N-aromatic amide compounds, preparation methods and uses thereof

Abstract

The present invention relates to N-aromatic amide compounds with formula (I) and/or (II) and preparation methods therefor, pharmaceutical compositions and pharmaceutical formulations containing the compounds with formula (I) and/or (II), and use of the compounds with formula (I) and/or (II) in preparing a medicament for the treatment of diseases related to androgens. The definitions of R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, W.sub.1, W.sub.2, W.sub.3, W.sub.4 and W.sub.5 in the formula are the same as those in the description. The compounds with the formula (I) and/or (II) are capable of binding to the androgen receptors and have activity for anti-androgen and degrading androgen receptor. The compounds can be used alone or as compositions for the treatment of various androgen-related diseases such as prostate cancer, prostate hyperplasia, breast cancer, bladder cancer, ovarian cancer and the like, and also for the treatment of acne, hirsutism, psilosis and other diseases. ##STR00001##

Claims

1. An N-aromatic amide compound of formula (IV) or a pharmaceutically acceptable salt or stereoisomer thereof: ##STR00101## wherein each of R.sub.1 and R.sub.2 is cyano group, nitro group, or trifluoromethyl group; each of R.sub.3 and R.sub.4 is C.sub.1-C.sub.6 alkyl group, or R.sub.3 and R.sub.4 together with carbon atom through which R.sub.3 and R.sub.4 are bound constitute a 3-6 membered cycloalkyl group; each of R.sub.5 and R.sub.6 is hydrogen atom, halogen, trifluoromethyl group, cyano group, nitro group, acetyl group, ##STR00102##  N-methylcarbamoyl group, C.sub.1-C.sub.6 alkyl group, aryl group or substituted aryl group; W.sub.1 is carbon atom or nitrogen atom; and each of R.sub.5 and R.sub.6 is bound to any bondable site of the group ##STR00103##

2. The N-aromatic amide compound or the pharmaceutically acceptable salt or stereoisomer thereof according to claim 1, wherein a stereoisomer of the compound is a racemic, levorotatory and/or dextrorotatory isomer.

3. The N-aromatic amide compound or the pharmaceutically acceptable salt or stereoisomer thereof according to claim 1, wherein the compound is selected from the group consisting of: ##STR00104## ##STR00105## ##STR00106##

4. A pharmaceutical composition, comprising the N-aromatic amide compound or the pharmaceutically acceptable salt or stereoisomer thereof according to claim 1.

Description

DESCRIPTION OF THE EMBODIMENTS

(1) The invention is further described in detail below by way of examples, which clearly represent only a part of the invention, instead of all of the invention. These examples are merely illustrative of the present invention and should not be understood as limitation to the protection scope of the invention. Based on the examples of the present invention, all other technical solutions obtained by those skilled in the art without paying creative labor are within the protection scope of the invention.

(2) In the examples, the abbreviation THF stands for tetrahydrofuran, DMSO-d.sub.6 stands for dimethyl sulfoxide-d6, DMSO stands for dimethyl sulphoxide, CDCl.sub.3 stands for deuterated chloroform, eq stands for equivalent weight, HPLC stands for high pressure liquid chromatography, PPh.sub.3 stands for triphenyl phosphine, PCy.sub.3 stands for tricyclohexyl phosphine, K.sub.3PO.sub.4 stands for potassium phosphate tribasic, DMF stands for dimethylformamide, Pd(PPh.sub.3).sub.4 stands for trtrakis(triphenyl phosphine)palladium, and DME stands for 1,2-dimethoxyethane.

(3) The .sup.1H NMR is determined by a Bruker AVANCE II 400 MHz NMR apparatus, wherein s stands for single peak, bs or brs stands for broad single peak, d stands for double peak, m stands for multiple peak, and Ar stands for aryl. Mass spectrum is determined by a Bruker amaZon SL Mass spectrometer. High resolution mass spectrum is determined by a Waters Acquity HPLC+Xeno G2-S TOF Mass. High pressure liquid chromatography is determined by a SHIMADZU CBM-20A. Thin layer chromatography is determined by a 60F254 silica gel plate (Merck).

I. EXAMPLES FOR PREPARING COMPOUNDS

Example 1

Preparation of N-(4-cyano-3-trifluoromethyl)-phenyl-2-[4-fluoro-6-(4-fluorophenyl)-1H-indolyl-1-yl]-2-methylpropanamide

(4) ##STR00038##

(5) First Step of Reaction

(6) Thionyl chloride (2.62 ml, 35.93 mmol, 1.2 eq) is added dropwise to a solution of 2-bromo-2-methyl propionic acid (5.00 g, 29.94 mmol) in 30 ml of anhydrous tetrahydrofuran (THF) at a temperature ranging from 0 to 12 Celsius degrees in 10 minutes. The resulting mixture is stirred under the same conditions for 2 hours. The internal temperature is adjusted to about −5 Celsius degrees. Triethylamine (Et.sub.3N) (5.42 ml, 38.92 mmol, 1.3 eq) is slowly added to the reaction mixture, with an internal temperature lower than 12 Celsius degrees. The resulting mixture is stirred under the same reaction conditions for 20 minutes, and a solution of 4-cyano-3-trifluoromethyl-phenylamine (5.57 g, 29.94 mmol) in 30 mL of anhydrous tetrahydrofuran is then added dropwise thereto, and the resulting mixture is stirred at 50 Celsius degrees for two hours. After the reaction is completed as determined by thin layer chromatography, the reaction mixture is cooled to 20±5 Celsius degrees, water (50 ml) and ethyl acetate (50 ml) are then added thereto. The resulting mixture is shortly stirred and separated, with the organic phase washed by salt solution (30 ml), dried by magnesium sulphate, filtered, and with the resulting organic phase dried by suction to obtain an oily substance. The oily substance is separated and purified by silica gel column chromatography (mobile phase: hexane:ethyl acetate=2:1) to obtain 8.68 g of 2-bromo-N-(4-cyano-3-trifluoromethyl-phenyl)-2-methylpropanamide, with a yield of 86.8% and a purity of 99% by HPLC (mobile phase: water and acetonitrile) (254 nm).

(7) Nuclear magnetic resonance spectrum: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.57 (s, 1H, NH), 8.38 (s, 1H, ArH), 8.24 (d, J=8.4 Hz, 1H, ArH), 8.15 (d, J=8.4 Hz, 1H, ArH), 2.01 (s, 6H, 2×CH.sub.3).

(8) Mass spectrum: (ESI, Positive): 335.00[M+H].sup.+.

(9) Second Step of Reaction

(10) 6-bromo-4-fluoro-1H-indole (1.00 g, 4.672 mmol) is added to a suspension of tetrakis (triphenyl phosphine) palladium ([Pd(PPh.sub.3).sub.4] (0.54 g, 0.4672 mmol) in 20 ml of dimethoxyethane (DME). The resulting mixture is stirred under argon at room temperature for 15 minutes. A solution of 4-fluoro-phenylboronic acid (0.66 g, 4.672 mmol) in 2.5 ml of ethanol is added to the above reaction mixture, and the resulting mixture is stirred under the same conditions for 10 minutes. Potassium carbonate (0.92 g, 7.008 mmol) is then dissolved in 2.0 ml of water and added to the above reaction mixture. The resulting reaction mixture is heated to reflux under argon for 2-3 hours. After the reaction is completed as determined by thin layer chromatography, salt solution (20 ml) and ethyl acetate (30 ml) are added to the reaction mixture. The resulting mixture is shortly stirred and separated, with the organic phase washed by salt solution (15 ml), dried by magnesium sulphate, filtered, and with the resulting organic phase dried by suction to obtain an oily substance. The oily substance is separated and purified by silica gel column chromatography (mobile phase: hexane:ethyl acetate=3:1) to obtain 0.66 g of brown powdery material, identified as 4-fluoro-6-(4-fluorophenyl)-1H-indole, with a yield of about 62%.

(11) Mass spectrum: (ESI, positive): 230.02[M+H].sup.+.

(12) The Third Step of Reaction

(13) In a 100 mL round bottom flask, 2-bromo-N-(4-cyano-3-trifluoromethyl-phenyl)-2-methylpropanamide (0.17 g, 0.500 mmol), 4-fluoro-6-(4-fluorophenyl)-1H-indole (0.22 g, 1.00 mmol), copper(I) bromide-dimethyl sulfide (11 mg, 0.05 mmol), triphenyl phosphine (PPh.sub.3) (13 mg, 0.05 mmol), and sodium hydroxide (22 mg, 0.56 mmol) are added, with 10 mL of anhydrous methylbenzene as solvent. The resulting mixture is heated to 50 Celsius degrees and stirred under argon for 12 hours. After the reaction is completed as determined by thin layer chromatography, the reaction mixture is cooled to 20±5 Celsius degrees, water (30 ml) and ethyl acetate (30 ml) are then added thereto. The resulting mixture is shortly stirred and separated, with the organic phase washed by salt solution (20 ml), dried by magnesium sulphate, filtered, and with the resulting organic phase dried by suction to obtain an oily substance. The oily substance is separated and purified by silica gel column chromatography (mobile phase: hexane:ethyl acetate=3:1 to 2:1) to obtain 73 mg of yellow powdery material, identified as N-(4-cyano-3-trifluoromethyl)-phenyl-2-[4-fluoro-6-(4-fluorophenyl)-1H-indolyl-1-yl]-2-methylpropanamide, with a yield of 30%.

(14) Nuclear magnetic resonance spectrum: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ10.43 (s, 1H, NH), 8.20 (d, J=2.0 Hz, 1H, ArH), 8.18-8.07 (m, 2H, ArH), 7.75 (d, J=3.6 Hz, 1H, indolyl-H), 7.52-7.48 (m, 2H, ArH), 7.27-7.22 (m, 2H, ArH), 7.17 (d, J=8.4 Hz, 1H, ArH), 7.14 (s, 1H, ArH), 6.68 (d, J=3.2 Hz, 1H, indolyl-H), 1.91 (s, 6H, 2×CH.sub.3).

(15) Mass spectrum: (ESI, Negative): 482.26 [M−H].sup.−.

Example 2

Preparation of N-(4-cyano-3-trifluoromethyl) phenyl-2-(5-fluoro-6-phenyl-1H-indolyl-1-yl)-2-methylpropanamide

(16) ##STR00039##

(17) First Step of Reaction

(18) The same as that of Example 1.

(19) Second Step of Reaction

(20) 6-bromo-5-fluoro-1H-indole (1.00 g, 4.672 mmol) is added to a suspension of tetrakis (triphenyl phosphine) palladium ([Pd(PPh.sub.3).sub.4] (0.54 g, 0.4672 mmol) in 20 ml of dimethoxyethane (DME). The resulting mixture is stirred under argon at room temperature for 15 minutes. A solution of phenylboronic acid (0.57 g, 4.672 mmol) in 2.5 ml of ethanol is added to the above reaction mixture, and the resulting mixture is stirred under the same conditions for 10 minutes. Potassium carbonate (0.97 g, 7.008 mmol) is then dissolved in 2.0 ml of water and added to the above reaction mixture. The resulting reaction mixture is heated to reflux under argon for 2-3 hours. After the reaction is completed as determined by thin layer chromatography, salt solution (20 ml) and ethyl acetate (30 ml) are added to the reaction mixture. The resulting mixture is shortly stirred and separated, with the organic phase washed by salt solution (15 ml), dried by magnesium sulphate, filtered, and with the resulting organic phase dried by suction to obtain an oily substance. The oily substance is separated and purified by silica gel column chromatography (mobile phase: hexane:ethyl acetate=3:1) to obtain 0.79 g of brown powdery material, identified as 5-fluoro-6-phenyl-1H-indole, with a yield of about 80%.

(21) Mass spectrum: (ESI, positive): 212.03[M+H].sup.+.

