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IκB kinase β (IKKβ or IKK2) is a key regulator of nuclear factor kappa B (NF-κB) and has received attention as a therapeutic target. Herein we report on the optimization of a series of 3,5-disubstituted-indole-7-carboxamides for oral activity. In doing so, we focused attention on potency, ligand efficiency (LE), and physicochemical properties and have identified compounds 24 and ( R )- 28 as having robust in vivo activity.

3,5-Disubstituted-indole-7-carboxamides as IKKβ Inhibitors: Optimization of Oral Activity via the C3 Substituent