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

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

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.

Citation

Bedwell, E. V., da Silva Emery, F., Clososki, G. C., & Steel, P. G. (2023). Synthesis and vectorial functionalisation of pyrazolo[3,4- c ]pyridines. RSC Advances, 13(49), 34391-34399. https://doi.org/10.1039/d3ra07458g

• Journal Article Type: Article
• Acceptance Date: Nov 9, 2023
• Online Publication Date: Nov 23, 2023
• Publication Date: Nov 23, 2023
• Deposit Date: Nov 29, 2023
• Publicly Available Date: Nov 29, 2023
• Journal: RSC Advances
• Publisher: Royal Society of Chemistry
• Peer Reviewed: Peer Reviewed
• Volume: 13
• Issue: 49
• Pages: 34391-34399
• DOI: https://doi.org/10.1039/d3ra07458g
• Public URL: https://durham-repository.worktribe.com/output/1949653