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

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-1 H -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 ZnCl 2 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.