Synthesis and vectorial functionalisation of pyrazolo[3,4-c]pyridines

Abstract

Heterocycles are a cornerstone of fragment-based drug discovery (FBDD) due to their prevalence in biologically active compounds. However, novel heterocyclic fragments are only valuable if they can be suitably elaborated to compliment a chosen target protein. Here we describe the synthesis of 5-halo-1H-pyrazolo[3,4-c]pyridine scaffolds and demonstrate how these compounds can be selectively elaborated along multiple growth-vectors. Specifically, N-1 and N-2 are accessed through protection-group and N-alkylation reactions; C-3 through tandem borylation and Suzuki–Miyaura cross-coupling reactions; C-5 through Pd-catalysed Buchwald–Hartwig amination; and C-7 through selective metalation with TMPMgCl^.LiCl followed by reaction with electrophiles or transmetalation to ZnCl₂ and Negishi cross-coupling. Linking multiple functionalisation strategies emulates a hit-to-lead pathway and demonstrates the utility of pyrazolo[3,4-c]pyridines to FBDD.