Preparation of pyrimidine derivatives as selective inhibitors of protein kinase Cθ with therapeutic uses.

Abstract

Disclosed are pyrimidine derivs. (shown as I; variables defined below; e.g. N'-[(trans-4-aminocyclohexyl)methyl]-N-(cyclohexylmethyl)-5-nitropyrimidine-2,4-diamine (shown as II)), which are useful as inhibitors of PKC-θ and are thus useful for treating a variety of diseases and disorders that are mediated or sustained through the activity of PKC-θ, including immunol. disorders and type II diabetes. This invention also relates to pharmaceutical compns. comprising these compds., methods of using these compds. in the treatment of various diseases and disorders, processes for prepg. these compds. and intermediates useful in these processes. For I: X is (un)substituted C1-6alkyl wherein 1 or 2 of the methylene units can be replaced by an O or S atom; Y is -NH-, -O- or -S-; R1 is: (un)substituted aryl or heteroaryl, C3-6cycloalkyl, -COR23, 2-oxo-1,2-dihydropyridinyl, benzodioxolyl, 2,3-dihydrobenzo[b]furanyl, 1-oxopyridinyl; R2 = CF3, cyano, halogen, nitro, C1-6alkylalkynyl, (un)substituted arylalkynyl; R3 = 4-aminocyclohexylmethyl, 4-amino-4-methylcyclohexylmethyl, 4-amino-3-hydroxycyclohexylmethyl (amino (un)substituted); addnl. details are given in the claims. All compds. I in the synthetic examples and tables were evaluated in the PKC-θ assay and have IC50's <1 μM. Many of these compds. I were also tested against Syk, Lyn, Veg-f and insulin receptor kinase to evaluate selectivity for PKC-theta inhibition; some were also tested against other kinases including CDK-2 and PLK; many demonstrated selectivity for the inhibition of PKC-θ as compared to ≥1 of the other kinases tested. Although the methods of prepn. are not claimed, prepns. and/or characterization data for many examples of I are included. For example, II was prepd. in 3 steps (63, 54, 35 %, resp.) starting with substitution of 2,4-dichloro-5-nitropyrimidine by tert-Bu (trans-4-aminomethylcyclohexyl)carbamate to give [4-[[(2-chloro-5-nitropyrimidin-4-yl)amino]methyl]cyclohexyl]carbamic acid tert-Bu ester, which underwent substitution with (cyclohexylmethyl)amine to give [4-[[[2-[(cyclohexylmethyl)amino]-5-nitropyrimidin-4-yl]amino]methyl]cyclohexyl]carbamic acid tert-Bu ester, which was deprotected to give II. [on SciFinder(R)]