Novel Substituted Triazolo Benzodiazepine Scaffolds to Explore Chemical Space

Abstract Efficient and concise routes to sets of novel triazolo-1,4-benzodiazepine scaffolds that are suitably functionalized for diversification at three positions to explore three-dimensional space with different substituents are described. One approach to these scaffolds features a simplified multicomponent assembly process to give an intermediate azido alkyne that undergoes a facile Huisgen dipolar cycloaddition. The triazolo-1,4-benzodiazepines thus produced may be endowed with aryl halide, secondary amino, alcohol, aldehyde or carboxylic acid groups as functional handles for orthogonal derivatization reactions. Modification of this approach enabled the facile synthesis of the related triazolo-1,4-benzodiazepin-6-ones, also bearing three functional handles. These convenient protocols were used to prepare multi-gram quantities of benzodiazepine analogs as precursors for generating compound libraries for screening campaigns.