR00085## wherein: W is: ##STR00086## R.sub.1 and R.sub.2 independently represent heteroaryl or substituted heteroaryl; n is 0, 1, 2 or 3; m is 0, 1 or 2; R.sub.3 represents C.sub.1-C.sub.4 alkyl, substituted C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.6 cycloalkyl, substituted C.sub.3-C.sub.6 cycloalkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, heteroaryl, substituted heteroaryl, heteroarylmethyl, or substituted heteroarylmethyl; R.sub.4 is hydrogen atom or C.sub.1-C.sub.4 alkyl; R.sub.5 is phenyl, substituted phenyl, heteroaryl or substituted heteroaryl; the heteroaryl represented by R.sub.1 and R.sub.2 is selected from furyl, pyrrolyl, thienyl, benzofuryl, indolyl or benzothienyl; the substituent of the substituted heteroaryl represented by R.sub.1 and R.sub.2 is selected from halogen, cyano, C.sub.1-C.sub.2 alkyl carbonyl, nitro, methoxyl or C.sub.1-C.sub.4 alkyl; the C.sub.1-C.sub.4 alkyl represented by R.sub.3 can be substituted by 1-3 fluorine atom(s); the substituent of the substituted cycloalkyl represented by R.sub.3 is selected from C.sub.1-C.sub.2 alkyl; the substituent of the substituted phenyl, substituted benzyl, substituted heteroaryl or substituted heteroarylmethyl represented by R.sub.3 is selected from halogen, C.sub.1-C.sub.2 alkoxy, nitro or C.sub.1-C.sub.2 alkyl; the heteroaryl represented by R.sub.3 is selected from furyl, thienyl, pyridyl or benzofuryl; the heteroarylmethyl represented by R.sub.3 is selected from furylmethyl, thenyl, picolyl, benzofurylmethyl or benzothenyl; the substituent of the substituted heteroaryl represented by R3 is selected from halogen, C1-C2 alkoxy, nitro or C1-C2 alkyl-substituted furyl, thienyl, pyridyl or benzofuryl; the substituent of the substituted heteroarylmethyl represented by R3 is selected from halogen, C1-C2 alkoxy, nitro or C1-C2 alkyl-substituted furylmethyl, thenyl, picolyl, benzofurylmethyl or benzothenyl; the heteroaryl represented by R.sub.5 is selected from furyl, pyrrolyl, thienyl, pyridyl, benzofuryl, benzothienyl or indolyl; and the substituent of the substituted phenyl or substituted heteroaryl represented by R.sub.5 is selected from halogen, C.sub.1-C.sub.2 alkoxy, nitro or C.sub.1-C.sub.2 alkyl.

2. The benzoisothiazole compound according to claim 1, characterized in that the hydrate is a hydrate containing 0.5-3 molecules of crystal water wherein the salt comprises a pharmaceutically acceptable anion.

3. The benzoisothiazole compound according to claim 2, characterized in that the salt further contains 0.5-6 molecules of crystal water.

4. A benzoisothiazole compound, characterized in that the compound is: I-1 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)furyl-2-carboxamide, I-2 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)thienyl-2-carboxamide, I-3 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)-1H-pyrrolyl-2-carboxamide, I-4 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)-1H-indolyl-2-carboxamide, I-5 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)benzofuryl-2-carboxamide, I-6 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)benzo[b]thienyl-2-carboxamide, I-7 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)-5-cyano-furyl-2-carboxamide, I-8 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)-3-tert-butylfuryl-2-carboxamide, I-9 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)-5-methyl-1 H-pyrrolyl-2-carboxamide, I-10 trans 5-acetyl-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl) ethyl)cyclohexyl)furyl-2-carboxamide, I-11 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)-3-methylthienyl-2-carboxamide, I-12 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)-3-bromothienyl-2-carboxamide, I-13 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)-3-methylbenzo[b]thienyl-2-carboxamide, I-14 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)-3-chlorobenzo[b]thienyl-2-carboxamide, I-15 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)-5-nitro-1H-indolyl-2-carboxamide, I-16 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)-5-methoxylbenzofuryl-2-carboxamide, I-17 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)-2-(thien-2-yl)acetamide, I-18 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)-2-(benzofuran-3-yl)acetamide, I-19 cis-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)furyl-2-carboxamide, I-20 cis-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)thienyl-2-carboxamide, I-21 cis-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)-1H-pyrrolyl-2-carboxamide, I-22 cis-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)-1H-indolyl-2-carboxamide, I-23 cis-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)benzofuryl-2-carboxamide, I-24 cis-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)benzo[b]thienyl-2-carboxamide, II-1 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)thienyl-2-sulfamide, II-2 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)-1H-pyrrolyl-3-sulfamide, II-3 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)furyl-2-sulfamide, II-4 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)benzo[b]thienyl-2-sulfamide, II-5 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)benzofuryl-2-sulfamide, II-6 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)-1H-indolyl-3-sulfamide, II-7 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)-5-cyanofuryl-2-sulfamide, II-8 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)-5-chlorofuryl-2-sulfamide, II-9 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)-5-methylfuryl-2-sulfamide, II-10 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)-5-tert-butylthienyl-2-sulfamide, II-11 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)-5-chlorobenzo[b]thienyl-2-sulfamide, II-12 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)-5-cyanobenzo[b]thienyl-2-sulfamide, II-13 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)-5-methylbenzo[b]thienyl-2-sulfamide, II-14 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)-5-nitrobenzo[b]thienyl-2-sulfamide, II-15 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)-5-methoxylbenzofuryl-2-sulfamide, II-16 cis-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)thienyl-2-sulfamide, II-17 cis-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)-1H-pyrrolyl-3-sulfamide, II-18 cis-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)furyl-2-sulfamide, II-19 cis-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)benzo[b]thienyl-2-sulfamide, II-20 cis-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)benzofuryl-2-sulfamide, II-21 cis-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)-1H-indolyl-3-sulfamide, II-22 cis-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)-5-methylfuryl-2-sulfamide, III-1 trans-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)methylcarbamate, III-2 trans-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)ethylcarbamate, III-3 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)isobutylcarbamate, III-4 trans-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)cyclopropylcarbamate, III-5 trans-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)cyclohexylcarbamate, III-6 trans-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)phenylcarbamate, III-7 trans-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)-3-methoxylphenylcarbamate, III-8 trans-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)-2-methylphenylcarbamate, III-9 trans-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)-4-chlorophenylcarbamate, III-10 trans-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)-4-nitrophenylcarbamate, III-11 trans-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)benzylcarbamate, III-12 trans-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)benzofuryl-2-methylcarbamate, III-13 trans-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)thienyl-2-methylcarbamate, III-14 cis-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)methylcarbamate, III-15 cis-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)ethylcarbamate, III-16 cis-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)benzylcarbamate, IV-1 trans-1-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)-3-phenylurea, IV-2 trans-1-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)-3-phenylethylurea, IV-3 trans-1-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)-3-(pyridin-3-yl)urea, IV-4 trans-1-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)-3-(furan-2-yl)urea, IV-5 trans-1-(benzo[b]thien-2-yl)-3-(4-(2-(4-(benzo[d]isothiazol-3-yl) piperazin-1-yl)ethyl)cyclohexyl)urea, IV-6 trans-3-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)-1-methyl-1-phenylurea, IV-7 trans-3-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)-1-butyl-1-phenylurea, IV-8 trans-3-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)-1-methyl-1-(thien-2-yl)urea, IV-9 trans-1-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)-3-(3-methoxylphenyl)urea, IV-10 trans-1-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)-3-(3-nitrophenyl)urea, IV-11 trans-1-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)-3-benzylurea, IV-12 cis-1-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)-3-phenylurea, IV-13 cis-1-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)-3-benzylurea, or IV-14 cis-1-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)-3-(furan-2-yl)urea, or a geometric isomer, free alkali, salt, hydrate or solvate thereof.

5. A composition for treating schizophrenia, characterized in that the composition comprises a therapeutically effective amount of an benzoisothiazole compound according to claim 1 or one or more of the geometric isomers, free alkalies, salts, hydrates or solvates thereof and a pharmaceutically acceptable carrier.

6. A method for treating schizophrenia, which comprises administering a therapeutically effective amount of a benzoisothiazole of claim 1 to a patient in need thereof.

7. A method for treating schizophrenia, which comprises administering a therapeutically effective amount of the composition of claim 5 to a patient in need thereof.

8. An anti-schizophrenia composition comprising a benzoisothiazole compound of claim j and a pharmaceutically acceptable carrier.

9. A composition for treating schizophrenia, wherein the composition comprises a therapeutically effective amount of one of the benzoisothiazole compounds according to claim 4, or a geometric isomer, free alkali, salt, hydrate or solvate thereof, and a pharmaceutically acceptable carrier.

10. A method for treating schizophrenia, which comprises administering a therapeutically effective amount of a benzoisothiazole compound of claim 4 to a patient in need thereof.

11. A method for treating schizophrenia, which comprises administering a therapeutically effective amount of the composition of claim 9 to a patient in need thereof.

12. An anti-schizophrenia composition comprising a benzoisothiazole compound of claim 4 and a pharmaceutically acceptable carrier.

Description

EXAMPLE 1

Preparation of trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)furyl-2-carboxamide (I-1) and the salt thereof

(1) Preparation of trans-N-tert-butoxycarbonyl-4-aminocyclohexylthanol (2)

(1) Trans-N-tert-butoxycarbonyl-4-aminocyclohexylacetic acid (128.5 g, 0.5 mol) and dichloromethane (1 L) were added into a 4-neck flask (2 L), and cooled under ice bath to 0 C., followed by the dropwise addition of triethylamine (1.25 mol). Isopropyl chloroformate (0.6 mol) was slowly added dropwise at the temperature not exceeding 5 C., and then stirred at room temperature (RM) for 3 h and cooled to 5 C. Cold water (500 mL) was added and then stirred for 0.5 h. Layers were separated, and the organic layer was washed with saturated saline (400 mL1), and evaporated to dryness. Under N.sub.2 protection, anhydrous THF (1 L) was added to the residue, and the temperature was reduced to 0 C. KBH.sub.4 (0.5 mol) was added slowly in portion at the temperature not exceeding 5 C., then stirred at RM for 3 h, and cooled below 5 C. Saturated ammonium chloride solution was slowly added dropwise until no bubbles were generated. The system was concentrated under reduced pressure to near dryness, and added with water (400 mL) and dichloromethane (500 mL) for distribution. The organic layer was washed sequentially with saturated Na.sub.2CO.sub.3 aqueous solution, water, and saturated saline, and evaporated to dryness, to give the intermediate trans-N-tert-butoxycarbonyl-4-aminocyclohxeylethanol (2) which was directly used for reaction in the next step.

(2) Preparation of trans-N-tert-butoxycarbonyl-4-aminocyclohexylethanol mesylate (3)

(2) Trans-N-tert-butoxycarbonyl-4-aminocyclohexyl ethanol (2) (48.6 g, 0.2 mol), triethylamine (0.6 mol) and dichloromethane (500 mL) were added into a 4-neck flask (2 L), and cooled under ice-bath to 0 C. The solution of methane sulfonyl chloride (0.24 mol) in dichloromethane (200 mL) was slowly added dropwise, and then stirred at RM for 4 h. The reaction solution was washed sequentially with water (300 mL2), 1% sodium hydroxide aqueous solution (300 mL2), water (300 mL1), and saturated saline (300 mL1), evaporated to dryness, and recrystallized with 95% ethanol, to give an off white solid (52.1 g, yield 81%).

(3) Preparation of Intermediate tert-butyl trans-N-4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexylcarbamate (4)

(3) Intermediate (3) (32.1 g, 0.1 mol), 3-(piperazin-1-yl)benzo[d]isothiazole (19.9 g, 0.09 mol), anhydrous potassium carbonate (37.3 g, 0.27 mol) and DMF (500 mL) were added into a single neck flask (1 L), reacted overnight at 60 C. and filtered. The filter cake was washed with DMF (60 mL2). The filtrate was combined and evaporated to dryness, and the residue was recrystallized with anhydrous ethanol, to give intermediate 4 (24.8 g, yield 62%).

(4) Preparation of Intermediate trans-4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexylamine (5)

(4) 4 (50 mmol), and dichloromethane (200 mL) were added into a 3-neck flask (500 mL), and trifluoroacetic acid (35 mL) was slowly added dropwise, and stirred overnight at RM. The system was washed sequentially with water (200 mL2), 5% sodium carbonate solution (150 mL2), and saturated saline (200 mL1). The organic layer was evaporated to dryness, to give a white solid (15.8 g, yield 91.7%).

(5) Preparation of the Target Compound I-1

(5) Compound 5 (0.23 mmol), triethylamine (0.75 mL) and dichloromethane (20 mL) were added into a 3-neck flask (50 mL), and cooled under ice-bath to 0 C. The solution of furyl-2-formyl chloride (0.28 mmol) in dichloromethane was slowly added dropwise, and then stirred at RM for 4 h. The system was washed sequentially with saturated Na.sub.2CO.sub.3 aqueous solution (5 mL1), water (5 mL1), and saturated saline (5 mL1), and evaporated to dryness, and the residue was recrystallized with 95% ethanol, to give a white solid I-1 (0.08 g, yield 79.4%).

(6) .sup.1H NMR (DMSO-d.sup.6, : ppm): 0.98-1.07 (m, 2H, A-H), 1.16-1.38 (m, 3H, A-H), 1.49-1.50 (m, 2H, A-H), 1.75-1.78 (m, 4H, A-H), 2.75 (t, 2H, J=7.6 Hz, NCH.sub.2), 3.03-3.13 (m, 4H, piperazine-CH.sub.2), 3.63-3.68 (m, 4H, piperazine-CH.sub.2), 3.76-3.77 (m, 1H, A-H), 6.59 (dd, 1H, J=8.0 Hz, 4.0 Hz, ArH), 7.06 (d, 1H, J=4.0 Hz, ArH), 7.46 (t, 1H, J=8.0 Hz, ArH), 7.58 (t, 1H, J=8.0 Hz, ArH), 8.03-8.08 (m, 2H, ArH), 8.23 (d, 1H, J=8.0 Hz, ArH).

(7) ESI-MS: 439 [M+H.sup.+]

(6) Preparation of the Hydrochloride of the Target Compound I-1

(8) Compound I-1 (1.0 mmol), 5% hydrochloric acid (1.0 mmol) and methanol (10 mL) were added into a single neck flask (50 mL), and stirred at RM for 1 h, to provide a clear reaction solution. The system was evaporated to dryness, added with isopropanol (5 mL) and stirred for 3 h. A white solid was precipitated and filtered, and the filter cake was baked to dryness, and recrystallized with 95% ethanol, to give the white solid (0.42 g, yield 88.1%).

(9) Elemental analysis: C.sub.24H.sub.30N.sub.4O.sub.2S.HCl (theoretical value %: C, 60.68; H, 6.58; N, 11.79; experimental value %: C, 60.46; H, 6.79; N, 11.54).

(7) Preparation of the Hydrobromide of the Target Compound I-1

(10) With compound I-1 (1.0 mmol) and 5% hydrobromic acid (1.0 mmol) as the starting materials, a white solid (0.45 g, yield 86.9%) was obtained in accordance with the method for preparing the hydrochloride of compound I-1.

(11) Elemental analysis: C.sub.24H.sub.30N.sub.4O.sub.2S.HBr (theoretical value %: C, 55.49; H, 6.01; N, 10.78; experimental value %: C, 55.62; H, 5.91; N, 10.89).

(8) Preparation of the Sulfate of the Target Compound I-1

(12) With compound I-1 (0.5 mmol) and 5% sulfuric acid (0.25 mmol) as the starting materials, a white solid (0.14 g, yield 57.5%) was obtained in accordance with the method for preparing the hydrochloride of compound I-1.

(13) Elemental analysis: C.sub.24H.sub.30N.sub.4O.sub.2S.SO.sub.4 (theoretical value %: C, 59.11; H, 6.41; N, 11.49; experimental value %: C, 59.30; H, 6.25; N, 11.28).

(9) Preparation of the Mesylate of the Target Compound I-1

(14) With compound I-1 (1 mmol) and methanesulfonic acid (1 mmol) as the starting materials, a white solid (0.41 g, yield 76.7%) was obtained in accordance with the method for preparing the hydrochloride of compound I-1.

(15) Elemental analysis: C.sub.24H.sub.30N.sub.4O.sub.2S.CH.sub.4O.sub.3S (theoretical value %: C, 56.16; H, 6.41; N, 10.48; experimental value %: C, 56.01; H, 6.29; N, 10.62).

EXAMPLE 2

Preparation of trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)thienyl-2-carboxamide (I-2) and the salt thereof

(16) With intermediate 5 (0.29 mmol) and thienyl-2-formyl chloride (0.35 mmol) as the starting materials, target compound I-2 (0.09 g, yield 66.7%) was obtained in accordance with the method for preparing compound I-1.

(17) .sup.1H NMR (DMSO-d.sup.6, : ppm): 0.99-1.07 (m, 2H, A-H), 1.11-1.18 (m, 5H, A-H), 1.78-1.86 (m, 4H, A-H), 2.39 (t, 2H, J=7.8 Hz, NCH.sub.2), 2.59-2.4 (m, 4H, piperazine-CH.sub.2), 3.44-3.49 (m, 4H, piperazine-CH.sub.2), 3.62-4.70 (m, 1H, A-H), 7.38 (dd, 1H, J=8.0 Hz, 4.0 Hz, ArH), 7.44 (t, 1H, J=7.6 Hz, ArH), 7.56 (t, 1H, J=7.6 Hz, ArH), 7.71 (d, 1H, J=4.0 Hz, ArH), 8.04-8.07 (m, 2H, ArH), 8.21 (d, 1H, J=8.0 Hz, ArH).

(18) ESI-MS: 455 [M+H.sup.+]

Preparation of the Mesylate of Compound I-2

(19) With compound I-2 (0.1 mmol) and methanesulfonic acid (0.1 mmol) as the starting materials, a white solid (0.05 g, yield 90.2%) was obtained in accordance with the method for synthesizing the hydrochloride of compound I-1.

(20) Elemental analysis: C.sub.24H.sub.30N.sub.4OS.sub.2.CH.sub.4O.sub.3S (theoretical value %: C, 54.52; H, 6.22; N, 10.17; experimental value %: C, 54.39; H, 6.41; N, 10.02).

Preparation of the Mesylate Hemihydrate of Compound I-2

(21) Compound I-2 (0.1 mmol), methanesulfonic acid (0.1 mmol), water (1 mL) and methanol (20 mL) were added into a single neck flask (50 mL), and stirred at RM for 1 h, to provide a clear reaction solution. The reaction solution was evaporated to dryness, to provide an oil. Isopropanol (5 mL) was added and stirred for 2 h. A white solid was precipitated and filtered, and the filter cake was baked to dryness, and recrystallized with 95% ethanol, to give the white solid (0.046 g, yield 82.3%).

(22) Elemental analysis: C.sub.24H.sub.30N.sub.4OS.sub.2.CH.sub.4O.sub.3S.H.sub.2O (theoretical value %: C, 53.64; H, 6.30; N, 10.01; experimental value %: C, 53.82; H, 6.19; N, 10.30).

EXAMPLE 3

Preparation of trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-1H-pyrrolyl-2-carboxamide (I-3) and the salt thereof

(23) Compound 5 (0.52 mmol), pyrrolyl-2-formic acid (0.44 mmol) and CH.sub.2Cl.sub.2 (20 mL) were added into a 3-neck flask (50 mL), and cooled under ice bath to 0 C. The solution of 4-dimethylaminopyridine (0.35 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbonyldiimino hydrochloride (0.52 mmol) in dichloromethane was slowly added dropwise, and then stirred at RM for 19 h. The system was washed sequentially with saturated Na.sub.2CO.sub.3 aqueous solution (5 mL2), water (5 mL1), and saturated saline (5 mL1), and evaporated to dryness, and the residue was recrystallized with 95% ethanol to give a white solid I-3 (0.12 g, yield 62.5%).

