Potent direct inhibitors of factor Xa based on the tetrahydroisoquinoline scaffold

► THIQ3CA analogs possess excellent direct FXa inhibition property. ► A potent dicarboxamide 47 displays Ki of 135 nM ► An additive relationship between two arms on the THIQ3CA core led to the design of 47. ► The inhibitors were assembled in only three high yielding steps. ► 47 displays >1852-fold selectivity for FXa inhibition over other coagulation enzymes.