Development of Amino-Pyrimidine Inhibitors of C-Jun N-terminal Kinase (JNK): Kinase Profiling Guided Optimization of a 1,2,3-Benzotriazole Lead

A series of amino-pyrimidines was developed based upon an initial kinase cross-screening hit from a CDK2 program. Kinase profiling and structure-based drug design guided the optimization from the initial 1,2,3-benzotriazole hit to a potent and selective JNK inhibitor, compound 24f (JNK1 and 2 IC(50)=16 and 66 nM, respectively), with bioavailability in rats and suitable for further in vivo pharmacological evaluation.