Reaction Steps
A solution of (+/−)-6-bromo-4-((6-(1-cyanocyclopropanecarbonyl)-6-azaspiro[3.4]octan-8-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide from Step 3 of Example 320 (15.0 mg, 0.033 mmol), 2-Methoxy-5-pyridineboronic acid (10.03 mg, 0.066 mmol) in 1,4-dioxane (437 μl) and potassium phosphate (2.0M) (49.2 μl, 0.098 mmol) was degassed for several minutes with N2 gas. 1,1′-Bis(diphenylphosphino)ferrocenepalladium(II) dichloride, dichloromethane (2.70 mg, 3.28 μmol) was added, degassing was continued for 1 more minute. The vial was sealed, and the contents were heated @ 105° C. for 50 minutes. HPLC and LC/MS indicated that the reaction had essentially proceeded to completion as no starting material was detected. (m/e 486.24, no Bromine pattern, M+H for desired product). After cooling to room temperature the reaction was diluted with methanol, filtered through a VWR 0.45 micron Nylon filter disc and the crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×150 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: 15-100% B over 15 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 afford 8.4 mg of the title compound. LC/MS: m/e 486.0 (M+H). 1H NMR (500 MHz, METHANOL-d4/CDCl3) δ 8.44 (dd, J=7.9, 2.5 Hz, 1H), 8.17 (d, J=9.4 Hz, 1H), 7.96 (ddd, J=8.4, 4.5, 2.5 Hz, 1H), 7.91 (dd, J=12.1, 1.7 Hz, 1H), 7.21-6.99 (m, 1H), 6.86 (d, J=8.4 Hz, 1H), 4.88 (d, J=1.5 Hz, 1H), 4.36 (dd, J=10.9, 5.0 Hz, 0.5H), 4.25 (d, J=10.9 Hz, 1H), 4.11 (d, J=10.9 Hz, 1H), 4.08 (d, J=2.5 Hz, 0.5H), 3.96 (d, J=1.5 Hz, 3H), 3.90 (dd, J=12.9, 4.5 Hz, 0.5H), 3.84-3.71 (m, 0.5H), 2.54-1.96 (m, 6H), 1.84-1.40 (m, 4H)