(22) The Third Step of Reaction

(23) In a 100 mL round bottom flask, 2-bromo-N-(4-cyano-3-trifluoromethyl-phenyl)-2-methylpropanamide (0.32 g, 0.9468 mmol), 5-fluoro-6-phenyl-1H-indole (0.40 g, 1.8937 mmol), copper(I) bromide-dimethyl sulfide (20 mg, 0.18937 mmol), triphenyl phosphine (25 mg, 0.18937 mmol), and sodium hydroxide (42 mg, 1.0415 mmol) are added, with 10 mL of anhydrous methylbenzene as solvent. The resulting mixture is heated to 50 Celsius degrees and stirred under argon for 12 hours. After the reaction is completed as determined by thin layer chromatography, the reaction mixture is cooled to 20±5 Celsius degrees, water (30 ml) and ethyl acetate (30 ml) are then added thereto. The resulting mixture is shortly stirred and separated, with the organic phase washed by salt solution (20 ml), dried by magnesium sulphate, filtered, and with the resulting organic phase dried by suction to obtain an oily substance. The oily substance is separated and purified by silica gel column chromatography (mobile phase: hexane:ethyl acetate=2:1) to obtain 0.11 g of light brown powdery material, identified as N-(4-cyano-3-trifluoromethyl)-phenyl-2-[5-fluoro-6-phenyl-1H-indolyl-1-yl]-2-methylpropanamide, with a yield of 25%.

(24) Nuclear magnetic resonance spectrum: .sup.1H NMR (400 MHz, DMSO-d.sub.6) 510.43 (s, 1H, NH), 8.26 (s, 1H, ArH), 8.14-8.08 (m, 2H, ArH), 7.77 (d, J=3.2 Hz, 1H, indolyl-H), 7.50 (d, J=11.6 Hz, 1H), 7.42-7.33 (m, 3H, ArH), 7.30 (s, 1H), 7.28 (d, J=7.2 Hz, 1H), 7.13 (d, J=6.4 Hz, 1H), 6.62 (d, J=2.8 Hz, 1H, indolyl-H), 1.89 (s, 6H, 2×CH.sub.3).

(25) Mass spectrum: (ESI, Negative): 464.36 [M−H].sup.−.

Example 3

Preparation of N-(4-cyano-3-trifluoromethyl)-phenyl-2-(5-fluoro-1H-indolyl-1-yl)-2-methylpropanamide

(26) ##STR00040##

(27) In a 100 mL round bottom flask, 2-bromo-N-(4-cyano-3-trifluoromethyl-phenyl)-2-methylpropanamide (0.20 g, 0.5968 mmol), 5-fluoro-1H-indole (0.16 g, 1.1963 mmol), copper(I) bromide-dimethyl sulfide (12.3 mg, 0.05868 mmol), triphenyl phosphine (15.7 mg, 0.05968 mmol), and sodium hydroxide (23.9 mg, 0.5968 mmol) are added, with 10 mL of anhydrous methylbenzene as solvent. The resulting mixture is heated to 50 Celsius degrees and stirred under argon for 12 hours. After the reaction is completed as determined by thin layer chromatography, the reaction mixture is cooled to 20±5 Celsius degrees, water (30 ml) and ethyl acetate (30 ml) are then added thereto. The resulting mixture is shortly stirred and separated, with the organic phase washed by salt solution (20 ml), dried by magnesium sulphate, filtered, and with the resulting organic phase dried by suction to obtain an oily substance. The oily substance is separated and purified by silica gel column chromatography (mobile phase: hexane:ethyl acetate=2:1) to obtain 0.13 g of light brown powdery material, identified as N-(4-cyano-3-trifluoromethyl)-phenyl-2-[5-fluoro-1H-indolyl-1-yl]-2-methylpropanamide, with a yield of 56%.

(28) Nuclear magnetic resonance spectrum: .sup.1H NMR (400 MHz, DMSO-d.sub.6) 510.29 (s, 1H, NH), 8.22 (d, J=2.0 Hz, 1H, ArH), 8.19 (dd, J=8.4 Hz, J=2.0 Hz, 1H, ArH), 8.09 (d, J=8.4 Hz, 1H, ArH), 7.71 (d, J=3.6 Hz, 1H, indolyl-H), 7.37 (dd, J=9.6 Hz, J=2.8 Hz, 1H), 7.12 (dd, J=9.2 Hz, J=4.0 Hz, 1H), 6.95 (dt, J=9.2 Hz, J=2.4 Hz, 1H), 6.57 (d, J=3.6 Hz, 1H, indolyl-H), 1.82 (s, 6H, 2×CH.sub.3).

(29) Mass spectrum: (ESI, Negative): 388.27 [M−H].sup.−.

Example 4

Preparation of N-(4-cyano-3-trifluoromethyl)-phenyl-2-(4-fluoro-1H-indolyl-1-yl)-2-methylpropanamide

(30) ##STR00041##

(31) In a 100 mL round bottom flask, 2-bromo-N-(4-cyano-3-trifluoromethyl-phenyl)-2-methylpropanamide (0.20 g, 0.5968 mmol), 4-fluoro-1H-indole (0.16 g, 1.1963 mmol), copper(I) bromide-dimethyl sulfide (12.3 mg, 0.05868 mmol), triphenyl phosphine (15.7 mg, 0.05968 mmol), and sodium hydroxide (23.9 mg, 0.5968 mmol) are added, with 10 mL of anhydrous methylbenzene as solvent. The resulting mixture is heated to 50 Celsius degrees and stirred overnight under argon. After the reaction is completed as determined by thin layer chromatography, the reaction mixture is cooled to 20±5 Celsius degrees, water (30 ml) and ethyl acetate (30 ml) are then added thereto. The resulting mixture is shortly stirred and separated, with the organic phase washed by salt solution (20 ml), dried by magnesium sulphate, filtered, and with the resulting organic phase dried by suction to obtain an oily substance. The oily substance is separated and purified by silica gel column chromatography (mobile phase: hexane:ethyl acetate=2:1) to obtain 0.11 g of yellow powdery material, identified as N-(4-cyano-3-trifluoromethyl)-phenyl-2-[4-fluoro-1H-indolyl-1-yl]-2-methylpropanamide, with a yield of 47.3%.

(32) Nuclear magnetic resonance spectrum: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.90 (s, 1H, ArH), 7.72 (d, J=8.4 Hz, 1H, ArH), 7.50 (br s, 1H, NH), 7.38 (d, J=3.2 Hz, 1H, indolyl-H), 7.28 (m, 1H, ArH), 7.10 (d, J=8.4 Hz, 1H), 6.99 (dd, J=9.2 Hz, J=2.0 Hz, 1H), 6.77 (dd, J=9.2 Hz, J=2.0 Hz, 1H), 6.74 (d, J=2.8 Hz, 1H, indolyl-H), 1.93 (s, 6H, 2×CH.sub.3).

(33) Mass spectrum: (ESI, Negative): 388.26 [M−H].sup.−.

Example 5

(34) Preparation of N-(4-cyano-3-trifluoromethyl)-phenyl-2-(6-fluoro-1H-indolyl-1-yl)-2-methylpropanamide

(35) ##STR00042##

(36) In a 100 mL round bottom flask, 2-bromo-N-(4-cyano-3-trifluoromethyl-phenyl)-2-methylpropanamide (0.20 g, 0.5968 mmol), 6-fluoro-1H-indole (0.16 g, 1.1963 mmol), copper(I) bromide-dimethyl sulfide (12.3 mg, 0.05868 mmol), triphenyl phosphine (15.7 mg, 0.05968 mmol), and sodium hydroxide ((23.9 mg, 0.5968 mmol) are added, with 10 mL of anhydrous methylbenzene as solvent. The resulting mixture is heated to 50 Celsius degrees and stirred overnight under argon. After the reaction is completed as determined by thin layer chromatography, the reaction mixture is cooled to 20±5 Celsius degrees, water (30 ml) and ethyl acetate (30 ml) are then added thereto. The resulting mixture is shortly stirred and separated, with the organic phase washed by salt solution (20 ml), dried by magnesium sulphate, filtered, and with the resulting organic phase dried by suction to obtain an oily substance. The oily substance is separated and purified by silica gel column chromatography (mobile phase: hexane:ethyl acetate=2:1) to obtain 0.12 g of yellow powdery material, identified as N-(4-cyano-3-trifluoromethyl)-phenyl-2-[6-fluoro-1H-indolyl-1-yl]-2-methylpropanamide, with a yield of 51.6%.

(37) Nuclear magnetic resonance spectrum: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.87 (d, J=1.6 Hz, 1H, ArH), 7.77 (d, J=8.4 Hz, 1H, ArH), 7.61 (dd, J=8.4 Hz, J=1.6 Hz, 1H, ArH), 7.51 (br s, 1H, NH), 7.35 (d, J=3.2 Hz, 1H, indolyl-H), 7.11 (dd, J=8.4H, J=4.0 Hz, 1H, ArH), 7.03 (dd, J=10.0 Hz, J=2.0 Hz, 1H), 6.84 (dd, J=8.8 Hz, J=2.2 Hz, 1H), 6.65 (d, J=3.0 Hz, 1H, indolyl-H), 1.95 (s, 6H, 2×CH.sub.3).

(38) Mass spectrum: (ESI, Negative): 388.30 [M−H].sup.−.

Example 6

Preparation of N-(4-cyano-3-trifluoromethyl)-phenyl-2-(5-nitro-1H-indolyl-1-yl)-2-methylpropanamide

(39) ##STR00043##

(40) In a 100 mL round bottom flask, 2-bromo-N-(4-cyano-3-trifluoromethyl-phenyl)-2-methylpropanamide (0.20 g, 0.5968 mmol), 5-nitro-1H-indole (0.194 g, 1.1963 mmol), copper(I) bromide-dimethyl sulfide (12.3 mg, 0.05868 mmol), triphenyl phosphine (15.7 mg, 0.05968 mmol), and sodium hydroxide (24 mg, 0.5968 mmol) are added, with 10 mL of anhydrous methylbenzene as solvent. The resulting mixture is heated to 50 Celsius degrees and stirred overnight under argon. After the reaction is completed as determined by thin layer chromatography, the reaction mixture is cooled to 20±5 Celsius degrees, water (30 ml) and ethyl acetate (30 ml) are then added thereto. The resulting mixture is shortly stirred and separated, with the organic phase washed by salt solution (20 ml), dried by magnesium sulphate, filtered, and with the resulting organic phase dried by suction to obtain an oily substance. The oily substance is separated and purified by silica gel column chromatography (mobile phase: dichloromethane:ethyl acetate=9:1) to obtain 0.10 g of light brown powdery material, identified as N-(4-cyano-3-trifluoromethyl)-phenyl-2-[5-nitro-1H-indolyl-1-yl]-2-methylpropanamide, with a yield of 40.2%.

(41) Nuclear magnetic resonance spectrum: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.45 (s, 1H, NH), 8.24 (s, 1H, ArH), 8.19 (d, J=8.4 Hz, 1H, ArH), 8.09 (d, J=8.4 Hz, 1H, ArH), 7.85-7.81 (m, 3H), 7.50 (d, J=8.8 Hz, 1H), 6.70 (d, J=3.2 Hz, 1H, indolyl-H), 1.90 (s, 6H, 2×CH.sub.3).

(42) Mass spectrum: (ESI, Negative): 415.29 [M−H].sup.−.

Example 7

Preparation of N-(4-cyano-3-trifluoromethyl) phenyl-2-(5-chloro-1H-indolyl-1-yl)-2-methylpropanamide

(43) ##STR00044##

(44) In a 100 mL round bottom flask, 2-bromo-N-(4-cyano-3-trifluoromethyl-phenyl)-2-methylpropanamide (0.20 g, 0.5968 mmol), 5-chloro-1H-indole (0.181 g, 1.1963 mmol), copper(I) bromide-dimethyl sulfide (12.3 mg, 0.05868 mmol), triphenyl phosphine (15.7 mg, 0.05968 mmol), and sodium hydroxide (24 mg, 0.5968 mmol) are added, with 10 mL of anhydrous methylbenzene as solvent. The resulting mixture is heated to 50 Celsius degrees and stirred overnight under argon. After the reaction is completed as determined by thin layer chromatography, the reaction mixture is cooled to 20±5 Celsius degrees, water (30 ml) and ethyl acetate (30 ml) are then added thereto. The resulting mixture is shortly stirred and separated, with the organic phase washed by salt solution (20 ml), dried by magnesium sulphate, filtered, and with the resulting organic phase dried by suction to obtain an oily substance. The oily substance is separated and purified by silica gel column chromatography (mobile phase: hexane:ethyl acetate=2:1) to obtain 0.13 g of yellow powdery material, identified as N-(4-cyano-3-trifluoromethyl)-phenyl-2-[5-chloro-1H-indolyl-1-yl]-2-methylpropanamide, with a yield of 53.7%.

