4-氰基哌啶盐酸盐

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: This compound was prepared by using procedures analogous to those described for the synthesis of Example 54, Step 3 starting from 2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)propanoic acid and piperidine-4-carbonitrile hydrochloride (and Cat. No.). LCMS (M+H)+: m/z=566.2. This compound was prepared

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Dichloromethane (2 mL) was added to 7-[6-(1H-imidazol-2-yl)pyridin-3-yl]-2,3-dihydro-1,4-benzoxazepin-4(5H)-carbonyl chloride was obtained in step 4 followed by diisopropylethylamine (0.12 mL, 0.65 mmol) and 4-cyanopiperidine hydrochloride (25 mg, 0.16 mmol). The mixture was stirred at room temperature for 30 min and then concentrated. Purification of the residue by preparative reverse phase HPLC (0.1% aqueous ammonium acetate-acetonitrile) provided the title compound (18 mg, 32% yield) as a colorless solid. 1H NMR (400 MHz, DMSO-d6): 12.84 (br. S, 1H), 8.86 (d, 1H), 8.11 (m, 2H), 7.71 (d, 1H), 7.61 (dd, 1H), 7.25 (br. s, 1H), 7.10 (br. s, 1H), 7.06 (d, 1H), 4.49 (s, 2H), 4.23 (m, 2H), 3.61 (m, 2H), 3.30 (m, 2H), 3.00 (m, 3H), 1.87 (m, 2H), 1.73 (m, 2H); MS (EI) for C24H24N6O2: 429 (MH+). was obtained in step 4 concentrated Purification of the residue by preparative reverse phase HPLC (0.1% aqueous ammonium acetate-acetonitrile)

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 2-methylpropyl 2-[4-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)phenyl]-1H-imidazole-1-carboxylate (361 mg, 0.92 mmol) was taken into dichloromethane (5 mL) followed by addition of DIPEA (0.32 mL, 1.84 mmol). The solution thus obtained was added slowly by syringe over several minutes to a solution of phosgene (20 W % in toluene, 0.49 mL, 0.93 mmol) diluted in dichloromethane (5 mL) and cooled to 0° C. The resulting mixture was stirred for 5 minutes then allowed to warm to room temperature and concentrated. The residue was taken back into dichloromethane (5 mL) followed by addition of DIPEA (0.48 mL, 2.76 mmol) and 4-cyanopiperidine hydrochloride salt (156 mg, 1.06 mmol) then stirred for 12 h. The mixture was concentrated then partitioned with ethyl acetate and 10% aqueous citric acid. The organic solution was washed with brine, dried over anhydrous sodium sulfate then filtered and concentrated. The residue was purified by silica gel chromatography (100% ethyl acetate) to give 2-methylpropyl 2-(4-{4-[(4-cyanopiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}phenyl)-1H-imidazole-1-carboxylate (296 mg, 61% yield) as a crystalline solid. MS (EI) for C30H33N5O4: 529 (MH+). The solution thus obtained to warm to room temperature concentrated then stirred for 12 h The mixture was concentrated then partitioned with ethyl acetate and 10% aqueous citric acid The organic solution was washed with brine dried over anhydrous sodium sulfate then filtered concentrated The residue was purified by silica gel chromatography (100% ethyl acetate)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: This compound was prepared by using procedures analogous to those described for the synthesis of Example 54, Step 3 starting from 2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)propanoic acid and piperidine-4-carbonitrile hydrochloride (and Cat. No.). LCMS (M+H)+: m/z=566.2. This compound was prepared

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: This compound was prepared by using procedures analogous to those described for the synthesis of Example 54, Step 3 starting from 2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)propanoic acid and piperidine-4-carbonitrile hydrochloride (and Cat. No.). LCMS (M+H)+: m/z=566.2. This compound was prepared

反应条件: temp:170.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 1.2 g of the resulting 4-piperidinecarbonitrile hydrochloride, 1.0 g 1-chloro-4-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalazine, 1.8 g diisopropylethylamine, and 10 ml 1-methyl-2-pyrrolidone was stirred at 170° C. for 2 hr and 30 min. After cooling, ethyl acetate was added to the reaction solution which was then washed with water and brine. After it was dried over anhydrous sodium sulfate, the solvent was evaporated and the resulting residue was purified by silica gel column chromatography. The resulting free compound was dissolved in ethyl acetate, then a solution of 4 N hydrochloric acid/ethyl acetate was added thereto, and the resulting crystals were collected by filtration to give 880 mg of the title compound as a yellow powder. After cooling was then washed with water and brine After it was dried over anhydrous sodium sulfate the solvent was evaporated the resulting residue was purified by silica gel column chromatography The resulting free compound was dissolved in ethyl acetate a solution of 4 N hydrochloric acid/ethyl acetate was added the resulting crystals were collected by filtration