(24) .sup.1H NMR (DMSO-d.sup.6, : ppm): 1.00-1.06 (m, 2H, A-H), 1.19-1.32 (m, 3H, A-H), 1.43-1.47 (m, 2H, A-H), 1.48-1.81 (m, 4H, A-H), 2.66 (t, 2H, J=7.4 Hz, NCH.sub.2), 2.88-2.91 (m, 4H, piperazine-CH.sub.2), 3.52-3.53 (m, 4H, piperazine-CH.sub.2) 3.63-3.66 (m, 1H, A-H), 6.04-6.06 (dd, 1H, J=3.2 Hz, J=2.4 Hz, ArH), 6.75-6.77 (m, 1H, ArH), 6.8-6.82 (m, 1H, ArH), 7.45 (t, 1H, J=8.0 Hz, ArH), 7.57 (t, 1H, J=8.0 Hz, ArH), 8.05-8.08 (m, 2H, ArH).

(25) ESI-MS: 438 [M+H.sup.+]

Preparation of the Hydrobromide of Compound I-3

(26) With compound I-3 (0.1 mmol) and 5% hydrobromic acid (0.1 mmol) as the starting materials, a white solid (0.04 g, yield 91.3%) was obtained in accordance with the method for synthesizing the hydrochloride of compound I-1.

(27) Elemental analysis: C.sub.24H.sub.31N.sub.5OS.HBr (theoretical value %: C, 55.59; H, 6.22; N, 13.51; experimental value %: C, 55.8; H, 6.07; N, 13.76).

EXAMPLE 4

Preparation of trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-1H-indolyl-2-carboxamide (I-4)

(28) With intermediate 5 (0.58 mmol) and indolyl-2-formic acid (0.48 mmol) as the starting materials, target compound I-4 (0.09 g, yield 38.5%) was obtained in accordance with the method for preparing compound I-3.

(29) .sup.1H NMR (DMSO-d.sup.6, : ppm): 1.05-1.1 (m, 2H, A-H), 1.24-1.45 (m, 5H, A-H), 1.81-1.90 (m, 4H, A-H), 2.41 (t, 2H, J=7.8 Hz, NCH.sub.2), 2.60-2.62 (m, 4H, piperazine-CH.sub.2), 3.45-3.47 (m, 4H, piperazine-CH.sub.2), 3.76-3.78 (m, 1H, A-H), 7.02-7.05 (m, 1H, ArH), 7.12 (s, 1H, ArH), 7.16-7.20 (m, 1H, ArH), 7.42-7.4 (m, 2H, ArH), 7.54-7.60 (m, 2H, ArH), 8.00-8.05 (m, 2H, ArH).

(30) ESI-MS: 488 [M+H.sup.+]

EXAMPLE 5

Preparation of trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)benzofuryl-2-carboxamide-5 and the salt thereof

(31) With intermediate 5 (1.0 mmol) and benzofuryl-2-formyl chloride (1.1 mmol) as the starting materials, target compound I-5 (0.39 g, yield 80.7%) was obtained in accordance with the method for preparing compound I-1.

(32) .sup.1H NMR (DMSO-d.sup.6, : ppm): 1.07-1.12 (m, 2, A-H), 1.25-1.46 (m, 5H, A-H), 1.83-1.91 (m, 4H, A-H), 2.44 (t, 2, J=7.8 Hz, NCH.sub.2), 2.61-2.62 (m, 4H, piperazine-CH.sub.2), 3.46-3.48 (m, 4H, piperazine-CH.sub.2), 3.77-3.79 (m, 1H, A-H), 7.11-7.13 (m, 3H, ArH), 7.20 (s, 1H, ArH), 7.32-7.34 (m, 2H, ArH), 7.51-7.53 (m, 1H, ArH), 7.78-7.80 (m, 1H, ArH), 8.22-8.25 (m, 1H, ArH).

(33) ESI-MS: 489 [M+H.sup.+]

Preparation of the Hydrochloride of Compound I-5

(34) With compound I-5 (0.2 mmol) and 5% hydrochloric acid (0.2 mmol) as the starting materials, a white solid (0.08 g, yield 76.3%) was obtained in accordance with the method for synthesizing the hydrochloride of compound I-1.

(35) Elemental analysis: C.sub.28H.sub.32N.sub.4O.sub.2S.HCl (theoretical value %: C, 64.04; H, 6.33; N, 10.67; experimental value %: C, 64.28; H, 6.47; N, 10.51).

Preparation of the Trifluoroacetate of Compound I-5

(36) With compound I-5 (0.2 mmol) and 5% trifluoracetic acid (0.2 mmol) as the starting materials, a white solid (0.10 g, yield 82.6%) was obtained in accordance with the method for synthesizing the hydrochloride of compound I-1.

(37) Elemental analysis: C.sub.28H.sub.32N.sub.4O.sub.2S.CF.sub.3CO.sub.2H (theoretical value %: C, 59.79; H, 5.52; N, 9.30; experimental value %: C, 59.61; H, 5.67; N, 9.13).

EXAMPLE 6

Preparation of trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)benzo[b]thienyl-2-carboxamide (I-6)

(38) With intermediate 5 (1.0 mmol) and benzo[b]thienyl-2-formyl chloride (1.1 mmol) as the starting materials, target compound I-6 (0.44 g, yield 87.0%) was obtained in accordance with the method for preparing compound I-1.

(39) .sup.1H NMR (DMSO-d.sup.6, : ppm): 1.06-1.10 (m, 2H, A-H), 1.23-1.41 (m, 4H, A-H), 1.80-1.87 (m, 5H, A-H), 2.42 (t, 2H, J=7.8 Hz, NCH.sub.2?), 2.63-2.65 (m, 4H), piperazine-CH.sub.2), 3.47-3.48 (m, 4H, piperazine-CH.sub.2), 3.76-3.78 (m, 1H, A-H), 7.12 (d, 1H, J=8.0 Hz, ArH), 7.23 (m, 2H, ArH), 7.35-7.36 (m, 2H, ArH), 7.54-7.56 (m, 2H, ArH), 7.71 (s, 1H, ArH), 8.19-8.22 (m, 1H, ArH).

(40) ESI-MS: 505 [M+H.sup.+]

EXAMPLE 7

Preparation of trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-5-cyano-furyl-2-carboxamide (I-7)

(41) With intermediate 5 (1.0 mmol) and 5-cyano-furyl-2-formyl chloride (1.2 mmol) as the starting materials, target compound I-7 (0.40 g, yield 86.3%) was obtained in accordance with the method for preparing compound I-1.

(42) .sup.1H NMR (DMSO-d.sup.6, : ppm): 1.01-1.09 (m, 2H, A-H), 1.19-1.40 (m, 3H, A-H), 1.52-1.53 (m, 2H, A-H), 1.77-1.81 (m, 4H, A-H), 2.78 (t, 2H, J=7.6 Hz, NCH.sub.2), 3.05-3.16 (m, 4H, piperazine-CH.sub.2), 3.64-3.70 (m, 4H, piperazine-CH.sub.2), 3.78-3.79 (m, 1H, A-H), 7.16 (d, 1H, J=8.0 Hz, ArH), 7.48-7.49 (m, 2H, ArH), 7.58 (t, 1H, J=0.0H-z, ArH), 8.25-8.27 (m, 2H, ArH).

(43) ESI-MS: 464 [M+H.sup.+]

EXAMPLE 8

(44) Preparation of trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-3-tert-butylfuryl-2-carboxamide (I-8) With intermediate 5 (1.0 mmol) and 3-tert-butylfuryl-2-formyl chloride (1.2 mmol) as the starting materials, target compound I-8 (0.38 g, yield 76.9%) was obtained in accordance with the method for preparing compound I-1.

(45) .sup.1H NMR (DMSO-d.sup.6, : ppm): 0.97-1.05 (m, 2H, A-H), 1.12 (s, 9H, A-H), 1.13-1.40 (m, 3H, A-H), 1.50-1.52 (m, 3H, A-H), 1.76-1.78 (m, 3H, A-H), 2.74 (t, 2H, J=7.6 Hz, NCH.sub.2), 3.05-3.14 (m, 4H, piperazine-CH.sub.2), 3.64-3.69 (m, 4H, piperazine-CH.sub.2), 3.78-3.79 (m, 1H, A-H), 6.56 (d, 1H, J=8.0 Hz, ArH), 7.44 (t, 1H, J=8.0H, ArH), 7.57 (t, 1H, J=0.0 Hz, ArH), 8.01-8.05 (m, 2H, ArH), 8.20 (d, 1H, J=8.0 Hz, ArH).

(46) ESI-MS: 495 [M+H.sup.+]

EXAMPLE 9

Preparation of trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-5-methyl-1H-pyrrolyl-2-carboxamide (I-9)

(47) With intermediate 5 (1.0 mmol) and 5-methyl-1H-pyrrolyl-2-formyl chloride (1.2 mmol) as the starting materials, target compound I-9 (0.26 g, yield 57.6%) was obtained in accordance with the method for preparing compound I-1.

(48) .sup.1H NMR (DMSO-d.sup.6, : ppm): 0.99-1.04 (m, 2H, A-H), 1.18-1.31 (m, 3H, A-H), 1.41-1.45 (m, 2H, A-H), 1.46-1.79 (m, 4H, A-H), 2.34 (s, 3H, A-H), 2.63 (t, 2H, J=7.4 Hz, NCH.sub.2), 2.86-2.89 (m, 4H, piperazine-CH.sub.2), 3.51-3.52 (m, 4H, piperazine-CH.sub.2) 3.62-3.64 (m, 1H, A-H), 6.01-6.03 (d, 1H, J=3.6 Hz, ArH), 7.32 (d, 1H, J=3.6 Hz, ArH), 7.43 (t, 1H, J=8.0 Hz, ArH), 7.55 (t, 1H, J=8.0 Hz, ArH), 8.02-8.06 (m, 2H, ArH).

(49) ESI-MS: 452 [M+H.sup.+]

EXAMPLE 10

Preparation of trans 5-acetyl-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)furyl-2-carboxamide (I-10)

(50) With intermediate 5 (1.0 mmol) and 5-acetyl-furyl-2-formyl chloride (1.2 mmol) as the starting materials, target compound I-10 (0.33 g, yield 68.5%) was obtained in accordance with the method for preparing compound I-1.

(51) .sup.1H NMR (DMSO-d.sup.6, : ppm): 1.01-1.09 (m, 2H, A-H), 1.18-1.40 (m, 3H, A-H), 1.51-1.52 (m, 2H, A-H), 1.76-1.79 (m, 4H, A-H), 2.77 (t, 2H, J=7.6 Hz, NCH.sub.2), 2.81 (s, 3H, A-H), 3.05-3.16 (m, 4H, piperazine-CH.sub.2), 3.65-3.70 (m, 4H, piperazine-CH.sub.2), 3.78-3.79 (m, 1H, A-H), 7.21 (d, 1H, J=8.0 Hz, ArH), 7.49 (m, 2H, ArH), 7.61 (t, 1H, J=8.0 Hz, ArH), 8.06-8.11 (m, 2H, ArH).

(52) ESI-MS: 481 [M+H.sup.+]

EXAMPLE 11

Preparation of trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-3-methylthienyl-2-carboxamide (I-11)

(53) With intermediate 5 (1.0 mmol) and 3-methylfuryl-2-formyl chloride (1.2 mmol) as the starting materials, target compound I-11 (0.41 g, yield 87.5%) was obtained in accordance with the method for preparing compound I-1.

(54) .sup.1H NMR (DMSO-d.sup.6, : ppm): 0.97-1.05 (m, 2H, A-H), 1.10-1.16 (m, 4H, A-H), 1.76-1.5 (m, 5, A-H), 2.31 (s, 3H, A-H), 2.38 (t, 2H, J=7.6 Hz, NCH.sub.2) 2.58-2.62 (m, 4H, piperazine-CH.sub.2), 3.43-3.47 (m, 4H, piperazine-CH.sub.2) 3.60-4.69 (m, 1H, A-H), 7.35 (d, 1H, J=8.0 Hz, ArH), 7.42 (t, 1H, J=7.6 Hz, ArH), 7.54 (t, 1H, J=7.6 Hz, ArH), 8.03-8.05 (m, 2H, ArH), 8.19 (d, 1H, J=8.0 Hz, ArH).

(55) ESI-MS: 469 [M+H.sup.+]

EXAMPLE 12

Preparation of trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-3-bromothienyl-2-carboxamide (I-12)

(56) With intermediate 5 (1.0 mmol) and 3-bromothienyl-2-formyl chloride (1.1 mmol) as the starting materials, target compound I-12 (0.47 g, yield 87.7%) was obtained in accordance with the method for preparing compound I-1.

(57) .sup.1H NMR (DMSO-d.sup.6, : ppm): 1.01-1.08 (m, 2H, A-H), 1.13-1.20 (m, 5H, A-H), 1.80-1.88 (m, 4H, A-H), 2.40 (t, 2H, J=7.8 Hz, NCH.sub.2), 2.60-2.65 (m, 4H, piperazine-CH.sub.2), 3.45-3.50 (m, 4H, piperazine-CH.sub.2), 3.64-4.72 (m, 1H, A-H), 742 (d, 1H, J=8.0 Hz, ArH), 7.46 (t, 1H, J=7.6 Hz, ArH), 7.5 (t, 1H, J=7.6 Hz, ArH), 8.08-8.12 (m, 2H, ArH), 8.32 (d, 1H, J=8.0 Hz, ArH).

(58) ESI-MS: 533 [M+H.sup.+]

EXAMPLE 13

Preparation of trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-3-methylbenzo[b]thienyl-2-carboxamide (I-13)

(59) With intermediate 5 (1.0 mmol) and 3-methylbenzo[b]thienyl-2-formyl chloride (1.2 mmol) as the starting materials, target compound I-13 (0.47 g, yield 87.7%) was obtained in accordance with the method for preparing compound I-1.

(60) .sup.1H NMR (DMSO-d.sup.6, : ppm): 1.05-1.09 (m, 2H, A-H), 1.22-1.40 (m, 4H, A-H), 1.78-1.85 (m, 5H, A-H), 2.41 (t, 2H, J=7.8 Hz, NCH.sub.2), 2.55 (s, 3H, A-H), 2.62-2.64 (m, 4H, piperazine-CH.sub.2), 3.46-3.48 (m, 4H, piperazine-CH.sub.2), 3.74-3.77 (m, 1H, A-H), 7.09 (d, 1H, J=8.0 Hz, ArH), 7.20 (m, 2H, ArH), 7.33-7.34 (m, 2H, ArH), 7.52-7.54 (m, 2H, ArH), 8.17-8.21 (m, 1H, ArH).

(61) ESI-MS: 519 [M+H.sup.+]

EXAMPLE 14

Preparation of trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-3-chlorobenzo[b]thienyl-2-carboxamide (I-14)

(62) With intermediate 5 (1.0 mmol) and 3-chlorobenzo[b]thienyl-2-formyl chloride (1.2 mmol) as the starting materials, target compound I-14 (0.44 g, yield 81.6%) was obtained in accordance with the method for preparing compound I-1.

(63) .sup.1H NMR (DMSO-d.sup.6, : ppm): 1.09-1.14 (m, 2H, A-H), 1.25-1.44 (m, 4H, A-H), 1.82-1.89 (m, 5H, A-H), 2.45 (t, 2H, J=7.6 Hz, NCH.sub.2), 2.66-2.68 (m, 4H, piperazine-CH.sub.2), 3.49-3.50 (m, 4H, piperazine-CH.sub.2), 3.77-3.80 (m, 1H, A-H), 7.21 (d, 1H, J=8.0 Hz, ArH), 7.34 (m, 2H, ArH), 7.46-7.48 (m, 2H, ArH), 7.67-7.69 (m, 2H, ArH), 8.32-8.34 (m, 1H, ArH).

(64) ESI-MS: 539 [M+H.sup.+]

EXAMPLE 15

Preparation of trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-5-nitro-1H-indolyl-2-carboxamide (I-15)

(65) With intermediate 5 (0.58 mmol) and 5-nitro-1H-indolyl-2-formic acid (0.48 mmol) as the starting materials, target compound I-15 (0.11 g, yield 41.2%) was obtained in accordance with the method for preparing compound I-3.

(66) .sup.1H NMR (DMSO-d.sup.6, : ppm): 1.11-1.17 (m, 2H, A-H), 1.29-1.50 (m, 5H, A-H), 1.85-1.94 (m, 4H, A-H), 2.46 (t, 2H, J=7.6 Hz, NCH.sub.2), 2.65-2.67 (m, 4H, piperazine-CH.sub.2), 3.51-3.53 (m, 4H, piperazine-CH.sub.2), 3.82-3.84 (m, 1H, A-H), 7.49 (d, 1H, J=8.0 Hz, ArH), 7.52 (s, 1H, ArH), 7.61-7.63 (m, 2H, ArH), 7.82 (d, 1H, J=8.4 Hz, ArH), 8.10-8.12 (m, 2H, ArH), 8.64 (s, 1H, ArH).

(67) ESI-MS: 533 [M+H.sup.+]

EXAMPLE 16

Preparation of trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-5-methoxylbenzofuryl-2-carboxamide (I-16)

(68) With intermediate 5 (1.0 mmol) and 5-methoxylbenzofuryl-2-formyl chloride (1.2 mmol) as the starting materials, target compound I-16 (0.39 g, yield 75.2%) was obtained in accordance with the method for preparing compound I-1.

(69) .sup.1H NMR (DMSO-d.sup.6, : ppm): 1.05-1.10 (m, 2H, A-H), 1.23-1.44 (m, 5H, A-H), 1.80-1.89 (m, 4H, A-H), 2.42 (t, 2H, J=7.6 Hz, NCH.sub.2), 2.59-2.61 (m, 4H, piperazine-CH.sub.2), 3.43-3.45 (m, 4H, piperazine-CH.sub.2), 3.75-3.77 (m, 1H, A-H), 4.05 (s, 3H, A-H), 7.18 (d, 1H, J=0.0 Hz, ArH), 7.30-7.32 (m, 3H, ArH), 7.48 (t, 1H, J=0.0 Hz, ArH), 7.52 (t, 1H, J=7.6 Hz, ArH), 7.82-7.85 (m, 2H, ArH).

(70) ESI-MS: 519 [M+H.sup.+]

EXAMPLE 17

Preparation of trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-2-(thien-2-yl)acetamide (I-17)

(71) With intermediate 5 (1.0 mmol) and thienyl-2-acetyl chloride (1.2 mmol) as the starting materials, target compound I-17 (0.27 g, yield 58.6%) was obtained in accordance with the method for preparing compound I-1.

(72) .sup.1H NMR (DMSO-d.sup.6, : ppm): 0.97-1.05 (m, 2H, A-H), 1.09-1.16 (m, 5H, A-H), 1.76-1.83 (m, 4H, A-H), 2.37 (t, 2H, J=7.8 Hz, NCH.sub.2), 2.56-2.62 (m, 4H, piperazine-CH.sub.2), 3.42-3.48 (m, 6H, A-H), 3.60-3.68 (m, 1H, A-H), 7.35 (dd, 1H, J=8.0 Hz, 4.0 Hz, ArH), 7.41 (t, 1H, J=7.6 Hz, ArH), 7.53 (t, 1H, J=7.6 Hz, ArH), 7.70 (d, 1H, J=4.0 Hz, ArH), 8.02-8.04 (m, 2H, ArH), 8.17 (d, 1H, J=8.0 Hz, ArH).

