Design, Synthesis, and Biological Evaluation of Pyrrolo[1,2-<i>a</i>]quinoxalin-4(5<i>H</i>)-one Derivatives as Potent and Orally Available Noncovalent Bruton’s Tyrosine Kinase (BTK) Inhibitors

Bruton's tyrosine kinase (BTK) is a therapeutic target for B-cell-driven malignancies. Most of the approved covalent BTK inhibitors are associated with treatment limitations due to off-target toxicity and drug resistance. Developing noncovalent BTK inhibitors is a promising strategy to address unmet clinical needs. Here, a novel series of pyrrolo[1,2-<i>a</i>]quinoxalin-4(5<i>H</i>)-one derivatives were designed and synthesized as noncovalent BTK inhibitors. Among them, representative compound <b>9</b> exhibited potent BTK inhibitory activity (IC₅₀ = 21.6 nM) and excellent selectivity against a panel of 468 kinases. Moreover, the oral exposure property of compound <b>9</b> was improved, and the antitumor efficacy of compound <b>9</b> (TGI = 64.4%) was superior to the lead <b>S2</b> (TGI = 28.7%) and Ibrutinib (TGI = 41.1%) in the U-937 xenograft models at an oral dosage of 50 mg/kg. All these results suggest that compound <b>9</b> is a potent, selective, and orally available noncovalent BTK inhibitor worthy of further development.