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 11.0 g of 1-benzyl-4-piperidinecarbonitrile was dissolved in 100 ml 1,2-dichloroethane, 7.1 ml 1-chloroethyl chloroformate was added thereto under ice-cooling. The mixture was stirred at room temperature for 15 min, and then heated under reflux for 1 hr and 20 min. After evaporating, 50 ml methanol was added thereto and it was heated under reflux for 1 hr. The reaction solution was evaporated, and the crystalline residue was washed with ethyl acetate and collected by filtration to give 8.0 g of 4-piperidinecarbonitrile hydrochloride as white crystals. under ice-cooling heated under reflux for 1 hr and 20 min After evaporating 50 ml methanol was added it was heated under reflux for 1 hr The reaction solution was evaporated the crystalline residue was washed with ethyl acetate collected by filtration

反应条件: temp:170.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 1.2 g of the resulting 4-piperidinecarbonitrile hydrochloride, 1.0 g 1-chloro-4-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalazine, 1.8 g diisopropylethylamine, and 10 ml 1-methyl-2-pyrrolidone was stirred at 170° C. for 2 hr and 30 min. After cooling, ethyl acetate was added to the reaction solution which was then washed with water and brine. After it was dried over anhydrous sodium sulfate, the solvent was evaporated and the resulting residue was purified by silica gel column chromatography. The resulting free compound was dissolved in ethyl acetate, then a solution of 4 N hydrochloric acid/ethyl acetate was added thereto, and the resulting crystals were collected by filtration to give 880 mg of the title compound as a yellow powder. After cooling was then washed with water and brine After it was dried over anhydrous sodium sulfate the solvent was evaporated the resulting residue was purified by silica gel column chromatography The resulting free compound was dissolved in ethyl acetate a solution of 4 N hydrochloric acid/ethyl acetate was added the resulting crystals were collected by filtration

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 11.0 g of 1-benzyl-4-piperidinecarbonitrile was dissolved in 100 ml 1,2-dichloroethane, 7.1 ml 1-chloroethyl chloroformate was added thereto under ice-cooling. The mixture was stirred at room temperature for 15 min, and then heated under reflux for 1 hr and 20 min. After evaporating, 50 ml methanol was added thereto and it was heated under reflux for 1 hr. The reaction solution was evaporated, and the crystalline residue was washed with ethyl acetate and collected by filtration to give 8.0 g of 4-piperidinecarbonitrile hydrochloride as white crystals. under ice-cooling heated under reflux for 1 hr and 20 min After evaporating 50 ml methanol was added it was heated under reflux for 1 hr The reaction solution was evaporated the crystalline residue was washed with ethyl acetate collected by filtration

反应条件: temp:170.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 1.2 g of the resulting 4-piperidinecarbonitrile hydrochloride, 1.0 g 1-chloro-4-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalazine, 1.8 g diisopropylethylamine, and 10 ml 1-methyl-2-pyrrolidone was stirred at 170° C. for 2 hr and 30 min. After cooling, ethyl acetate was added to the reaction solution which was then washed with water and brine. After it was dried over anhydrous sodium sulfate, the solvent was evaporated and the resulting residue was purified by silica gel column chromatography. The resulting free compound was dissolved in ethyl acetate, then a solution of 4 N hydrochloric acid/ethyl acetate was added thereto, and the resulting crystals were collected by filtration to give 880 mg of the title compound as a yellow powder. After cooling was then washed with water and brine After it was dried over anhydrous sodium sulfate the solvent was evaporated the resulting residue was purified by silica gel column chromatography The resulting free compound was dissolved in ethyl acetate a solution of 4 N hydrochloric acid/ethyl acetate was added the resulting crystals were collected by filtration

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 11.0 g of 1-benzyl-4-piperidinecarbonitrile was dissolved in 100 ml 1,2-dichloroethane, 7.1 ml 1-chloroethyl chloroformate was added thereto under ice-cooling. The mixture was stirred at room temperature for 15 min, and then heated under reflux for 1 hr and 20 min. After evaporating, 50 ml methanol was added thereto and it was heated under reflux for 1 hr. The reaction solution was evaporated, and the crystalline residue was washed with ethyl acetate and collected by filtration to give 8.0 g of 4-piperidinecarbonitrile hydrochloride as white crystals. under ice-cooling heated under reflux for 1 hr and 20 min After evaporating 50 ml methanol was added it was heated under reflux for 1 hr The reaction solution was evaporated the crystalline residue was washed with ethyl acetate collected by filtration

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Prepared according to the method of example 51, using 2,6-dichloro-N-(cyclohexylethyl)-5-quinolinecarboxamide (Example 94 (d)) (0.35 g), and 4-cyanopiperidine hydrochloride (0.25 g) to afford the title compound (0.12 g). Prepared