(73) ESI-MS: 469 [M+H.sup.+]

EXAMPLE 18

Preparation of trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-2-(benzofuran-3-yl)acetamide (I-18)

(74) With intermediate 5 (1.0 mmol) and benzofuryl-3-acetyl chloride (1.2 mmol) as the starting materials, target compound I-18 (0.32 g, yield 64.1%) was obtained in accordance with the method for preparing compound I-1.

(75) .sup.1H NMR (DMSO-d.sup.6, : ppm): 1.04-1.09 (m, 2H, A-H), 1.22-1.42 (m, 5H, A-H), 1.81-1.89 (m, 4H, A-H), 2.41 (t, 2H, J=7.8 Hz, NCH.sub.2), 2.58-2.59 (m, 4H, piperazine-CH.sub.2), 3.43-3.45 (m, 4H, piperazine-CH.sub.2), 3.75-3.77 (m, 1H, A-H), 4.02 (s, 2H, A-H), 7.09-7.12 (m, 3H, ArH), 7.30-7.32 (m, 2H, ArH), 7.50-7.52 (m, 1H, ArH), 7.75-7.87 (m, 1H, ArH), 7.91 (s, 1H, ArH), 8.23-8.26 (m, 1H, ArH).

(76) ESI-MS: 503 [M+H.sup.+]

EXAMPLE 19

Preparation of cis-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)furyl-2-carboxamide (I-19) and the salt thereof

(77) (1) Preparation of Intermediate 7

(78) Cis-4-acetylaminocyclohexylacetic acid (6) (1.0 mol), 95% ethanol (1 L), and concentrated hydrochloric acid (300 mL) were added into a single neck flask (2 L), refluxed overnight, and evaporated to dryness. Anhydrous ethanol (500 mL) was added to the residue, evaporated to dryness, neutralized with triethylamine (300 mL), and added with acetone (1.5 L). The system was cooled to 0 C., and then the solution of tert-butoxyformic anhydride (1.2 mol) in acetone was slowly added dropwise, stirred for 30 h, and evaporated to dryness. The residue was stirred in 80% ethanol (250 mL), and filtered, and the filter cake was washed with water to give the intermediate 7 (203 g, yield 87.7%).

(79) (2) Preparation of Intermediate 11

(80) Intermediate 11 was prepared from intermediate 7 by the same method as the method for preparing intermediate 5 from material 1 in scheme one.

(81) (3) Preparation of I-19

(82) With intermediate 11 (0.1 mol) and furyl-2-formyl chloride (0.12 mol) as the starting materials, target compound I-19 (32.06 g, yield 73.1%) was obtained in accordance with the method for preparing compound I-1.

(83) .sup.1H NMR (DMSO-d.sup.6, : ppm): 1.03-1, 12 (m, 2H, A-H), 1.21-1.53 (m, 3H, A-H), 1.54-1.55 (m, 2H, A-H), 1.80-1.83 (m, 4H, A-H), 2.81 (t, 2H, J=7.0 Hz, NCH.sub.2), 3.08-3.18 (m, 4H, piperazine-CH.sub.2), 3.68-3.73 (m, 4H, piperazine-CH.sub.2), 3.80-3.81 (m, 1H, A-H), 6.63 (dd, 1H, J=8.0 Hz, 4.0 Hz, ArH), 7.11 (d, 1H, J=4.0 Hz, ArH), 7.50 (t, 1H, J=8.0 Hz, ArH), 7.62 (t, 1H, J=8.0 Hz, ArH), 8.07-8.12 (m, 2H, ArH), 8.28 (d, 1H, J=8.0 Hz, ArH).

(84) ESI-MS: 439 [M+H.sup.+]

(85) (4) Preparation of the Hydrochloride of Compound I-19

(86) With compound I-19 (1 mmol) and 5% hydrochloric acid (1 mmol) as the starting materials, a white solid (0.40 g, yield 83.9%) was obtained in accordance with the method for preparing the hydrochloride of compound compound I-1.

(87) Elemental analysis: C.sub.24H.sub.30N.sub.4O.sub.2S.HCl (theoretical value %: C, 60.68; H, 6.58; N, 11.79; experimental value %: C, 60.77; H, 6.36; N, 11.91).

EXAMPLE 20

Preparation of cis-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)thienyl-2-carboxamide (I-20)

(88) With intermediate 11 (1.0 mmol) and thienyl-2-formyl chloride (1.2 mmol) as the starting materials, target compound I-20 (0.32 g, yield 70.1%) was obtained in accordance with the method for preparing compound I-1.

(89) .sup.1H NMR (DMSO-d.sup.6, : ppm): 1.03-1.12 (m, 2H, A-H), 1.15-1.22 (m, 5H, A-H), 1.83-1.91 (m, 4H, A-H), 2.43 (t, 2H, J=7.8 Hz, NCH.sub.2), 2.63-2.68 (m, 4H, piperazine-CH.sub.2), 3.47-3.42 (m, 4H, piperazine-CH.sub.2), 3.65-4.73 (m, 1H, A-H), 7.42 (dd, 1H, J=8.0 Hz, 4.0 Hz, ArH), 7.48 (t, 1H, J=7.6 Hz, ArH), 7.59 (t, 1H, J=7.6 Hz, ArH), 7.74 (d, 1H, J=4.0 Hz, ArH), 8.04-8.07 (m, 2H, r-H), 8.24 (d, 1H, J=8.0 Hz, ArH).

(90) ESI-MS: 455 [M+H.sup.+]

EXAMPLE 21

Preparation of cis-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-1H-pyrrolyl-2-carboxamide (I-21)

(91) With intermediate 11 (1.0 mmol) and pyrrolyl-2-formic acid (0.85 mmol) as the starting materials, target compound I-21 (0.28 g, yield 75.2%) was obtained in accordance with the method for preparing compound I-3.

(92) .sup.1H NMR (DMSO-d.sup.6, : ppm): 1.06-1.12 (m, 2H, A-H), 1.25-1.38 (m, 3H, A-H), 1.48-1.52 (m, 2H, A-H), 1.53-1.86 (m, 4H, A-H), 2.73 (t, 2H, J=7.4 Hz, NCH.sub.2), 2.94-2.97 (m, 4H, piperazine-CH.sub.2), 3.57-3.58 (m, 4H, piperazine-CH.sub.2) 3.68-3.71 (m, 1H, A-H), 6.10-6.12 (dd, 1H, J=3.2 Hz, J=2.4 Hz, ArH), 6.81-6.83 (m, 1H, ArH), 6.87-6.88 (m, 1H, ArH), 7.51 (t, 1H, J=8.0 Hz, ArH), 7.63 (t, 1H, J=0.0H-z, ArH), 8.11-8.13 (m, 2H, ArH).

(93) ESI-MS: 438 [M+H.sup.+]

EXAMPLE 22

Preparation of cis-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-1H-indolyl-2-carboxamide (I-22)

(94) With intermediate 11 (0.58 mmol) and indolyl-2-formic acid (0.48 mmol) as the starting materials, target compound I-22 (0.12 g, yield 51.3%) was obtained in accordance with the method for preparing compound I-3.

(95) .sup.1H NMR (DMSO-d.sup.6, : ppm): 1.12-1.18 (m, 2H, A-H), 1.31-1.52 (m, 5H, A-H), 1.88-1.96 (m, 4H, A-H), 2.50 (t, 2H, J=7.8 Hz, NCH.sub.2), 2.67-2.69 (m, 4H, piperazine-CH.sub.2), 3.52-3.54 (m, 4H, piperazine-CH.sub.2), 3.83-3.86 (m, 1H, A-H), 7.09-7.11 (m, 1H, ArH), 7.18 (s, 1H, ArH), 7.22-7.27 (m, 1H, ArH), 7.48-7.53 (m, 2H, ArH), 7.61-7.67 (m, 2H, ArH), 8.07-8.13 (m, 2H, ArH).

(96) ESI-MS: 488 [M+H.sup.+]

EXAMPLE 23

Preparation of cis-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)benzofuryl-2-carboxamide (I-23)

(97) With intermediate 11 (1.0 mmol) and benzofuryl-2-formyl chloride (1.1 mmol) as the starting materials, target compound I-23 (0.36 g, yield 74.5%) was obtained in accordance with the method for preparing compound I-1.

(98) .sup.1H NMR (DMSO-d.sup.6, : ppm): 1.10-1.15 (m, 2H, A-H), 1.28-1.49 (m, 5H, A-H), 1.86-1.94 (m, 4H, A-H), 2.47 (t, 2, J=7.8 Hz, NCH.sub.2), 2.64-2.65 (m, 4H, piperazine-CH.sub.2), 3.49-3.51 (m, 4H, piperazine-CH.sub.2), 3.80-3.82 (m, 1H, A-H), 7.14-7.16 (m, 3H, ArH), 7.23 (s, 1H, ArH), 7.35-7.37 (m, 2H, ArH), 7.54-7.56 (m, 1H, ArH), 7.82-7.84 (m, 1H, ArH), 8.26-8.29 (m, 1H, ArH).

(99) ESI-MS: 489 [M+H.sup.+]

EXAMPLE 24

Preparation of cis-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)benzo[b]thienyl-2-carboxamide (I-24)

(100) With intermediate 11 (1.0 mmol) and benzo[b]thienyl-2-formyl chloride (1.1 mmol) as the starting materials, target compound I-24 (0.39 g, yield 77.1%) was obtained in accordance with the method for preparing compound I-1.

(101) .sup.1H NMR (DMSO-d.sup.6, : ppm): 1.12-1.16 (m, 2H, A-H), 1.29-1.47 (m, 4H, A-H), 1.86-1.93 (m, 5H, A-H), 2.47 (t, 2H, J=7.8 Hz, NCH.sub.2), 2.68-2.70 (m, 4H, piperazine-CH.sub.2), 3.52-3.53 (m, 4H, piperazine-CH.sub.2), 3.82-3.84 (m, 1H, A-H), 7.18 (d, 1H, J=8.0 Hz, ArH), 7.29 (m, 2H, ArH), 7.40-7.41 (m, 2H, ArH), 7.59-7.61 (m, 2H, ArH), 7.76 (s, 1H, ArH), 8.25-8.26 (m, 1H, ArH).

(102) ESI-MS: 505 [M+H.sup.+]

EXAMPLE 25

Preparation of trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)thienyl-2-sulfamide (-1) and the salt thereof

(103) With intermediate 5 (2.9 mmol) and thienyl-2-sulfonyl chloride (3.5 mmol) as the starting materials, target compound -1 (0.5 g, yield 35.2%) was obtained in accordance with the method for preparing compound I-1.

(104) .sup.1H NMR (DMSO-d.sup.6, : ppm): 0.93-0.98 (m, 2H, A-H), 1.17-1.25 (m, 3H, A-H), 1.55-1.60 (m, 2H, A-H), 1.66-1.71 (m, 4H, A-H), 2.69 (t, 2H, J=7.8 Hz, NCH.sub.2), 2.94-2.98 (m, 1H, A-H), 3.11-3.14 (m, 4H, piperazine-CH.sub.2), 3.41-3.44 (m, 4H, piperazine-CH.sub.2), 7.21 (t, 1H, J=4.0 Hz, ArH), 7.52 (t, 1H, J=8.0 Hz, ArH), 7.62-7.65 (m, 2H, ArH), 7.87 (d, 1H, J=4.0 Hz, ArH), 8.0-8.12 (m, 2H, ArH).

(105) ESI-MS: 491 [M+H.sup.+]

Preparation of the Hydrobromide of Compound -1

(106) With compound -1 (1 mmol) and 5% hydrobromic acid (1 mmol) as the starting materials, a white solid (0.48 g, yield 83.4%) was obtained in accordance with the method for preparing the hydrochloride of compound I-1.

(107) Elemental analysis: C.sub.24H.sub.30N.sub.4O.sub.2S.sub.3.HBr (theoretical value %: C, 48.33; H, 5.47; N, 9.80; experimental value %: C, 48.51; H, 5.62; N, 9.57).

Preparation of the Sulfate of Compound -1

(108) With compound -1 (0.5 mmol) and 5% sulfuric acid (0.25 mmol) as the starting materials, a white solid (0.16 g, yield 58.8%) was obtained in accordance with the method for preparing the hydrochloride of compound I-1.

(109) Elemental analysis: C.sub.24H.sub.30N.sub.4O.sub.2S.sub.3.H.sub.2SO.sub.4 (theoretical value %: C, 51.18; H, 5.79; N, 10.38; experimental value %: C, 51.02; H, 5.96; N, 10.14).

EXAMPLE 26

Preparation of trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-1H-pyrrolyl-3-sulfamide (-2)

(110) With intermediate 5 (1.0 mmol) and pyrrolyl-3-sulfonyl chloride (1.2 mmol) as the starting materials, target compound -2 (0.30 g, yield 62.7%) was obtained in accordance with the method for preparing compound I-1.

(111) .sup.1H NMR (DMSO-d.sup.6, : ppm): 0.98-1.13 (m, 2H, A-H), 1.24-1.31 (m, 3H, A-H), 1.59-1.64 (m, 2H, A-H), 1.71-1.76 (m, 4H, A-H), 2.71 (t, 2H, J=7.8 Hz, NCH.sub.2), 2.99-3.01 (m, 1H, A-H), 3.16-3.19 (m, 4H, piperazine-CH.sub.2) 3.47-3.50 (m, 4H, piperazine-CH.sub.2), 6.14-6.16 (d, 1H, J=0.4.0 Hz, ArH), 0.8-6.88 (m, 2H, ArH), 7.51 (t, 1H, J=8.0 Hz, ArH), 7.60 (t, 1H, J=8.0 Hz, ArH), 8.07-8.10 (m, 2H, ArH).

(112) ESI-MS: 474 [M+H.sup.+]

EXAMPLE 27

Preparation of trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)furyl-2-sulfamide (-3)

(113) With intermediate 5 (1.0 mmol) and furyl-2-sulfonyl chloride (1.2 mmol) as the starting materials, target compound -3 (0.28 g, yield 59.7%) was obtained in accordance with the method for preparing compound I-1.

(114) .sup.1H NMR (DMSO-d.sup.6, : ppm): 0.92-0.97 (m, 2H, A-H), 1.16-1.24 (m, 3H, A-H), 1.54-1.59 (m, 2H, A-H), 1.64-1.69 (m, 4H, A-H), 2.67 (t, 2H, J=7.8 Hz, NCH.sub.2), 2.93-2.97 (m, 1H, A-H), 3.09-3.13 (m, 4H, piperazine-CH.sub.2), 3.40-3.43 (m, 4H, piperazine-CH.sub.2), 7.19 (t, 1H, J=4.0 Hz, ArH), 7.51 (t, 1H, J=8.0 Hz, ArH), 7.64-7.67 (m, 2H, ArH), 7.89 (d, 1H, J=40 Hz, ArH), 8.07-8.13 (m, 2H, ArH).

(115) ESI-MS: 475 [M+H.sup.+]

EXAMPLE 28

Preparation of trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)benzo[b]thienyl-2-sulfamide (-4)

(116) With intermediate 5 (1.0 mmol) and benzo[b]thienyl-2-sulfonyl chloride (1.2 mmol) as the starting materials, target compound -4 (0.39 g, yield 7.4%) was obtained in accordance with the method for preparing compound I-1.

(117) .sup.1H NMR (DMSO-d.sup.6, : ppm): 1.01-1.05 (m, 2H, A-H), 1.18-1.36 (m, 4H, A-H), 1.75-1.82 (m, 5H, A-H), 2.37 (t, 2H, J=7.8 Hz, NCH.sub.2), 2.95-2.98 (m, 1H, A-H), 3.15-3.18 (m, 4H, piperazine-C-2), 3.45-3.48 (m, 4H, piperazine-CH.sub.2), 7.08 (d, 1H, J=8.0 Hz, ArH), 7.19 (m, 2H, ArH), 7.31-7.32 (m, 2H, ArH), 7.50-7.52 (m, 2H, ArHT), 7.69 (s, 1H, ArH), 8.16-8.19 (m, 1H, ArH).

(118) ESI-MS: 541 [M+H.sup.+]

EXAMPLE 29

Preparation of trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)benzofuryl-2-sulfamide (-5) and the salt thereof

(119) With intermediate 5 (1.0 mmol) and benzofuryl-2-sulfonyl chloride (1.2 mmol) as the starting materials, target compound -5 (0.36 g, yield 68.1%) was obtained in accordance with the method for preparing compound I-1.

(120) .sup.1H NMR (DMSO-d.sup.6, : ppm): 1.03-1.08 (m, 2H, A-H), 1.21-1.42 (m, 5H, A-H), 1.79-1.87 (m, 4H, A-H), 2.40 (t, 2H, J=7.8 Hz, NCH.sub.2), 2.93-2.96 (m, 1H, A-H), 3.13-3.16 (m, 4H, piperazine-CH.sub.2), 3.43-3.46 (m, 4H, piperazine-CH.sub.2), 7.14-7.16 (m, 3H, H, 7.23 (s, 1H, ArH), 7.34-7.36 (m, 2H, ArH), 7.54-7.56 (m, 1H, ArH), 7.81-7.83 (m, 1H, ArH), 8.25-8.26 (m, 1H, ArH).

(121) ESI-MS: 525 [M+H.sup.+]

Preparation of the Hydrochloride of Compound -5

(122) With compound -5 (0.2 mmol) and 5% HCl (0.2 mmol) as the starting materials, a white solid (0.10 g, yield 88.3%) was obtained in accordance with the method for preparing the hydrochloride of compound I-1.

(123) Elemental analysis: C.sub.27H.sub.32N.sub.4O.sub.3S.sub.2.HCl (theoretical value %: C, 57.79; H, 5.93; N, 9.98; experimental value %: C, 57.58; H, 5.72; N, 9.86).

Preparation of the Trifluoroacetate of Compound -5

(124) With compound -5 (0.2 mmol) and 5% trifluoracetic acid (0.2 mmol) as the starting materials, a white solid (0.10 g, yield 81.6%) was obtained in accordance with the method for preparing the hydrochloride of compound I-1.

(125) Elemental analysis: C.sub.27H.sub.32N.sub.4O.sub.3S.sub.2.CF.sub.3CO.sub.2H (theoretical value %: C, 54.53; H, 5.21; N, 8.77; experimental value %: C, 54.72; H, 5.03; N, 8.64).

EXAMPLE 30

Preparation of trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-1H-indolyl-3-sulfamide (-6)

(126) With intermediate 5 (1.0 mmol) and indolyl-3-sulfonyl chloride (1.2 mmol) as the starting materials, target compound -6 (0.22 g, yield 42.3%) was obtained in accordance with the method for preparing compound I-1.

(127) .sup.1H NMR (DMSO-d.sup.6, : ppm): 0.94-0.99 (m, 2H, A-H), 1.18-1.2 (m, 3H, A-H), 1.56-1.61 (m, 2H, A-H), 1.67-1.72 (m, 4H, A-H), 2.70 (t, 2H, J=7.8 Hz, NCH.sub.2), 2.95-2.99 (m, 1H, A-H), 3.12-3.15 (m, 4H, piperazine-CH.sub.2), 3.42-3.45 (m, 4H, piperazine-CH.sub.2), 7.02-7.03 (m, 2H, ArH), 7.23 (t, 1H, J=8.0 Hz, ArH), 7.54 (t, 1H, J=8.0 Hz, ArH), 7.58 (d, 1H, J=4.0 Hz, ArH), 7.61 (s, 1H, ArH), 7.90 (d, 1H, J=4.0 Hz, ArH), 8.06-8.12 (m, 2H, ArH).

(128) ESI-MS: 524 [M+H.sup.+]

EXAMPLE 31

Preparation of trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-5-cyanofuryl-2-sulfamide (-7)

(129) With intermediate 5 (1.0 mmol) and 5-cyanofuryl-2-sulfonyl chloride (1.2 mmol) as the starting materials, target compound -7 (0.39 g, yield 78.6%) was obtained in accordance with the method for preparing compound I-1.

