Example 32
A mixture of methyl 3-((6-chloro-3-((methyl-d3)carbamoyl)pyridazin-4-yl)amino)-4-methoxy-5-(2-methyl-2H-1,2,3-triazol-4-yl)benzoate (95 mg, 0.218 mmol), cyclopropanecarboxamide (93 mg, 1.092 mmol), Pd2(dba)3, Chloroform adduct (22.57 mg, 0.022 mmol), xantphos (25.3 mg, 0.044 mmol) and Cs2CO3 (285 mg, 0.874 mmol) in dioxane (1.5 mL) was degassed by bubbling N2 through the mixture for 5 minutes. The reaction vessel was sealed and heated to 130° C. for 30 minutes. The reaction mixture was concentrated to dryness and the residue was suspended in water. The pH was adjusted to ˜2 with 1N HCl. The suspension was filtered and washed with water, followed by ethyl ether. Drying afforded a residue of 101 mg, of which 20 mg was dissolved in DMSO and 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 ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with ammonium acetate; Gradient: a 0-minute hold at 11% B, 11-61% 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 methyl 3-((6-(cyclopropanecarboxamido)-3-((methyl-d3)carbamoyl)-pyridazin-4-yl)amino)-4-methoxy-5-(2-methyl-2H-1,2,3-triazol-4-yl)benzoate (6.2 mg, 28.1% yield). MS (M+1) m/z: 484.1 (M+H)+. LC retention time 1.56 [I]. 1H NMR (500 MHz, DMSO-d6) δ 11.33 (br s, 1H), 11.06 (br s, 1H), 9.15 (br s, 1H), 8.32 (br s, 1H), 8.15 (s, 1H), 8.08 (br s, 1H), 7.99 (br s, 1H), 4.25 (br s, 3H), 3.86 (br s, 3H), 3.73 (br s, 3H), 2.06 (br d, J=1.2 Hz, 1H), 0.90-0.71 (m, 4H).
