C-5 substituted heteroaryl-3-pyridinecarbonitriles as PKCθ inhibitors: Part II

We previously reported that a 3-pyridinecarbonitrile analog with a furan substituent at C-5 and a 4-methylindol-5-ylamino substituent at C-4, 1, was a potent inhibitor of PKCθ (IC50 = 4.5 nM). Replacement of the C-5 furan ring of 1 with bicyclic heteroaryl rings, led to compounds with significantly improved potency against PKCθ. Analog 6b with a 4-methylindol-5-ylamino group at C-4 and a 5-[(4-methylpiperazin-1-yl)methyl]-1-benzofuran-2-yl group at C-5 had an IC50 value of 0.28 nM for the inhibition of PKCθ.

Graphical abstractAnalog 6b with a 4-methylindol-5-ylamino group at C-4 and a 5-[(4-methylpiperazin-1-yl)methyl]-1- benzofuran-2-yl group at C-5 had an IC50 value of 0.28 nM for the inhibition of PKCθ.Figure optionsDownload full-size imageDownload as PowerPoint slide