(130) .sup.1H NMR (DMSO-d.sup.6, : ppm): 0.95-1.00 (m, 2H, A-H), 1.19-1.27 (m, 3H, A-H), 1.57-1.62 (m, 2H, A-H), 1.67-1.72 (m, 4H, A-H), 2.70 (t, 2H, J=7.8 Hz, NCH.sub.2), 2.97-3.01 (m, 1H, A-H), 3.12-3.16 (m, 4H, piperazine-CH.sub.2), 3.43-3.46 (m, 4H, piperazine-CH.sub.2), 7.24 (d, 1H, J=8.0 Hz, ArH), 7.56-7.57 (m, 2H, ArH), 7.66 (t, 1H, J=8.0 Hz, ArH), 8.33-8.35 (m, 2H, ArH).

(131) ESI-MS: 500 [M+H.sup.+]

EXAMPLE 32

Preparation of trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-5-chlorofuryl-2-sulfamide (-8)

(132) With intermediate 5 (1.0 mmol) and 5-chlorofuryl-2-sulfonyl chloride (1.2 mmol) as the starting materials, target compound -8 (0.27 g, yield 53.3%) was obtained in accordance with the method for preparing compound I-1.

(133) .sup.1H NMR (DMSO-d.sup.6, : ppm): 0.94-0.99 (m, 2H, A-H), 1.18-1.26 (m, 3H, A-H), 1.56-1.61 (m, 2H, A-H), 1.66-1.71 (m, 4H, A-H), 2.69 (t, 2H, J=7.8 Hz, NCH.sub.2), 2.95-2.99 (m, 1H, A-H), 3.11-3.15 (m, 4H, piperazine-CH.sub.2), 3.42-3.45 (m, 4H, piperazine-CH.sub.2), 7.22 (d, 1H, J=0.0 Hz, ArH), 7.54-7.55 (m, 2H, ArH), 7.63 (t, 1H, J=8.0 Hz, ArH), 8.31-8.33 (m, 2H, ArH).

(134) ESI-MS: 509 [M+H.sup.+]

EXAMPLE 33

Preparation of trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-5-methylfuryl-2-sulfamide (-9)

(135) With intermediate 5 (1.0 mmol) and 5-methylfuryl-2-sulfonyl chloride (1.2 mmol) as the starting materials, target compound -9 (0.29 g, yield 59.6%) was obtained in accordance with the method for preparing compound I-1.

(136) .sup.1H NMR (DMSO-d.sup.6, : ppm): 0.91-0.96 (m, 2H, A-H), 1.14-1.22 (m, 3H, A-H), 1.53-1.58 (m, 2H, A-H), 1.63-1.68 (m, 4H, A-H), 2.41 (m, 3H, A-H), 2.64 (t, 2H, J=7.8 Hz, NCH.sub.2), 2.91-2.95 (m, 1H, A-H), 3.07-3.12 (m, 4H, piperazine-CH.sub.2), 3.38-3.42 (m, 4H, piperazine-CH.sub.2), 7.08 (d, 1H, J=8.0 Hz, ArH), 7.40-7.41 (m, 2H, ArH), 7.49 (t, 1H, J=0.0 Hz, ArH), 8.17-8.19 (m, 2H, ArH).

(137) ESI-MS: 489 [M+H.sup.+]

EXAMPLE 34

Preparation of trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-5-tert-butylthienyl-2-sulfamide (-10)

(138) With intermediate 5 (1.0 mmol) and 5-tert-butylthienyl-2-sulfonyl chloride (1.2 mmol) as the starting materials, target compound -10 (0.18 g, yield 32.5%) was obtained in accordance with the method for preparing compound I-1.

(139) .sup.1H NMR (DMSO-d.sup.6, : ppm): 0.90-0.95 (m, 2H, A-H), 1.14-1.22 (m, 3H, A-H), 1.47 (s, 9H, A-H), 1.53-1.57 (m, 2H, A-H), 1.63-1.68 (m, 4H, A-H), 2.66 (t, 2H, J=7.8 Hz, NCH.sub.2), 2.91-2.95 (m, 1H, A-H), 3.08-3.11 (m, 4H, piperazine-CH.sub.2), 3.38-3.41 (m, 4H, piperazine-CH.sub.2), 7.06 (d, 1H, J=8.0 Hz, ArH), 7.38-7.39 (m, 2H, ArH), 7.47 (t, 1H, J=8.0 Hz, ArH), 8.15-8.17 (m, 2H, ArH).

(140) ESI-MS: 547 [M+H.sup.+]

EXAMPLE 35

Preparation of trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-5-chlorobenzo[b]thienyl-2-sulfamide (-11)

(141) With intermediate 5 (1.0 mmol) and 5-chlorobenzo[b]thienyl-2-sulfonyl chloride (1.2 mmol) as the starting materials, target compound -11 (0.23 g, yield 39.4%) was obtained in accordance with the method for preparing compound I-1.

(142) .sup.1H NMR (DMSO-d.sup.6, : ppm): 1.05-1.09 (m, 2H, A-H), 1.22-1.40 (m, 4H, A-H), 1.79-1.86 (m, 5H, A-H), 2.41 (t, 2H, J=7.8 Hz, NCH.sub.2), 2.99-3.02 (m, 1H, A-H), 3.19-3.22 (m, 4H, piperazine-CH.sub.2), 3.49-3.52 (m, 4H, piperazine-CH.sub.2), 7.32 (d, 1H, J=8.0 Hz, ArH), 7.35 (s, 1H, ArH), 7.44-7.46 (m, 2H, ArH), 7.65 (d, 1H, J=8.4 Hz, ArH), 7.93-7.95 (m, 2H, ArH), 8.47 (s, 1H, ArH).

(143) ESI-MS: 575 [M+H.sup.+]

EXAMPLE 36

Preparation of trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-5-cyanobenzo[b]thienyl-2-sulfamide (-12)

(144) With intermediate 5 (1.0 mmol) and 5-cyanobenzo[b]thienyl-2-sulfonyl chloride (1.2 mmol) as the starting materials, target compound -12 (0.34 g, yield 60.7%) was obtained in accordance with the method for preparing compound I-1.

(145) .sup.1H NMR (DMSO-d.sup.6, : ppm): 1.10-1.14 (m, 2H, A-H), 1.27-1.45 (m, 4H, A-H), 1.84-1.91 (m, 5H, A-H), 2.46 (t, 2H, J=7.8 Hz, NCH.sub.2), 3.04-3.07 (m, 1H, A-H), 3.24-3.27 (m, 4H, piperazine-CH.sub.2), 3.54-3.57 (m, 4H, piperazine-CH.sub.2), 7.37 (d, 1H, J=0.0 Hz, ArH), 7.41 (s, 1H, ArH), 7.51-7.53 (m, 2H, ArH), 7.70 (d, 1H, J=8.4 Hz, ArH), 7.98-8.01 (m, 2H, ArH), 8.53 (s, 1H, ArH).

(146) ESI-MS: 566 [M+H.sup.+]

EXAMPLE 37

Preparation of trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-5-methylbenzo[b]thienyl-2-sulfamide (-13)

(147) With intermediate 5 (1.0 mmol) and 5-cyanobenzo[b]thienyl-2-sulfonyl chloride (1.2 mmol) as the starting materials, target compound -13 (0.34 g, yield 60.7%) was obtained in accordance with the method for preparing compound I-1.

(148) .sup.1H NMR (DMSO-d.sup.6, : ppm): 0.99-1.03 (m, 2H, A-H), 1.16-1.34 (m, 4H, A-H), 1.73-1.80 (m, 5H, A-H), 2.28 (s, 3H, A-H), 2.35 (t, 2H, J=7.8 Hz, NCH.sub.2), 2.93-2.96 (m, 1H, A-H), 3.13-3.16 (m, 4H, piperazine-CH.sub.2), 3.43-3.46 (m, 4H, piperazine-CH.sub.2), 7.26 (d, 1H, J=8.0 Hz, ArH), 7.29 (s, 1H, ArH), 7.38-7.40 (m, 2H, ArH), 7.59 (d, 1H, J=8.4H-z, ArH), 7.87-7.89 (m, 2H, ArH), 8.41 (s, 1H, ArH).

(149) ESI-MS: 555 [M+H.sup.+]

EXAMPLE 38

Preparation of trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-5-nitrobenzo[b]thienyl-2-sulfamide (-14)

(150) With intermediate 5 (1.0 mmol) and 5-nitrobenzo[b]thienyl-2-sulfonyl chloride (1.2 mmol) as the starting materials, target compound -14 (0.29 g, yield 49.2%) was obtained in accordance with the method for preparing compound I-1.

(151) .sup.1H NMR (DMSO-d.sup.6, : ppm): 1.14-1.1 (m, 2H, A-H), 1.31-1.49 (m, 4H, A-H), 1.88-1.95 (m, 5H, A-H), 2.50 (t, 2H, J=7.8 Hz, NCH.sub.2), 3.08-3.11 (m, 1H, A-H), 3.28-3.31 (m, 4H, piperazine-CH.sub.2), 3.58-3.61 (m, 4H, piperazine-CH.sub.2), 7.41 (d, 1H, J=8.0 Hz, ArH), 7.45 (s, 1H, ArH), 7.55-7.57 (m, 2H, ArH), 7.75 (d, 1H, J=8.4 Hz, ArH), 8.02-8.05 (m, 2H, ArH), 8.58 (s, 1H, ArH).

(152) ESI-MS: 586 [M+H.sup.+]

EXAMPLE 39

Preparation of trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-5-methoxylbenzofuryl-2-sulfamide (-15)

(153) With intermediate 5 (1.0 mmol) and 5-methoxylbenzofuryl-2-sulfonyl chloride (1.2 mmol) as the starting materials, target compound -15 (0.25 g, yield 44.1%) was obtained in accordance with the method for preparing compound I-1.

(154) .sup.1H NMR (DMSO-d.sup.6, : ppm): 1.00-1.05 (m, 2H, A-H), 1.18-1.39 (m, 5H, A-H), 1.76-1.84 (m, 4H, A-H), 2.37 (t, 2H, J=7.8 Hz, NCH.sub.2), 2.90-2.93 (m, 1H, A-H), 3.10-3.13 (m, 4H, piperazine-CH.sub.2), 3.40-3.43 (m, 4H, piperazine-CH.sub.2), 3.76 (s, 3H, A-H), 7.20 (d, 1H, J=8.0 Hz, ArH), 7.32-7.34 (m, 3H, ArH), 7.51 (t, 1H, J=8.0 Hz, ArH), 7.54 (t, 1H, J=7.6 Hz, ArH), 7.84-7.87 (m, 2H, ArH).

(155) ESI-MS: 571 [M+H.sup.+]

EXAMPLE 40

Preparation of cis-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)thienyl-2-sulfamide (-16) and the salt thereof

(156) With intermediate 11 (1.0 mmol) and thienyl-2-sulfonyl chloride (1.2 mmol) as the starting materials, target compound -16 (0.19 g, yield 38.7%) was obtained in accordance with the method for preparing compound I-1.

(157) .sup.1H NMR (DMSO-d.sup.6, : ppm): 0.98-1.03 (m, 2H, A-H), 1.23-1.31 (m, 3H, A-H), 1.61-1.66 (m, 2H, A-H), 1.72-1.77 (m, 4H, A-H), 2.75 (t, 2H, J=7.8 Hz, NCH.sub.2), 3.00-3.04 (m, 1H, A-H), 3.17-3.20 (m, 4H, piperazine-CH.sub.2), 3.47-3.50 (m, 4H, piperazine-CH.sub.2), 7, 27 (t, 1H, J=4.0 Hz, ArH), 7.58 (t, 1H, J=8.0 Hz, ArH), 7.68-7.71 (m, 2H, ArH), 7.93 (d, 1H, J=4.0 Hz, ArH), 8.12-8.18 (m, 2H, ArH).

(158) ESI-MS: 491 [M+H.sup.+]

Preparation of the Hydrobromide of Compound -16

(159) With compound -16 (0.1 mmol) and 5% hydrobromic acid (0.1 mmol) as the starting materials, a white solid (0.05 g, yield 90.5%) was obtained in accordance with the method for preparing the hydrochloride of compound I-1.

(160) Elemental analysis: C.sub.23H.sub.30N.sub.4O.sub.2S.sub.3.HBr (theoretical value %: C, 48.33; H, 5.47; N, 9.80; experimental value %: C, 48.17; H, 5.65; N, 10.02).

EXAMPLE 41

Preparation of cis-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-1H-pyrrolyl-3-sulfamide (-17)

(161) With intermediate 11 (1.0 mmol) and pyrrolyl-3-sulfonyl chloride (1.2 mmol) as the starting materials, target compound -17 (0.28 g, yield 58.5%) was obtained in accordance with the method for preparing compound I-1.

(162) .sup.1H NMR (DMSO-d.sup.6, : ppm): 1.04-1.19 (m, 2H, A-H), 1.31-1.38 (m, 3H, A-H), 1.66-1.71 (m, 2H, A-H), 1.78-1.83 (m, 4H, A-H), 2.78 (t, 2H, J=7.8 Hz, NCH.sub.2), 3.06-3.08 (m, 1H, A-H), 3.23-3.26 (m, 4H, piperazine-CH.sub.2) 3.54-3.57 (m, 4H, piperazine-CH.sub.2), 6.20-6.22 (d, 1H, J=0.4.0 Hz, ArH), 6.92-6.94 (m, 2H, ArH), 7.57 (t, 1H, J=0.0 Hz, ArH), 7.66 (t, 1H, J=8.0 Hz, ArH), 8.13-8.16 (m, 2H, ArH).

(163) ESI-MS: 474 [M+H.sup.+]

EXAMPLE 42

Preparation of cis-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)furyl-2-sulfamide (-18)

(164) With intermediate 11 (1.0 mmol) and furyl-2-sulfonyl chloride (1.2 mmol) as the starting materials, target compound -18 (0.31 g, yield 66.1%) was obtained in accordance with the method for preparing compound I-1.

(165) .sup.1H NMR (DMSO-d.sup.6, : ppm): 0.96-1.01 (m, 2H, A-H), 1.20-1.28 (m, 3H, A-H), 1.58-1.63 (m, 2H, A-H), 1.68-1.73 (m, 4H, A-H), 2.71 (t, 2H, J=7.8 Hz, NCH.sub.2), 2.97-3.01 (m, 1H, A-H), 3.13-3.17 (m, 4H, piperazine-CH.sub.2), 3.44-3.47 (m, 4H, piperazine-CH.sub.2), 7.23 (t, 1H, J=4.0 Hz, ArH), 7.55 (t, 1H, J=8.0 Hz, ArH), 7.68-7.71 (m, 2H, ArH), 7.93 (d, 1H, J=4.0 Hz, ArH), 8.12-8.18 (m, 2H, ArH).

(166) ESI-MS: 475 [M+H.sup.+]

EXAMPLE 43

Preparation of cis-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)benzo[b]thienyl-2-sulfamide (-19)

(167) With intermediate 11 (1.0 mmol) and benzo[b]thienyl-2-sulfonyl chloride (1.2 mmol) as the starting materials, target compound -19 (0.42 g, yield 80.0%) was obtained in accordance with the method for preparing compound I-1.

(168) .sup.1H NMR (DMSO-d.sup.6, : ppm): 1.05-1.09 (m, 2H, A-H), 1.22-1.40 (m, 4H, A-H), 1.79-1.86 (m, 5H, A-H), 2.41 (t, 2H, J=7.8 Hz, NCH.sub.2), 2.99-3.02 (m, 1H, A-H), 3.19-3.22 (m, 4H, piperazine-CH.sub.2), 3.49-3.52 (m, 4H, piperazine-CH.sub.2), 7.13 (d, 1H, J=8.0 Hz, ArH), 7.24 (m, 2H, ArH), 7.36-7.37 (m, 2H, ArH), 7.55-7.57 (m, 2H, ArH), 7.74 (s, 1H, ArH), 8.21-8.24 (m, 1H, ArH).

(169) ESI-MS: 541 [M+H.sup.+]

EXAMPLE 44

Preparation of cis-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)benzofuryl-2-sulfamide (-20)

(170) With intermediate 11 (1.0 mmol) and benzofuryl-2-sulfonyl chloride (1.2 mmol) as the starting materials, target compound -20 (0.32 g, yield 60.5%) was obtained in accordance with the method for preparing compound I-1.

(171) .sup.1H NMR (DMSO-d.sup.6, : ppm): 1.10-1.15 (m, 2H, A-H), 1.28-1.49 (m, 5H, A-H), 1.86-1.94 (m, 4H, A-H), 2.47 (t, 2H, J=7.8 Hz, NCH.sub.2), 2.99-3.02 (m, 1H, A-H), 3.20-3.23 (m, 4H, piperazine-CH.sub.2), 3.50-3.53 (m, 4H, piperazine-CH.sub.2) 7.21-7.23 (m, 3H, ArH), 7.30 (s, 1H, ArH), 7.41-7.43 (m, 2H, ArH), 7.61-7.63 (m, 1H, ArH), 7.8-7.90 (m, 1H, ArH), 8.32-8.33 (m, 1H, ArH).

(172) ESI-MS: 525 [M+H.sup.+]

EXAMPLE 45

Preparation of cis-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-1H-indolyl-3-sulfamide (-21)

(173) With intermediate 11 (1.0 mmol) and indolyl-3-sulfonyl chloride (1.2 mmol) as the starting materials, target compound -21 (0.26 g, yield 50.0%) was obtained in accordance with the method for preparing compound I-1.

(174) .sup.1H NMR (DMSO-d.sup.6, : ppm): 0.99-1.04 (m, 2H, A-H), 1.23-1.31 (m, 3H, A-H), 1.61-1.66 (m, 2H, A-H), 1.72-1.77 (m, 4H, A-H), 2.75 (t, 2H, J=7.8 Hz, NCH.sub.2), 3.02-3.06 (m, 1H, A-H), 3.17-3.20 (m, 4H, piperazine-CH.sub.2), 3.47-3.50 (m, 4H, piperazine-CH.sub.2), 7.07-7.08 (m, 2H, ArH), 7.28 (t, 1H, J=8.0 Hz, ArH), 7.59 (t, 1H, J=8.0 Hz, ArH), 7.63 (d, 1H, J=4.0 Hz, ArH), 7.66 (m, 1H, ArH), 7.95 (d, 1H, J=4.0 Hz, ArH), 8.12-8.17 (m, 2H, ArH).

(175) ESI-MS: 524 [M+H.sup.+]

EXAMPLE 46

Preparation of cis-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-5-methylfuryl-2-sulfamide (-22)

(176) With intermediate 11 (1.0 mmol) and 5-methylfuryl-2-sulfonyl chloride (1.2 mmol) as the starting materials, target compound -22 (0.33 g, yield 67.8%) was obtained in accordance with the method for preparing compound I-1.

(177) .sup.1H NMR (DMSO-d.sup.6, : ppm): 0.97-1.02 (m, 2H, A-H), 1.20-1.28 (m, 3H, A-H), 1.59-1.64 (m, 2H, A-H), 1.69-1.74 (m, 4H, A-H), 2.47 (s, 3H, A-H), 2.70 (t, 2H, J=7.8 Hz, NCH.sub.2), 2.97-3.01 (m, 1H, A-H), 3.13-3.18 (m, 4H, piperazine-CH.sub.2), 3.44-3.48 (m, 4H, piperazine-CH.sub.2), 7.14 (d, 1H, J=8.0 Hz, ArH), 7.46-7.47 (m, 2H, ArH), 7.55 (t, 1H, J=0.0 Hz, ArH), 8.22-8.24 (m, 2H, ArH).

