Synthesis of Nitrogen‐Containing Heterocyclic Scaffolds and Applications in Scaffold Hopping: Development of an Aripiprazole Analog

Heteroaromatic ring systems play a crucial role in drug development because they modulate physicochemical properties and expand the range of molecular interactions compared to non‐heterocyclic aromatic rings. They are also widely represented among approved drugs. Among heteroatoms, nitrogen is the most prevalent in the diverse scaffold space of heterocyclic drugs, including those generated by fragment‐based drug discovery approach. In this work, we show the synthesis of a set of novel or underexplored nitrogen heterocyclic fragments, obtained in three to five steps in moderate yields. In total, 12 fused [6,6] saturated/unsaturated bicycles were synthesized, which fulfill the general rule of fragment‐like compounds. These heterocycles increased the fragment space of the CRAFT library and showed potential application in scaffold‐hopping strategies for drug design. As a proof of concept, 2,6‐naphthyridin‐3‐ol 2 was used to replace the 7‐hydroxy‐3,4‐dihydroquinolin‐2(1 H )‐one core of aripiprazole 41 , generating 3‐(4‐(4‐(2,3‐dichlorophenyl)piperazin‐1‐yl)butoxy)‐2,6‐naphthyridine 40, that effectively blocked cocaine‐induced hyperactivity in rodents at 20 mg/kg without inducing catalepsy, displaying a pharmacological profile similar to aripiprazole and demonstrating promising antipsychotic potential.