4-Methylpyrazole → 4-((3S,4S)-1-(1-cyanocyclopropanecarbonyl)-4-methylpyrrolidin-3-ylamino)-6-(4-methyl-1H-pyrazol-1-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide

Participants

Reaction Conditions

Reaction Steps

The title compound was prepared from 20 mg (0.046 mmol) of 6-bromo-4-((3S,4S)-1-(1-cyanocyclopropanecarbonyl)-4-methylpyrrolidin-3-ylamino)pyrrolo[1,2-b]pyridazine-3-carboxamide (prepared from the product of Step 1 of Example 158 using the methods previously described in Step 1 of Example 191 by replacing cyanoacetic acid with cyclopropylcyanoacetic acid), potassium carbonate (32.0 mg, 0.232 mmol), 4-methyl-1H-pyrazole (15.2 mg, 0.18 mmol), (1S,2S)—N1,N2-dimethylcyclohexane-1,2-diamine (13.2 mg, 0.09 mmol) and dioxane (0.30 mL). The resulting mixture was sparged with argon for ˜5 min. then copper iodide (17.7 mg, 0.09 mmol) was added and the mixture was heated at 100° C. for 3 h. After cooling to rt, the mixture was purified by preparative LC/MS using 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: 10-100% 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 afford 6.8 mg of the title compound. Analytical LCMS (method H) retention time=1.98 min. (MH+ 433.2). 1H NMR (500 MHz, METHANOL-d4, appeared as rotomers) δ 8.39-8.32 (m, 1H), 8.14 (s, 1H), 8.07 (dd, J=12.4, 1.5 Hz, 1H), 7.98 (d, J=7.4 Hz, 1H), 7.69-7.64 (m, 1H), 7.34-7.24 (m, 1H), 5.20-5.00 (m, 2H), 4.55-4.41 (m, 3H), 4.13-3.90 (m, 3H), 3.04-2.80 (m, 1H), 2.34 (s, 3H), 1.99-1.65 (m, 4H), 1.49-1.38 (m, 4H).

Provenance & Evidence