A further example of a substantial, affinity improvement upon cyclization is provided by Ma. et al., who reported that macrocyclization of 3-(5-aminopyrazolo[1,5-a]pyrimidin-3-yl)phenol (10) with a flexible 5-atom linker to give 11 resulted in increases in potency against a set of kineses ranging from ~30-fold for TGFbR2 to ~800-fold for ALK2 (Figure ). In this case, however, the substantial improvement in potency likely resulted in part from new interactions made by the linker atoms in addition to the entropic effect of freezing out the few rotatable bonds that exist in the acyclic precursor.