Synthesis of Substituted Indazoles With Potential Kinase Inhibitory Activity
Achraf Hibot1, Abderrafia Hafid2, Mostafa Khouili2
1Laboratory of Medicinal Chemistry, Department of Pharmacology, Toxicology and Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain.
Abstract:
In this work, a versatile and efficient synthetic strategy for the selective N-1 alkylation of nitro-substituted 3-haloindazoles was developed using a complex base of NaH/t-BuOK. Various alkylating agents were employed under an argon atmosphere in DMF. This method successfully yielded several N-1-alkylated indazole derivatives, including 1-benzyl-3-chloro-6-nitro-1H-indazole, 1-benzyl-3-bromo-6-nitro-1H-indazole, and related analogs, with good to excellent yields (62%-100%). Subsequent amination reactions of the 3-bromoindazole intermediates with anilines provided N-arylindazoles at the C-3 position in moderate yields (11%-70%). In parallel, Suzuki-Miyaura cross-coupling reactions with boronic acids provided direct access to arylindazoles at the C-3 position with yields ranging from 54% to 92%. Of the compounds evaluated biologically, 16 and 18c stand out, having shown high inhibition of CDK2 (100% at 10 μM), while 13e and 16 showed maximum inhibition of ERK2 (100% at 10 μM), both proteins implicated in cancer.
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