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

• Published in: Bioorganic & medicinal chemistry letters 2011-06, Vol.21 (12), p.3743-3748
• Main Authors: Thomas, Mathew, Huang, Wei-Sheng, Wen, David, Zhu, Xiaotian, Wang, Yihan, Metcalf, Chester A., Liu, Shuangying, Chen, Ingrid, Romero, Jan, Zou, Dong, Sundaramoorthi, Raji, Li, Feng, Qi, Jiwei, Cai, Lisi, Zhou, Tianjun, Commodore, Lois, Xu, Qihong, Keats, Jeff, Wang, Frank, Wardwell, Scott, Ning, Yaoyu, Snodgrass, Joseph T., Broudy, Marc I., Russian, Karin, Iuliucci, John, Rivera, Victor M., Sawyer, Tomi K., Dalgarno, David C., Clackson, Tim, Shakespeare, William C.
• Format: Article
• Language: English
• Subjects: Administration, Oral; Alkynes - chemical synthesis; Alkynes - chemistry; Alkynes - pharmacology; Aniline Compounds - chemical synthesis; Aniline Compounds - chemistry; Aniline Compounds - pharmacology; animal models; Animals; Antineoplastic agents; BCR–ABL inhibitors; Biological and medical sciences; chemistry; Chronic myeloid leukemia; Cyclization; Disease Models, Animal; Fusion Proteins, bcr-abl - antagonists & inhibitors; Fusion Proteins, bcr-abl - genetics; Gatekeeper mutant; General aspects; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Medical sciences; Mice; Models, Molecular; Molecular Structure; Monocycles; mutants; Mutation; Pharmacology. Drug treatments; Ponatinib; Rats; Structure-Activity Relationship; Toluene - chemical synthesis; Toluene - chemistry; Toluene - pharmacology
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2011.04.060

We 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. 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.