Design, Synthesis, and Evaluation of 2-Methyl- and 2-Amino-N-aryl-4,5-dihydrothiazolo[4,5-h]quinazolin-8-amines as Ring-Constrained 2-Anilino-4-(thiazol-5-yl)pyrimidine Cyclin-Dependent Kinase Inhibitors

Following the recent discovery and development of 2-anilino-4-(thiazol-5-yl)pyrimidine cyclin dependent kinase (CDK) inhibitors, a program was initiated to evaluate related ring-constrained analogues, specifically, 2-methyl- and 2-amino-N-aryl-4,5-dihydrothiazolo[4,5-h]quinazolin-8-amines for inhibition of CDKs. Here we report the rational design, synthesis, structure-activity relationships (SARs), and cellular mode-of-action profile of these second generation CDK inhibitors. Many of the analogues from this chemical series inhibit CDKs with very low nanomolar K-i values. The most potent compound reported in this study inhibits CDK2 with an IC50 of 0.7 nM ([ATP] = 100 mu M). Furthermore, an X-ray crystal structure of 2-methyl-N-(3-(nitro)phenyl)-4,5-dihydrothiazolo[4,5-h]quinazolin-8-amine (11g), a representative from the chemical series in complex with cyclin A-CDK2, is reported, confirming the design rationale and expected binding mode within the CDK2 ATP binding pocket.