Growth vector elaboration of fragments: regioselective functionalization of 5-hydroxy-6-azaindazole and 3-hydroxy-2,6-naphthyridine.

Autor:	Eliandro da Silva Júnior P; Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Departmento de Ciências Farmacêuticas, Universidade de São Paulo, Ribeirão Preto 14040-903, Brazil. flavioemery@usp.br., de Melo SMG; Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Departmento de Ciências Farmacêuticas, Universidade de São Paulo, Ribeirão Preto 14040-903, Brazil. flavioemery@usp.br., de Paula MH; Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Departmento de Ciências Farmacêuticas, Universidade de São Paulo, Ribeirão Preto 14040-903, Brazil. flavioemery@usp.br., Vessecchi R; Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Av. Bandeirantes, 3900, Ribeirão Preto, SP, 14040-901, Brazil., Opatz T; Department of Chemistry, Johannes Gutenberg University Mainz, Duesbergweg 10-14, Mainz 55128, Germany., Day JEH; Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, UK., Ganesan A; School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, UK. a.ganesan@uea.ac.uk., da Silva Emery F; Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Departmento de Ciências Farmacêuticas, Universidade de São Paulo, Ribeirão Preto 14040-903, Brazil. flavioemery@usp.br.; Center for the Research and Advancement in Fragments and molecular Targets (CRAFT), Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, RIbeirão Preto, São Paulo, Brasil.
Jazyk:	angličtina
Zdroj:	Organic & biomolecular chemistry [Org Biomol Chem] 2022 Sep 28; Vol. 20 (37), pp. 7483-7490. Date of Electronic Publication: 2022 Sep 28.
DOI:	10.1039/d2ob00968d
Abstrakt:	This article discusses the reactivity of 6-azaindazole (1) and 2,6-naphthyridine (2), proposed to be "heteroaromatic rings of the future," which would be useful for fragment-based drug discovery (FBDD) campaigns, developing growth vectors for fragment elaboration by selectively functionalizing different positions on the rings. The pyridone oxygens and pyrazole nitrogen can be functionalized selectively. Arylation at the α-carbon of the pyridone moiety was achieved by a transition metal-free radical cross-coupling using aryl hydrazines. This method proceeded under mild conditions without the need for protection of the hydroxypyridine. Additionally, we developed a method for the regioselective C-3 functionalization of heterocycle 1 via N -sulfonamide rearrangement. This method involved a novel regioselective base-mediated N-C migration of the N-1 sulfonamide to yield the C-3 sulfone. This procedure is also applicable for indazole C-3 functionalization and mechanistic studies of the rearrangement suggest that an intermolecular process is involved. These reactions enable the fragment elaboration of heterocycles 1 and 2 in several growth vectors to facilitate their use in FBDD.
Databáze:	MEDLINE
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