Probing 2H-indazoles as template for SGK1, Tie2 and SRC kinase inhibitors

The broader and systematic application of a novel scaffold is often hampered by the unavailability of a short and reliable synthetic access. We investigated a new strategy for the design and synthesis of an array of N2-substituted aza-2H-indazole derivatives as potential kinase inhibitors. Guided by a rational ligand alignment approach to qualify the so far underrepresented aza-2H-indazole scaffold, indazoles were connected in N2-position with a phenyl spacer and an arylsulfonamide or amide linkage. Initial profiling against a panel of 30 kinases confirmed the in silico predicted selectivity bias. A synthesized focused library of 52 different aza-2H-indazole derivatives showed good initial selective inhibition against SGK1, Tie2 and SRC kinase with the best representatives having IC50s in the range of up to 500 nM. In a comparative computational study, these data were analyzed and rationalized in the light of docking studies.