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: ##STR00001## or a solvate, hydrate or pharmaceutically acceptable salt thereof; wherein:R.sup.1, R.sup.2, R.sup.9, R.sup.10, R.sub.a, R.sup.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; andR.sup.3 is --CO.sub.2R.sup.d, --CO.sub.2M, --OH, --NHR.sup.d, --SO.sub.2R.sup.d, --NHCONHR.sup.d, optionally-substituted amidino or optionally-substituted guanidino;or R.sup.3--X-- is hydrogen or an electron pair;R.sup.4 is oxygen or --NR.sup.9R.sup.10;R.sup.5 is cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, aralkyl, heteroarylalkyl, or a saturated or partially unsaturated heterocycle, each of which is optionally substituted; andR.sup.6, R.sup.7 and R.sup.8 are independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, a saturated or partially unsaturated heterocycle, cycloalkylalkyl, aralkyl or heteroarylalkyl, each of which is optionally substituted; or R.sup.6 and R.sup.7, 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.sup.a.