2-piperidin-4-ylacetamide;hydrochloride

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: An orange solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(trifluoromethoxy)benzamide (14A, 69 mg, 0.186 mmol), 2-(piperidin-4-yl)acetamide hydrochloride (40 mg, 0.279 mmol), and N,N-diisopropylethylamine (96 mg, 0.745 mmol) in DMF (1.8 mL) was stirred at 100° C. for 2 h, cooled to 80° C., and stirred overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, filtered, and then purified by preparatory HPLC (30-40% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (13.1 mg, 15%). 1H NMR (DMSO-d6) δ: 10.96 (s, 1H), 8.02-8.14 (m, 2H), 7.44 (d, J=7.8 Hz, 2H), 7.26 (br. s., 1H), 7.23 (s, 1H), 6.74 (br. s., 1H), 6.08 (s, 1H), 4.36 (d, J=12.4 Hz, 2H), 2.90-3.03 (m, 2H), 2.31 (s, 3H), 1.97-2.01 (m, 2H), 1.89-1.97 (m, 1H), 1.74 (d, J=11.6 Hz, 2H), 1.24-1.38 (m, 2H); ESI-MS: m/z 477.4 (M+H)+. After cooling to room temperature filtered purified by preparatory HPLC (30-40% MeCN/H2O gradient+0.01% TFA)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 100 mg, 0.290 mmol), 2-(piperidin-4-yl)acetamide hydrochloride (82 mg, 0.58 mmol), and N,N-diisopropylethylamine (112 mg, 0.870 mmol) in DMF (2.0 mL) was stirred at 100° C. for 3 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 (30-35% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (44.4 mg, 34%). 1H NMR (DMSO-d6) δ: 10.84 (s, 1H), 7.89-8.10 (m, 2H), 7.53-7.66 (m, 2H), 7.33 (br. s., 1H), 7.28 (s, 1H), 6.81 (br. s., 1H), 6.16 (s, 1H), 4.44 (d, J=12.6 Hz, 2H), 3.00-3.12 (m, 2H), 2.37 (s, 3H), 1.94-2.14 (m, 3H), 1.81 (d, J=13.1 Hz, 2H), 1.41-1.53 (m, 6H), 1.30-1.41 (m, 2H); ESI-MS: m/z 451.2 (M+H)+. was then purified by preparatory HPLC (30-35% MeCN/H2O gradient+0.01% TFA)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: An orange solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(trifluoromethoxy)benzamide (14A, 69 mg, 0.186 mmol), 2-(piperidin-4-yl)acetamide hydrochloride (40 mg, 0.279 mmol), and N,N-diisopropylethylamine (96 mg, 0.745 mmol) in DMF (1.8 mL) was stirred at 100° C. for 2 h, cooled to 80° C., and stirred overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, filtered, and then purified by preparatory HPLC (30-40% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (13.1 mg, 15%). 1H NMR (DMSO-d6) δ: 10.96 (s, 1H), 8.02-8.14 (m, 2H), 7.44 (d, J=7.8 Hz, 2H), 7.26 (br. s., 1H), 7.23 (s, 1H), 6.74 (br. s., 1H), 6.08 (s, 1H), 4.36 (d, J=12.4 Hz, 2H), 2.90-3.03 (m, 2H), 2.31 (s, 3H), 1.97-2.01 (m, 2H), 1.89-1.97 (m, 1H), 1.74 (d, J=11.6 Hz, 2H), 1.24-1.38 (m, 2H); ESI-MS: m/z 477.4 (M+H)+. After cooling to room temperature filtered purified by preparatory HPLC (30-40% MeCN/H2O gradient+0.01% TFA)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 100 mg, 0.290 mmol), 2-(piperidin-4-yl)acetamide hydrochloride (82 mg, 0.58 mmol), and N,N-diisopropylethylamine (112 mg, 0.870 mmol) in DMF (2.0 mL) was stirred at 100° C. for 3 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 (30-35% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (44.4 mg, 34%). 1H NMR (DMSO-d6) δ: 10.84 (s, 1H), 7.89-8.10 (m, 2H), 7.53-7.66 (m, 2H), 7.33 (br. s., 1H), 7.28 (s, 1H), 6.81 (br. s., 1H), 6.16 (s, 1H), 4.44 (d, J=12.6 Hz, 2H), 3.00-3.12 (m, 2H), 2.37 (s, 3H), 1.94-2.14 (m, 3H), 1.81 (d, J=13.1 Hz, 2H), 1.41-1.53 (m, 6H), 1.30-1.41 (m, 2H); ESI-MS: m/z 451.2 (M+H)+. was then purified by preparatory HPLC (30-35% MeCN/H2O gradient+0.01% TFA)