2-methyl-1-piperidin-4-ylpropan-1-ol

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

Procedure: A mixture of 9-methyl-2-(2-methylbenzoimidazol-1-yl)-6-morpholin-4-yl-9H-purine-8-carbaldehyde (200 mg, 0.53 mmol), 2-methyl-1-piperidin-4-yl-propan-1-ol (125 mg, 0.79 mmol) and 4 Å molecular sieves (1.0 g) in 1,2-dichloroethane (10 mL) was stirred at RT under nitrogen atmosphere for 1.5 h. Sodium triacetoxyborohydride (167 mg, 0.79 mmol) was added and the resulting reaction mixture was stirred at RT for 16 h. The solvent was reduced in vacuo and the residue was loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was washed with DCM/MeOH, the desired product was subsequently eluted using a mixture of 2M NH3 in MeOH and DCM. The residue was purified by column chromatography (Si—PCC, MeOH:DCM: gradient 0:100 to 5:95) followed by a further purification (Si—PCC, acetone:cyclohexane: gradient 10:90 to 40:60). The solvents were reduced in vacuo to afford 346 as a white solid (114 mg, 41%). LCMS (Method G): RT 6.81 min, [M+H]+ 519. 1H NMR (400 MHz, CH3OH-d4): δ 8.06-8.05 (1 H, m), 7.56-7.55 (1 H, m), 7.25-7.24 (2 H, m), 4.29 (4 H, br s), 3.84 (3 H, s), 3.81 (4 H, t, J=4.74 Hz), 3.74 (2 H, s), 2.98-2.95 (3 H, m), 2.86 (3 H, s), 2.11 (2 H, m), 1.84 (1 H, m), 1.72-1.71 (1 H, m), 1.57-1.20 (4 H, m), 0.87 (6 H, dd, J=15.35, 6.73 Hz) the resulting reaction mixture was stirred at RT for 16 h The cartridge was washed with DCM/MeOH the desired product was subsequently eluted a mixture of 2M NH3 in MeOH and DCM The residue was purified by column chromatography (Si—PCC, MeOH:DCM: gradient 0:100 to 5:95) followed by a further purification (Si—PCC, acetone:cyclohexane: gradient 10:90 to 40:60)

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

Procedure: 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 2-methyl-1-(piperidin-4-yl)propan-1-ol (142 mg, 0.604 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 (59 mg, 23%). 1H NMR (METHANOL-d4) δ: 7.99 (d, J=2.3 Hz, 1H), 7.92-7.97 (m, 2H), 7.61-7.69 (m, 2H), 7.39 (s, 1H), 6.32 (d, J=2.5 Hz, 1H), 4.55 (d, J=12.4 Hz, 2H), 2.93-3.14 (m, 3H), 2.02 (d, J=1.0 Hz, 1H), 1.58-1.89 (m, 5H), 1.57 (s, 6H), 0.96 (dd, 6H). ESI-MS: m/z 452.0 (M+H)+. was then purified by preparatory HPLC, 5-95% (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-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 200 mg, 0.604 mmol) and 2-methyl-1-(piperidin-4-yl)propan-1-ol (142 mg, 0.604 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 (59 mg, 23%). 1H NMR (METHANOL-d4) δ: 7.99 (d, J=2.3 Hz, 1H), 7.92-7.97 (m, 2H), 7.61-7.69 (m, 2H), 7.39 (s, 1H), 6.32 (d, J=2.5 Hz, 1H), 4.55 (d, J=12.4 Hz, 2H), 2.93-3.14 (m, 3H), 2.02 (d, J=1.0 Hz, 1H), 1.58-1.89 (m, 5H), 1.57 (s, 6H), 0.96 (dd, 6H). ESI-MS: m/z 452.0 (M+H)+. was then purified by preparatory HPLC, 5-95% (MeCN/H2O gradient+0.01% TFA)