This invention provides novel compounds, and pharmaceutically acceptable derivatives thereof, that are useful as caspase inhibitors. These compounds have the general formula I:
where R
1
, R
2
, and R
3
are as described herein, Ring A contains zero to two double bonds, each X is independently selected from nitrogen or carbon, at least one X in Ring A is a nitrogen, Ring A is optionally substituted as described, and may be fused to a saturated or unsaturated five to seven membered ring containing zero to three heteroatoms, and provided that when X
3
is a carbon, a substituent on X
3
is attached by an atom other than nitrogen.
A fluorous linker-assisted synthetic protocol has been developed for preparation of sclerotigenin-type benzodiazepine-quinazolinone library containing 144 analogues. Amide coupling of fluorous trimethoxybenzyl (TMB)-protected amino esters with anthranilic acids followed by base-promoted cyclizations afforded 4-benzodiazepine-2,5-diones. Further derivatization of benzodiazepinediones by reacting with azidobenzoyl chlorides, cyclization, and fluorous linker cleavage afforded the desired compound library. The reaction intermediates were purified by fluorous solid-phase extraction (F-SPE) and final products were further purified by prep-HPLC.