(178) ESI-MS: 489 [M+H.sup.+]

EXAMPLE 47

Preparation of trans-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)methylcarbamate (-1)

(179) With intermediate 5 (1.0 mmol) and methyl chloroformate (1.1 mmol) as the starting materials, target compound -1 (0.36 g, yield 88.7%) was obtained in accordance with the method for preparing compound I-1.

(180) .sup.1H NMR (DMSO-d.sup.6, : ppm): 0.93-1.02 (m, 2H, A-H), 1.20-1.31 (m, 3H, A-H), 1.40-1.41 (m, 2H, A-H), 1.73-1.81 (m, 4H, A-H), 2.53 (t, 2H, J=7.8 Hz, NCH.sub.2), 2.62-2.65 (m, 4H, piperazine-CH.sub.2), 3.17-3.22 (m, 1H, A-H), 3.4-3.49 (m, 4H, piperazine-CH.sub.2), 3.77 (s, 3H, A-H), 7.46 (t, 1H, J=8.0 Hz, ArH), 7.59 (t, 1H, J=8.0 Hz, ArH), 8.09-8.11 (m, 2H, ArH).

(181) ESI-MS: 403 [M+H.sup.+]

EXAMPLE 48

Preparation of trans-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)ethylcarbamate (-2)

(182) With intermediate 5 (1.0 mmol) and ethyl chloroformate (1.1 mmol) as the starting materials, target compound -2 (0.38 g, yield 91.0%) was obtained in accordance with the method for preparing compound I-1.

(183) .sup.1H NMR (DMSO-d.sup.6, : ppm): 0.92-1.01 (m, 2H, A-H), 1.15 (t, 3H, J=8.0 Hz, A-H), 1.19-1.30 (m, 3H, A-H), 1.39-1.40 (m, 2H, A-H), 1.72-1.80 (m, 4H, A-H), 2.51 (t, 2H, J=7.8 Hz, NCH.sub.2), 2.60-2.63 (m, 4H, piperazine-CH.sub.2), 3.16-3.21 (m, 1H, A-H), 3.44-3.47 (m, 4H, piperazine-CH.sub.2), 3.96 (q, 2H, J=8.0 Hz, A-H), 7.44 (t, 1H, J=8.0 Hz, ArH), 7.57 (t, 1H, J=8.0 Hz, ArH), 8.06-8.08 (m, 2H, ArH).

(184) ESI-MS: 417 [M+H.sup.+]

EXAMPLE 49

Preparation of trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)isobutylcarbamate (-3)

(185) With intermediate 5 (1.0 mmol) and isobutyl chloroformate (1.2 mmol) as the starting materials, target compound -3 (0.40 g, yield 90.7%) was obtained in accordance with the method for preparing compound I-1.

(186) .sup.1H NMR (DMSO-d.sup.6, : ppm): 0.89 (d, 6H, J=8.0 Hz, A-H), 0.91-1.00 (m, 2H, A-H), 1.18-1.29 (m, 3H, A-H), 1.37-1.39 (m, 3H, A-H), 1.70-1.78 (m, 4H, A-H), 2.50 (t, 2H, J=7.8 Hz, NCH.sub.2), 2.58-2.61 (m, 4H, piperazine-CH.sub.2), 3.14-3.19 (m, 1H, A-H), 3.42-3.45 (m, 4H, piperazine-CH.sub.2), 3.92 (d, 2H, J=8.0 Hz, A-H), 7.41 (t, 1H, J=8.0 Hz, ArH), 7.54 (t, 1H, J=8.0 Hz, ArH), 8.03-8.05 (m, 2H, ArH).

(187) ESI-MS: 445 [M+H.sup.+]

EXAMPLE 50

Preparation of trans-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)cyclopropylcarbamate (-4)

(188) With intermediate 5 (1.0 mmol) and cyclopropyl chloroformate (1.2 mmol) as the starting materials, target compound -4 (0.35 g, yield 81.4%) was obtained in accordance with the method for preparing compound I-1.

(189) .sup.1H NMR (DMSO-d.sup.6, : ppm): 0.61-0.65 (m, 2H, A-H), 0.80-0.84 (m, 2H, A-H), 0.93-1.04 (m, 2H, A-H), 1.21-1.32 (m, 3H, A-H), 1.39-1.41 (m, 2H, A-H), 1.74-1.82 (m, 4H, A-H), 2.52 (t, 2H, J=7.8 Hz, NCH.sub.2), 2.62-2.65 (m, 4H, piperazine-CH.sub.2), 2.75-2.77 (m, 1, A-H), 3.17-3.22 (m, 1H, A-H), 3.46-3, 49 (m, 4H, piperazine-CH.sub.2), 7.45 (t, 1H, J=8.0 Hz, ArH), 7.58 (t, 1H, J=8.0 Hz, ArH), 8.07-8.10 (m, 2H, ArH).

(190) ESI-MS: 429 [M+H.sup.+]

EXAMPLE 51

Preparation of trans-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)cyclohexylcarbamate (-5)

(191) With intermediate 5 (1.0 mmol) and cyclohexyl chloroformate (1.2 mmol) as the starting materials, target compound -5 (0.35 g, yield 73.6%) was obtained in accordance with the method for preparing compound I-1.

(192) .sup.1H NMR (DMSO-d.sup.6, : ppm): 0.89-0.98 (m, 2H, A-H), 1.16-1.27 (m, 8, A-H), 1.36-1.37 (m, 5H, A-H), 1.69-1.77 (m, 7H, A-H), 2.48 (t, 2H, J=7.8 Hz, NCH.sub.2), 2.57-2.60 (m, 4H, piperazine-CH.sub.2), 3.13-3.18 (m, 1H, A-H), 3.41-3.44 (m, 4H, piperazine-CH.sub.2), 3.93 (m, 1H, A-H), 7.41 (t, 1H, J=8.0 Hz, ArH), 7.55 (t, 1H, J=0.0 Hz, ArH), 8.02-8.04 (m, 2H, ArH).

(193) ESI-MS: 471 [M+H.sup.+]

EXAMPLE 52

Preparation of trans-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) cyclohexyl)phenylcarbamate (-6)

(194) With intermediate 5 (1.0 mmol) and phenyl chloroformate (1.2 mmol) as the starting materials, target compound -6 (0.37 g, yield 80.7%) was obtained in accordance with the method for preparing compound I-1.

(195) .sup.1H NMR (DMSO-d.sup.6, : ppm): 0.93-1.01 (m, 2H, A-H), 1.14-1.23 (m, 3H, A-H), 1.30-1.32 (m, 2H, A-H), 1.72-1.81 (m, 4H, A-H), 2.40 (t, 2H, J=7.8 Hz, NCH.sub.2), 2.54-2.58 (m, 4H, piperazine-CH.sub.2), 3.21-3.27 (m, 1H, A-H), 3.68-3.72 (m, 4H, piperazine-CH.sub.2), 7.24-7.33 (m, 5H, ArH), 7.41 (t, 1H, J=8.0 Hz, ArH), 7.54 (t, 1H, J=8.0 Hz, ArH), 8.04-8.10 (m, 2H, ArH).

(196) ESI-MS: 465 [M+H.sup.+]

EXAMPLE 53

Preparation of trans-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-3-methoxylphenylcarbamate (-7)

(197) With intermediate 5 (1.0 mmol) and 3-methoxyphenyl chloroformate (1.2 mmol) as the starting materials, target compound -7 (0.31 g, yield 61.9%) was obtained in accordance with the method for preparing compound I-1.

(198) .sup.1H NMR (DMSO-d.sup.6, : ppm): 0.92-1.00 (m, 2H, A-H), 1.13-1.22 (m, 3H, A-H), 1.29-1.31 (m, 2H, A-H), 1.71-1.80 (m, 4H, A-H), 2.39 (t, 2H, J=7.8 Hz, NCH.sub.2), 2.52-2.56 (m, 4H, piperazine-CH.sub.2), 3.20-3.26 (m, 1H, A-H), 3.66-3.70 (m, 4H, piperazine-CH.sub.2), 3.92 (s, 3H, A-H), 7.02-7.10 (m, 4H, ArH), 7.39 (t, 1H, J=8.0 Hz, ArH), 7.52 (t, 1H, J=8.0 Hz, ArH), 8.01-8.07 (m, 2H, ArH).

(199) ESI-MS: 495 [M+H.sup.+]

EXAMPLE 54

Preparation of trans-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-2-methylphenylcarbamate (-8)

(200) With intermediate 5 (1.0 mmol) and 2-methylphenyl chloroformate (1.2 mmol) as the starting materials, target compound -8 (0.35 g, yield 73.1%) was obtained in accordance with the method for preparing compound I-1.

(201) .sup.1H NMR (DMSO-d.sup.6, : ppm): 0.90-0.98 (m, 2H, A-H), 1.11-1.20 (m, 3H, A-H), 1.27-1.29 (m, 2H, A-H), 1.69-1.78 (m, 4H, A-H), 2.10 (s, 3H, A-H), 2.39 (t, 2H, J=7.8 Hz, NCH.sub.2), 2.51-2.55 (m, 4H, piperazine-CH.sub.2), 3.18-3.24 (m, 1H, A-H), 3.65-3.69 (m, 4H, piperazine-CH.sub.2), 7.22-7.30 (m, 4H, ArH), 7.40 (t, 1H, J=8.0 Hz, ArH), 7.53 (t, 1H, J=8.0 Hz, ArH), 8.03-8.09 (m, 2H, ArH).

(202) ESI-MS: 479 [M+H.sup.+]

EXAMPLE 55

Preparation of trans-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-4-chlorophenylcarbamate (-9)

(203) With intermediate 5 (1.0 mmol) and 4-chlorophenyl chloroformate (1.2 mmol) as the starting materials, target compound -9 (0.38 g, yield 76.4%) was obtained in accordance with the method for preparing compound I-1.

(204) .sup.1H NMR (DMSO-d.sup.6, : ppm): 0.98-1.06 (m, 2H, A-H), 1.19-1.28 (m, 3H, A-H), 1.35-1.37 (m, 2H, A-H), 1.77-1.86 (m, 4H, A-H), 2.45 (t, 2H, J=7.8 Hz, NCH.sub.2), 2.59-2.63 (m, 4H, piperazine-CH.sub.2), 3.26-3.32 (m, 1H, A-H), 3.73-3.77 (m, 4H, piperazine-CH.sub.2), 7.34-7.41 (m, 4H, ArH), 7.49 (t, 1H, J=8.0 Hz, ArH), 7.62 (t, 1H, J=8.0 Hz, ArH), 8.12-8.18 (m, 2H, ArH).

(205) ESI-MS: 499 [M+H.sup.+]

EXAMPLE 56

Preparation of trans-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-4-nitrophenylcarbamate (-10)

(206) With intermediate 5 (1.0 mmol) and 4-nitrophenyl chloroformate (1.2 mmol) as the starting materials, target compound i-10 (0.43 g, yield 85.1%) was obtained in accordance with the method for preparing compound I-1.

(207) .sup.1H NMR (DMSO-d.sup.6, : ppm): 1.02-1.10 (m, 2H, A-H), 1.23-1.32 (m, 3H, A-H), 1.40-1.42 (m, 2H, A-H), 1.82-1.91 (m, 4H, A-H), 2.48 (t, 2H, J=7.8 Hz, NCH.sub.2), 2.64-2.68 (m, 4H, piperazine-CH.sub.2), 3.31-3.37 (m, 1H, A-H), 3.78-3.82 (m, 4H, piperazine-CH.sub.2), 7.44 (d, 2H, J=8.0 Hz, ArH), 7.57 (t, 1H, J=8.0 Hz, ArH), 7.69 (t, 1H, J=8.0 Hz, ArH), 8.19 (d, 2H, J=8.0 Hz, ArH), 8.23-8.28 (m, 2H, ArH).

(208) ESI-MS: 510 [M+H.sup.+]

EXAMPLE 57

Preparation of trans-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)benzylcarbamate (-1)

(209) With intermediate 5 (1.0 mmol) and benzyl chloroformate (1.2 mmol) as the starting materials, target compound -11 (0.39 g, yield 82.4%) was obtained in accordance with the method for preparing compound I-1.

(210) .sup.1H NMR (DMSO-d.sup.6, : ppm): 0.94-1.02 (m, 2H, A-H), 1.15-1.24 (m, 3H, A-H), 1.31-1.33 (m, 2H, A-H), 1.73-1.82 (m, 4H, A-H), 2.41 (t, 2H, J=7.8 Hz, NCH.sub.2), 2.55-2.59 (m, 4H, piperazine-CH.sub.2), 3.22-3.28 (m, 1H, A-H), 3.69-3.73 (m, 4H, piperazine-CH.sub.2), 5.00 (s, 2H, A-H), 7.30-7.39 (m, 5H, ArH), 7.45 (t, 1H, J=0.0 Hz, ArH), 7.58 (t, 1H, J=8.0 Hz, ArH), 8.07-8.13 (m, 2H, ArH).

(211) ESI-MS: 479 [M+H.sup.+]

EXAMPLE 58

Preparation of trans-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)benzofuryl-2-methylcarbamate (-12)

(212) With intermediate 5 (1.0 mmol) and benzofuryl-2-methyl chloroformate (1.2 mmol) as the starting materials, target compound -12 (0.25 g, yield 47.8%) was obtained in accordance with the method for preparing compound I-1.

(213) .sup.1H NMR (DMSO-d.sup.6, : ppm): 1.05-1.13 (m, 2H, A-H), 1.26-1.35 (m, 3H, A-H), 1.42-1.44 (m, 2H, A-H), 1.83-1.92 (m, 4H, A-H), 2.51 (t, 2H, J=78 Hz, NCH.sub.2), 2.66-2.70 (m, 4H, piperazine-CH.sub.2), 3.33-3.39 (m, 1H, A-H), 3.80-3.84 (m, 4H, piperazine-CH.sub.2), 5.03 (s, 2H, A-H), 7.22-7.24 (m, 3H, ArH), 7.31 (s, 1H, ArH), 7.42-7.46 (m, 2H, ArH), 7.62-7.64 (m, 1H, ArH), 7.88-7.90 (m, 1H, ArH), 8.31-8.34 (m, 1H, ArH).

(214) ESI-MS: 519 [M+H.sup.+]

EXAMPLE 59

Preparation of trans-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)thienyl-2-methylcarbamate (-13)

(215) With intermediate 5 (1.0 mmol) and thienyl-2-methyl chloroformate (1.2 mmol) as the starting materials, target compound -13 (0.29 g, yield 59.3%) was obtained in accordance with the method for preparing compound I-1.

(216) .sup.1H NMR (DMSO-d.sup.6, : ppm): 0.98-1.06 (m, 2H, A-H), 1.22-1.31 (m, 3H, A-H), 1.38-1.40 (m, 2H, A-H), 1.81-1.90 (m, 4H, A-H), 2.49 (t, 2H, J=7.8 Hz, NCH.sub.2), 2.63-2.67 (m, 4H, piperazine-CH.sub.2), 3.30-3.36 (m, 1H, A-H), 3.77-3.81 (m, 4H, piperazine-CH.sub.2), 5.13 (s, 2H, A-H), 7.45 (dd, 1H, J=8.0 Hz, 4.0 Hz, ArH), 7.51 (t, 1H, J=7.6 Hz, ArH), 7.63 (t, 1H, J=7.6 Hz, ArH), 7.78 (d, 1H, J=4.0 Hz, ArH), 8.11-8.14 (m, 2H, ArH), 8.29 (d, 1H, J=8.0 Hz, ArH).

(217) ESI-MS: 485 [M+H.sup.+]

EXAMPLE 60

Preparation of cis-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)methylcarbamate (-14)

(218) With intermediate 11 (1.0 mmol) and methyl chloroformate (1.2 mmol) as the starting materials, target compound -14 (0.33 g, yield 81.3%) was obtained in accordance with the method for preparing compound I-1.

(219) .sup.1H NMR (DMSO-d.sup.6, : ppm): 0.97-1.06 (m, 2H, A-H), 1.24-1.35 (m, 3H, A-H), 1.44-1.45 (m, 2H, A-H), 1.77-1.85 (m, 4H, A-H), 2.57 (t, 2H, J=7.8 Hz, NCH.sub.2), 2.66-2.69 (m, 4H, piperazine-CH.sub.2), 3.21-3.26 (m, 1H, A-H), 3.50-3.53 (m, 4H, piperazine-CH.sub.2), 3.81 (s, 3H, A-H), 7.50 (t, 1H, J=8.0 Hz, ArH), 7.63 (t, 1H, J=8.0 Hz, ArH), 8.13-8.15 (m, 2H, ArH).

(220) ESI-MS: 403 [M+H.sup.+]

EXAMPLE 61

Preparation of cis-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)ethylcarbamate (-15)

(221) With intermediate 11 (1.0 mmol) and ethyl chloroformate (1.2 mmol) as the starting materials, target compound -15 (0.36 g, yield 86.2%) was obtained in accordance with the method for preparing compound I-1.

(222) .sup.1H NMR (DMSO-d.sup.6, : ppm): 0.95-1.04 (m, 2H, A-H), 1.18 (t, 3H, J=8.0 Hz, A-H), 1.22-1.33 (m, 3H, A-H), 1.42-1.43 (m, 2H, A-H), 1.75-1.83 (m, 4H, A-H), 2.54 (t, 2H, J=7.8 Hz, NCH.sub.2), 2.63-2.66 (m, 4H, piperazine-CH.sub.2), 3.19-3.24 (m, 1H, A-H), 3.47-3.450 (m, 4H, piperazine-CH.sub.2), 3.99 (q, 2H, J=8.0 Hz, A-H), 7.47 (t, 1H, J=8.0 Hz, ArH), 7.60 (t, 1H, J=8.0 Hz, ArH), 8.09-8.11 (m, 2H, ArH).

(223) ESI-MS: 417 [M+H.sup.+]

EXAMPLE 62

Preparation of cis-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)benzylcarbamate (-16)

(224) With intermediate 11 (1.0 mmol) and benzyl chloroformate (1.2 mmol) as the starting materials, target compound -16 (0.32 g, yield 67.6%) was obtained in accordance with the method for preparing compound I-1.

(225) .sup.1H NMR (DMSO-d.sup.6, : ppm): 0.97-1.05 (m, 2H, A-H), 1.18-1.27 (m, 3H, A-H), 1.34-1.36 (m, 2H, A-H), 1.76-1.85 (m, 4H, A-H), 2.44 (t, 2H, J=7.8 Hz, NCH.sub.2), 2.58-2.62 (m, 4H, piperazine-CH.sub.2), 3.25-3.31 (m, 1H, A-H), 3.72-3.76 (m, 4H, piperazine-CH.sub.2), 5.04 (s, 2H, A-H), 7.34-7.43 (m, 5H, ArH), 7.49 (t, 1H, J=8.0 Hz, ArH), 7.62 (t, 1H, J=8.0 Hz, ArH), 8.11-8.17 (m, 2H, ArH).

(226) ESI-MS: 479 [M+H.sup.+]

EXAMPLE 63

Preparation of trans-1-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-3-phenylurea (-1) and the salt thereof

(227) Triphosgene (0.48 mmol) and dichloromethane (10 mL) were added into a 3-neck flask (50 mL), and cooled under ice bath to 10 C.5 C. The solution of compound 5 (0.44 mmol) and triethylamine (1 mL) in dichloromethane (10 mL) was slowly added dropwise, and stirred for 2 h by maintaining the temperature between 10 C. and 5 C. Aniline (0.88 mmol) and isopropanol (5 mL) were added into a 3-neck flask (50 mL), and the reaction solution was cooled under ice bath to 10 C.0 C. The above reaction solution was slowly added dropwise to the system, stirred for 2 h by maintaining the temperature was controlled between 10 C. and 5 C., and reacted at RM for 12 h. The system was washed sequentially with ammonium chloride aqueous solution (10 mL2), water (10 mL1), and saturated saline (10 mL2), and evaporated to dryness, and the residue was recrystallized with 95% ethanol to give a white solid IV-1 (0.16 g, yield 80.4%).

