Structure-based design of novel pyrrolo[1,2-a]quinoxalin-4(5H)-one derivatives as potent noncovalent Bruton's tyrosine kinase (BTK) inhibitors

Bruton's tyrosine kinase (Btk) is a promising target for the treatment of B cell malignancies. Developing noncovalent Btk inhibitors is a promising strategy to address the treatment limitations of covalent Btk inhibitors including off-target toxicity and acquired resistance. Our group previously discovered a novel noncovalent Btk Inhibitor S2 with pyrrolo[1,2-α]quinoxalin-4(5H)-one as the scaffold. To further reduce the synthetic difficulty and improve physicochemical properties, we designed and synthesized a new series of ring-opening pyrrolo[1,2-α]quinoxalin-4(5H)-one derivatives based on the docking mode of S2 with Btk. Among them, the representative compound 10 exhibited potent Btk inhibitory activity (IC₅₀ = 24.7 nM). Compared with S2, compound 10 had lower structural rigidity, lipophilicity (cLogP: 4.2 vs 5.5), and molecular weight (MW: 490 vs 510), and was easier to prepare. Further study showed that compound 10 exhibited potent antitumor activities in lymphoma cells. The favorable physicochemical properties and in vitro activities suggested that compound 10 was a promising noncovalent Btk inhibitors worthy of further exploration.

BTK; Noncovalent inhibitors; Pyrrolo[1,2-a]quinoxalin-4(5H)-one.