(45) Nuclear magnetic resonance spectrum: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.36 (s, 1H, NH), 8.21 (d, J=2.0 Hz, 1H, ArH), 8.18 (dd, J=8.4 Hz, J=2.0 Hz, 1H, ArH), 8.07 (d, J=8.4 Hz, 1H, ArH), 7.73 (d, J=3.2 Hz, 1H, indolyl-H), 7.41 (s, 1H), 7.11-7.08 (m, 2H), 6.64 (d, J=3.2 Hz, 1H, indolyl-H), 1.84 (s, 6H, 2×CH.sub.3).

(46) Mass spectrum: (ESI, Negative): 403.12[M−H].sup.−.

Example 8

Preparation of N-(4-cyano-3-trifluoromethyl)-phenyl-2-(5-trifluoromethyl-1H-indolyl-1-yl)-2-methylpropanamide

(47) ##STR00045##

(48) In a 100 mL round bottom flask, 2-bromo-N-(4-cyano-3-trifluoromethyl-phenyl)-2-methylpropanamide (0.20 g, 0.5968 mmol), 5-trifluoromethyl-1H-indole (0.22 g, 1.1963 mmol), copper(I) bromide-dimethyl sulfide (12.3 mg, 0.05868 mmol), triphenyl phosphine (15.7 mg, 0.05968 mmol), and sodium hydroxide (24 mg, 0.5968 mmol) are added, with 10 mL of anhydrous methylbenzene as solvent. The resulting mixture is heated to 50 Celsius degrees and stirred overnight under argon. After the reaction is completed as determined by thin layer chromatography, the reaction mixture is cooled to 20±5 Celsius degrees, water (30 ml) and ethyl acetate (30 ml) are then added thereto. The resulting mixture is shortly stirred and separated, with the organic phase washed by salt solution (20 ml), dried by magnesium sulphate, filtered, and with the resulting organic phase dried by suction to obtain an oily substance. The oily substance is separated and purified by silica gel column chromatography (mobile phase: hexane:ethyl acetate=2:1) to obtain 0.15 g of yellow powdery material, identified as N-(4-cyano-3-trifluoromethyl)-phenyl-2-[5-trifluoromethyl-1H-indolyl-1-yl]-2-methylpropanamide, with a yield of 57%.

(49) Nuclear magnetic resonance spectrum: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.35 (s, 1H, NH), 8.25 (d, J=1.6 Hz, 1H, ArH), 8.17 (dd, J=8.4 Hz, J=1.6 Hz, 1H, ArH), 8.10 (d, J=8.4 Hz, 1H, ArH), 7.78 (d, J=3.2 Hz, 1H, indolyl-H), 7.40 (m, 1H), 7.12-7.07 (m, 2H), 6.62 (d, J=3.2 Hz, 1H, indolyl-H), 1.87 (s, 6H, 2×CH.sub.3).

(50) Mass spectrum: (ESI, Negative): 438.25[M−H].sup.−.

Example 9

Preparation of N-(4-cyano-3-trifluoromethyl)-phenyl-2-(5-cyano-1H-indolyl-1-yl)-2-methylpropanamide

(51) ##STR00046##

(52) In a 100 mL round bottom flask, 2-bromo-N-(4-cyano-3-trifluoromethyl-phenyl)-2-methylpropanamide (0.20 g, 0.5968 mmol), 5-cyano-1H-indole (0.17 g, 1.1963 mmol), copper(I) bromide-dimethyl sulfide (12.3 mg, 0.05868 mmol), triphenyl phosphine (15.7 mg, 0.05968 mmol), and sodium hydroxide (24 mg, 0.5968 mmol) are added, with 10 mL of anhydrous methylbenzene as solvent. The resulting mixture is heated to 50 Celsius degrees and stirred overnight under argon. After the reaction is completed as determined by thin layer chromatography, the reaction mixture is cooled to 20±5 Celsius degrees, water (30 ml) and ethyl acetate (30 ml) are then added thereto. The resulting mixture is shortly stirred and separated, with the organic phase washed by salt solution (20 ml), dried by magnesium sulphate, filtered, and with the resulting organic phase dried by suction to obtain an oily substance. The oily substance is separated and purified by silica gel column chromatography (mobile phase: hexane:ethyl acetate=2:1) to obtain 90 mg of yellow powdery material, identified as N-(4-cyano-3-trifluoromethyl)-phenyl-2-(5-cyano-1H-indolyl-1-yl]-2-methylpropanamide, with a yield of 38%.

(53) Nuclear magnetic resonance spectrum: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.37 (s, 1H, NH), 8.27 (s, 1H, ArH), 8.19 (d, J=8.4 Hz, 1H, ArH), 8.05 (d, J=8.4 Hz, 1H, ArH), 7.78 (d, J=3.2 Hz, 1H, indolyl-H), 7.51 (d, J=8.6 Hz, 1H), 7.32 (d, J=8.6 Hz, 1H), 6.60 (d, J=3.2 Hz, 1H, indolyl-H), 1.85 (s, 6H, 2×CH.sub.3).

(54) Mass spectrum: (ESI, Negative): 395.20[M−H].sup.−.

Example 10

Preparation of N-(4-cyano-3-trifluoromethyl)-phenyl-2-(5-fluoro-1H-2,3-dihydroindolyl-1-yl)-2-methylpropanamide

(55) ##STR00047##

(56) In a 100 mL round bottom flask, 2-bromo-N-(4-cyano-3-trifluoromethyl-phenyl)-2-methylpropanamide (0.20 g, 0.5968 mmol), 5-fluoro-1H-2,3-dihydroindole (0.163 g, 1.1963 mmol), copper(I) bromide-dimethyl sulfide (12.3 mg, 0.05868 mmol), tricyclohexyl phosphine (16.7 mg, 0.05968 mmol), tripotassium phosphate (0.152 g, 0.7162 mmol), and sodium hydroxide (24 mg, 0.5968 mmol) are added, with 10 mL of anhydrous methylbenzene as solvent. The resulting mixture is heated to 50 Celsius degrees and stirred overnight under argon. After the reaction is completed as determined by thin layer chromatography, the reaction mixture is cooled to 20±5 Celsius degrees, water (30 ml) and ethyl acetate (30 ml) are then added thereto. The resulting mixture is shortly stirred and separated, with the organic phase washed by salt solution (20 ml), dried by magnesium sulphate, filtered, and with the resulting organic phase dried by suction to obtain an oily substance. The oily substance is separated and purified by silica gel column chromatography (mobile phase: dichloromethane:ethyl acetate=9:1) to obtain 47 mg of yellow powdery material, identified as N-(4-cyano-3-trifluoromethyl)-phenyl-2-(5-fluoro-1H-2,3-dihydroindolyl-1-yl)-2-methylpropanamide, with a yield of 20%.

(57) Nuclear magnetic resonance spectrum: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.78 (s, 1H, NH), 7.95 (d, J=2.0 Hz, 1H, ArH), 7.60 (d, J=8.4 Hz, 1H, ArH), 7.41 (d, J=8.4 Hz, 1H, ArH), 6.85 (m, 1H), 6.41-6.37 (m, 2H), 3.36-3.33 (m, 1H), 3.10-3.04 (m, 2H), 2.98-2.95 (m, 1M), 1.87 (s, 6H, 2×CH.sub.3).

(58) Mass spectrum: (ESI, Negative): 390.29[M−H].sup.−.

Example 11

Preparation of N-(4-cyano-3-trifluoromethyl)-phenyl-2-(5,6-difluoro-1H-2,3-dihydroindolyl-1-yl)-2-methylpropanamide

(59) ##STR00048##

(60) In a 100 mL round bottom flask, 2-bromo-N-(4-cyano-3-trifluoromethyl-phenyl)-2-methylpropanamide (0.20 g, 0.5968 mmol), 5,6-difluoro-1H-2,3-dihydroindole (0.185 g, 1.1963 mmol), copper(I) bromide-dimethyl sulfide (12.3 mg, 0.05868 mmol), tricyclohexyl phosphine (16.7 mg, 0.05968 mmol), tripotassium phosphate (0.152 g, 0.7162 mmol), and sodium hydroxide (24 mg, 0.5968 mmol) are added, with 10 mL of anhydrous methylbenzene as solvent. The resulting mixture is heated to 50 Celsius degrees and stirred overnight under argon. After the reaction is completed as determined by thin layer chromatography, the reaction mixture is cooled to 20±5 Celsius degrees, water (30 ml) and ethyl acetate (30 ml) are then added thereto. The resulting mixture is shortly stirred and separated, with the organic phase washed by salt solution (20 ml), dried by magnesium sulphate, filtered, and with the resulting organic phase dried by suction to obtain an oily substance. The oily substance is separated and purified by silica gel column chromatography (mobile phase: dichloromethane:ethyl acetate=9:1) to obtain 54 mg of yellow powdery material, identified as N-(4-cyano-3-trifluoromethyl)-phenyl-2-(5,6-difluoro-1H-2,3-dihydroindolyl-1-yl)-2-methylpropanamide, with a yield of 22%.

(61) Nuclear magnetic resonance spectrum: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.05 (br s, 1H, NH), 8.05 (d, J=2.0 Hz, 1H, ArH), 7.91 (dd, J=8.4 Hz, J=2.0 Hz, 1H, ArH), 7.64 (d, J=8.4 Hz, 1H, ArH), 6.68 (t, J=8.8 Hz, 1H), 6.39 (m, 1H), 3.42-3.37 (m, 2H), 3.02-2.94 (m, 2H), 1.88 (s, 6H, 2×CH.sub.3).

(62) Mass spectrum: (ESI, Negative): 408.28[M−H].sup.−.

Example 12

Preparation of N-(3-chloro-4-cyano) phenyl-2-(5-fluoro-1H-indolyl-1-yl)-2-methylpropanamide

(63) ##STR00049##

(64) First Step of Reaction

(65) Thionyl chloride (2.62 ml, 35.93 mmol, 1.2 eq) is added dropwise to a solution of 2-bromo-2-methyl propionic acid (5.00 g, 29.94 mmol) in 30 ml of anhydrous tetrahydrofuran at a temperature ranging from 0 to 12 Celsius degrees in 10 minutes. The resulting mixture is stirred under the same conditions for 2 hours. The internal temperature is adjusted to about −5 Celsius degrees. Triethylamine (Et.sub.3N) (5.42 ml, 38.92 mmol, 1.3 eq) is slowly added to the reaction mixture, with an internal temperature lower than 12 Celsius degrees. The resulting mixture is stirred under the same reaction conditions for 20 minutes, and a solution of 3-chloro-4-cyano-phenylamine (4.57 g, 29.94 mmol) in 30 mL of anhydrous tetrahydrofuran is then added dropwise thereto, and the resulting mixture is stirred at 50 Celsius degrees for two hours. After the reaction is completed as determined by thin layer chromatography, the reaction mixture is cooled to 20±5 Celsius degrees, water (50 ml) and ethyl acetate (50 ml) are then added thereto. The resulting mixture is shortly stirred and separated, with the organic phase washed by salt solution (30 ml), dried by magnesium sulphate, filtered, and with the resulting organic phase dried by suction to obtain an oily substance. The oily substance is separated and purified by silica gel column chromatography (mobile phase: dichloromethane:ethyl acetate=19:1) to obtain 6.77 g of light yellow powdery material, identified as 2-bromo-N-(3-chloro-4-cyano-phenyl)-2-methylpropanamide, with a yield of 75% and a purity of 99% by HPLC (mobile phase: water and acetonitrile) (254 nm).

(66) Nuclear magnetic resonance spectrum: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.43 (s, 1H, NH), 8.43 (s, 1H, ArH), 8.34 (d, J=8.6 Hz, 1H, ArH), 8.28 (d, J=8.6 Hz, 1H, ArH), 2.05 (s, 6H, 2×CH.sub.3).

(67) Mass spectrum: (ESI, Positive): 301.02[M+H].sup.+.