(228) .sup.1H NMR (DMSO-d.sup.6, : ppm): 0.96-1.13 (m, 3H, A-H), 1.26-1.28 (m, 2H, A-H), 1.39-1.40 (m, 2H, A-H), 1.75-1.87 (m, 4H, A-H), 2.40 (t, 2H, J=7.8 Hz, NCH.sub.2), 2.61-2.64 (m, 4H, piperazine-CH.sub.2), 3.34-3.36 (m, 1H, A-H), 3.46-3.49 (m, 4H, piperazine-CH.sub.2), 7.23-7.25 (m, 1 t, ArH), 7.35 (dd, 2H, J=8.4 Hz, J=8.0 Hz, ArH), 7.40 (d, 2H, J=8.0 Hz, ArH) 7.48 (t, 1H, J=8.0 Hz, ArH), 7.61 (t, 1H, J=8.0 Hz, ArH), 8.07-8.11 (m, 2H, ArH).

(229) ESI-MS: 464 [M+H.sup.+]

Preparation of the hydro bromide of compound -1

(230) With compound -1 (0.1 mmol) and 5% hydrobromic acid (0.1 mmol) as the starting materials, a white solid (0.04 g, yield 79.2%) was obtained in accordance with the method for preparing the hydrochloride of compound I-1.

(231) Elemental analysis: C.sub.26H.sub.33N.sub.50S.HBr (theoretical value %: C, 57.35; H, 6.29; N, 12.86; experimental value %: C, 57.21; H, 6.14; N, 12.98).

Preparation of the Mesylate of Compound -1

(232) With compound -1 (0.1 mmol) and methanesulfonic acid (0.1 mmol) as the starting materials, a white solid (0.05 g, yield 81.8%) was obtained in accordance with the method for preparing the hydrochloride of compound I-1.

(233) Elemental analysis: C.sub.26H.sub.33N.sub.50S.H.sub.4O.sub.3S (theoretical value %: C, 57.35; H, 6.29; N, 12.86; experimental value %: C, 57.21; H, 6.14; N, 12.98).

Preparation of the p-Tosylate Trihydrate of Compound -1

(234) Compound -1 (1.0 mmol), p-toluene sulfonic acid (1.0 mmol), water (2 mL) and methanol (20 mL) were added into a single neck flask (50 mL), and stirred at RM for 1.5 h to provide a clear reaction solution. The reaction solution was evaporated to dryness, to provide an oil. Isopropanol (10 mL) was added and stirred for 5 h. A white solid was precipitated and filtered, and the filter cake was baked to dryness, recrystallized with 95% ethanol to give the white solid (0.47 g, yield 68.1%).

(235) Elemental analysis: C.sub.26H.sub.33N.sub.50S.C.sub.7H.sub.8O.sub.3S.3H.sub.2O (theoretical value %: C, 57.45; H, 6.87; N, 10.15; experimental value %: C, 57.68; H, 6.61; N, 10.34).

EXAMPLE 64

Preparation of trans-1-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-3-phenylethylurea (-2)

(236) With intermediate 5 (1.0 mmol) and phenylethylamine (2.0 mmol) as the starting materials, target compound -2 (0.41 g, yield 83.8%) was obtained in accordance with the method for preparing compound -1.

(237) .sup.1H NMR (DMSO-d.sup.6, : ppm): 0.92-1.09 (m, 3H, A-H), 1.22-1.24 (m, 2H, A-H), 1.36-1.37 (m, 2H, A-H), 1.71-1.84 (m, 4H, A-H), 2.37 (t, 2H, J=7.8 Hz, NCH.sub.2), 2.44 (t, 2H, J=8.0 Hz, A-H), 2.57-2.60 (m, 4H, piperazine-CH.sub.2), 3.30-3.32 (m, 1H, A-H), 3.42-3.45 (m, 4H, piperazine-CH.sub.2), 3.86 (t, 2H, J=8.0 Hz, A-H), 7.19-7.25 (m, 3H, ArH), 7.27-7.31 (m, 2H, ArH) 7.40 (t, 1H, J=8.0 Hz, ArH), 7.53 (t, 1H, J=0.0 Hz, ArH), 8.01-8.04 (m, 2H, ArH).

(238) ESI-MS: 492 [M+H.sup.+]

EXAMPLE 65

Preparation of trans-1-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-3-(pyridin-3-yl)urea (-3)

(239) With intermediate 5 (1.0 mmol) and 3-aminopyridine (2.0 mmol) as the starting materials, target compound -3 (0.27 g, yield 58.1%) was obtained in accordance with the method for preparing compound -1.

(240) .sup.1H NMR (DMSO-d.sup.6, : ppm): 0.98-1.15 (m, 3H, A-H), 1.29-1.31 (m, 2H, A-H), 1.42-1.43 (m, 2H, A-H), 1.78-1.90 (m, 4H, A-H), 2.42 (t, 2H, J=7.8 Hz, NCH.sub.2), 2.63-2.66 (m, 4H, piperazine-CH.sub.2), 3.36-3.38 (m, 1H, A-H), 3.49-3.52 (m, 4H, piperazine-CH.sub.2), 7.32 (dd, 1H, J=0.4 Hz, J=8.0 Hz, ArH), 7.53 (t, 1H, J=8.0 Hz, ArH), 7.67 (t, 1H, J=0.0 Hz, ArH), 7.92-7.94 (m, 2H, ArH), 8.16-8.20 (m, 2H, ArH), 8.82 (s, 1H, ArH).

(241) ESI-MS: 465 [M+H.sup.+]

EXAMPLE 66

Preparation of trans-1-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-3-(furan-2-yl)urea (-4) and the salt thereof

(242) With intermediate 5 (1.0 mmol) and 2-aminofuran (2.0 mmol) as the starting materials, target compound -4 (0.39 g, yield 85.4%) was obtained in accordance with the method for preparing compound -1.

(243) .sup.1H NMR (DMSO-d.sup.6, : ppm): 0.92-1.15 (m, 3H, A-H), 1.29-1.31 (m, 2H, A-H), 1.42-1.43 (m, 2H, A-H), 1.78-1.90 (m, 4H, A-H), 2.43 (t, 2H, J=7.8 Hz, NCH.sub.2), 2.64-2.67 (m, 4H, piperazine-CH.sub.2), 3.37-3.39 (m, 1H, A-H), 3.49-3.52 (m, 4H, piperazine-CH.sub.2), 6.62 (dd, 1H, J=8.0 Hz, 4.0 Hz, ArH), 7.09 (d, 1H, J=41.0 Hz, ArH), 7.50 (t, 1H, J=8.0 Hz, ArH), 7.62 (t, 1H, J=8.0 Hz, ArH), 8.07-8.12 (m, 2H, ArH), 8.23 (d, 1H, J=0.0 Hz, ArH).

(244) ESI-MS: 454 [M+H.sup.+]

Preparation of the Hydrobromide of Compound -4

(245) With compound -4 (0.1 mmol) and 5% hydrobromic acid (0.1 mmol) as the starting materials, a white solid (0.03 g, yield 62.7%) was obtained in accordance with the method for preparing the hydrochloride of compound I-1.

(246) Elemental analysis: C.sub.24H.sub.31N.sub.5O.sub.2S.HBr (theoretical value %: C, 53.93; H, 6.03; N, 13.10; experimental value %: C, 53.78; H, 6.26; N, 12.95).

EXAMPLE 67

Preparation of trans-1-(benzo[b]thien-2-yl)-3-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)urea (-5)

(247) With intermediate 5 (1.0 mmol) and 2-aminobenzo[b]thiophene (2.0 mmol) as the starting materials, target compound -5 (0.26 g, yield 49.6%) was obtained in accordance with the method for preparing compound -1.

(248) .sup.1H NMR (DMSO-d.sup.6, : ppm): 0.93-1.16 (m, 3H, A-H), 1.28-1.30 (m, 2H, A-H), 1.41-1.42 (m, 2H, A-H), 1.77-1.89 (m, 4H, A-H), 2.44 (t, 2H, J=7.8 Hz, NCH.sub.2), 2.63-2.66 (m, 4H, piperazine-CH.sub.2), 3.36-3.38 (m, 1H, A-H), 3.48-3.51 (m, 4H, piperazine-CH.sub.2), 6.67 (s, 1H, ArH), 7.13 (d, 1H, J=8.0 Hz, ArH), 7.25 (m, 2H, ArH), 7.36-7.37 (m, 2H, ArH), 7.56-7.58 (m, 2H, ArH), 8.20-8.23 (m, 1H, ArH).

(249) ESI-MS: 520 [M+H.sup.+]

EXAMPLE 68

Preparation of trans-3-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-1-methyl-1-phenylurea (-6)

(250) With intermediate 5 (1.0 mmol) and N-methylaniline (2.0 mmol) as the starting materials, target compound -6 (0.26 g, yield 49.6%) was obtained in accordance with the method for preparing compound -1.

(251) .sup.1H NMR (DMSO-d.sup.6, : ppm): 0.95-1.12 (m, 3H, A-H), 1.25-1.27 (m, 2H, A-H), 1.38-1.39 (m, 2H, A-H), 1.74-1.86 (m, 4H, A-H), 2.39 (t, 2H, J=7.8 Hz, NCH.sub.2), 2.60-2.63 (m, 4H, piperazine-CH.sub.2), 3.33-3.35 (m, 1H, A-H), 3.98 (s, 3H, A-H), 3.44-3.47 (m, 4H, piperazine-CH.sub.2), 7.21-7.23 (m, 1H, ArH), 7.32 (dd, 2H, J=8.4 Hz, J=8.0 Hz, ArH), 7.38 (d, 2H, J=0.0 Hz, ArH) 7.47 (t, 1H, J=8.0 Hz, ArH), 7.60 (t, 1H, J=8.0 Hz, ArH), 8.06-8.10 (m, 2H, ArH).

(252) ESI-MS: 478 [M+H.sup.+]

EXAMPLE 69

Preparation of trans-3-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-1-butyl-1-phenylurea (-7)

(253) With intermediate 5 (1.0 mmol) and N-butylaniline (2.0 mmol) as the starting materials, target compound -7 (0.27 g, yield 52.4%) was obtained in accordance with the method for preparing compound -1.

(254) .sup.1H NMR (DMSO-d.sup.6, : ppm): 0.89 (t, 3H, J=8.0 Hz, A-H), 0.94-1.12 (m, 5H, A-H), 1.24-1.27 (m, 2H, A-H), 1.41-1.43 (m, 4H, A-H), 1.73-1.85 (m, 4H, A-H), 2.38 (t, 2H, J=7.8 Hz, NCH.sub.2), 2.59-2.61 (m, 4H, piperazine-CH.sub.2), 3.32-3.34 (m, 1H, A-H), 3.44-3.46 (m, 4H, piperazine-CH.sub.2), 4.01 (t, 2H, J=8.0 Hz, A-H), 7.18-7.20 (m, 1H, ArH), 7.30 (dd, 2H, J=8.4 Hz, J=8.0 Hz, ArH), 7.36 (d, 2H, J=8.0 Hz, ArH) 7.44 (t, 1H, J=8.0 Hz, ArH), 7.57 (t, 1H, J=0.0 Hz, ArH), 8.03-8.7 (m, 2H, ArH).

(255) ESI-MS: 520 [M+H.sup.+]

EXAMPLE 70

Preparation of trans-3-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-1-methyl-1-(thien-2-yl)urea (-8)

(256) With intermediate 5 (1.0 mmol) and N-methylthienyl-2-amine (2.0 mmol) as the starting materials, target compound -8 (0.29 g, yield 60.7%) was obtained in accordance with the method for preparing compound -1.

(257) .sup.1H NMR (DMSO-d.sup.6, : ppm): 0.91-1.14 (m, 3H, A-H), 1.28-1.30 (m, 2H, A-H), 1.41-1.42 (m, 2H, A-H), 1.77-1.89 (m, 4H, A-H), 2.42 (t, 2H, J=7.8H, NCH.sub.2), 2.63-2.66 (m, 4H, piperazine-CH.sub.2), 3.12 (s, 3H, A-H), 3.35-3.37 (m, 1H, A-H), 3.47-3.50 (m, 4H, piperazine-CH.sub.2), 6.60 (dd, 1H, J=8.0 Hz, 4.0 Hz, ArH), 7.07 (d, 1H, J=4.0 Hz, ArH), 7.48 (t, 1H, J=8.0 Hz, ArH), 7.61 (t, 1H, J=8.0 Hz, ArH), 8.05-8.10 (m, 2H, ArH), 8.23 (d, 1H, J=8.0 Hz, ArH).

(258) ESI-MS: 484 [M+H.sup.+]

EXAMPLE 71

Preparation of trans-1-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-3-(3-methoxyphenyl)urea (-9)

(259) With intermediate 5 (1.0 mmol) and 3-methoxyaniline (2.0 mmol) as the starting materials, target compound -9 (0.35 g, yield 71.8%) was obtained in accordance with the method for preparing compound -1.

(260) .sup.1H NMR (DMSO-d.sup.6, : ppm): 0.94-1.1 (m, 3H, A-H), 1.23-1.25 (m, 2H, A-H), 1.36-1.37 (m, 2H, A-H), 1.72-1.84 (m, 4H, A-H), 2.36 (t, 2H, J=7.8 Hz, NCH.sub.2), 2.59-2.62 (m, 4H, piperazine-CH.sub.2), 3.32-3.34 (m, 1H, A-H), 3.44-3.47 (m, 4H, piperazine-CH.sub.2), 3.76 (s, 3H, A-H), 6.98-7.07 (m, 4H, ArH), 7.35 (t, 1H, J=8.0 Hz, ArH), 7.48 (t, 1H, J=8.0 Hz, ArH), 8.03-8.09 (m, 2H, ArH).

(261) ESI-MS: 494 [M+H.sup.+]

EXAMPLE 72

Preparation of trans-1-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-3-(3-nitrophenyl)urea (-10) and the salt thereof

(262) With intermediate 5 (1.0 mmol) and 3-nitroaniline (2.0 mmol) as the starting materials, target compound -10 (0.20 g, yield 39.6%) was obtained in accordance with the method for preparing compound -1.

(263) .sup.1H NMR (DMSO-d.sup.6, : ppm): 1.0-1.18 (m, 3H, A-H), 1.31-1.33 (m, 2H, A-H), 1.44-1.45 (m, 2H, A-H), 1.80-1.92 (m, 4H, A-H), 2.45 (t, 2H, J=7.8 Hz, NCH.sub.2), 2.66-2.69 (m, 4H, piperazine-CH.sub.2), 3.40-3.42 (m, 1H, A-H), 3.51-3.54 (m, 4H, piperazine-CH.sub.2), 7.41 (m, 2H, ArH), 7.48 (t, 1H, J=8.0 Hz, ArH), 7.68-7.70 (m, 2H, A-H), 8.14-8.20 (m, 2H, ArH), 8.42 (s, 1H, ArH).

(264) ESI-MS: 509 [M+H.sup.+]

Preparation of the Hydrobromide of Compound -10

(265) With compound -410 (0.1 mmol) and 5% trifluoracetic acid (0.1 mmol) as the starting materials, a white solid (0.05 g, yield 79.2%) was obtained in accordance with the method for preparing the hydrochloride of compound I-1.

(266) Elemental analysis: C.sub.26H.sub.32N.sub.6O.sub.3S.CF.sub.3CO.sub.2H (theoretical value %: C, 54.01; H, 5.34; N, 13.50; experimental value %: C, 54.27; H, 5.09; N, 13.36).

EXAMPLE 73

Preparation of trans-1-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-3-benzoylurea (-1)

(267) With intermediate 5 (0.44 mmol) and benzylamine (0.88 mmol) as the starting materials, target compound -11 (0.18 g, yield 87.0%) was obtained in accordance with the method for preparing compound -1.

(268) .sup.1H NMR (DMSO-d.sup.6, : ppm): 0.94-1.1 (m, 3H, A-H), 1.24-1.26 (m, 2H, A-H), 1.38-1.39 (m, 2H, A-H), 1.73-1.85 (m, 4H, A-H), 2.38 (t, 2H, J=7.8 Hz, NCH.sub.2), 2.59-2.62 (m, 4H, piperazine-CH.sub.2), 3.32-3.34 (m, 1H, A-H), 3.44-3.47 (m, 4H, piperazine-CH.sub.2), 4.20 (s, 2H, A-H), 7.21-7.27 (m, 3H, ArH), 7.30-7.34 (m, 2H, ArH) 7.44 (t, 1H, J=8.0 Hz, ArH), 7.57 (t, 1H, J=8.0 Hz, ArH), 8.04-8.07 (m, 2H, ArH).

(269) ESI-MS: 478 [M+H.sup.+]

EXAMPLE 74

Preparation of cis-1-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-3-phenylurea (-12)

(270) With intermediate 11 (1.0 mmol) and aniline (2.0 mmol) as the starting materials, target compound -12 (0.34 g, yield 82.6%) was obtained in accordance with the method for preparing compound -1.

(271) .sup.1H NMR (DMSO-d.sup.6, : ppm): 1.02-1.19 (m, 3H, A-H), 1.32-1.34 (m, 2H, A-H), 1.45-1.46 (m, 2H, A-H), 1.81-1.93 (m, 4H, A-H), 2.46 (t, 2H, J=7.8 Hz, NCH.sub.2), 2.67-2.70 (m, 4H, piperazine-CH.sub.2), 3.40-3.42 (m, 1H, A-H), 3.52-3.55 (m, 4H, piperazine-CH.sub.2), 7.29-7.31 (m, 1H, ArH), 7.41 (dd, 2H, J=8.4 Hz, J=0.0 Hz, ArH), 7.46 (d, 2H, J=8.0 Hz, ArH) 7.55 (t, 1H, J=8.0 Hz, ArH), 7.67 (t, 1H, J=8.0 Hz, ArH), 8.14-8.18 (m, 2H, ArH).

(272) ESI-MS: 464 [M+H.sup.+]

EXAMPLE 75

Preparation of cis-1-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-3-benzoylurea (-13)

(273) With intermediate 11 (1.0 mmol) and benzylamine (2.0 mmol) as the starting materials, target compound -13 (0.38 g, yield 80.5%) was obtained in accordance with the method for preparing compound -1.

(274) .sup.1H NMR (DMSO-d.sup.6, : ppm): 0.99-1.16 (m, 3H, A-H), 1.29-1.31 (m, 2H, A-H), 1.43-1.44 (m, 2H, A-H), 1.78-1.90 (m, 4H, A-H), 2.43 (t, 2H, J=7.8 Hz, NCH.sub.2), 2.64-2.67 (m, 4H, piperazine-CH.sub.2), 3.37-3.39 (m, 1H, A-H), 3.49-3.52 (m, 4H, piperazine-CH.sub.2), 4.23 (s, 2H, A-H), 7.26-7.32 (m, 3H, ArH), 7.34-7.38 (m, 2H, ArH) 7.49 (t, 1H, J=8.0 Hz, ArH), 7.62 (t, 1H, J=8.0 Hz, ArH), 8.09-8.12 (m, 2H, ArH).

(275) ESI-MS: 478 [M+H.sup.+]

EXAMPLE 76

Preparation of cis-1-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-3-(furan-2-yl)urea (-14) and the salt thereof

(276) With intermediate 11 (1.0 mmol) and 2-aminofuran (2.0 mmol) as the starting materials, target compound -14 (0.37 g, yield 81.3%) was obtained in accordance with the method for preparing compound -1.

