Discovery of 5-(arenethynyl) hetero-monocyclic derivatives as potent inhibitors of BCR–ABL including the T315I gatekeeper mutant

Ponatinib (AP24534) was previously identified as a pan-BCR–ABL inhibitor that potently inhibits the T315I gatekeeper mutant, and has advanced into clinical development for the treatment of refractory or resistant CML. In this study, we explored a novel series of five and six membered monocycles as alternate hinge-binding templates to replace the 6,5-fused imidazopyridazine core of ponatinib. Like ponatinib, these monocycles are tethered to pendant toluanilides via an ethynyl linker. Several compounds in this series displayed excellent in vitro potency against both native BCR–ABL and the T315I mutant. Notably, a subset of inhibitors exhibited desirable PK and were orally active in a mouse model of T315I-driven CML.

Graphical abstractWe describe the design, synthesis and structure–activity relationship studies for a series of hetero-monocyclic ponatinib analogues as potent inhibitors of BCR–ABL, including the T315I mutant.Figure optionsDownload full-size imageDownload as PowerPoint slide