| Abstract
| - A series of substituted 4-(4-fluoro-1H-indol-5-yloxy)pyrrolo[2,1-f][1,2,4]triazine-based inhibitors of vascular endothelial growthfactor receptor-2 kinase is reported. Structure−activity relationshipstudies revealed that a methyl group at the 5-position and a substitutedalkoxy group at the 6-position of the pyrrolo[2,1-f][1,2,4]triazine coregave potent compounds. Biochemical potency, kinase selectivity, andpharmacokinetics of the series were optimized and in vitro safetyliabilities were minimized to afford BMS-540215 (12), which demonstrated robust preclinical in vivo activity in human tumor xenograftmodels. The l-alanine prodrug of 12, BMS-582664 (21), is currentlyunder evaluation in clinical trials for the treatment of solid tumors.
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