(277) .sup.1H NMR (DMSO-d.sup.6, : ppm): 0.96-1.19 (m, 3H, A-H), 1.33-1.35 (m, 2H, A-H), 1.46-1.47 (m, 2H, A-H), 1.82-1.94 (m, 4H, A-H), 2.47 (t, 2H, J=7.8 Hz, NCH.sub.2), 2.68-2.71 (m, 4H, piperazine-CH.sub.2), 3.41-3.43 (m, 1H, A-H), 3.53-3.56 (m, 4H, piperazine-CH.sub.2), 6.65 (dd, 1H, J=80 Hz, 4.0 Hz, ArH), 7.13 (d, 1H, J=4.0 Hz, ArH), 7.55 (t, 1H, J=8.0 Hz, ArH), 7.67 (t, 1H, J=8.0 Hz, ArH), 8.11-8.16 (m, 2H, ArH), 8.27 (d, 1H, J=8.0 Hz, ArH).

(278) ESI-MS: 454 [M+H.sup.+]

Preparation of the Sulfate of Compound -4

(279) With compound -14 (0.5 mmol) and 5% sulfuric acid (0.25 mmol) as the starting materials, a white solid (0.15 g, yield 60.3%) was obtained in accordance with the method for preparing the hydrochloride of compound I-1.

(280) Elemental analysis: C.sub.24H.sub.31N.sub.5O.sub.2S.H.sub.2SO.sub.4 (theoretical value %: C, 57.35; H, 6.42; N, 13.93; experimental value %: C, 57.16; H, 0.58; N, 13.67).

Preparation of the Mesylate of Compound -14

(281) With compound -14 (1.0 mmol) and methanesulfonic acid (1.0 mmol) as the starting materials, a white solid (0.43 g, yield 78.1%) was obtained in accordance with the method for preparing the hydrochloride of compound I-1.

(282) Elemental analysis: C.sub.24H.sub.31N.sub.5O.sub.2S.CH.sub.4O.sub.3S (theoretical value %: C, 54.62; H, 6.42; N, 12.74; experimental value %: C, 54.8; H, 6.31; N, 12.93).

EXAMPLE 77

(283) TABLE-US-00002 1. Tablet: the compound of the present invention 10 mg sucrose 150 mg corn starch 37 mg magnesium stearate 3 mg

(284) Preparation method: the active ingredient, sucrose and corn starch are mixed, humidified with water, stirred uniformly, dried, crushed and sieved, added with magnesium stearate, mixed uniformly, and tableted. Each tablet weighs 200 mg, containing 10 mg active ingredient.

EXAMPLE 78

(285) TABLE-US-00003 2. Injection: the compound of the present invention 5 mg water for injection 95 mg

(286) Preparation method: the active ingredient is dissolved in water for injection, mixed uniformly, and filtered. The resulting solution is dispensed into ampoules under sterile condition at 10 mg/ampoule, and the content of active ingredients is 0.5 mg/ampoule.

EXAMPLE 79

Dopamine D2 Receptor Binding Test

(287) 1. Experimental Materials:

(288) (1) D.sub.2 receptor Cell Transfection:

(289) This experiment utilizes the plasmid vector containing the gene of D.sub.2 receptor protein for transfecting HEK293 cells by calcium phosphate transfection method. By culturing the transfected cells in culture medium containing G418 and selecting cell clones followed by radioligand binding test, a stable cell strain capable of expressing the D.sub.2 receptor protein stably is finally obtained.

(290) (2) Materials for the Receptor Binding Test:

(291) Isotopic ligand [.sup.3H] Spiperone (113.0 Ci/mmol) purchased from Sigma Corporation; (+) spiperone purchased from RBI Corporation; GF/B glassfiber filter purchased from Whatman Corporation; imported and subpackaged Tris; PPO and POPOP purchased from Shanghai No. 1 Reagent Factory; and fat-soluble scintillation fluid. Beckman LS-6500 multifunction liquid scintillation counter.

(292) 2. Experimental Methods: (1) Cells:

(293) HEK-293 cells are infected with the recombinant viruses containing various genes. 48-72 h later, receptor proteins are massively expressed on the membrane. The cells are centrifuged at 1000 rpm for 5 min, then the culture supernatant is discarded and the cell pellets are collected, preserved in refrigerator at 20 C., and resuspended with Tris-HCl reaction buffer (pH=7.5) before use.

(294) (2) Competitive Receptor Binding Test:

(295) The compound to be tested, the radioligand (20 L for each) and the receptor protein (160 L) are added to a reaction tube, wherein the compound to be tested and the positive drug both have the final concentration of 10 mol/L.

(296) After being incubated in water bath at 30 C. for 50 min, the tube is immediately transferred to ice bath to stop the reaction. The mixture is subjected to rapid suction filtration through GF/C glassfiber filter on Millipore cell sample collector, washed with eluent (50 mM Tris-HCl, pH 7.5) (3 mL3) and dried under microwave for 5-6 min. The filter is transferred to a centrifuge tube (0.5 mL), added with 500 L fat-soluble scintillation fluid, left in the dark for over min, and counted to determine the radioactivity intensity. The percentage inhibition ratio for each compound to inhibit the isotopic ligand binding is calculated with the following equation:
inhibition ratio (1%)=(total binding tube CPMcompound CPM)/(total binding tube CPMnon-specific binding tube CPM)100%

(297) Each compound is tested in duplicate, and the tests are carried out independently twice.

(298) Compounds with an inhibition ratio of over 95% are subjected to the receptor binding test at a series of concentrations so as to determine half maximal inhibitory concentration (IC.sub.50, the concentration of the compound required for inhibiting 50% binding of [.sup.3H]-Spiperone to D.sub.2 receptor). Each concentration is tested in duplicate, and tests are carried out independently twice for each compound.

(299) Ki=IC.sub.50(1[L]/K.sub.D (Ki: the affinity of the drug to the receptor, L: the concentration of the radioligand, K.sub.D: the value of the affinity of the radioligand to the receptor)

(300) The results of the D.sub.2 receptor binding test are shown in Table 1 below.

(301) TABLE-US-00004 TABLE 1 Affinity of the compound to D.sub.2 receptor (Ki: nmol) No. Ki value I-1 2.90 I-2 0.19 I-3 0.21 I-4 0.43 I-5 0.32 I-6 1.81 I-7 4.65 I-8 18.71 I-9 2.57 I-10 5.04 I-11 4.81 I-12 3.15 I-13 1.78 I-14 9.43 I-15 21.34 I-16 1.05 I-17 0.27 I-18 0.23 I-19 0.82 I-20 1.20 I-21 2.96 I-22 1.90 I-23 1.73 I-24 10.75 -1 0.43 -2 3.07 -3 1.98 -4 1.69 -5 0.58 -6 3.62 -7 8.54 -8 10.75 -9 7.38 -10 17.12 -11 9.76 -12 8.82 -13 4.50 -14 6.49 -15 3.03 -16 1.75 -17 2.94 -18 1.22 -19 1.78 -20 6.40 -21 1.01 -22 2.09 -1 1.18 -2 0.71 -3 8.67 -4 3.26 -5 11.84 -6 3.19 -7 1.93 -8 2.07 -9 4.33 -10 12.41 -11 1.60 -12 5.73 -13 2.54 -14 2.26 -15 1.97 -16 0.98 -1 1.06 -2 9.15 -3 0.88 -4 0.80 -5 6.77 -6 1.45 -7 14.82 -8 0.92 -9 3.01 -10 3.64 -11 1.40 -12 1.86 -13 1.02 -14 2.07

(302) The results show that compound I-1 etc. have strong or moderate affinity to dopamine D.sub.2 receptor.

EXAMPLE 80

Dopamine D3 Receptor Binding Test

(303) The experiment is carried out by the method according to Journal of Pharmacology and Experimental Therapeutics 2010, 333(1): 328. With [.sup.3H]methyl-spiperone (0.3 nM) as the ligand and (+)-butaclamol (10 LM) for determining non-specific binding, binding tests are carried out on human recombinant D.sub.3 receptor (expressed in CHO cells).

(304) The results of the D.sub.3 receptor binding test are shown in Table 2.

(305) TABLE-US-00005 TABLE 2 Affinity of the compound to D.sub.3 receptor (Ki: nmol) No. Ki value I-1 0.13 I-2 0.056 I-3 0.31 I-4 0.029 I-5 0.078 I-6 0.035 I-7 3.21 I-8 2.78 I-9 1.43 I-10 6.98 I-11 0.37 I-12 1.02 I-13 1.42 I-14 2.86 I-15 4.03 I-16 1.87 I-17 0.10 I-18 0.18 I-19 0.25 I-20 0.19 I-21 0.84 I-22 0.071 I-23 1.04 I-24 3.80 -1 0.043 -2 0.57 -3 0.062 -4 1.03 -5 0.085 -6 2.76 -7 8.19 -8 4.51 -9 1.73 -10 7.09 -11 3.60 -12 1.99 -13 0.85 -14 9.37 -15 2.18 -16 0.23 -17 0.093 -18 5.37 -19 1.70 -20 2.01 -21 0.92 -22 1.44 -1 0.10 -2 0.058 -3 0.093 -4 1.81 -5 4.30 -6 0.74 -7 1.05 -8 8.49 -9 11.58 -10 7.12 -11 0.061 -12 6.53 -13 0.95 -14 0.087 -15 0.46 -16 1.03 -1 1.42 -2 3.81 -3 0.068 -4 1.04 -5 10.02 -6 0.13 -7 8.22 -8 5.80 -9 2.71 -10 4.15 -11 0.18 -12 2.05 -13 0.67 -14 2.30
The results show that compound I-1 etc. have strong affinity to D.sub.3 receptor, which is comparable to that of the positive drug RGH-18. It is shown in combination with the results of Example 79 that, the compounds of this class also possess good D.sub.3/D.sub.2 receptor selectivity.

EXAMPLE 81

5-HT1A Receptor Binding Test

(306) 1. Experimental Materials:

(307) The isotopic ligand of 5-H.sub.1A receptor [.sup.3H]0.8-OH-DPAT (purchased from PE Corporation), (+)5-hydroxytryptamine (purchased from Sigma Corporation), GF/B glassfiber filter (purchased from Whatman Corporation), fat-soluble scintillation fluid: PPO and POPOP (purchased from Shanghai No. 1 Reagent Factory), toluene (purchased from Sinopharm Chemical Reagent Co., Ltd), and Tris (imported and subpackaged).

(308) Cells: HEK-293 cells stably expressing 5-HT.sub.1A receptors as obtained by gene recombination are cultured for 3-5 days in cell culture medium DMEM supplemented with 10% serum. The cells are collected with PBS and centrifuged at 4 C. and 3000 rpm for 10 min, the supernatant is then discarded, and the cell pellets are collected, preserved in refrigerator at 80 C., and resuspended with D.sub.1 Binding Buffer (pH 7.4) before use.

(309) 2. Experimental Methods:

(310) Competitive inhibition ratio of each compound at the concentration of 10 mol/L to inhibit the binding of [.sup.3H]8-OH-DPAT to 5-HT.sub.1A receptor is determined for primary screening.

(311) Compounds with an inhibition ratio of over 95% are subjected to the receptor binding test at a series of concentrations so as to determine half maximal inhibitory concentration (IC.sub.50, the concentration of the compound required for inhibiting 50% binding of [.sup.3H]8-OH-DPAT to 5-HT.sub.1A receptor). Each concentration is tested in duplicate, and tests are carried out independently twice for each compound.

(312) TABLE-US-00006 Total binding tube [.sup.3H].8-OH-DPAT 20 L D.sub.1 Binding Buffer 20 L Cells 160 L Non-specific tube [.sup.3H].8-OH-DPAT 20 L 5-HT(10.sup.4) 20 L Cells 160 L Tube with the [.sup.3H].8-OH-DPAT 20 L compound to be tested The compound to be tested 20 L Cells 160 L

(313) The components are mixed to homogeneity, and then the above tubes are transferred to water bath at 30 C. (1 h), removed into ice bath immediately, and suction filtered on Harvest (with ice cold Tris eluate for 5 times). The filter membrane is dried over medium heat for 8 min, removed into a centrifuge tube (0.5 mL), added with scintillation fluid, and left standed for 30 min before measurement.
1%=(total binding CPMthe tested compound CPM)/(total binding CPMnon-specific CPM)100%
Ki=IC.sub.50/(1+[L]/K.sub.D) (Ki: the affinity of the drug to the receptor, L: the concentration of the radioligand, K.sub.D: the value of the affinity of the radioligand to the receptor)

(314) The results of the 5-HT.sub.1A receptor binding test are shown in Table 3 below.

(315) TABLE-US-00007 TABLE 3 Affinity of the compound to 5-HT.sub.1A receptor (Ki: nmol) No. Ki value I-1 1.30 I-2 1.10 I-3 0.52 I-4 7.60 I-5 8.96 I-6 3.54 I-7 4.01 I-8 10.23 I-9 1.78 I-10 5.19 I-11 2.84 I-12 3.62 I-13 4.07 I-14 9.02 I-15 8.45 I-16 6.20 I-17 0.98 I-18 7.55 I-19 1.37 I-20 3.06 I-21 3.78 I-22 6.95 I-23 5.48 I-24 10.11 -1 3.30 -2 7.58 -3 2.87 -4 5.79 -5 10.64 -6 17.15 -7 6.08 -8 3.96 -9 2.10 -10 7.09 -11 18.37 -12 1.99 -13 8.66 -14 12.75 -15 7.19 -16 4.48 -17 6.71 -18 2.54 -19 7.03 -20 5.19 -21 8.50 -22 2.02 -1 1.14 -2 0.20 -3 4.72 -4 3.95 -5 1.69 -6 0.58 -7 2.10 -8 3.93 -9 5.12 -10 9.30 -11 0.79 -12 2.63 -13 1.76 -14 2.55 -15 0.97 -16 2.14 -1 3.65 -2 8.03 -3 1.79 -4 2.64 -5 14.81 -6 4.60 -7 10.79 -8 3.92 -9 2.88 -10 9.07 -11 5.30 -12 5.14 -13 4.83 -14 6.09

(316) The results show that compound I-1 etc. have strong affinity to 5-HT.sub.1A receptor, which is comparable to that of RGH-188.

EXAMPLE 82

5-HT2A Receptor Binding Test

(317) 1. Experimental Materials

(318) (1) 5-HT.sub.2A Cell Transfection:

(319) This experiment utilizes the plasmid vector containing the gene of the 5-HT.sub.2A receptor protein for transfecting HEK293 cells by calcium phosphate transfection method. By culturing the transfected cells in culture medium containing G418 and selecting cell clones followed by radioligand binding test, a stable cell strain capable of expressing the 5-HT.sub.2A receptor protein stably is finally obtained.

(320) (2) Materials for the Receptor Binding Test:

(321) Isotopic ligand [.sup.3H]-Ketanserin (67.0 Ci/mmol) purchased from PerkinElmer Corporation; (+) spiperone purchased from RBI Corporation; GF/B glassfiber filter purchased from Whatman Corporation; imported and subpackaged Tris; PPO and POPOP purchased from Shanghai No. 1 Reagent Factory; and fat-soluble scintillation fluid. Beckman LS-6500 multifunction liquid scintillation counter.

(322) 2. Experimental Methods

(323) HEK-293 cells are infected with the recombinant viruses containing various genes. 48-72 h later, receptor proteins are massively expressed on the membrane. The cells are centrifuged at 1000 rpm for 5 min, then the culture supernatant is discarded and the cell pellets are collected, preserved in refrigerator at 20 C., and resuspended with Tris-HCl reaction buffer (PH 7.7) before use.

(324) Competitive receptor binding test: the compound to be tested, the radioligand (10 l for each) and the receptor protein (80 l) are added to a reaction tube, wherein the compound to be tested and the positive drug both have the final concentration of 10 mol/L. After being incubated in water bath at 37 C. for 15 min, the tube is immediately transferred to ice bath to stop the reaction. The mixture is subjected to rapid suction filtration through GF/B glassfiber filter on Millipore cell sample collector, washed with eluent (50 mM Tris-HCl, PH 7.7) (3 ml3) and dried in microwave oven for 8-9 min. The filter is transferred to a centrifuge tube (0.5 mL), added with 500 L fat-soluble scintillation fluid, left in the dark for over 30 min, and counted to determine the radioactivity intensity. The percentage inhibition ratio for each compound to inhibit the isotopic ligand binding is calculated with the following equation:
inhibition ratio (1%)=(total binding tube CPMcompound CPM)/(total binding tube CPMnon-specific binding tube CPM)100%

(325) Each compound is tested in duplicate, and the tests are carried out independently twice.

(326) Compounds with an inhibition ratio of over 95% are subjected to the receptor binding test at a series of concentrations so as to determine half maximal inhibitory concentration (IC.sub.50, the concentration of the compound required for inhibiting 50% binding of [.sup.3H]-Ketanserin to 5-HT.sub.2A receptor). Each concentration is tested in duplicate, and tests are carried out independently twice for each compound.

(327) Ki=IC.sub.50/(1+[L]/K.sub.D) (Ki: the affinity of the drug to the receptor, L: the concentration of the radioligand, K.sub.D: the value of the affinity of the radioligand to the receptor)

(328) The results of the 5-HT.sub.2A receptor binding test are shown in Table 4 below.

(329) TABLE-US-00008 TABLE 4 Affinity of the compound to 5-HT.sub.2A receptor (Ki: nmol) No. Ki value I-1 0.23 I-2 0.15 I-3 0.29 I-4 0.64 I-5 0.86 I-6 0.72 I-7 1.03 I-8 2.55 I-9 1.28 I-10 3.79 I-11 2.01 I-12 2.89 I-13 4.90 I-14 3.52 I-15 2.65 I-16 1.12 I-17 1.02 I-18 1.87 I-19 0.98 I-20 0.57 I-21 0.81 I-22 1.33 I-23 1.78 I-24 2.00 -1 0.30 -2 1.06 -3 0.44 -4 0.88 -5 0.69 -6 1.47 -7 2.10 -8 1.96 -9 2.01 -10 5.58 -11 3.39 -12 5.20 -13 0.93 -14 4.62 -15 1.29 -16 0.50 -17 1.01 -18 0.74 -19 2.05 -20 1.83 -21 3.97 -22 1.65 -1 1.16 -2 0.53 -3 3.09 -4 2.28 -5 1.63 -6 0.66 -7 1.42 -8 4.96 -9 8.01 -10 12.50 -11 0.37 -12 2.58 -13 0.60 -14 1.23 -15 0.89 -16 0.76 -1 0.83 -2 4.21 -3 0.49 -4 1.04 -5 8.93 -6 2.36 -7 10.69 -8 1.07 -9 2.84 -10 5.01 -11 0.91 -12 2.40 -13 1.27 -14 1.82

(330) The results show that compound I-1 etc. have strong affinity to 5-HT.sub.2A receptor.

(331) Summary of the Results of the Above In Vitro Receptor Binding Tests:

(332) Compound I-1 etc. have strong affinity to 5-HT.sub.1A and D.sub.3 receptor (Ki<10 nmol), which is similar to that of RGH-188; and strong affinity to 5-HT.sub.2A receptor, which is obviously superior to that of RGH-188. Such compounds have strong or moderate affinity to D.sub.2 receptor, and most of the compounds have a D.sub.3/D.sub.2 receptor selectivity of greater than 10:1, which is superior to that of RGH-188 (with a selectivity of less than 10:1), indicating that such compounds have the potential of improving cognitive impairment, while the side effect may be lower than that of RGH-188.

(333) The results of the affinity of the preferred compounds to four receptors are shown in Table 5 below.

