Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare disease leading to progressive soft tissue heterotopic ossification with no curative treatment available to date. It is caused by gain-of-function mutations in the BMP type I receptor kinase ALK2, triggering a search for efficacious small-molecule inhibitors. We optimized a chemical series of 2-aminopyrazine-3-carboxamides (Figure 1) for metabolic stability and off-target selectivity and identified a novel potent and selective ALK2 kinase inhibitor with excellent oral bioavailability in preclinical species, showing full suppression of heterotopic ossification in a pediatric mouse model of skeletal muscle injury-induced FOP.