Synthesis and Biological Evaluation of N2-Substituted 2,4-Diamino-6-cyclohexylmethoxy-5-nitrosopyrimidines and Related 5-Cyano-NNO-azoxy Derivatives as Cyclin-Dependent Kinase2 (CDK2) Inhibitors

The potent and selective cyclin-dependent kinase2 (CDK2) inhibitor NU6027 (6-cyclohexylmethoxy-5-nitroso-2,4-diaminopyrimidine) was used as the lead for the synthesis of a series of analogues in order to provide further insight into the structure-activity relationships for 2,4-diaminopyrimidine CDK2 inhibitors. Aliphatic amino substituents were introduced at position2. The use of linear or less sterically hindered amines gave rise to compounds endowed with slightly better activity than the lead; on the other hand, the compounds were less active if a bulkier amino substituent was used. Substitution of the 5-nitroso group with a 5-cyano-NNO-azoxy moiety afforded a new class of inhibitors, the activity of which against CDK2 was found to be similar to that of the nitroso series. The most active nitroso compound was 8b ((2S)-2-[(4-amino-6-cyclohexylmethoxy-5-nitrosopyrimidin-2-yl)amino]propan-1-ol; IC50=0.16m), while in the 5-cyano-NNO-azoxy series the most active compound was 9b (4-amino-5-[(Z)-cyano-NNO-azoxy]-2-{[(2S)-1-hydroxypropan-2-yl]amino}-6-cyclohexylmethoxypyrimidine; IC50=0.30m). Taken together, these new analogues of NU6027 enhance our understanding of the structure-activity relationships for 2,4-diaminopyrimidine CDK2 inhibitors.