TTK/Mps1 is a key kinase controlling progression of cell division via 
participation in the mitotic spindle assembly checkpoint and is overexpressed in 
a number of human cancers. Herein we report the discovery of 
4-(4-aminopyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamides as a potent, novel class 
of TTK inhibitors. The series was identified by means of bioisosteric 
replacement of the related imidazopyrazine and imidazopyridazine scaffolds. 
Optimization led to the identification of compounds with excellent potency 
(Ki=0.8nM) and exceptional kinase selectivity. The SAR indicates a strong 
dependence of activity on the presence of the N-cyclopropyl-2-methylbenzamide 
moiety delineating the geometry for 1½ type kinase inhibitor. Molecular modeling 
indicates the extensive and optimal contacts, mediated through H-bonds and 
hydrophobic interactions, are responsible for the selectivity and potency of the 
inhibitors. The compounds demonstrate a strong anti-proliferative activity in a 
panel of human cancer cell lines (HCT116 GI50<15nM) and good rodent 
pharmacokinetics (oral %F 97%).