Example 33
A mixture of 6-chloro-4-((2-methoxy-4-methyl-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (20 mg, 0.051 mmol), cyclopropanecarboxamide (8.71 mg, 0.102 mmol), Pd2(dba)3, chloroform adduct (5.29 mg, 5.12 μmol), xantphos (5.92 mg, 10.23 μmol) and Cs2CO3 (66.7 mg, 0.205 mmol) in dioxane (0.5 mL) was degassed by bubbling N2 through the mixture for 5 minutes. The reaction vessel was sealed and heated to 130° C. for 45 minutes. The reaction mixture was diluted with DMF. The mixture was filtered through a 0.45 micron nylon filter and the filtrate was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 200 mm×19 mm, 5-μm
particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: a 0-minute hold at 13% B, 13-53% B over 20 minutes, then a 0-minute hold at 100% B; Flow Rate: 20 mL/min; Column Temperature: 25 C. Fraction collection was triggered by MS signals. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford 6-(cyclopropanecarboxamido)-4-((2-methoxy-4-methyl-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (8.4 mg, 37.4%). MS (M+1) m/z: 440.3 (M+H)+. LC retention time 1.48 [I]. 1H NMR (500 MHz, DMSO-d6) δ 11.28 (s, 1H), 10.79 (s, 1H), 9.09 (s, 1H), 8.08 (s, 1H), 7.86 (s, 1H), 7.39 (d, J=8.2 Hz, 1H), 7.16 (d, J=8.2 Hz, 1H), 4.22 (s, 3H), 3.41 (s, 3H), 2.19 (s, 3H), 2.12-2.04 (m, 1H), 0.87-0.77 (m, 4H).
