The pyrazolo[1,5-a]pyrimidine LDN-193189 is a potent inhibitor of activin receptor-like kinase 2 (ALK2) but is nonselective for highly homologous ALK3 and shows only modest kinome selectivity. Herein, we describe the discovery of a novel series of potent and selective ALK2 inhibitors by replacing the quinolinyl with a 4-(sulfamoyl)naphthyl, yielding ALK2 inhibitors that exhibit not only excellent discrimination versus ALK3 but also high kinome selectivity. In addition, the optimized compound 23 demonstrates good ADME and in vivo pharmacokinetic properties.

Jiang, Jian-Kang; Huang, Xiuli; Shamim, Khalida; Patel, Paresma R; Lee, Arthur; Wang, Amy; Nguyen, Kimloan; Tawa, Gregory; Cuny, Gregory D; Yu, Paul B; Zheng, Wei; Xu, Xin; Sanderson, Philip; Huang, Wenwei;