Mutant activin receptor-like kinase-2 (ALK2) is associated with the pathogenesis of fibrodysplasia ossificans progressiva, making it an attractive target for therapeutic intervention. We synthesized a new series of bicyclic pyrazoles and evaluated their mutant ALK2 enzyme inhibitory activities, leading to the identification of 8 as the most potent inhibitor. This compound showed moderate microsomal metabolic stability and human ether-a-go-go related gene (hERG) safety. In C2C12 cells carrying mutant ALK2 (R206H), 8 efficiently inhibited the bone morphogenetic protein (BMP)-induced alkaline phosphatase activity.

中文翻译：

---

新型双环吡唑类作为有效的 ALK2 (R206H) 抑制剂，用于治疗进展性骨化纤维发育不良

突变激活素受体样激酶 2 (ALK2) 与骨化纤维发育不良的发病机制有关，使其成为治疗干预的有吸引力的目标。我们合成了一系列新的双环吡唑并评估了它们的突变 ALK2 酶抑制活性，从而确定8是最有效的抑制剂。该化合物表现出中等的微粒体代谢稳定性和人类 ether-a-go-go 相关基因 (hERG) 安全性。在携带突变 ALK2 (R206H) 的 C2C12 细胞中，8有效抑制了骨形态发生蛋白 (BMP) 诱导的碱性磷酸酶活性。