(68) Second Step of Reaction

(69) In a 100 mL round bottom flask, 2-bromo-N-(3-chloro-4-cyano-phenyl)-2-methylpropanamide (0.30 g, 0.9948 mmol), (5-fluoro-phenyl)-1H-indole (0.269 g, 1.9896 mmol), copper(I) bromide-dimethyl sulfide (20.5 mg, 0.0994 mmol), triphenyl phosphine (26.1 mg, 0.09948 mmol), tripotassium phosphate (0.25 g, 1.1938 mmol), and sodium hydroxide (44 mg, 0.56 mmol) are added, with 10 mL of anhydrous methylbenzene as solvent. The resulting mixture is heated to 50 Celsius degrees and stirred under argon for 14 hours. After the reaction is completed as determined by thin layer chromatography, the reaction mixture is cooled to 20±5 Celsius degrees, water (30 ml) and ethyl acetate (30 ml) are then added thereto. The resulting mixture is shortly stirred and separated, with the organic phase washed by salt solution (20 ml), dried by magnesium sulphate, filtered, and with the resulting organic phase dried by suction to obtain an oily substance. The oily substance is separated and purified by silica gel column chromatography (mobile phase: dichloromethane:ethyl acetate=19:1 to 9:1) to obtain 0.145 g of yellow powdery material, identified as N-(3-chloro-4-cyano) phenyl-2-[5-fluoro-1H-indolyl-1-yl]-2-methylpropanamide, with a yield of 41%.

(70) Nuclear magnetic resonance spectrum: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.60 (br s, 1H, NH), 7.79 (d, J=2.0 Hz, 1H, ArH), 7.52 (d, J=8.4 Hz, 1H, ArH), 7.38-7.26 (m, 2H), 7.22-7.18 (m, 3H), 6.61 (d, J=3.2 Hz, 1H, indolyl-H), 1.90 (s, 6H, 2×CH.sub.3).

(71) Mass spectrum: (ESI, Negative): 354.02 [M−H].sup.−.

Example 13

Preparation of N-(4-cyano-3-trifluoromethyl)-phenyl-2-[3-fluoro-4-(4-fluorophenyl)-1H-pyrazolyl-1-yl]-2-methylpropanamide

(72) ##STR00050##

(73) First Step of Reaction

(74) The same as that of Example 1.

(75) Second Step of Reaction

(76) In a 100 mL round bottom flask, 3-fluoro-4-bromo-1H-pyrazole (2.00 g, 12.124 mmol), 4-fluoro-phenylboronic acid (2.04 g, 14.549 mmol), palladium (II) acetate (54 mg, 0.2424 mmol), triphenyl phosphine (0.128 g, 0.483 mmol), and potassium carbonate (3.36 g, 24.248 mmol) are added, with 20 mL of ethazine and 10 mL of water as solvent. The resulting mixture is heated to reflux and stirred under argon for 3-4 hours. After the reaction is completed as determined by thin layer chromatography, water (30 ml) and ethyl acetate (30 ml) are added to the reaction mixture. The resulting mixture is shortly stirred and separated, with the organic phase washed by salt solution (30 ml), dried by magnesium sulphate, filtered, and with the resulting organic phase dried by suction to obtain an oily substance. The oily substance is separated and purified by silica gel column chromatography (mobile phase: hexane:ethyl acetate=2:1 to 1:1) to obtain 0.66 g of light yellow powdery material, identified as 3-fluoro-4-(4-fluorophenyl)-1H-pyrazole, with a yield of 30%.

(77) Mass spectrum: (ESI, positive): 181.07[M+H].sup.+.

(78) The Third Step of Reaction

(79) In a 100 mL round bottom flask, 2-bromo-N-(4-cyano-3-trifluoromethyl-phenyl)-2-methylpropanamide (0.40 g, 1.1936 mmol), 3-fluoro-4-(4-fluorophenyl)-1H-pyrazole (0.43 g, 2.38727 mmol), copper(I) bromide-dimethyl sulfide (25 mg, 0.11936 mmol), triphenyl phosphine (31 mg, 0.11936 mmol), tripotassium phosphate (0.304 g, 1.4323 mmol) and sodium hydroxide (53 mg, 1.3130 mmol) are added, with 10 mL of anhydrous methylbenzene as solvent. The resulting mixture is heated to 50 Celsius degrees and stirred under argon for 12 hours. After the reaction is completed as determined by thin layer chromatography, the reaction mixture is cooled to 20±5 Celsius degrees, water (30 ml) and ethyl acetate (35 ml) are then added thereto. The resulting mixture is shortly stirred and separated, with the organic phase washed by salt solution (25 ml), dried by magnesium sulphate, filtered, and with the resulting organic phase dried by suction to obtain an oily substance. The oily substance is separated and purified by silica gel column chromatography (mobile phase: hexane:ethyl acetate=3:1 to 2:1) to obtain 0.26 g of light yellow powdery material, identified as N-(4-cyano-3-trifluoromethyl)-phenyl-2-[3-fluoro-4-(4-fluorophenyl)-1H-pyrazolyl-1-yl]-2-methylpropanamide, with a yield of 50%.

(80) Nuclear magnetic resonance spectrum: .sup.1H NMR (400 MHz, DMSO-d.sub.6) 510.14 (s, 1H, NH), 8.33 (d, J=1.6 Hz, 1H, ArH), 8.21 (dd, J=8.2 Hz, J=1.6 Hz, 1H, ArH), 8.11 (d, J=8.2 Hz, 1H, ArH), 8.05 (d, J=3.0 Hz, 1H, pyrazolyl-H), 7.86-7.82 (m, 2H), 7.25-7.21 (m, 2H), 1.86 (s, 6H, 2×CH.sub.3).

(81) Mass spectrum: (ESI, Negative): 433.27 [M−H].sup.−.

Example 14

The Preparation of N-(4-cyano-3-trifluoromethyl)-phenyl-2-[4-(4-fluorophenyl)-1H-pyrazolyl-1-yl]-2-methylpropanamide

(82) ##STR00051##

(83) First Step of Reaction

(84) The same as that of Example 1.

(85) Second Step of Reaction

(86) In a 100 mL round bottom flask, 4-bromo-1H-pyrazole (1.00 g, 6.8041 mmol), 4-fluoro-phenylboronic acid (1.14 g, 8.1649 mmol), palladium (II) acetate (30 mg, 0.1361 mmol), triphenyl phosphine (71.4 g, 0.2722 mmol), and potassium carbonate (1.88 g, 13.6082 mmol) are added, with 20 mL of ethazine and 10 mL of water as solvent. The resulting mixture is heated to reflux and stirred under argon for 3-4 hours. After the reaction is completed as determined by thin layer chromatography, water (30 ml) and ethyl acetate (30 ml) are added to the reaction mixture. The resulting mixture is shortly stirred and separated, with the organic phase washed by salt solution (30 ml), dried by magnesium sulphate, filtered, and with the resulting organic phase dried by suction to obtain an oily substance. The oily substance is separated and purified by silica gel column chromatography (mobile phase: hexane:ethyl acetate=2:1 to 1:1) to obtain 0.55 g of light yellow powdery material, identified as 4-(4-fluorophenyl)-1H-pyrazole, with a yield of 50%.

(87) Mass spectrum: (ESI, positive): 163.02[M+H].sup.+.

(88) The Third Step of Reaction

(89) In a 100 mL round bottom flask, 2-bromo-N-(4-cyano-3-trifluoromethyl-phenyl)-2-methylpropanamide (0.40 g, 1.1936 mmol), 4-(4-fluorophenyl)-1H-pyrazole (0.39 g, 2.38727 mmol), copper(I) bromide-dimethyl sulfide (25 mg, 0.11936 mmol), triphenyl phosphine (31 mg, 0.11936 mmol), tripotassium phosphate (0.304 g, 1.4323 mmol) and sodium hydroxide (53 mg, 1.3130 mmol) are added, with 10 mL of anhydrous methylbenzene as solvent. The resulting mixture is heated to 50 Celsius degrees and stirred under argon for 12 hours. After the reaction is completed as determined by thin layer chromatography, the reaction mixture is cooled to 20±5 Celsius degrees, water (30 ml) and ethyl acetate (35 ml) are then added thereto. The resulting mixture is shortly stirred and separated, with the organic phase washed by salt solution (25 ml), dried by magnesium sulphate, filtered, and with the resulting organic phase dried by suction to obtain an oily substance. The oily substance is separated and purified by silica gel column chromatography (mobile phase: hexane:ethyl acetate=3:1 to 2:1) to obtain 0.28 g of white powdery material, identified as N-(4-cyano-3-trifluoromethyl)-phenyl-2-[4-(4-fluorophenyl)-1H-pyrazolyl-1-yl]-2-methylpropanamide, with a yield of 56.4%.

(90) Nuclear magnetic resonance spectrum: .sup.1H NMR (400 MHz, DMSO-d.sub.6) 510.12 (s, 1H, NH), 8.31 (d, J=2.0 Hz, 1H, ArH), 8.18 (dd, J=8.4 Hz, J=2.0 Hz, 1H, ArH), 8.10 (d, J=8.4 Hz, 1H, ArH), 8.03 (d, J=3.0 Hz, 1H, pyrazolyl-H), 7.84-7.80 (m, 2H), 7.23-7.19 (m, 2H), 1.86 (s, 6H, 2×CH.sub.3).

(91) Mass spectrum: (ESI, Negative): 415.27 [M−H].sup.−.

Example 15

Preparation of N-(4-cyano-3-trifluoromethyl)-phenyl-2-(4-fluoro-1H-pyrazolyl-1-yl)-2-methylpropanamide

(92) ##STR00052##

(93) In a 100 mL round bottom flask, 2-bromo-N-(4-cyano-3-trifluoromethyl-phenyl)-2-methylpropanamide (0.40 g, 1.1936 mmol), 4-fluoro-1H-pyrazole (0.21 g, 2.38727 mmol), copper(I) bromide-dimethyl sulfide (25 mg, 0.11936 mmol), triphenyl phosphine (31 mg, 0.11936 mmol), tripotassium phosphate (0.304 g, 1.4323 mmol) and sodium hydroxide (53 mg, 1.3130 mmol) are added, with 10 mL of anhydrous methylbenzene as solvent. The resulting mixture is heated to 50 Celsius degrees and stirred under argon for 12 hours. After the reaction is completed as determined by thin layer chromatography, the reaction mixture is cooled to 20±5 Celsius degrees, water (30 ml) and ethyl acetate (35 ml) are then added thereto. The resulting mixture is shortly stirred and separated, with the organic phase washed by salt solution (25 ml), dried by magnesium sulphate, filtered, and with the resulting organic phase dried by suction to obtain an oily substance. The oily substance is separated and purified by silica gel column chromatography (mobile phase: hexane:ethyl acetate=3:1 to 2:1) to obtain 0.15 g of white powdery material, identified as N-(4-cyano-3-trifluoromethyl)-phenyl-2-(4-fluoro-1H-pyrazolyl-1-yl)-2-methylpropanamide, with a yield of 37%.

(94) Nuclear magnetic resonance spectrum: .sup.1H NMR (400 MHz, DMSO-d.sub.6) 510.05 (s, 1H, NH), 8.27 (d, J=2.0 Hz, 1H, ArH), 8.16 (dd, J=8.4 Hz, J=2.0 Hz, 1H, ArH), 8.14 (d, J=4.4 Hz, 1H, -H), 8.10 (d, J=8.4 Hz, 1H, ArH), 7.57 (d, J=4.0 Hz, 1H, pyrazolyl-H), 1.77 (s, 6H, 2×CH.sub.3).

(95) Mass spectrum: (ESI, Negative): 339.26 [M−H].sup.−.

Example 16

Preparation of N-(4-cyano-3-trifluoromethyl)-phenyl-2-(3-fluoro-1H-pyrazolyl-1-yl)-2-methylpropanamide

(96) ##STR00053##

(97) In a 100 mL round bottom flask, 2-bromo-N-(4-cyano-3-trifluoromethyl-phenyl)-2-methylpropanamide (0.40 g, 1.1936 mmol), 3-fluoro-1H-pyrazole (0.21 g, 2.38727 mmol), copper(I) bromide-dimethyl sulfide (25 mg, 0.11936 mmol), triphenyl phosphine (31 mg, 0.11936 mmol), tripotassium phosphate (0.304 g, 1.4323 mmol) and sodium hydroxide (53 mg, 1.3130 mmol) are added, with 10 mL of anhydrous methylbenzene as solvent. The resulting mixture is heated to 50 Celsius degrees and stirred under argon for 12 hours. After the reaction is completed as determined by thin layer chromatography, the reaction mixture is cooled to 20±5 Celsius degrees, water (30 ml) and ethyl acetate (35 ml) are then added thereto. The resulting mixture is shortly stirred and separated, with the organic phase washed by salt solution (25 ml), dried by magnesium sulphate, filtered, and with the resulting organic phase dried by suction to obtain an oily substance. The oily substance is separated and purified by silica gel column chromatography (mobile phase: hexane:ethyl acetate=3:1 to 2:1) to obtain 0.12 g of white powdery material, identified as N-(4-cyano-3-trifluoromethyl)-phenyl-2-(3-fluoro-1H-pyrazolyl-1-yl)-2-methylpropanamide, with a yield of 30%.

