Substituted 1,4-diazepines and uses thereof

摘要

The present invention is directed to novel 1,4-diazepines, pharmaceutical compositions thereof, and the use thereof as inhibitors of HDM2-p53 interactions. Compounds have Formula I: or a solvate, hydrate or pharmaceutically acceptable salt thereof; wherein: R¹, R², R⁹, R¹⁰, R_a, R^d and M are defined herein; X is a bivalent radical of: an alkane, a cycloalkane, an optionally-substituted arene, an optionally-substituted heteroarene, an optionally-substituted arylalkane or an optionally-substituted heteroarylalkane; and R³ is -CO₂R^d, -CO₂M, -OH, -NHR^d, -SO₂R^d, -NHCONHR^d, optionally-substituted amidino or optionally-substituted guanidino; or R³-X- is hydrogen or an electron pair; R⁴ is oxygen or -NR⁹R¹⁰; R⁵ is cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, aralkyl, heteroarylalkyl, or a saturated or partially unsaturated heterocycle, each of which is optionally substituted; and R⁶, R⁷ and R⁸ are independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, a saturated or partially unsaturated heterocycle, cycloalkylalkyl, aralkyl or heteroarylalkyl, each of which is optionally substituted; or R⁶ and R⁷, together with the carbon atom to which they are attached form a 3- to 7-membered carbocyclic ring optionally substituted 1 to 3 times with R^a.