Synthesis of Substituted Indazoles With Potential Kinase Inhibitory Activity.

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.