1-甲酰高哌嗪

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 1.28 g (10 mmol) of 1,4-diazepane-1-carbaldehyde and 0.33 g (11 mmol) of paraformaldehyde in 13 ml of dioxane is heated at 80° C. until a homogeneous solution is obtained. 1.70 g (10 mmol) of 3-trifluoromethylphenylacetylene in solution in 7 ml of dioxane and 1.81 g (10 mmol) of copper diacetate are added. The mixture is heated at 80° C. for 4 hours. It is cooled to ambient temperature and diluted with 75 ml of ethyl acetate. The organic phase is washed with 25 ml of 30% ammonia solution and with saturated aqueous sodium chloride solution. It is dried over sodium sulphate and evaporated to dryness. The residue is purified by chromatography on silica gel, eluting with a 98/2/0.2 then 96/4/0.4 and 94/6/0.6 mixture of dichloromethane, methanol and 30% ammonia, to give 2.67 g of product in the form of a yellow oil. is obtained The mixture is heated at 80° C. for 4 hours It is cooled to ambient temperature The organic phase is washed with 25 ml of 30% ammonia solution and with saturated aqueous sodium chloride solution It is dried over sodium sulphate evaporated to dryness The residue is purified by chromatography on silica gel eluting with a 98/2/0.2 96/4/0.4 and 94/6/0.6 mixture of dichloromethane, methanol and 30% ammonia

反应条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 1.28 g (10 mmol) of 1,4-diazepane-1-carbaldehyde and 0.33 g (11 mmol) of paraformaldehyde in 13 ml of dioxane is heated at 80° C. until a homogeneous solution is obtained. 1.70 g (10 mmol) of 3-trifluoromethylphenylacetylene in solution in 7 ml of dioxane and 1.81 g (10 mmol) of copper diacetate are added. The mixture is heated at 80° C. for 4 hours. It is cooled to ambient temperature and diluted with 75 ml of ethyl acetate. The organic phase is washed with 25 ml of 30% ammonia solution and with saturated aqueous sodium chloride solution. It is dried over sodium sulphate and evaporated to dryness. The residue is purified by chromatography on silica gel, eluting with a 98/2/0.2 then 96/4/0.4 and 94/6/0.6 mixture of dichloromethane, methanol and 30% ammonia, to give 2.67 g of product in the form of a yellow oil. is obtained The mixture is heated at 80° C. for 4 hours It is cooled to ambient temperature The organic phase is washed with 25 ml of 30% ammonia solution and with saturated aqueous sodium chloride solution It is dried over sodium sulphate evaporated to dryness The residue is purified by chromatography on silica gel eluting with a 98/2/0.2 96/4/0.4 and 94/6/0.6 mixture of dichloromethane, methanol and 30% ammonia

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

实验步骤: 2-Chloro-1-phenyl-1H-indole-3-carboxaldehyde is reacted with [1,4]diazepane-1-carboxaldehyde as described in Example 1 to afford 2-(4-formyl-[1,4]diazepan-1-yl)-1-phenyl-1H-indole-3-carboxaldehyde (97% yield) as a yellow solid. LC/MS: MS 348 (M+H); RT 2.77 min; (CDCl3): 10.26 (1H, d), 8.22 (1H, d), 8.00 (0.5H, s), 7.86 (0.5H, s), 7.47-7.69(3H, m), 7.23-7.38 (3H, m), 7.17(1H, t), 6.97 (1H, d), 3.25-3.70 (8H, m), 1.50-1.73(2H, m).

反应条件: temp:0.00; pressure:0.00; stir:

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

实验步骤: 2-Chloro-1-phenyl-1H-indole-3-carboxaldehyde is reacted with [1,4]diazepane-1-carboxaldehyde as described in Example 1 to afford 2-(4-formyl-[1,4]diazepan-1-yl)-1-phenyl-1H-indole-3-carboxaldehyde (97% yield) as a yellow solid. LC/MS: MS 348 (M+H); RT 2.77 min; (CDCl3): 10.26 (1H, d), 8.22 (1H, d), 8.00 (0.5H, s), 7.86 (0.5H, s) 7.47-7.69(3H, m), 7.23-7.38 (3H, m), 7.17(1H, t), 6.97 (1H, d), 3.25-3.70 (8H, m), 1.50-1.73(2H, m).

反应条件: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 3,4,5-trimethoxybenzyl chloride (10.5 g), N-formyl homopiperazine (6.82 g), potassium carbonate (8 g) and ethyl acetate (40 ml) is heated at 50-60° C. for 4 hours. After addition of water the reaction mixture is shaken thoroughly. The organic layer is separated, washed with water, dried and evaporated under reduced pressure. To the residue is added 10% hydrochloric acid (20 ml), and the mixture is extracted with ethyl acetate. The aqueous layer is made alkaline (>pH 9) with a 20% aqueous solution of sodium hydroxide, and extracted with methylene chloride. The extract solution is evaporated under reduced pressure. To the residue is added 10% hydrochloric acid (15 ml), and the mixture is stirred at 100° C. for 3 hours. The reaction mixture is made alkaline with a 20% aqueous solution of sodium hydroxide, and extracted with ethyl acetate. The extract solution is dried and evaporated under reduced pressure. The residue is converted to the hydrochloride in a mixture of ethyl acetate and ethanol to yield 1-(3,4,5-trimethoxybenzyl) homopiperazine dihydrochloride (2.7 g) as colorless powdery crystals, m.p. 216°-220° C. The organic layer is separated washed with water dried evaporated under reduced pressure To the residue is added 10% hydrochloric acid (20 ml) the mixture is extracted with ethyl acetate extracted with methylene chloride The extract solution is evaporated under reduced pressure To the residue is added 10% hydrochloric acid (15 ml) the mixture is stirred at 100° C. for 3 hours extracted with ethyl acetate The extract solution is dried evaporated under reduced pressure The residue is converted to the hydrochloride in a mixture of ethyl acetate and ethanol

