Example 54
To a solution of rac-6-cyclopropoxy-2-(1S,3R)-3-hydroxy-3-methylcyclohexyl)-2H-indazole-5-carboxylic acid (100 mg, 0.3 mmol), HATU (115 mg, 0.3 mmol) and DIPEA (534, 0.3 mmol) in THF (10 mL) under N2 atmosphere was added pyrazolo[1,5-a]pyrimidin-3-amine (Int I-5) (41 mg, 0.3 mmol). The resulting solution was stirred at rt for 2 h. The reaction was quenched with water (1 mL). The mixture was purified directly by prep. chiral-HPLC (Chiralpak® IA, 5 μm 20 mm×250 mm; isocratic with 50% MTBE (0.5% 2N NH3-MeOH) in MeOH; 50 mL/min) to afford rel-6-cyclopropoxy-2-(1S,3R)-3-hydroxy-3-methylcyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide—Isomer 1 (42 mg, 42%, 100% ee) and rel-6-cyclopropoxy-2-(1S,3R)-3-hydroxy-3-methylcyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide—Isomer 2 (46 mg, 46%, 100% ee), both as yellow solids. The 1H NMR and MS obtained for both products were identical. 1H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.07 (dd, 1H), 8.75 (s, 1H), 8.58 (s, 1H), 8.55 (dd, 1H), 5.53 (s, 1H), 7.51 (s, 1H), 7.05 (dd, 1H), 4.50-4.64 (m, 1H), 4.19-4.25 (m, 1H), 1.94-2.11 (m, 3H), 1.72-1.86 (m, 2H), 1.63 (br. d, 1H), 1.37-1.56 (m, 2H), 1.25 (s, 3H), 1.01-1.11 (m, 2H), 0.93-1.03 (m, 2H). MS ESI, m/z=447 [M+H]+.
