Design, synthesis and evaluation of novel 5-phenylpyridin-2(1H)-one derivatives as potent reversible Bruton’s tyrosine kinase inhibitors

• Novel 5-phenylpyridin-2(1H)-one derivatives were designed, synthesized and evaluated for Btk inhibitors.
• Some compounds exhibited excellent Btk inhibition in vitro assay.
• Compound 16b possessed better PK properties and favorable anti-RA activity in vivo.

A series of novel reversible Btk inhibitors has been designed based on the structure of the recently reported preclinical drug RN486. The synthesis and SAR of these compounds are described. Among these derivatives, compound 16b was identified to be a potent and orally available reversible agent with satisfactory Btk enzymatic and cellular inhibition in vitro, as well as favorable PK properties and inhibition of arthritis in vivo.

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