As has been shown, the oral kinase inhibitors described above occupy a distinct region in MC structure-property space. In this prior work, a set of macrocyclic drugs and clinical candidates, as well as several available synthetic MC libraries, were evaluated with respect to a set of 90 physicochemical and structural molecular descriptors, many specifically designed to capture the special features of macrocyclic compounds. The results showed that most of the oral drugs and clinical candidates reside in a well-defined region of property space that was termed Zone 1 (Figure ). Interestingly, however, the five oral ATP-competitive kinase inhibitors exist in a separate region of property space designated Zone 2, indicating that they have distinct structural and physicochemical properties compared to other MC drugs. In particular, the analysis suggested that, relative to most other oral MC drugs, compounds in Zone 2 have simpler, less densely decorated MC rings, a lower proportion of sp 3 -hybridized carbons, and less oxygen-rich substituents. 7