Reaction Steps
(N-cyclopropyl-1-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-2,4′-bipyridin-2′-yl)piperidin-4-amine) was prepared in the following manner. To a 20 mL reaction flask was added 1-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-2,4′-bipyridin-2′-yl)piperidin-4-ol (30 mg, 0.056 mmol) and 0.8 mL of methylene chloride. This solution was charged with triethylamine (0.10 mL, 0.69 mmol) and dropwise addition of methane sulfonyl chloride (MsCl, approx. 20 mg, 0.18 mmol). The resulting solution was stirred for 2 hours, followed by quenching with water, ethyl acetate extraction (3×30 mL), and the organic extracts were transferred to a 10 mL volume resealable vessel. The residue in the vessel was charged with 2 mL cyclopropylamine (excess, co-solvent) and 0.5 mL of THF. The vessel was sealed and heated for 6 hours at 90° C. Upon cooling, the contents of the vessel were concentrated to a volume of 1 mL and directly subjected to reverse phase separation (gradient, C-18 support, 10 to 70%, acetonitrile:water) to give (N-cyclopropyl-1-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-2,4′-bipyridin-2′-yl)piperidin-4-amine). 1H NMR (400 MHz, D3 acetonitrile) δ ppm 8.71 (br s, 1H), 8.41 (s, 1H) 8.26 (d, J=7.2 Hz, 1H), 7.99 (app d, J=6.7 Hz, 2H), 7.85 (d, J=6.2 Hz, 1H), 7.73 (br s, 1H), 7.63 (s, 1H), 7.42 (d, J=6.4 Hz, 1H), 7.39 (app q, J=6.8 Hz, 1H), 7.20 (d, J=7.2 Hz, 1H), 7.05 (dt, J=8.6, 1.9 Hz, 1H), 6.99-6.82 (m, 1H), 5.27 (d, J=6.4 Hz, 1H), 4.54 (app d, J=10 Hz, 2H), 4.00 (app q, J=3.9 Hz, 1H), 3.69-3.62 (m, 1H), 3.46 (app d, J=5.8 Hz, 1H), 2.98 (app q, J=4.2 Hz, 2H), 2.73 (br s, 2H), 2.47-2.35 (m, 1H), 2.13 (app dd, J=5.6 Hz, 2H), 2.08-2.03 (m, 2H), 1.89-1.86 (m, 1H), 0.82-0.66 (m, 5H). LRMS observed m/z 575.3 major ion (calcd for M+H, 575.3).
