A suspension of tert-butyl 1-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamate (compound 1e) (150 mg, 0.269 mmol), crude 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine 6a (177 mg, 0.57 mmol), Pd(dppf)Cl2 (22 mg, 0.03 mmol, Strem) and aqueous Na2CO3, 2.0 M (0.27 mL, 0.54 mmol) in dioxane (3 mL) was capped, degassed and backfilled with argon. The reaction was heated at 120° C. in a microwave for 45 min. The reaction mixture was diluted with EtOAc (75 mL) and washed with saturated NaHCO3 solution (50 mL) and brine (75 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluent: 0.5-3.5% MeOH/DCM), affording tert-butyl 1-(6-(1-(tetrahydro-2H-pyran-2-yl)-5-(3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamate (94 mg, 52% yield). MS (ESI, pos. ion) m/z: 664.3 (M+1). A solution of tert-butyl 1-(6-(1-(tetrahydro-2H-pyran-2-yl)-5-(3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamate (87 mg, 0.13 mmol) in dioxane (3 mL) was treated with HCl, 36.5-38.0% (0.11 mL, 1.31 mmol). The reaction mixture was heated at 90° C. After 3 h, the reaction mixture was cooled to 23° C. and concentrated. The residue (as HCl salt) was free-based using a Silicycle Si-propylsulfonic acid ion exchange column (catalog # R51230B). The compound was diluted in MeOH and added to a pad of the resin (wetted and flushed with 10 mL MeOH). It was flushed with MeOH (50 mL), and then the product was “released” using 2.0 M NH3 in MeOH solution (50 ml). The final filtrate was concentrated, affording 1-(6-(5-(3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-amine. MS (ESI, pos. ion) m/z: 480.2 (M+1).
