Dichloromethane → N-(3-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-4-methylphenyl)-2-(hydroxymethyl)morpholine-4-carboxamide

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To a solution of triphosgene (22.7 mg, 0.0765 mmol) and N,N-diisopropylethylamine (0.20 mL, 1.1 mmol) in methylene chloride (4.0 mL, 62 mmol) was added a solution of N-(7-(5-amino-2-methylphenyl)isoquinolin-3-yl)cyclopropanecarboxamide (59.9 mg, 0.189 mmol) and N,N-diisopropylethylamine (0.10 mL, 0.57 mmol) in methylene chloride (2.0 mL, 31 mmol). The resulting mixture was stirred at room temperature for 5 minutes, and then morpholin-2-ylmethanol (37.5 mg, 0.320 mmol) was added. The reaction mixture was stirred at room temperature for an additional 30 minutes, and then filtered through silica which was rinsed with ethyl acetate, and evaporated in vacuo. The crude product was purified via reverse phase HPLC and lyophilized to yield 34.6 mg (40%) of N-(3-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-4-methylphenyl)-2-(hydroxymethyl)morpholine-4-carboxamide. LCMS (ESI): RT (min)=3.964, M+H=461.2, method=E; 1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 9.18 (s, 1H), 8.56 (s, 1H), 8.47 (s, 1H), 7.98 (s, 1H), 7.91 (d, J=8.5 Hz, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.50-7.37 (m, 2H), 7.21 (d, J=8.2 Hz, 1H), 4.82 (t, J=5.5 Hz, 1H), 4.04 (d, J=12.9 Hz, 2H), 3.97-3.81 (m, 3H), 2.90 (t, J=6.0 Hz, 2H), 2.64 (dd, J=12.9, 10.0 Hz, 2H), 2.21 (s, 3H), 2.11-2.03 (m, 1H), 0.86 (m, 4H).

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