Pyrazolone based TGFbR1 kinase inhibitors

Interruption of TGFb signaling through inhibition of the TGFbR1 kinase domain may prove to have beneficial effect in both fibrotic and oncological diseases. Herein we describe the SAR of a novel series of TGFbR1 kinase inhibitors containing a pyrazolone core. Most TGFbR1 kinase inhibitors described to date contain a core five-membered ring bearing N as H-bond acceptor. Described herein is a novel strategy to replace the core structure with pyrazolone ring, in which the carbonyl group is designed as an H-bond acceptor to interact with catalytic Lys 232.