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0 °C

To a solution of (R)-tert-butyl 3-aminopiperidine-1-carboxylate (0.28 g, 1.32 mmol) in DMF (10 mL) was treated with NaH (0.056 g, 2.34 mmol) and stirred for 15 min. The reaction mixture was cooled to 0° C. and 3-(2-chloropyrimidin-4-yl)-5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.5 g, 1.17 mmol) was added. The resulting mixture was stirred at RT for 2 h. The reaction mixture was quenched with ice cold water and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated to yield crude compound. Purification by silica gel column chromatography, eluting with 5-15% EtOAc and hexanes to obtain (3R)-tert-butyl 3-(4-(5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrimidin-2-ylamino)piperidine-1-carboxylate (0.2 g, 18%). MS (ESI, pos. ion) m/z: 591.1 (M+1). To a solution of (3R)-tert-butyl 3-(4-(5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrimidin-2-ylamino)piperidine-1-carboxylate (0.3 g, 0.5 mmol) in EtOAc (10 mL) was added EtOAc-HCl (10 mL) and stirred at RT for 16 h. The reaction mixture was quenched with saturated NaHCO3 solution and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated. The crude product was purified by reverse-phase preparative HPLC (using a AG/PP/C18-15/021 column, eluting with gradient, A: 5% TFE+0.01% TFA in Water; B: ACN). The title compound was obtained. MS (ESI, pos. ion) m/z: 407.2 (M+1).

1. stirringThe resulting mixture was stirred at RT for 2 h
2. customThe reaction mixture was quenched with ice cold water
3. extractionextracted with EtOAc
4. dry with materialThe organic layer was dried over Na2SO4
5. filtrationfiltered
6. concentrationconcentrated
7. customto yield crude compound
8. customPurification by silica gel column chromatography
9. washeluting with 5-15% EtOAc and hexanes