Reaction Steps
To a solution of cyanocyclopropanecarboxylic acid (3.67 mg, 0.033 mmol) in DCM (330 μl) were added DIEA (14.41 μl, 0.083 mmol) and BOP (17.52 mg, 0.040 mmol). The solution was stirred at room temperature for 10 minutes. 2-(1-Methyl-1H-pyrazol-4-yl)-8-(((3S,4S)-4-methylpyrrolidin-3-yl)amino)imidazo[1,2-b]pyridazine-7-carboxamide, TFA (15 mg, 0.033 mmol) was added. The reaction mixture was stirred at room temperature for another 30 min and concentrated to give an orange oil. The oil was partitioned between ethyl acetate and water. The organic layer was washed with (sat.) sodium chloride, dried with sodium sulfate, filtered and concentrated. The crude product was purified via preparative LCMS (prep. LCMS Method A) to afford 8-(((3S,4S)-1-(1-cyanocyclopropanecarbonyl)-4-methylpyrrolidin-3-yl)amino)-2-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine-7-carboxamide (8.5 mg, 0.020 mmol, 59.4% yield) as an off-white solid. 1H NMR (500 MHz, DMSO-d6, 2 rotamers) δ 10.74 (d, J=8.4 Hz, 1H), 10.69 (d, J=8.9 Hz, 1H), 8.48 (br. s., 1H), 8.47 (br. s., 1H), 8.28 (s, 1H), 8.27 (s, 1H), 8.12 (s, 2H), 8.01 (br. s., 2H), 7.88 (s, 1H), 7.87 (s, 1H), 7.41 (br. s., 2H), 6.00-5.88 (m, 1H), 5.82 (d, J=5.9 Hz, 1H), 4.25 (dd, J=10.9, 5.0 Hz, 1H), 4.13 (dd, J=10.2, 7.7 Hz, 2H), 3.92 (d, J=3.5 Hz, 1H), 3.88 (s, 6H), 3.79 (dd, J=12.6, 5.2 Hz, 1H), 3.69 (dd, J=12.1, 7.7 Hz, 1H), 3.58 (s, 1H), 3.54-3.50 (m, 1H), 2.80-2.74 (m, 1H), 2.72-2.65 (m, 1H), 1.64-1.52 (m, 6H), 1.50-1.45 (m, 1H), 1.39-1.34 (m, 1H), 1.08 (d, J=6.9 Hz, 3H), 1.04 (d, J=6.9 Hz, 3H). HPLC/LCMS (Method F): m/z 434.10 ([M+H]+), Rt. 1.066 min.
