Utilization of Triazine Scaffolds as Potential Caspase Inhibitors Related to Q-VD-OPH

Quinolyl-valyl-O-methylaspartyl-[-2,6-difluorophenoxy]methyl ketone (Q-VD(OMe)-OPH) is a next generation broad spectrum caspase inhibitor with potential promise as a therapeutic agent. In seeking to both reduce the peptidic features and increase the efficacy of caspase inhibitors, we have chosen to examine derivatives based upon the triazine scaffold. The typical protocol for rapid analog synthesis upon this scaffold involves the initial introduction of an aryl amine, followed by substitution at the secondary site by a more nucleophilic amine input. Finally, introduction of the third amine input usually requires extended heating. So as to avert this heating step we have elected to instead utilize the introduction of two oxygen-based nucleophiles followed by addition of the aspartyl phenoxy methyl ketone warhead portion.