(98) Nuclear magnetic resonance spectrum: .sup.1H NMR (400 MHz, DMSO-d.sub.6) 510.05 (s, 1H, NH), 8.27 (d, J=2.0 Hz, 1H, ArH), 8.16 (dd, J=8.4 Hz, J=2.0 Hz, 1H, ArH), 8.10 (d, J=8.4 Hz, 1H, ArH), 7.95 (d, J=3.0 Hz, 1H, pyrazolyl-H), 6.11 (m, 1H), 1.79 (s, 6H, 2×CH.sub.3).

(99) Mass spectrum: (ESI, Negative): 339.25 [M−H].sup.−.

Example 17

Preparation of N-(4-cyano-3-trifluoromethyl)-phenyl-2-(4-chloro-1H-pyrazolyl-1-yl)-2-methylpropanamide

(100) ##STR00054##

(101) In a 100 mL round bottom flask, 2-bromo-N-(4-cyano-3-trifluoromethyl-phenyl)-2-methylpropanamide (0.40 g, 1.1936 mmol), 4-chloro-1H-pyrazole (0.245 g, 2.38727 mmol), copper(I) bromide-dimethyl sulfide (25 mg, 0.11936 mmol), triphenyl phosphine (31 mg, 0.11936 mmol), tripotassium phosphate (0.304 g, 1.4323 mmol) and sodium hydroxide (53 mg, 1.3130 mmol) are added, with 10 mL of anhydrous methylbenzene as solvent. The resulting mixture is heated to 50 Celsius degrees and stirred under argon for 14 hours. After the reaction is completed as determined by thin layer chromatography, the reaction mixture is cooled to 20±5 Celsius degrees, water (30 ml) and ethyl acetate (35 ml) are then added thereto. The resulting mixture is shortly stirred and separated, with the organic phase washed by salt solution (25 ml), dried by magnesium sulphate, filtered, and with the resulting organic phase dried by suction to obtain an oily substance. The oily substance is separated and purified by silica gel column chromatography (mobile phase: hexane:ethyl acetate=3:1 to 2:1) to obtain 0.233 g of white powdery material, identified as N-(4-cyano-3-trifluoromethyl)-phenyl-2-(4-chloro-1H-pyrazolyl-1-yl)-2-methylpropanamide, with a yield of 55%.

(102) Nuclear magnetic resonance spectrum: .sup.1H NMR (400 MHz, DMSO-d.sub.6) 510.04 (s, 1H, NH), 8.26 (s, 1H, ArH), 8.23 (s, 1H, pyrazolyl-H), 8.15 (d, J=8.6 Hz, 1H, ArH), 8.10 (d, J=8.6 Hz, 1H, ArH), 7.36 (s, 1H, pyrazolyl-H), 1.79 (s, 6H, 2×CH.sub.3).

(103) Mass spectrum: (ESI, Negative): 355.08[M−H].sup.−.

Example 18

Preparation of N-(4-cyano-3-trifluoromethyl)-phenyl-2-(4-trifluormethyl-1H-pyrazolyl-1-yl)-2-methylpropanamide

(104) ##STR00055##

(105) In a 100 mL round bottom flask, 2-bromo-N-(4-cyano-3-trifluoromethyl-phenyl)-2-methylpropanamide (0.40 g, 1.1936 mmol), 4-trifluoromethyl-1H-pyrazole (0.325 g, 2.38727 mmol), copper(I) bromide-dimethyl sulfide (25 mg, 0.11936 mmol), triphenyl phosphine (31 mg, 0.11936 mmol), tripotassium phosphate (0.304 g, 1.4323 mmol) and sodium hydroxide (53 mg, 1.3130 mmol) are added, with 10 mL of anhydrous methylbenzene as solvent. The resulting mixture is heated to 50 Celsius degrees and stirred under argon for 14 hours. After the reaction is completed as determined by thin layer chromatography, the reaction mixture is cooled to 20±5 Celsius degrees, water (30 ml) and ethyl acetate (35 ml) are then added thereto. The resulting mixture is shortly stirred and separated, with the organic phase washed by salt solution (25 ml), dried by magnesium sulphate, filtered, and with the resulting organic phase dried by suction to obtain an oily substance. The oily substance is separated and purified by silica gel column chromatography (mobile phase: hexane:ethyl acetate=2:1) to obtain 0.144 g of white powdery material, identified as N-(4-cyano-3-trifluoromethyl)-phenyl-2-(4-trifluoromethyl-1H-pyrazolyl-1-yl)-2-methylpropanamide, with a yield of 31%.

(106) Nuclear magnetic resonance spectrum: .sup.1H NMR (400 MHz, DMSO-d.sub.6) 510.04 (s, 1H, NH), 8.42 (s, 1H, pyrazolyl-H), 8.25 (d, J=2.0 Hz, 1H, ArH), 8.17 (dd, J=8.2 Hz, J=2.0 Hz, 1H, ArH), 8.11 (d, J=8.2 Hz, 1H, ArH), 7.90 (s, 1H, pyrazolyl-H), 1.85 (s, 6H, 2×CH.sub.3).

(107) Mass spectrum: (ESI, Negative): 389.21[M−H].sup.−.

Example 19

Preparation of N-(4-cyano-3-trifluoromethyl)-phenyl-2-(4-nitro-1H-pyrazolyl-1-yl)-2-methylpropanamide

(108) ##STR00056##

(109) In a 100 mL round bottom flask, 2-bromo-N-(4-cyano-3-trifluoromethyl-phenyl)-2-methylpropanamide (0.40 g, 1.1936 mmol), 4-nitro-1H-pyrazole (0.27 g, 2.38727 mmol), copper(I) bromide-dimethyl sulfide (25 mg, 0.11936 mmol), triphenyl phosphine (31 mg, 0.11936 mmol), tripotassium phosphate (0.304 g, 1.4323 mmol) and sodium hydroxide (53 mg, 1.3130 mmol) are added, with 10 mL of anhydrous methylbenzene as solvent. The resulting mixture is heated to 50 Celsius degrees and stirred overnight under argon. After the reaction is completed as determined by thin layer chromatography, the reaction mixture is cooled to 20±5 Celsius degrees, water (30 ml) and ethyl acetate (35 ml) are then added thereto. The resulting mixture is shortly stirred and separated, with the organic phase washed by salt solution (25 ml), dried by magnesium sulphate, filtered, and with the resulting organic phase dried by suction to obtain an oily substance. The oily substance is separated and purified by silica gel column chromatography (mobile phase: hexane:ethyl acetate=2:1) to obtain 0.17 g of light yellow powdery material, identified as N-(4-cyano-3-trifluoromethyl)-phenyl-2-(4-nitro-1H-pyrazolyl-1-yl)-2-methylpropanamide, with a yield of 39%.

(110) Nuclear magnetic resonance spectrum: .sup.1H NMR (400 MHz, DMSO-d.sub.6) 510.02 (s, 1H, NH), 8.88 (s, 1H, pyrazolyl-H), 8.34 (s, 1H, pyrazolyl-H), 8.25 (d, J=1.2 Hz, 1H, ArH), 8.16 (dd, J=8.6 Hz, J=1.2 Hz, 1H, ArH), 8.11 (d, J=8.6 Hz, 1H, ArH), 1.84 (s, 6H, 2×CH.sub.3).

(111) Mass spectrum: (ESI, Negative): 366.19[M−H].sup.−.

Example 20

Preparation of N-(4-cyano-3-trifluoromethyl)-phenyl-2-(4-cyano-1H-pyrazolyl-1-yl)-2-methylpropanamide

(112) ##STR00057##

(113) In a 100 mL round bottom flask, 2-bromo-N-(4-cyano-3-trifluoromethyl-phenyl)-2-methylpropanamide (0.40 g, 1.1936 mmol), 4-cyano-1H-pyrazole (0.222 g, 2.38727 mmol), copper(I) bromide-dimethyl sulfide (25 mg, 0.11936 mmol), triphenyl phosphine (31 mg, 0.11936 mmol), tripotassium phosphate (0.304 g, 1.4323 mmol) and sodium hydroxide (53 mg, 1.3130 mmol) are added, with 10 mL of anhydrous methylbenzene as solvent. The resulting mixture is heated to 50 Celsius degrees and stirred overnight under argon. After the reaction is completed as determined by thin layer chromatography, the reaction mixture is cooled to 20±5 Celsius degrees, water (30 ml) and ethyl acetate (35 ml) are then added thereto. The resulting mixture is shortly stirred and separated, with the organic phase washed by salt solution (25 ml), dried by magnesium sulphate, filtered, and with the resulting organic phase dried by suction to obtain an oily substance. The oily substance is separated and purified by silica gel column chromatography (mobile phase: hexane:ethyl acetate=2:1 to 1:1) to obtain 0.182 g of light yellow powdery material, identified as N-(4-cyano-3-trifluoromethyl)-phenyl-2-(4-cyano-1H-pyrazolyl-1-yl)-2-methylpropanamide, with a yield of 45%.

(114) Nuclear magnetic resonance spectrum: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ10.01 (s, 1H, NH), 8.63 (s, 1H, pyrazolyl-H), 8.25 (d, J=1.2 Hz, 1H, ArH), 8.14 (dd, J=8.8 Hz, J=1.2 Hz, 1H, ArH), 8.13 (s, 1H, pyrazolyl-H), 8.10 (d, J=8.8 Hz, 1H, ArH), 1.82 (s, 6H, 2×CH.sub.3).

(115) Mass spectrum: (ESI, Negative): 346.23[M−H].sup.−.

Example 21

Preparation of 1-{1-[(4-cyano-3-trifluoromethyl-phenyl)-amino]-2-methyl-1-oxopropyl-2-yl}-N-methyl-1H-pyrazolyl-4-formamide

(116) ##STR00058##

(117) In a 100 mL round bottom flask, 2-bromo-N-(4-cyano-3-trifluoromethyl-phenyl)-2-methylpropanamide (0.40 g, 1.1936 mmol), 1H-pyrazolyl-4-N-methylformamide (0.30 g, 2.38727 mmol), copper(I) bromide-dimethyl sulfide (25 mg, 0.11936 mmol), triphenyl phosphine (31 mg, 0.11936 mmol), tripotassium phosphate (0.304 g, 1.4323 mmol) and sodium hydroxide (53 mg, 1.3130 mmol) are added, with 10 mL of anhydrous methylbenzene as solvent. The resulting mixture is heated to 50 Celsius degrees and stirred overnight under argon. After the reaction is completed as determined by thin layer chromatography, the reaction mixture is cooled to 20±5 Celsius degrees, water (30 ml) and ethyl acetate (35 ml) are then added thereto. The resulting mixture is shortly stirred and separated, with the organic phase washed by salt solution (25 ml), dried by magnesium sulphate, filtered, and with the resulting organic phase dried by suction to obtain an oily substance. The oily substance is separated and purified by silica gel column chromatography (mobile phase: hexane:ethyl acetate=3:1 to 2:1) to obtain 45 mg of light yellow powdery material, identified as 1-{1-[(4-cyano-3-trifluoromethyl-phenyl)-amino]-2-methyl-1-oxopropyl-2-yl}-N-methyl-1H-pyrazolyl-4-formamide, with a yield of 10%.

(118) Nuclear magnetic resonance spectrum: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ10.03 (s, 1H, NH), 8.52-8.48 (m, 2H, NH+ pyrazolyl-H), 8.25 (d, J=1.2 Hz, 1H, ArH), 8.15 (dd, J=8.0 Hz, J=1.2 Hz, 1H, ArH), 8.09 (d, J=8.0 Hz, 1H, ArH), 8.02 (s, 1H, pyrazolyl-H), 1.82 (s, 6H, 2×CH.sub.3), 1.37 (s, 3H, CH.sub.3).