(334) TABLE-US-00009 TABLE 5 Affinities of compound I-1 etc. and RGH-188 to D.sub.2, D.sub.3, 5-HT.sub.1A, and 5-HT.sub.2A receptors (Ki: nmol) No. D.sub.2 D.sub.3 5-HT.sub.1A 5-HT.sub.2A I-1 2.90 0.13 1.30 0.23 I-2 0.19 0.056 1.10 0.15 I-3 0.21 0.31 0.52 0.29 I-4 0.43 0.029 7.60 0.64 I-5 0.32 0.078 8.96 0.86 I-6 1.81 0.035 3.54 0.72 I-7 4.65 3.21 4.01 1.03 I-8 18.71 2.78 10.23 2.55 I-9 2.57 1.43 1.78 1.28 I-10 5.04 6.98 5.19 3.79 I-11 4.81 0.37 2.84 2.01 I-12 3.15 1.02 3.62 2.89 I-13 1.78 1.42 4.07 4.90 I-14 9.43 2.86 9.02 3.52 I-15 21.34 4.03 8.45 2.65 I-16 1.05 1.87 6.20 1.12 I-17 0.27 0.10 0.98 1.02 I-18 0.23 0.18 7.55 1.87 I-19 0.82 0.25 1.37 0.98 I-20 1.20 0.19 3.06 0.57 I-21 2.96 0.84 3.78 0.81 I-22 1.90 0.071 6.95 1.33 I-23 1.73 1.04 5.48 1.78 I-24 10.75 3.80 10.11 2.00 -1 0.43 0.043 3.30 0.30 -2 3.07 0.57 7.58 1.06 -3 1.98 0.062 2.87 0.44 -4 1.69 1.03 5.79 0.88 -5 0.58 0.085 10.64 0.69 -6 3.62 2.76 17.15 1.47 -7 8.54 8.19 6.08 2.10 -8 10.75 4.51 3.96 1.96 -9 7.38 1.73 2.10 2.01 -10 17.12 7.09 7.09 5.58 -11 9.76 3.60 18.37 3.39 -12 8.82 1.99 1.99 5.20 -13 4.50 0.85 8.66 0.93 -14 6.49 9.37 12.75 4.62 -15 3.03 2.18 7.19 1.29 -16 1.75 0.23 4.48 0.50 -17 2.94 0.093 6.71 1.01 -18 1.22 5.37 2.54 0.74 -19 1.78 1.70 7.03 2.05 -20 6.40 2.01 5.19 1.83 -21 1.01 0.92 8.50 3.97 -22 2.09 1.44 2.02 1.65 -1 1.18 0.10 1.14 1.16 -2 0.71 0.058 0.20 0.53 -3 8.67 0.093 4.72 3.09 -4 3.26 1.81 3.95 2.28 -5 11.84 4.30 1.69 1.63 -6 3.19 0.74 0.58 0.66 -7 1.93 1.05 2.10 1.42 -8 2.07 8.49 3.93 4.96 -9 4.33 11.58 5.12 8.01 -10 12.41 7.12 9.30 12.50 -11 1.60 0.061 0.79 0.37 -12 5.73 6.53 2.63 2.58 -13 2.54 0.95 1.76 0.60 -14 2.26 0.087 2.55 1.23 -15 1.97 0.46 0.97 0.89 -16 0.98 1.03 2.14 0.76 -1 1.06 1.42 3.65 0.83 -2 9.15 3.81 8.03 4.21 -3 0.88 0.068 1.79 0.49 -4 0.80 1.04 2.64 1.04 -5 6.77 10.02 14.81 8.93 -6 1.45 0.13 4.60 2.36 -7 14.82 8.22 10.79 10.69 -8 0.92 5.80 3.92 1.07 -9 3.01 2.71 2.88 2.84 -10 3.64 4.15 9.07 5.01 -11 1.40 0.18 5.30 0.91 -12 1.86 2.05 5.14 2.40 -13 1.02 0.67 4.83 1.27 -14 2.07 2.30 6.09 1.82 RGH-188 0.78 0.09 2.16 20.50

EXAMPLE 83

In Vivo Anti-Schizophrenia Activity Tests for the Compounds

(335) 1. Apomorphine Model:

(336) (1) Establishment of Apomorphine-Induced Schizophrenic Mouse Model

(337) 96 inbred C57BL/6 mice, half male and half female, are randomly divided into 8 groups for weight balance: a blank control group, a model control group, groups of the compounds as recited in the claims in gradient dosages (0.12, 0.22, 0.35, 0.40, and 0.90 mg.Math.kg.sup.1) and RGH-188 group (0.40 mg.Math.kg.sup.1). The drugs are administered by gastric gavage. The model control group is given the same volume of solvent by gastric gavage. 30 min after the administration of the compound to be tested, apomorphine solution (dissolved in 0.1% ascorbic acid) is intraperitoneally injected at 10.0 mL.Math.kg.sup.1 body weight of mice to induce the establishment of the schizophrenic mouse model.

(338) (2) Observation of Stereotyped Behaviors

(339) After apomorphine is administered to the mice, the mice are observed as to whether stereotyped behaviors such as tail erection and wall-climbing etc. appear during the first 30 seconds of the periods of 6-10, 11-15, 16-20, 21-25, 26-30, 31-35, 36-40, 41-45, 46-50, 51-55, and 56-60 min, and are scored according to the following standards: 0, indicating no behaviors as stated above are observed in the 30 seconds (t<1 sec); 1, indicating discontinuous and moderate behaviors as stated above are observed in the 30 seconds (1 sec<t<3 sec); and 2, indicating continuous and intense behaviors as stated above are observed in the 30 seconds (t>3 sec). Total score of the stereotyped behaviors of the mice such as tail erection and wall-climbing in the 60 minutes is calculated. Calculation of ED.sub.50: improvement ratio=(score of the stereotyped behaviors in the model control groupscore of the stereotyped behaviors in the administration group)/score of the stereotyped behaviors in the model control group100%, which is fitted into a regression equation for calculating ED.sub.50.

(340) (3) Administration and Post-Administration Observation

(341) Mice are weighed on the day of administration, and the dosage is determined according to the body weight. The clinical response symptoms of the animals shall be recorded during the administration and test procedures.

(342) (4) Statistical Method

(343) All the data are presented in xSD and processed with SPSS 17.0 software. The means of two samples are compared with t test and one-way ANOVA. p<0.05 indicates significant difference.

(344) (5) Experimental Results

(345) Detailed results are shown in Table 6Table 8.

(346) TABLE-US-00010 TABLE 6 Effects of the single oral administration of compound I-6 on the total stereotyped behaviors in the Apo.-induced schizophrenic mouse model Score of Dosages stereotyped Improvement Group n (mg .Math. kg.sup.1) behaviors ratio (%) Blank control 12 0.17 0.39 group Model control 12 26.33 5.26** group RGH-188 group 12 0.40 6.41 3.16 75.64 I-6 group 12 0.12 23.02 8.32 12.59 I-6 group 12 0.22 15.52 6.25.sup.# 41.07 I-6 group 12 0.35 5.48 4.61.sup.## 79.48 I-6 group 12 0.40 4.01 3.65.sup.## 84.80 I-6 group 12 0.90 0.71 0.94.sup.## 97.29 *P < 0.05, **P < 0.01, compared with the blank control group; .sup.#P < 0.05, .sup.##P < 0.01, compared with the model control group

(347) The inhibition of the stereotyped behaviors of the mice caused by compounds I-1, I-4, and I-22 in this model is determined by the same method at reasonably designed administration dosages. Detailed results can be found in

(348) TABLE-US-00011 TABLE 7 Inhibition of the total stereotyped behaviors in Apo.-induced schizophrenic mouse model by the single oral administration of compounds I-1, I-4, I-6 and I-22 Compound ED.sub.50 (mg/Kg) I-1 0.28 I-4 0.37 I-6 0.23 I-22 0.59

(349) The inhibition of the stereotyped behaviors of the mice caused by the compounds of , , and class in this model is determined by the same method at reasonably designed administration dosages. Detailed results can be found in Table 8.

(350) TABLE-US-00012 TABLE 8 ED.sub.50 values of the representative compounds of other classes in this model Compound ED.sub.50 (mg/Kg) Compound ED.sub.50 (mg/Kg) -1 0.20 -11 0.10 -3 0.30 -14 0.45 -5 0.64 -3 0.12 -17 0.38 -6 0.48 -3 0.76 -11 0.53

(351) The results of this test show that: As compared with the blank control group, the model control group shows significantly increased total stereotyped behaviors (P<0.01), indicating that apomorphine induces the development of schizophrenic symptoms in mice. As compared with the model control group, the positive drug RGH-188 and the compounds as recited in the claims all can significantly reduce the stereotyped behaviors in mice, and thus the compounds of the present invention have great effect of treating schizophrenic positive symptoms, given that the apomorphine-induced schizophrenia mnodel is a classical model for the positive symptoms of schizophrenia. At the same dosage (0.40 mg/Kg), compound I-6 has a greater improvement ratio than RGH-188 for the stereotyped behaviors in mice, indicating a better in vivo activity of compound I-6 than that of RGH-188.

(352) 2. MK-801 Model:

(353) (1) Establishment of MK-801-Induced Schizophrenic Mouse Model

(354) 80 inbred C57BL/6 mice, half male and half female, are randomly divided into 8 groups for gender and weight balance: a blank control group, a model control group, RGH-188 (0.05 mg/Kg) control group, and groups of the compounds as recited in the claims in gradient dosages (0.02, 0.03, 0.05, 0.09, and 0.15 mg/kg). Each animal is conditioned in a soundproof box for 30 min on the day before the experiment. On the next day, 30 min after the administration of the compound to be tested, 0.025 mg/mL MK-801 solution is intraperitoneally injected at 10.0 mL/kg body weight of mice to induce the establishment of the schizophrenic mouse model. The blank control group is intraperitoneally injected with the same volume of normal saline.

(355) (2) Observation of Open-Field Movement

(356) After MK-801 is administered, the mouse is placed into the soundproof box immediately, and the total distance of spontaneous movement of the mouse in 60 min is observed and recorded.
Improvement ratio=(the total distance of movement in the model control groupthe total distance of movement in the administration group)/(the total distance of movement in the model control group)*100%

(357) A regression equation is obtained according to the above equation, and ED.sub.50 is obtained by calculation.

(358) (3) Experiment Observation

(359) Mice are weighed on the day of administration, and the dosage is determined according to the body weight. The clinical response symptoms of the animals are recorded during the test procedure.

(360) (4) Statistical Method

(361) All the data are presented in xSD and processed with SPSS 17.0 software. The means of two samples are compared with t test and one-way ANOVA. p<0.05 indicates significant difference.

(362) (5) Experimental Results

(363) Detailed results are shown in Table 9Table 1.

(364) TABLE-US-00013 TABLE 9 Effects of the single oral administration of compound I-6 on the total distance of the open-field movement in the MK-801-induced schizophrenic mouse model (x SD) Total distance of the spontaneous Animal Dosages movement Improvement Group number (mg/kg) (cm) ratio (%) Normal 10 10112.28 3186.36 control group Model 10 28896.87 6547.22** control group RGH-188 10 0.05 15847.04 7432.19 45.16 group I-6 group 10 0.02 19482.27 11047.75 32.58 I-6 group 10 0.03 17280.33 9364.31 40.20 I-6 group 10 0.05 11145.52 6988.56.sup.# 61.43 I-6 group 10 0.09 7796.38 4382.94.sup.## 73.02 I-6 group 10 0.15 3360.71 734.45.sup.## 88.37 *P < 0.05, **P < 0.01, compared with the normal control group; .sup.#P < 0.05, .sup.##P < 0.01, compared with the model control group

(365) TABLE-US-00014 TABLE 10 Effects of the single oral administration of compounds I-1, I-4, I-6, and I-22 on the total distance of the open-field movement in the MK-801-induced schizophrenic mouse model (ED.sub.50 ) Compound ED.sub.50 (mg/Kg) I-1 0.052 I-4 0.073 I-6 0.038 I-22 0.062

(366) The effects of the representative compounds of , , and classes on the open-field movement in mice are determined in this model by the same method at reasonably designed administration dosages.

(367) TABLE-US-00015 TABLE 11 ED.sub.50 values of the representative compounds of other classes in this model Compound ED.sub.50 (mg/Kg) Compound ED.sub.50 (mg/Kg) -1 0.074 -11 0.092 -3 0.047 -14 0.058 -5 0.088 -3 0.11 -17 0.053 -6 0.084 -3 0.061 -11 0.060

(368) The results of the test show that: As compared with the blank control group, MK-801 ip. can successfully induce significantly increased distance of the open-field movement in mice, indicating that MK-801 can induce the development of schizophrenic symptoms in mice. As compared with model group, RGH-188 and the compounds as recited in the claims can significantly improve the total distance of the open-field movement in mice, and thus the compounds of the present invention have great effect of treating schizophrenic negative symptoms, given that the open-field movement model induced by MK-801 is a conventional model for the negative symptoms of schizophrenia. At the same dosage (0.05 mg/Kg), compound I-6 has a greater improvement ratio than RGH-188 for the open-field movement in mice, indicating a better activity of compound I-6 than that of RGH-188 in this model.

EXAMPLE 84

(369) Acute toxicity tests for compounds I-1, I-4, I-6, and I-22

(370) (1) Experimental Scheme Toxicity symptoms and death in the ICR mice after the oral administration of RGH-188, compound I-1 etc. are observed for comparing the acute toxicity. Vehicle preparation: an appropriate amount of tween-80 is weighed and diluted with deionized water to a concentration of 5% (g/v) tween-80. Administration preparation: the compounds to be tested are weighed, respectively, and formulated into suspensions at concentrations of 6.25, 12.50, 25.00, 50.00 and 100.00 mg/mL (corresponding to 125, 250, 500, 1000, 2000 mg/kg, respectively) with 5% tween-80 solution. Administration route: the administration routes for the compounds to be tested and the vehicle control group (0.5% tween-8) are both through oral administration. Administration frequency: single administration, fasted overnight before administration. Administration capacity: 20 mL/Kg.

(371) Observation of general symptoms: the animals are observed at about 0.5, 1, 2, 4, and 6 hours respectively, after the first administration on the first day, and observed twice a day, one in the morning and one in the afternoon, on the second to the sixth day. Observed objects include but are not limited to general condition, behavior activity, gait and posture, eye, mouth, nose, gastrointestinal tract, skin and hair, and genitourinary tract. (2) Statistical Analysis

(372) Body weight is expressed in meanSD. Comparison among groups is carried out with Levene's test and one-way ANOVA, followed by Dunnet t test if there exists a difference.

(373) (3) Experimental Results are Shown in Table 12

(374) TABLE-US-00016 TABLE 12 Results of the aute toxicity tests for single oral administration of compounds I-1, I-4, I-6, I-22 and RGH-188 Tested compound LD.sub.50 (mg/Kg) I-1 1670 mg/Kg I-4 >2000 mg/Kg I-6 >2000 mg/Kg I-22 1530 mg/Kg RGH-188 760 mg/Kg

(375) The results show that among the above tested compounds, compounds I-4 and I-6 both have the LD.sub.50 of greater than 2000 mg/kg, indicating their acute toxicity is far below that of RGH-188 (760 mg/kg), and compounds I-1 and I-22 have the LD.sub.50 values of 1670 mg/Kg and 1530 mg/Kg, respectively, indicating a better safety than that of RGH-188.

EXAMPLE 85

(376) Acute toxicity tests for the representative compounds of II, III, and IV classes

(377) (1) The acute toxicity of the representative compounds of , , classes is investigated with the method of Example 81.

(378) (2) Experimental results are shown in Table 13

(379) TABLE-US-00017 TABLE 13 Results of the acute toxicity tests for single oral administration of the representative compounds of , , classes and RGH-188 Tested Tested compound LD.sub.50 (mg/Kg) compound LD .sub.50 (mg/Kg) -1 >2000 mg/Kg -14 1080 mg/Kg -3 >2000 mg/Kg -3 >2000 mg/Kg -5 1105 mg/Kg -6 1390 mg/Kg -17 1860 mg/Kg -11 >2000 mg/Kg -3 >2000 mg/Kg RGH-188 760 mg/Kg -11 1240 mg/Kg

(380) The results show that among the above tested compounds, compounds -1, -3, -3, -3, and -11 all have the LD.sub.50 of greater than 2000 mg/Kg, indicating their acute toxicity is far below that of RGH-188 (760 mg/Kg), and compounds -5, -17, -11, -14, -6 have the LD.sub.50 values of 1105 mg/Kg, 1860 mg/Kg, 1240 mg/Kg, 1080 mg/Kg and 1390 mg/Kg, respectively, indicating a better safety than that of RGH-188.

EXAMPLE 86

(381) Bacterial Reverse Mutation Tests for Compounds I-1, I-4, I-6, and I-22

(382) Compounds I-1, RGH-188 etc. are investigated by the reverse mutation test with histidine-auxotrophic strains of salmonella typhimurium as to whether they lead to a gene mutation, so as to evaluate their potential mutagenicity.

(383) (1) Formulation Method

(384) 0.0303 g compound to be tested is accurately weighed before use, and completely dissolved in a certain amount of the solvent DMSO under a sterile and ultrasonic condition to formulate a solution with the highest concentration of 100000.0 g/mL, which is then serially diluted at a 1:2 (v/v) ratio to obtain solutions of 9 different concentrations, i.e. 33333.0, 11111.0, 3704.0, 1235.0, 412.0, 137.0, 46.0 and 15.0 g/mL.

(385) (2) Negative Control DMSO

(386) (3) Positive Control

(387) TABLE-US-00018 Without metabolic With metabolic activation system (S9) activation system (+S9) Batch Final Batch Final Strain Name Company number concentration Name Company number concentration TA98 2-nitrofluorene Aldrich 09213BA 4 g/well 2-aminoanthracene Aldrich 15216JA 0.6 g/well TA100 sodium Sigma 043K0056 0.4 g/well 2-aminoanthracene Aldrich 15216JA 0.6 g/well azide

(388) (4) Strains

(389) Histidine-auxotrophic mutant strains TA98 and TA100 of Salmonella typhimurium are purchased from MolTox Corporation, under the batch numbers of 4367D and 4370D, respectively.

(390) (5) Metabolic Activation System

(391) The metabolic activation system (S9) is purchased from MolTox Corporation, with the specification of 2 mL/bottle, the batch number of 2548, and the protein content of 38.5 mg/mL. It is the liver homogenate of the SD male rate induced with 500 mg/kg polychlorobiphenyl (Aroclor 1254).

(392) S9, coenzyme , glucose-6-phosphate, etc. are mixed to form the hepatic microsomal enzyme system (S9 mixture) before use.

(393) (6) Official Experiment

(394) The official experiment consists of two parallel tests with or without the metabolic activation system. By a standard plate incorporation method, the melted top layer culture medium (500 L) containing 0.6% agar, 0.5% NaCl, 0.5 mM biotin and 0.5 mM histidine is mixed with the following materials: the solution of the compound to be tested (or negative/positive control) (20 L) overnight culture broth (25 L) S9 mixture solution or 0.2 M sodium phosphate buffer (pH=7.4) (100 L),

(395) The mixture is shaken to homogeneity, plated on a prefabricated V-B underlayer medium, coagulated at RM, and placed inversely and incubated in a 37 C. incubator for 72 h, and the results are observed. In the official experiment, negative and positive control groups are provided for each strain, and each group is tested in duplicate wells.

(396) (7) Experimental Results

(397) Compounds I-1, 1-4, 1-6, I-22 and RGH-188 do not lead to obviously increased number of colonies with reverse mutations at any of the tested dosages, no matter there is S9 or not in the experimental system. Ames tests for all the tested compounds are negative.

EXAMPLE 87

(398) Bacterial reverse mutation tests for the representative compounds of , , and classes

(399) (1) The bacterial reverse mutation tests for compounds -1, -3, -5, -17, -3, -11, -14, -3, -6, and -11 are carried out with the method of Example 87.

(400) (2) Experimental Results

(401) Compounds -1, -3, -5, -17, -3, -11, -14, -3, -6, -11 and RGH-188 do not lead to obviously increased number of colonies with reverse mutations at any of the tested dosages, no matter there is S9 or not in the experimental system. Ames tests for all the tested compounds are negative.