This thesis describes the exploration of epoxy-bridged fused polycycles as starting frameworks for the synthesis of pharmaceutically relevant nitrogen containing polycycles and the generation of a compound library for early-stage drug discovery.
Exploiting a gold-catalysed double annulation process, a range of epoxy-bridged fused polycycles were synthesised and the reactivity of the embedded amidine functionality was investigated to generate a diverse set of sp3-rich nitrogen containing polycyclic architectures. Following the Diversity Oriented Synthesis principle (DOS), five different scaffolds were generated from a single pluripotent framework based on the deachydro-1,6-napthyridine core. Further three other scaffolds were generated starting from an octahydro-pyranopyridine framework, for a total of nine scaffolds investigated during these studies. The synthesis scale-up and reactivity of the final architectures was studied to assess their suitability as starting points for a compound library generation.
Chemoinformatic analysis was performed using Knime and Datawarrior, and three different libraries were designed and synthesised based on the newly synthesised scaffolds to deliver a set of 103 compounds, all compliant with the recent medicinal chemistry trends. Chemical space coverage of the newly synthesised compounds was performed via principal component comparing the library compounds with a set of marketed drugs and molecules undergoing clinical trials.