Hydrochloric Acid → HCID 57414888, compound

Participants

Reaction Steps

To a solution of (2R,6S,13aS,14aR,16aS)-6-amino-N-(cyclopropylsulfonyl)-12,12-difluoro-5,16-dioxo-2-(quinoxalin-2-yloxy)octadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide, Hydrochloric Acid (Example 2a, 8.05 mg, 0.012 mmol) in DMF (120 μl) was added pyridine (7 μl, 0.087 mmol) followed by 5-methylisoxazole-3-carboxylic acid (2.28 mg, 0.018 mmol) and then HATU (7.04 mg, 0.019 mmol). The reaction mixture was stirred at room temperature overnight, diluted with ethyl acetate, cooled to 0° C. and neutralized with HCl (4 N in dioxane, 22 μl; diluted with ethyl acetate). The mixture was concentrated and purified by prep-TLC (ethyl acetate) to provide the title compound N-((2R,6S,13aS,14aR,16aS)-14a-(cyclopropylsulfonylcarbamoyl)-12,12-difluoro-5,16-dioxo-2-(quinoxalin-2-yloxy)octadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)-5-methylisoxazole-3-carboxamide (7.65 mg, 10.29 μmol, 86% yield) MS (ESI): m/z=744.3 [M+H]. Example 2 provided an IC50 of >1.0 nM in a 1a enzyme assay; an IC50 of >1.0 nM in a 1b enzyme assay; a HLM stability value of <50 μl/min/mg; an EC50 of >5.0 nM in a replicon cell line assay in a 1a-H77 background, and an EC50 of >5.0 nM in a replicon cell line assay in a 1b-con1 background.

Provenance & Evidence