反应条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 1.28 g (10 mmol) of 1,4-diazepane-1-carbaldehyde and 0.33 g (11 mmol) of paraformaldehyde in 13 ml of dioxane is heated at 80° C. until a homogeneous solution is obtained. 1.70 g (10 mmol) of 3-trifluoromethylphenylacetylene in solution in 7 ml of dioxane and 1.81 g (10 mmol) of copper diacetate are added. The mixture is heated at 80° C. for 4 hours. It is cooled to ambient temperature and diluted with 75 ml of ethyl acetate. The organic phase is washed with 25 ml of 30% ammonia solution and with saturated aqueous sodium chloride solution. It is dried over sodium sulphate and evaporated to dryness. The residue is purified by chromatography on silica gel, eluting with a 98/2/0.2 then 96/4/0.4 and 94/6/0.6 mixture of dichloromethane, methanol and 30% ammonia, to give 2.67 g of product in the form of a yellow oil. is obtained The mixture is heated at 80° C. for 4 hours It is cooled to ambient temperature The organic phase is washed with 25 ml of 30% ammonia solution and with saturated aqueous sodium chloride solution It is dried over sodium sulphate evaporated to dryness The residue is purified by chromatography on silica gel eluting with a 98/2/0.2 96/4/0.4 and 94/6/0.6 mixture of dichloromethane, methanol and 30% ammonia

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

实验步骤: A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 86 mg, 0.25 mmol) and 1,4-diazepane-1-carbaldehyde (97 mg, 0.75 mmol) in DMF (1.0 mL) was stirred at 100° C. for 2 h. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC (25-35% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (84.4 mg, 77%). 1H NMR (DMSO-d6) δ: 10.86 (s, 1H), [1:1 ratio of rotamers: 8.09 (s, 1H); 7.93 (s, 1H)], 7.98 (d, J=8.3 Hz, 2H), 7.61 (d, J=8.6 Hz, 2H), 7.14 (d, J=2.8 Hz, 1H), 6.16 (s, 1H), 4.25-4.39 (m, 3H), 3.55-3.71 (m, 4H), 3.46-3.54 (m, 1H), 2.37 (s, 3H), 1.97-2.09 (m, 1H), 1.86-1.97 (m, 1H), 1.45 (s, 6H); ESI-MS: m/z 437.3 (M+H)+. was then purified by preparatory HPLC (25-35% MeCN/H2O gradient+0.01% TFA)

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

实验步骤: A solution of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 200 mg, 0.604 mmol) and 1,4-diazepane-1-carbaldehyde (116 mg, 0.906 mmol) in Dioxane (6 mL) was stirred at 85° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC, 5-95% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (127.7 mg, 50%). 1H NMR (METHANOL-d4) δ: 8.12 (s, 1H), 7.89-7.99 (m, 3H), 7.63-7.69 (m, 2H), 7.34 (s, 1H), 6.24-6.29 (m, 1H), 4.43 (t, J=5.8 Hz, 1H), 4.32-4.37 (m, 1H), 4.09 (t, J=6.2 Hz, 1H), 3.98-4.04 (m, 1H), 3.78 (t, J=5.9 Hz, 2H), 3.60-3.71 (m, 2H), 2.13-2.22 (m, 1H), 2.06 (t, 1H), 1.56 (s, 6H). ESI-MS: m/z 423.1 (M+H)+. was then purified by preparatory HPLC, 5-95% (MeCN/H2O gradient+0.01% TFA)

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

实验步骤: A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 86 mg, 0.25 mmol) and 1,4-diazepane-1-carbaldehyde (97 mg, 0.75 mmol) in DMF (1.0 mL) was stirred at 100° C. for 2 h. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC (25-35% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (84.4 mg, 77%). 1H NMR (DMSO-d6) δ: 10.86 (s, 1H), [1:1 ratio of rotamers: 8.09 (s, 1H); 7.93 (s, 1H)], 7.98 (d, J=8.3 Hz, 2H), 7.61 (d, J=8.6 Hz, 2H), 7.14 (d, J=2.8 Hz, 1H), 6.16 (s, 1H), 4.25-4.39 (m, 3H), 3.55-3.71 (m, 4H), 3.46-3.54 (m, 1H), 2.37 (s, 3H), 1.97-2.09 (m, 1H), 1.86-1.97 (m, 1H), 1.45 (s, 6H); ESI-MS: m/z 437.3 (M+H)+. was then purified by preparatory HPLC (25-35% MeCN/H2O gradient+0.01% TFA)