(119) Mass spectrum: (ESI, Negative): 378.31[M−H].sup.−.

Example 22

Preparation of N-(6-cyano-5-trifluoromethyl-pyridyl-3-yl)-2-(4-fluoro-1H-pyrazolyl-1-yl-2-methylpropanamide

(120) ##STR00059##

(121) First Step of Reaction

(122) Thionyl chloride (2.62 ml, 35.93 mmol) is added dropwise to a solution of 2-bromo-2-methyl propionic acid (5.00 g, 29.94 mmol) in 30 ml of anhydrous tetrahydrofuran at a temperature ranging from 0 to 12 Celsius degrees in 10 minutes. The resulting mixture is stirred under the same conditions for 2 hours. The internal temperature is adjusted to about −5 Celsius degrees. Triethylamine (Et.sub.3N) (5.42 ml, 38.92 mmol) is slowly added to the reaction mixture, with an internal temperature lower than 12 Celsius degrees. The resulting mixture is stirred under the same reaction conditions for 20 minutes, and a solution of 5-amino-3-trifluoromethyl-2-cyanopyridine (5.60 g, 29.94 mmol) in 20 mL of anhydrous tetrahydrofuran is then added dropwise thereto, and the resulting mixture is stirred at 50 Celsius degrees for two hours. After the reaction is completed as determined by thin layer chromatography, the reaction mixture is cooled to 20±5 Celsius degrees, water (50 ml) and ethyl acetate (50 ml) are then added thereto. The resulting mixture is shortly stirred and separated, with the organic phase washed by salt solution (30 ml), dried by magnesium sulphate, filtered, and with the resulting organic phase dried by suction to obtain an oily substance. The oily substance is separated and purified by silica gel column chromatography (mobile phase: dichloromethane:ethyl acetate=9:1) to obtain 8.0 g of 2-bromo-N-(6-cyano-5-trifluoromethyl-pyridyl-3-yl)-2-methylpropanamide, with a yield of 80% and a purity of 99% by HPLC (mobile phase: water and acetonitrile) (254 nm).

(123) Nuclear magnetic resonance spectrum: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.73 (s, 1H, NH), 9.39 (d, J=2.0 Hz, 1H, ArH), 8.81 (d, J=2.0 Hz, 1H, ArH), 2.03 (s, 6H, 2×CH.sub.3).

(124) Mass spectrum: (ESI, Positive): 335.9951 [M+H].sup.+.

(125) Second Step of Reaction

(126) In a 100 mL round bottom flask, 2-bromo-N-(6-cyano-5-trifluoromethyl-pyridyl-3-yl)-2-methylpropanamide (0.30 g, 0.8926 mmol), 4-fluoro-1H-pyrazol (0.154 g, 1.7852 mmol), copper(I) bromide-dimethyl sulfide (18.3 mg, 0.08926 mmol), triphenyl phosphine (23.4 mg, 0.08926 mmol), tripotassium phosphate (0.227 g, 1.0711 mmol), and sodium hydroxide (39.3 mg, 0.9818 mmol) are added, with 10 mL of anhydrous methylbenzene as solvent. The resulting mixture is heated to 50 Celsius degrees and stirred under argon for 15 hours. After the reaction is completed as determined by thin layer chromatography, the reaction mixture is cooled to 20±5 Celsius degrees, water (30 ml) and ethyl acetate (35 ml) are then added thereto. The resulting mixture is shortly stirred and separated, with the organic phase washed by salt solution (25 ml), dried by magnesium sulphate, filtered, and with the resulting organic phase dried by suction to obtain an oily substance. The oily substance is separated and purified by silica gel column chromatography (mobile phase: dichloromethane:ethyl acetate=9:1) to obtain 0.11 g of light yellow powdery material, identified as N-(6-cyano-5-trifluoromethyl-pyridyl-3-yl)-2-(4-fluoro-1H-pyrazolyl-1-yl-2-methylpropanamide, with a yield of 36%.

(127) Nuclear magnetic resonance spectrum: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ10.29 (s, 1H, NH), 9.12 (d, J=2.0 Hz, 1H, ArH), 8.47 (d, J=2.0 Hz, 1H, ArH), 8.15 (d, J=4.8 Hz, 1H, pyrazolyl-H), 7.56 (d, J=4.0 Hz, 1H, pyrazolyl-H), 1.79 (s, 6H, 2×CH.sub.3).

(128) Mass spectrum: (ESI, Negative): 340.19[M−H].sup.−.

Example 23

Preparation of N-(4-cyano-3-trifluoromethyl)-phenyl-1-(4-fluoro-1H-pyrazolyl-1-yl)-cyclobutane-formamide

(129) ##STR00060##

(130) First Step of Reaction

(131) Thionyl chloride (2.45 ml, 33.52 mmol) is added dropwise to a solution of 1-bromo-cyclobutane-formic acid (5.00 g, 27.93 mmol) in 30 ml of anhydrous tetrahydrofuran at a temperature ranging from 0 to 12 Celsius degrees in 10 minutes. The resulting mixture is stirred under the same conditions for 2 hours. The internal temperature is adjusted to about −5 Celsius degrees. Triethylamine (Et.sub.3N) (5.06 ml, 36.31 mmol) is slowly added to the reaction mixture, with an internal temperature lower than 12 Celsius degrees. The resulting mixture is stirred under the same reaction conditions for 20 minutes, and a solution of 4-cyano-3-trifluoromethyl-phenylamine (5.20 g, 27.93 mmol) in 20 mL of anhydrous tetrahydrofuran is then added dropwise thereto, and the resulting mixture is stirred at 50 Celsius degrees for three hours. After the reaction is completed as determined by thin layer chromatography, the reaction mixture is cooled to 20±5 Celsius degrees, water (50 ml) and ethyl acetate (50 ml) are then added thereto. The resulting mixture is shortly stirred and separated, with the organic phase washed by salt solution (30 ml), dried by magnesium sulphate, filtered, and with the resulting organic phase dried by suction to obtain an oily substance. The oily substance is separated and purified by silica gel column chromatography (mobile phase: hexane:ethyl acetate=2:1) to obtain 7.95 g of yellow powdery material, identified as 1-bromo-N-(4-cyano-3-trifluoromethyl-phenyl)-cyclobutane-formamide, with a yield of 82% and a purity of 98.5% by HPLC (mobile phase: water and acetonitrile) (254 nm).

(132) Nuclear magnetic resonance spectrum: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.5 (s, 1H, NH), 8.36 (d, J=1.6 Hz, 1H, ArH), 8.23 (dd, J=8.4 Hz, J=1.6 Hz, 1H, ArH), 8.13 (d, J=8.4 Hz, 1H, ArH), 2.90-2.86 (m, 2H), 2.65-2.60 (m, 2H), 2.03-1.92 (m, 2H).

(133) Mass spectrum: (ESI, Positive): 347.0002 [M+H].sup.+.

(134) Second Step of Reaction

(135) In a 100 mL round bottom flask, 1-bromo-N-(4-cyano-3-trifluoromethyl-phenyl)-cyclobutane-formamide (0.30 g, 0.8642 mmol), 4-fluoro-1H-pyrazol (0.149 g, 1.7285 mmol), copper(I) bromide-dimethyl sulfide (17.8 mg, 0.08642 mmol), triphenyl phosphine (22.7 mg, 0.08642 mmol), tripotassium phosphate (0.22 g, 1.0366 mmol), and sodium hydroxide (38 mg, 0.9507 mmol) are added, with 10 mL of anhydrous methylbenzene as solvent. The resulting mixture is heated to 50 Celsius degrees and stirred under argon for 15 hours. After the reaction is completed as determined by thin layer chromatography, the reaction mixture is cooled to 20±5 Celsius degrees, water (30 ml) and ethyl acetate (35 ml) are then added thereto. The resulting mixture is shortly stirred and separated, with the organic phase washed by salt solution (25 ml), dried by magnesium sulphate, filtered, and with the resulting organic phase dried by suction to obtain an oily substance. The oily substance is separated and purified by silica gel column chromatography (mobile phase: hexane:ethyl acetate=2:1) to obtain 0.106 g of light yellow powdery material, identified as N-(4-cyano-3-trifluoromethyl)-phenyl-1-(4-fluoro-1H-pyrazolyl-1-yl)-cyclobutane-formamide, with a yield of 35%.

(136) Nuclear magnetic resonance spectrum: .sup.1H NMR (400 MHz, DMSO-d.sub.6) 510.02 (s, 1H, NH), 8.26 (d, J=2.0 Hz, 1H, ArH), 8.15-8.15 (m, 2H, ArH+pyrazolyl-H), 8.11 (d, J=8.4 Hz, 1H, ArH), 7.55 (d, J=4.0 Hz, 1H, pyrazolyl-H), 2.89-2.85 (m, 2H), 2.65-2.59 (m, 2H), 2.02-1.91 (m, 2H), 1.78 (s, 6H, 2×CH.sub.3).

(137) Mass spectrum: (ESI, Negative): 351.19[M−H].sup.−.

Example 24

Preparation of N-(6-cyano-5-trifluoromethyl-pyridyl-3-yl)-1-(4-fluoro-1H-pyrazolyl-1-yl)-cyclobutane-formamide

(138) ##STR00061##

(139) First Step of Reaction

(140) Thionyl chloride (2.45 ml, 33.52 mmol) is added dropwise to a solution of 1-bromo-cyclobutane-formic acid (5.00 g, 27.93 mmol) in 30 ml of anhydrous tetrahydrofuran at a temperature ranging from 0 to 12 Celsius degrees in 10 minutes. The resulting mixture is stirred under the same conditions for 2 hours. The internal temperature is adjusted to about −5 Celsius degrees. Triethylamine (Et.sub.3N) (5.06 ml, 36.31 mmol) is slowly added to the reaction mixture, with an internal temperature lower than 12 Celsius degrees. The resulting mixture is stirred under the same reaction conditions for 20 minutes, and a solution of 5-amino-3-trifluoromethyl-2-cyanopyridine (5.23 g, 27.93 mmol) in 20 mL of anhydrous tetrahydrofuran is then added dropwise thereto, and the resulting mixture is stirred at 50 Celsius degrees for three hours. After the reaction is completed as determined by thin layer chromatography, the reaction mixture is cooled to 20±5 Celsius degrees, water (50 ml) and ethyl acetate (50 ml) are then added thereto. The resulting mixture is shortly stirred and separated, with the organic phase washed by salt solution (30 ml), dried by magnesium sulphate, filtered, and with the resulting organic phase dried by suction to obtain an oily substance. The oily substance is separated and purified by silica gel column chromatography (mobile phase: dichloromethane:ethyl acetate=9:1) to obtain 7.70 g of yellow powdery material, identified as 1-bromo-N-(6-cyano-5-trifluoromethyl-pyridyl-3-yl)-cyclobutane-formamide, with a yield of 75% and a purity of 98.5% by HPLC (mobile phase: water and acetonitrile) (254 nm).

(141) Nuclear magnetic resonance spectrum: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.77 (s, 1H, NH), 9.40 (d, J=2.0 Hz, 1H, ArH), 8.85 (d, J=2.0 Hz, 1H, ArH), 2.82-2.78 (m, 2H), 2.59-2.53 (m, 2H), 2.04-1.95 (m, 2H).

(142) Mass spectrum: (ESI, Positive): 347.09951 [M+H].sup.+.

(143) Second Step of Reaction

(144) In a 100 mL round bottom flask, 1-bromo-N-(6-cyano-5-trifluoromethyl-pyridyl-3-yl)-2-cyclobutane-formamide (0.30 g, 0.8618 mmol), 4-fluoro-1H-pyrazol (0.148 g, 1.7236 mmol), copper(I) bromide-dimethyl sulfide (17.7 mg, 0.08618 mmol), triphenyl phosphine (22.6 mg, 0.08618 mmol), tripotassium phosphate (0.22 g, 1.0341 mmol), and sodium hydroxide (38 mg, 0.9480 mmol) are added, with 10 mL of anhydrous methylbenzene as solvent. The resulting mixture is heated to 50 Celsius degrees and stirred under argon for 15 hours. After the reaction is completed as determined by thin layer chromatography, the reaction mixture is cooled to 20±5 Celsius degrees, water (30 ml) and ethyl acetate (35 ml) are then added thereto. The resulting mixture is shortly stirred and separated, with the organic phase washed by salt solution (25 ml), dried by magnesium sulphate, filtered, and with the resulting organic phase dried by suction to obtain an oily substance. The oily substance is separated and purified by silica gel column chromatography (mobile phase: dichloromethane:ethyl acetate=9:1) to obtain 82 mg of yellow powdery material, identified as N-(6-cyano-5-trifluoromethyl-pyridyl-3-yl)-1-(4-fluoro-1H-pyrazolyl-1-yl)-cyclobutane-formamide, with a yield of 27%.

