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

Elizabeth V Bedwell; Flavio da Silva Emery; Giuliano C Clososki; Patrick G Steel

doi:10.1039/d3ra07458g

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

RSC Adv. 2023 Nov 23;13(49):34391-34399. doi: 10.1039/d3ra07458g. eCollection 2023 Nov 22.

Authors

Elizabeth V Bedwell¹, Flavio da Silva Emery², Giuliano C Clososki², Patrick G Steel¹

Affiliations

¹ Department of Chemistry, University of Durham South Road Durham DH1 3LE UK p.g.steel@durham.ac.uk.
² Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Departamento de Ciências Farmacêuticas, Universidade de São Paulo Ribeirão Preto SP Brazil.

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.