Identification of azepinone fused tetracyclic heterocycles as new chemotypes with protein kinase inhibitory activities

The design and synthesis of small tetracyclic heterocycles which bear two new regioisomeric 2-carboxyethyl-1H-pyrrole-annulated indoloazepinone scaffolds is described. An azepinone motif, which is inherent in the structures of many well studied protein kinase inhibitors, serves as prominent structural feature of the new compounds. Concise access to the new regioisomeric tetracyclic derivatives was accomplished through amide coupling of appropriate pyrrole and indole precursors followed by an intramolecular Heck coupling reaction of the intermediate amide conjugates. Preliminary evaluation of newly synthesized tetracyclic molecules against a panel of protein kinases indicated their inhibitory activities and revealed promising selectivity profiles. The new compounds displayed no significant antiproliferative activity against MCF-7 cancer cells. Interestingly, derivative 19a exhibited selective TAK1 kinase inhibitory activity and figures as a promising chemotype for the discovery of new TAK1 inhibitors.

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