Substituted imidazo[5,1-d][1,2,3,5]tetrazines for the treatment of cancer

New synthetic methods to provide access to previously unexplored functionality at the C8 position of substituted imidazo[5,1-d][1,2,3,5]tetrazines of Formula I. Through synthesis and evaluation of a suite of compounds with a range of aqueous stabilities (from 0.5 to 40 hours), a predictive model for imidazotetrazine hydrolytic stability based on the Hammett constant of the C8 substituent was derived. Promising compounds were identified that possess activity against a panel of GBM cell lines, appropriate hydrolytic and metabolic stability, and brain-to-serum ratios dramatically elevated relative to TMZ, leading to lower hematological toxicity profiles and superior activity to TMZ in a mouse model of GBM.