Reaction Steps
N-(2-chloropyrimidin-5-yl)-6-(ethylcarbamoylamino)-4-(3-pyridylamino)pyridine-3-carboxamide (i) was prepared by coupling 4-anilino-6-(ethylcarbamoylamino)pyridine-3-carboxylic acid and 2-chloropyrimidin-5-amine. Compound (i) (30 mg, 73 woe, ethyl 4-methylpiperidine-4-carboxylate hydrochloride (23 mg, 0.11 mmol), N-ethyl-N-isopropyl-propan-2-amine (50 mmol, 0.29 mmol) and DMSO (2 mL) were combined and heated for 2 hr at 80° C. followed by 2 hr at 90° C. The reaction mixture was partitioned between EtOAc (50 mL) and saturated NH4Cl solution (50 mL). The organic layer was separated and further washed with saturated aqueous sodium hydrogen carbonate (50 mL) and brine (50 mL). The organic layer was separated and concentrated to give a crude oil. Flash chromatography on silica, eluting with 0-100% EtOAc gradient in n-heptane, gave crude product. Further flash chromatography (C18 column), eluting with 20-60% acetonitrile gradient in water (containing 0.1% formic acid), afforded Compound 136 (35 mg, 88%). 1H NMR (400 MHz, Acetone) δ 10.24 (s, 1H), 9.56 (s, 1H), 8.74-8.68 (m, 3H), 8.62 (d, J=2.6 Hz, 1H), 8.57 (s, 1H), 8.44 (s, 1H), 8.41 (dd, J=4.7, 1.3 Hz, 1H), 7.79 (ddd, J=8.4, 2.5, 1.5 Hz, 1H), 7.45 (dd, J=8.2, 4.7 Hz, 1H), 7.07 (d, J=4.4 Hz, 1H), 4.36 (dt, J=13.9, 4.4 Hz, 2H), 4.21 (q, J=7.1 Hz, 2H), 3.34-3.26 (m, 4H), 2.16 (s, 2H), 1.51-1.43 (m, 2H), 1.29 (dd, J=9.4, 4.8 Hz, 3H), 1.25 (s, 3H), 1.17 (t, J=7.2 Hz, 3H), [M+H]+ m/z=548.29.