(145) Nuclear magnetic resonance spectrum: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.25 (s, 1H, NH), 9.10 (d, J=2.0 Hz, 1H, ArH), 8.72 (d, J=2.0 Hz, 1H, ArH), 8.13 (d, J=4.8 Hz, 1H, pyrazolyl-H), 7.51 (d, J=4.0 Hz, 1H, pyrazolyl-H), 2.91-2.86 (m, 2H), 2.67-2.60 (m, 2H), 2.05-1.93 (m, 2H), 1.89 (s, 6H, 2×CH.sub.3).

(146) Mass spectrum: (ESI, Negative): 352.21[M−H].sup.−.

Example 25

Preparation of 2-(4-bromo-3-fluoro-1H-pyrazolyl-1-yl)-N-(4-cyano-3-trifluoromethyl)-phenyl-2-methylpropanamide

(147) ##STR00062##

(148) In a 100 mL round bottom flask, 2-bromo-N-(4-cyano-3-trifluoromethyl-phenyl)-2-methylpropanamide (0.40 g, 1.1936 mmol), 4-bromo-3-fluoro-1H-pyrazol (0.394 g, 2.38727 mmol), copper(I) bromide-dimethyl sulfide (25 mg, 0.11936 mmol), triphenyl phosphine (31 mg, 0.11936 mmol), tripotassium phosphate (0.304 g, 1.4323 mmol), and sodium hydroxide (53 mg, 1.3130 mmol) are added, with 10 mL of anhydrous methylbenzene as solvent. The resulting mixture is heated to 50 Celsius degrees and stirred under argon for 14 hours. After the reaction is completed as determined by thin layer chromatography, the reaction mixture is cooled to 20±5 Celsius degrees, water (30 ml) and ethyl acetate (35 ml) are then added thereto. The resulting mixture is shortly stirred and separated, with the organic phase washed by salt solution (25 ml), dried by magnesium sulphate, filtered, and with the resulting organic phase dried by suction to obtain an oily substance. The oily substance is separated and purified by silica gel column chromatography (mobile phase: hexane:ethyl acetate=3:1 to 2:1) to obtain 0.24 g of almost white powdery material, identified as 2-(4-bromo-3-fluoro-1H-pyrazolyl-1-yl)-N-(4-cyano-3-trifluoromethyl)-phenyl-2-methylpropanamide, with a yield of 48%.

(149) Nuclear magnetic resonance spectrum: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.04 (s, 1H, NH), 8.25 (d, J=2.0 Hz, 1H, ArH), 8.16-8.14 (m, 2H, ArH+pyrazolyl-H), 8.10 (d, J=8.4 Hz, 1H, ArH), 1.84 (s, 6H, 2×CH.sub.3).

(150) Mass spectrum: (ESI, Negative): 417.02 [M−H].sup.−.

Example 26

Preparation of 2-(3,4-difluoro-1H-pyrazolyl-1-yl)-N-(4-cyano-3-trifluoromethyl)-phenyl-2-methylpropanamide

(151) ##STR00063##

(152) In a 100 mL round bottom flask, 2-(4-bromo-3-fluoro-1H-pyrazolyl-1-yl)-N-(4-cyano-3-trifluoromethyl) phenyl-2-methylpropanamide (0.20 g, 0.4771 mmol) is added, with 4 mL of anhydrous tetrahydrofuran as solvent. The resulting mixture is stirred under argon for 5 minutes, and then cooled to −78 Celsius degrees with a dry ice-acetone bath. A solution of 2.5 mol of N-butyllithium (0.382 ml, 0.9542 mmol) is added to the above reaction mixture, and the resulting mixture is stirred under the same conditions for 15 minutes. A solution of N-fluorobenzenesulfonimide (0.15 g, 0.4771 mmol) in 2.0 ml of anhydrous tetrahydrofuran is then added to the above reaction mixture. The resulting reaction mixture is gradually returned to room temperature and stirred under argon for 15 hours. After the reaction is completed as determined by thin layer chromatography, salt solution (20 ml) and ethyl acetate (30 ml) are then added thereto. The resulting mixture is shortly stirred and separated, with the organic phase washed by salt solution (25 ml), dried by magnesium sulphate, filtered, and with the resulting organic phase dried by suction to obtain an oily substance. The oily substance is separated and purified by silica gel column chromatography (mobile phase: dichloromethane:ethyl acetate=9:1) to obtain 43 mg of light yellow powdery material, identified as 2-(3,4-difluoro-1H-pyrazolyl-1-yl)-N-(4-cyano-3-trifluoromethyl)-phenyl-2-methylpropanamide, with a yield of 25%.

(153) Nuclear magnetic resonance spectrum: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.36 (s, 1H, NH), 8.43 (d, J=2.0 Hz, 1H, ArH), 8.22 (dd, J=8.0 Hz, J=2.0 Hz, 1H, ArH), 8.10 (d, J=8.0 Hz, 1H, ArH), 7.85 (m, 1H, pyrazolyl-H), 1.90 (s, 6H, 2×CH.sub.3).

(154) Mass spectrum: (ESI, Negative): 357.16 [M−H].sup.−.

Example 27

Preparation of 2-(3-chloro-4-methyl-1H-pyrazolyl-1-yl)-N-(4-cyano-3-trifluoromethyl)-phenyl-2-methylpropanamide

(155) ##STR00064##

(156) In a 100 mL round bottom flask, 2-bromo-N-(4-cyano-3-trifluoromethyl-phenyl)-2-methylpropanamide (0.40 g, 1.1936 mmol), 3-chloro-4-methyl-1H-pyrazol (0.278 g, 2.38727 mmol), copper(I) bromide-dimethyl sulfide (25 mg, 0.11936 mmol), triphenyl phosphine (31 mg, 0.11936 mmol), tripotassium phosphate (0.304 g, 1.4323 mmol), and sodium hydroxide (53 mg, 1.3130 mmol) are added, with 10 mL of anhydrous methylbenzene as solvent. The resulting mixture is heated to 50 Celsius degrees and stirred under argon for 14 hours. After the reaction is completed as determined by thin layer chromatography, the reaction mixture is cooled to 20±5 Celsius degrees, water (30 ml) and ethyl acetate (35 ml) are then added thereto. The resulting mixture is shortly stirred and separated, with the organic phase washed by salt solution (25 ml), dried by magnesium sulphate, filtered, and with the resulting organic phase dried by suction to obtain an oily substance. The oily substance is separated and purified by silica gel column chromatography (mobile phase: hexane:ethyl acetate=3:1 to 2:1) to obtain 0.16 g of almost white powdery material, identified as 2-(3-chloro-4-methyl-1H-pyrazolyl-1-yl)-N-(4-cyano-3-trifluoromethyl)-phenyl-2-methylpropanamide, with a yield of 36.4%.

(157) Nuclear magnetic resonance spectrum: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.00 (s, 1H, NH), 8.22 (d, J=1.0 Hz, 1H, ArH), 8.13 (dd, J=8.4 Hz, 1H, ArH), 8.10 (d, J=8.4 Hz, 1H, ArH), 7.91 (s, 1H, pyrazolyl-H), 1.91 (s, 3H, CH.sub.3), 1.82 (s, 6H, 2×CH.sub.3).

(158) Mass spectrum: (ESI, Negative): 369.12 [M−H].sup.−.

Example 28

Preparation of 2-(3-bromo-4-chloro-1H-pyrazolyl-1-yl)-N-(4-cyano-3-trifluoromethyl)-phenyl-2-methylpropanamide

(159) ##STR00065##

(160) In a 100 mL round bottom flask, 2-bromo-N-(4-cyano-3-trifluoromethyl-phenyl)-2-methylpropanamide (0.40 g, 1.1936 mmol), 3-bromo-3-chloro-1H-pyrazol (0.433 g, 2.38727 mmol), copper(I) bromide-dimethyl sulfide (25 mg, 0.11936 mmol), triphenyl phosphine (31 mg, 0.11936 mmol), tripotassium phosphate (0.304 g, 1.4323 mmol), and sodium hydroxide (53 mg, 1.3130 mmol) are added, with 10 mL of anhydrous methylbenzene as solvent. The resulting mixture is heated to 50 Celsius degrees and stirred under argon for 14 hours. After the reaction is completed as determined by thin layer chromatography, the reaction mixture is cooled to 20±5 Celsius degrees, water (30 ml) and ethyl acetate (35 ml) are then added thereto. The resulting mixture is shortly stirred and separated, with the organic phase washed by salt solution (25 ml), dried by magnesium sulphate, filtered, and with the resulting organic phase dried by suction to obtain an oily substance. The oily substance is separated and purified by silica gel column chromatography (mobile phase: hexane:ethyl acetate=3:1 to 2:1) to obtain 0.22 g of white powdery material, identified as 2-(3-bromo-4-chloro-1H-pyrazolyl-1-yl)-N-(4-cyano-3-trifluoromethyl)-phenyl-2-methylpropanamide, with a yield of 42.3%.

(161) Nuclear magnetic resonance spectrum: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.01 (s, 1H, NH), 8.24-8.21 (m, 2H, ArH+pyrazolyl-H), 8.13 (d, J=8.8 Hz, 1H, ArH), 8.10 (d, J=8.8 Hz, 1H, ArH), 1.81 (s, 6H, 2×CH.sub.3).

(162) Mass spectrum: (ESI, Negative): 433.01 [M−H].sup.−.

Example 29

Preparation of 2-(3-fluoro-4-chloro-1H-pyrazolyl-1-yl)-N-(4-cyano-3-trifluoromethyl)-phenyl-2-methylpropanamide

(163) ##STR00066##

(164) In a 100 mL round bottom flask, 2-(3-bromo-4-chloro-1H-pyrazolyl-1-yl)-N-(4-cyano-3-trifluoromethyl) phenyl-2-methylpropanamide (0.20 g, 0.4591 mmol) is added, with 4 mL of anhydrous tetrahydrofuran as solvent. The resulting mixture is stirred under argon for 5 minutes, and then cooled to −78 Celsius degrees with a dry ice-acetone bath. A solution of 2.5 mol of N-butyllithium (0.367 ml, 0.9182 mmol) is added to the above reaction mixture, and the resulting mixture is stirred under the same conditions for 15 minutes. A solution of N-fluorobenzenesulfonimide (0.145 g, 0.4591 mmol) in 2.0 ml of anhydrous tetrahydrofuran is then added to the above reaction mixture. The resulting reaction mixture is gradually returned to room temperature and stirred under argon for 15 hours. After the reaction is completed as determined by thin layer chromatography, salt solution (20 ml) and ethyl acetate (30 ml) are then added thereto. The resulting mixture is shortly stirred and separated, with the organic phase washed by salt solution (25 ml), dried by magnesium sulphate, filtered, and with the resulting organic phase dried by suction to obtain an oily substance. The oily substance is separated and purified by silica gel column chromatography (mobile phase: dichloromethane:ethyl acetate=9:1) to obtain 50 mg of yellow powdery material, identified as 2-(3-fluoro-4-chloro-1H-pyrazolyl-1-yl)-N-(4-cyano-3-trifluoromethyl)-phenyl-2-methylpropanamide, with a yield of 29%.

(165) Nuclear magnetic resonance spectrum: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.35 (s, 1H, NH), 8.44 (d, J=1.6 Hz, 1H, ArH), 8.23 (dd, J=8.2 Hz, J=1.6 Hz, 1H, ArH), 8.11 (d, J=8.2 Hz, 1H, ArH), 7.97 (d, J=3.6 Hz, 1H, pyrazolyl-H), 1.89 (s, 6H, 2×CH.sub.3).

(166) Mass spectrum: (ESI, Negative): 373.10 [M−H].sup.−.

