Reaction Steps
A mixture of 6-bromo-4-(((3S,4S)-1-(5-cyanopyrimidin-2-yl)-4-ethylpyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (20 mg, 0.044 mmol, from Step 1), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (31.0 mg, 0.132 mmol, from Step 2), and PdCl2(dppf)-CH2Cl2 adduct (7.17 mg, 8.79 μmol) was pumped under vacuum and backfilled with nitrogen three times. A 2 M aqueous solution of potassium phosphate tribasic (0.066 mL, 0.132 mmol) and N,N-dimethylformamide (0.5 mL) were added. The mixture was immediately pumped under vacuum and backfilled with nitrogen three times, sealed and placed in a 90° C. heating block for 3 h, then cooled to room temperature. The mixture was filtered to remove the insoluble material. The filtrate was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 0-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound (9.4 mg, 44% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.16 (d, J=7.4 Hz, 1H), 8.77 (d, J=3.0 Hz, 1H), 8.67 (d, J=3.0 Hz, 1H), 8.28 (d, J=2.5 Hz, 1H), 8.21 (s, 1H), 8.13 (d, J=2.0 Hz, 1H), 8.00-7.90 (m, 1H), 7.25 (d, J=1.5 Hz, 1H), 6.48 (d, J=9.4 Hz, 1H), 5.09-4.91 (m, 1H), 4.09-3.94 (m, 2H), 3.85 (d, J=12.4 Hz, 1H), 3.51 (s, 3H), 2.66-2.55 (m, 1H), 1.64 (quin, J=7.4 Hz, 2H), 0.96 (t, J=7.4 Hz, 3H); MS (ES+) m/z: 484.2 (M+H); LC retention time: 1.19 min (analytical LCMS Method I).
