1-methylsulfonyl-1,4-diazepane;hydrochloride

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Reaction between 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde and 1-methanesulfonyl-[1,4]diazepane hydrochloride salt using procedure C yielded 2-chloro-6-(4-methanesulfonyl-[1,4]diazepan-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine. This compound was subjected to procedure A to yield the desired final compound which was purified using flash chromatography.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Crude 4-Methanesulfonyl-[1,4]diazepane-1-carboxylic acid tert-butyl ester (1.23 g) was stirred in anhydrous methanol (10 ml). 2M hydrogen chloride in ether (22 ml) was added. The reaction mixture was stirred at room temperature. After 5 minutes a precipitate formed, addition of anhydrous methanol (5 ml) caused this to dissolve. The reaction mixture was stirred overnight at room temperature. The solvents were removed in vacuo to yield 1.06 g of 1-methanesulfonyl-[1,4]diazepane hydrochloride salt. After 5 minutes a precipitate formed this to dissolve The reaction mixture was stirred overnight at room temperature The solvents were removed in vacuo

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Reaction between 2-chloro-4-morpholin-4-yl-thieno[2,3-d]pyrimidine-6-carbaldehyde and 1-methanesulfonyl-[1,4]diazepane hydrochloride salt using General Procedure C (reductive amination) yielded 2-chloro-6-(4-methanesulfonyl-[1,4]diazepan-1-ylmethyl)-4-morpholin-4-yl-thieno[2,3-d]pyrimidine.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Crude 4-methanesulfonyl-[1,4]diazepane-1-carboxylic acid tert-butyl ester (1.23 g) was stirred in anhydrous methanol (10 ml). 2M hydrogen chloride in ether (22 ml) was added. The reaction mixture was stirred at room temperature. After 5 minutes a precipitate formed, addition of anhydrous methanol (5 ml) caused this to dissolve. The reaction mixture was stirred overnight at room temperature. The solvents were removed in vacuo to yield 1.06 g of 1-methanesulfonyl-[1,4]diazepane hydrochloride salt. After 5 minutes a precipitate formed this to dissolve The reaction mixture was stirred overnight at room temperature The solvents were removed in vacuo

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Reaction between 2-chloro-4-morpholin-4-yl-thieno[2,3-d]pyrimidine-6-carbaldehyde and 1-methanesulfonyl-[1,4]diazepane hydrochloride salt using General Procedure C (reductive amination) yielded 2-chloro-6-(4-methanesulfonyl-[1,4]diazepan-1-ylmethyl)-4-morpholin-4-yl-thieno[2,3-d]pyrimidine.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Reaction between 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde and 1-methanesulfonyl-[1,4]diazepane hydrochloride salt using procedure C yielded 2-chloro-6-(4-methanesulfonyl-[1,4]diazepan-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine. This compound was subjected to procedure A to yield the desired final compound which was purified using flash chromatography.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Reaction between 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde and 1-methanesulfonyl-[1,4]diazepane hydrochloride salt using procedure C yielded 2-chloro-6-(4-methanesulfonyl-[1,4]diazepan-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine. This compound was subjected to procedure A to yield the desired final compound which was purified using flash chromatography.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Crude 4-Methanesulfonyl-[1,4]diazepane-1-carboxylic acid tert-butyl ester (1.23 g) was stirred in anhydrous methanol (10 ml). 2M hydrogen chloride in ether (22 ml) was added. The reaction mixture was stirred at room temperature. After 5 minutes a precipitate formed, addition of anhydrous methanol (5 ml) caused this to dissolve. The reaction mixture was stirred overnight at room temperature. The solvents were removed in vacuo to yield 1.06 g of 1-methanesulfonyl-[1,4]diazepane hydrochloride salt. After 5 minutes a precipitate formed this to dissolve The reaction mixture was stirred overnight at room temperature The solvents were removed in vacuo

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Crude 4-Methanesulfonyl-[1,4]diazepane-1-carboxylic acid tert-butyl ester (1.23 g) was stirred in anhydrous methanol (10 ml). 2M hydrogen chloride in ether (22 ml) was added. The reaction mixture was stirred at room temperature. After 5 minutes a precipitate formed, addition of anhydrous methanol (5 ml) caused this to dissolve. The reaction mixture was stirred overnight at room temperature. The solvents were removed in vacuo to yield 1.06 g of 1-methanesulfonyl-[1,4]diazepane hydrochloride salt. After 5 minutes a precipitate formed this to dissolve The reaction mixture was stirred overnight at room temperature The solvents were removed in vacuo

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 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), 1-(methylsulfonyl)-1,4-diazepane hydrochloride (107 mg, 0.50 mmol), and N,N-diisopropylethylamine (116 mg, 0.90 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 (30-30% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (93.0 mg, 76%). 1H NMR (DMSO-d6) δ: 10.87 (s, 1H), 7.99 (d, J=8.8 Hz, 2H), 7.61 (d, J=8.6 Hz, 2H), 7.16 (s, 1H), 6.16 (s, 1H), 4.32 (t, J=5.3 Hz, 2H), 4.00 (t, J=5.9 Hz, 2H), 3.53 (t, J=5.3 Hz, 2H), 3.36-3.45 (m, 2H), 2.90 (s, 3H), 2.37 (s, 3H), 1.95-2.15 (m, 2H), 1.45 (s, 6H); ESI-MS: m/z 487.3 (M+H)+. was then purified by preparatory HPLC (30-30% MeCN/H2O gradient+0.01% TFA)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 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), 1-(methylsulfonyl)-1,4-diazepane hydrochloride (107 mg, 0.50 mmol), and N,N-diisopropylethylamine (116 mg, 0.90 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 (30-30% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (93.0 mg, 76%). 1H NMR (DMSO-d6) δ: 10.87 (s, 1H), 7.99 (d, J=8.8 Hz, 2H), 7.61 (d, J=8.6 Hz, 2H), 7.16 (s, 1H), 6.16 (s, 1H), 4.32 (t, J=5.3 Hz, 2H), 4.00 (t, J=5.9 Hz, 2H), 3.53 (t, J=5.3 Hz, 2H), 3.36-3.45 (m, 2H), 2.90 (s, 3H), 2.37 (s, 3H), 1.95-2.15 (m, 2H), 1.45 (s, 6H); ESI-MS: m/z 487.3 (M+H)+. was then purified by preparatory HPLC (30-30% MeCN/H2O gradient+0.01% TFA)