Example 30

Preparation of 2-(3-chloro-4-cyano-1H-pyrazolyl-1-yl)-N-(4-cyano-3-trifluoromethyl)-phenyl-2-methylpropanamide

(167) ##STR00067##

(168) In a 100 mL round bottom flask, 2-bromo-N-(4-cyano-3-trifluoromethyl-phenyl)-2-methylpropanamide (0.40 g, 1.1936 mmol), 3-chloro-4-cyano-1H-pyrazol (0.304 g, 2.38727 mmol), copper(I) bromide-dimethyl sulfide (25 mg, 0.11936 mmol), triphenyl phosphine (31 mg, 0.11936 mmol), tripotassium phosphate (0.304 g, 1.4323 mmol), and sodium hydroxide (53 mg, 1.3130 mmol) are added, with 10 mL of anhydrous methylbenzene as solvent. The resulting mixture is heated to 50 Celsius degrees and stirred under argon for 14 hours. After the reaction is completed as determined by thin layer chromatography, the reaction mixture is cooled to 20±5 Celsius degrees, water (30 ml) and ethyl acetate (35 ml) are then added thereto. The resulting mixture is shortly stirred and separated, with the organic phase washed by salt solution (25 ml), dried by magnesium sulphate, filtered, and with the resulting organic phase dried by suction to obtain an oily substance. The oily substance is separated and purified by silica gel column chromatography (mobile phase: hexane:ethyl acetate=3:1 to 2:1) to obtain 0.16 g of white powdery material, identified as 2-(3-chloro-4-cyano-1H-pyrazolyl-1-yl)-N-(4-cyano-3-trifluoromethyl)-phenyl-2-methylpropanamide, with a yield of 35%.

(169) Nuclear magnetic resonance spectrum: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.99 (s, 1H, NH), 8.69 (s, 1H, pyrazolyl-H), 8.21 (s, 1H, ArH), 8.12 (d, J=8.4 Hz, H, ArH), 8.10 (d, J=8.4 Hz, 1H, ArH), 1.83 (s, 6H, 2×CH.sub.3).

(170) Mass spectrum: (ESI, Negative): 380.15 [M−H].sup.−.

II. EXAMPLES FOR PREPARING FORMULATIONS

Example A for Formulation: Preparation of an Injection

(171) (i). Formulation Composition:

(172) TABLE-US-00001 Compound of Example 15 25 g Polysorbate 80 20 g Mannitol 10 g Iniection water to 5000 ml 1000 pcs

(173) (ii). Preparation Method:

(174) In accordance with the formulation composition, the compound of example 15, polysorbate 80 and mannitol are added to 4000 ml of injection water. The resulting mixture is stirred and dissolved, and thereafter injection water is then added until the total volume of the resulting mixture reaches 5000 ml. The resulting mixture is further stirred, and sterilized by filtration through microporous filter (0.22 μM), and the filtrate is aseptically filled in 5 ml of ampoules with 5 ml filtrate per ampoule (spec: 25 mg per ampoule), sealed and sterilized.

Example B for Formulation: Preparation of a Tablet

(175) (i). Formulation Composition:

(176) Formulation 2-1 Formulation for Tablet with Formula I (Weight Per 1000 Tablets)

(177) TABLE-US-00002 Compound of Example 15 200 g Lactose 100 g Microcrystalline cellulose 60 g Pregelatinized starch 40 g Carboxymethyl starch sodium 40 g Aerosil 4 g Magnesium stearate 4 g 0.3% HPMC appropriate amount 1000 pieces

(178) Formulation 2-2 Formulation for Tablet with Formula I (Weight Per 1000 Tablets)

(179) TABLE-US-00003 Compound of Example 15 50 g Lactose 50 g Microcrystalline cellulose 15 g Pregelatinized starch 10 g Carboxymethyl starch sodium 10 g Aerosil 0.1 g Magnesium stearate 1 g 0.3% HPMC appropriate amount 1000 pieces

(180) Formulation 2-3 Formulation for Tablet with Formula I (Weight Per 1000 Tablets)

(181) TABLE-US-00004 Compound of Example 15 10 g Lactose 10 g Microcrystalline cellulose 3 g Pregelatinized starch 2 g Carboxymethyl starch sodium 2 g Aerosil 0.02 g Magnesium stearate 0.2 g 0.3% HPMC appropriate amount 1000 pieces

(182) (ii) Preparation Method:

(183) The compound of Example 15, lactose and part of microcrystalline cellulose are micronize in a ratio of 200:100:40, and the remaining microcrystalline cellulose, pregelatinized starch, Aerosil and carboxymethyl starch sodium in accordance with the formulation which are sieved by 80 mesh are added therein and well mixed, and thereafter 0.3% HPMC solution is added therein to prepare soft material which is then granulated with 18 mesh. The resulting granule is dried at 60 Celsius degrees (controlling the moisture content of the granule at about 3%), and magnesium stearate sieved with 80 mesh is added and mixed with the granule. The resulting granule is sieved with 16 mesh, tableted and packaged.

III. BIOLOGICAL ACTIVITY DETECTION

(184) Reagents and instruments: radiolabeled dihydrotestosterone (DHT-d3) and unlabeled dihydrotestosterone (DHT) purchased from Sigma-Aldrich (St. Louis, Mo.), scintillation solution purchased from Perkin Elmer Life Sciences (Boston, Mass.), hydroxyapatite (HAP) suspension purchased from Bio-Rad Laboratories (Hercules, Calif.), buffer (containing 10 mM Tris, 1.5 mM disodium EDTA, 0.25 M sucrose, 10 mM sodium molybdate and 1 mM PMSF, pH value adjusted to 7.4), and hydroxyapatite (HAP) solution (containing 50 mM Tris and 1 mM KH.sub.2PO.sub.4, pH value adjusted to 7.4).

(185) In the present invention, the biological activity of the N-aromatic amide compounds with the formula (I) and/or (II) is measured accord to the following method. The compounds of the present invention obtained from the preparing examples and the control compounds are respectively dissolved in DMSO to prepare mother liquors with certain concentrations, which are diluted into several concentration gradients with DMSO, that are further diluted with buffer to have concentrations ranging from 10.sup.−1 nM to 10.sup.4 nM and stored in a refrigerator at 4 Celsius degrees for use. The androgen receptor (prepared from the prostate of male SD rats, 200-250 g of male Sprague-Dawley rats) and the radiolabeled dihydrotestosterone (DHT-d3, 84 Ci/mmol) are added to the buffer and well mixed for preparing reaction solution. The concentration gradients of the diluted compounds are respectively added into the reaction solution and well mixed, and the resulting mixtures are incubated at 4 Celsius degrees for 15 hours, so that the compounds and the dihydrotestosterone can fully react with the androgen receptor. Thereafter, the hydroxyapatite (HAP) suspension is added therein, well mixed, incubated for 10 minutes at 4 Celsius degrees, and centrifuged for removing the supernatant containing free dihydrotestosterone. The dihydrotestosterone bound to the androgen receptor is adsorbed in the hydroxyapatite and thus retained in the precipitated particles, thereby separating the bound and unbound radiolabelled ligands. A scintillation solution is added to the precipitate, well mixed, and detected for the radioactivity intensity using a WALLACE MicroBeta Trilux Scintillator (Perkin Elmer). The detected radioactivity intensity values for the concentration gradients are processed to obtain values of IC.sub.50 and K.sub.i. The specific biological activity (the competition results between androgen receptor ligand and radioligand) is shown in the following table:

(186) TABLE-US-00005 IC.sub.50 K.sub.i Compound Structural Formula Log P (μM) (μM) Bicalutumide (Control) 2.57 0.637 1.25 (R) Bicalutumide (Control) 2.57 0.264 0.518 Enzalutamide (Control) 0 4.56 0.218 2.75 Compound of Example 1 6.16 0.546 Compound of Example 2 6.00 0.337 Compound of Example 3 4.32 0.215 0.367 Compound of Example 4 4.32 0.246 0.491 Compound of Example 5 4.32 0.227 0.314 Compound of Example 6 0.261 0.421 Compound of Example 7 4.72 0.253 0.295 Compound of Example 8 5.09 0.357 0.440 Compound of Example 9 4.20 0.232 0.445 Compound of Example 10 0 4.81 0.437 0.387 Compound of Example 11 4.97 0.505 0.505 Compound of Example 12 3.96 0.205 0.351 Compound of Example 13 5.18 0.416 Compound of Example 14 4.56 0.760 Compound of Example 15 2.88 0.125 Compound of Example 16 3.35 0.147 Compound of Example 17 3.28 0.116 Compound of Example 18 3.64 0.168 Compound of Example 19 Compound of Example 20 0 2.76 0.107 Compound of Example 21 1.87 Compound of Example 22 1.97 0.073 Compound of Example 23 2.94 0.115 Compound of Example 24 2.02 0.068 Compound of Example 25 4.18 0.091 Compound of Example 26 3.51 0.075 Compound of Example 27 4.11 0.133 Compound of Example 28 4.52 0.159 Compound of Example 29 3.91 0.105 Compound of Example 30 00 3.66 0.088

(187) Comparing the test compounds and the positive control groups, the following conclusions can be drawn:

(188) Example 1 (IC.sub.50=0.546 μM), Example 2 (IC.sub.50=0.337 μM), Example 3 (IC.sub.50=0.215 μM), Example 4 (IC.sub.50=0.246 μM), Example 5 (IC.sub.50=0.227 μM), Example 6 (IC.sub.50=0.261 μM), Example 7 (IC.sub.50=0.253 μM), Example 8 (IC.sub.50=0.357 μM), Example 9 (IC.sub.50=0.232 μM), Example 10 (IC.sub.50=0.437 μM), Example 11 (IC.sub.50=0.505 μM), Example 12 (IC.sub.50=0.205 μM) and Example 13 (IC.sub.50=0.416 μM) have significantly stronger antagonism to the androgen receptor than the bicalutumide (IC.sub.50=0.637 μM) positive control groups.

(189) Example 15 (IC.sub.50=0.125 μM), Example 16 (IC.sub.50=0.147 μM), Example 17 (IC.sub.50=0.116 μM), Example 18 (IC.sub.50=0.168 μM), Example 20 (IC.sub.50=0.107 μM), Example 22 (IC.sub.50=0.073 μM), Example 23 (IC.sub.50=0.115 μM), Example 24 (IC.sub.50=0.068 μM), Example 25 (IC.sub.50=0.091 μM), Example 26 (IC.sub.50=0.075 μM), Example 27 (IC.sub.50=0.133 μM), Example 28 (IC.sub.50=0.159 μM), Example 29 (IC.sub.50=0.105 μM) and Example 30 (IC.sub.50=0.088 μM) have significantly stronger antagonism to the androgen receptor than the latest generation of new anti-prostate cancer drug, enzalutamide (IC.sub.50=0.215 μM) positive control group.

(190) Example 3 (K.sub.i=0.367 μM), Example 4 (IC.sub.50=0.491 μM), Example 5 (K.sub.i=0.314 μM), Example 6 (K.sub.i=0.421 μM), Example 7 (K.sub.i=0.295 μM), Example 8 (K.sub.i=0.440 μM), Example 9 (K.sub.i=0.445 μM), Example 10 (K.sub.i=0.387 μM), Example 11 (K.sub.i=0.505 μM) and Example 12 (K.sub.i=0.351 μM) have stronger binding activity to the androgen receptor than bicalutumide control group (K.sub.i=1.25 μM), and much stronger binding activity to the androgen receptor than enzalutamide control group (K.sub.i=2.75 μM).

(191) The detection results for the biological activity in the above table shows that, in comparison with the positive control groups (bicalutumide, and enzalamine), the compounds of the present invention are capable of binding more strongly to the androgen receptor and have stronger activity for anti-androgen receptor. Therefore, a new N-aromatic amide drug for anti-androgen which is safer and more effective than the existing drugs can be developed, and has an important value and status in the treatment of androgen-related diseases.

(192) The compounds of the present invention can be used alone or as compositions for the prevention or treatment of various androgen-related diseases, such as prostate cancer, prostate hyperplasia, breast cancer, bladder cancer, and ovarian cancer, and also for the prevention or treatment of acne, hirsutism, psilosis and other diseases.

(193) The above description is merely exemplary embodiments and examples of the present invention and is not intended to limit the scope of the invention, and any equivalent structure or equivalent process change made depending on the contents of this specification, or those directly or indirectly used in other related technical fields, fall in the scope of the present invention.