Synthesis and biological evaluation of 5-substituted O4-alkylpyrimidines as CDK2 inhibitors

Abstract

CDK2 inhibitory structure–activity relationships have been explored for a range of 5-substituted O⁴-alkylpyrimidines. Variation of the 5-substituent in the 2,6-diaminopyrimidine series confirmed the 5-nitroso substituent as optimal, and showed that 5-formyl and 5-acetyl substituents were also tolerated at this position. A series of O⁴-alkyl-N²-aryl-5-substituted-6-aminopyrimidines revealed interesting structure–activity relationships. In the 5-nitroso series, the optimum O⁴-alkyl substituents were cyclohexylmethyl or sec-butyl, combined with a 2-sulfanilyl group. By contrast, in the N²-arylsulfonamido-5-formyl series, the cyclohexylmethyl compound showed relatively poor activity compared with the sec-butyl derivative (22j, (R)-4-(4-amino-6-sec-butoxy-5-formylpyrimidin-2-ylamino)benzenesulfonamide; CDK2 IC₅₀ = 0.8 nM). Similarly, in the N²-arylsulfonamido-5-(hydroxyiminomethyl) series the O⁴-sec-butyl substituent conferred greater potency than the cyclohexylmethyl (23c, (rac)-4-(4-amino-6-sec-butoxy-5-(hydroxyiminomethyl)pyrimidin-2-ylamino)benzenesulfonamide; CDK2 IC₅₀ = 7.4 nM). The 5-formyl derivatives show selectivity for CDK2 over other CDK family members, and are growth inhibitory in tumour cells (e.g.22j, GI₅₀ = 0.57 μM).