Skeletal Diversity for Sizable Combinatorial Libraries of Drug-like Heterocyclic Compounds

The exclusive role of heterocyclic compounds for drug discovery is best documented by the occurrence of a heterocyclic moiety in current drugs; the majority of drugs are heterocyclic compounds. Consequently, a substantial effort has been dedicated to the development of chemistries, both solidand solution-phase, for combinatorial syntheses of heterocyclic libraries. Traditionally, generic combinatorial libraries contained one heterocyclic scaffold and the library diversity was created through derivatization of the common heterocyclic core by diverse R groups, portrayed below for a three combinatorial step library (R, R and R in the structure below). Albeit building blocks for a generic library were selected among the most diverse ones, the library diversity was limited by the presence of one identical core structure (Het Core). Not surprisingly, building blocks (BB) for introduction of R groups were also selected among heterocyclic compounds (Het BB) and compounds containing two heterocyclic moieties connected by a spacer were synthesized.