Emerging approaches for the syntheses of bicyclic imidazo[1,2-x]- heterocycles

Imidazo-[1,2-x]heterocycles are versatile building blocks for use in both a 'drug hunters' quest to discover new leads and a chemical biologists search for effective molecular tools in 'cell perturbation' studies. At the front end of the drug discovery flow chart, the last 5-10 years have witnessed the discovery of new high-throughput methodologies which very quickly have enabled access to virtual libraries of these chemo-types in the realm of 10⁷ derivatives. Interestingly, these often neglected cores in patent cooperation treaty (PCT) applications appear in several highly effective marketed drugs, completing the medicinal chemists search for clinical success. Such rigid chemo-types, all containing a bridgehead nitrogen atom, are thus poised for an ever increasing impact on the discovery and development of new molecular therapeutics. The following mini-review will briefly cover therapeutic utility, chemical methodologies and automation developed to enable preparation of arrays of these chemo-types in a high-throughput manner. Synthetic emphasis is placed on a 3-component-3-center isocyanide based multi-component reaction (IMCR), which spans solution, solid phase, flourous and microwave assisted organic synthesis.