Piperidine-based heterocyclic oxalyl amides as potent p38a MAP kinase inhibitors

The design and synthesis of a new class of p38a MAP kinase inhibitors based on 4-fluorobenzylpiperidine heterocyclic oxalyl amides are described. Many of these compounds showed low-nanomolar activities in p38a enzymatic and cell-based cytokine TNFa production inhibition assays. The optimal linkers between the piperidine and the oxalyl amide were found to be [6,5] fused ring heterocycles. Substituted indoles and azaindoles were favored structural motifs in the cellular assay.