Hydrochloric Acid → HCID 57415387, compound

Participants

Reaction Steps

To (2R,6S,13aS,14aR,16aS)-6-amino-2-(3-(benzo [d]thiazol-2-yl)quinoxalin-2-yloxy)-N-(cyclopropylsulfonyl)-12,12-difluoro-5,16-dioxooctadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide, Hydrochloric Acid (Example 14a, 16.1 mg, 0.020 mmol) was added DMF (200 μl) and diisopropylethylamine (25 μl, 0.14 mmol). To the yellow solution was added 5-methylisoxazole-3-carboxylic acid (3.85 mg, 0.030 mmol) followed by HATU (13.89 mg, 0.037 mmol). The reaction mixture was stirred at rt 2 h, cooled to 0° C. and neutralized with HCl (4 N in dioxane, 36 μl, diluted with EA). The solution was concentrated under reduced pressure and purified by prep-TLC (dichloromethane/EA=1/1, 2×) to provide the title compound N-((2R,6S,13aS,14aR,16aS)-2-(3-(benzo [d]thiazol-2-yl)quinoxalin-2- yloxy)-14a-(cyclopropylsulfonylcarbamoy1)-12,12-difluoro-5,16-dioxooctadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)-5-methylisoxazole-3-carboxamide (14.3 mg, 81% yield). MS (ESI): m/z=877.1 [M+H], 875.2 [M−H]. Example 14 provided an IC50 of between 0.1 and 0.5 nM in a 1a enzyme assay; an IC50 of between 0.1 and 0.5 nM in a 1b enzyme assay; a HLM stability value of <50 μl/min/mg; an EC50 of between 2.0 and 5.0 nM in a replicon cell line assay in a 1a-H77 background, and an EC50 of between 1.0 and 2.0 nM in a replicon cell line assay in a 1-con1 background.

Provenance & Evidence