Structural optimization of 2-(2-aminopyridin-4-yl)-N-(3-carbamoyl-1H-pyrazol-4-yl)-1,3-oxazole-4-carboxamide derivatives as potent interleukin-1 receptor-associated kinase 4 inhibitors.

Interleukin-1 receptor-associated kinase 4 (IRAK4) is an essential component in signaling pathways downstream of Toll-like receptor/interleukin (IL)-1 receptor and has attracted much interest as a therapeutic target for a wide range of inflammatory and autoimmune diseases as well as cancers. In our efforts to enhance the IRAK4 inhibitory activity of AS2444697 (2) derivatives reported in our previous studies, a structure-activity relationship study on 1-methyl-1H-pyrazole analogs of 2 was conducted. Results revealed that the introduction of an amino group at the 2-position of the pyridin-4-yl group and substitution with lower alkyls and fluorinated ones at the amino nitrogen are effective for improving activity. This was particularly evident in isobutyl (14), cyclopropyl (45), cyclopropylmethyl (15), 2,2-difluoroethyl (18), and 2,2,2-trifluoroethyl (19), and led to more than 10-fold higher activity than the unsubstituted pyridin-4-yl derivative 5. In addition, bridged-ring substituents such as 3-hydroxyadamantan-1-yl (58) gave a similar effect to the lower alkyls. Further, the CYP1A2 induction assay revealed that 58 possesses markedly lower potency than the lower-alkylated derivatives. Finally, even in the series of 1-(oxan-4-yl)-1H-pyrazole analogs, we confirmed the favorable effect of the amino group substituted with the lower alkyls and fluorinated ones listed above for enhancing IRAK4 inhibitory activity, while maintaining low potency for CYP1A2 induction similarly to 2. The representative compounds 47 and 35, bearing cyclopropyl and 2,2,2-trifluoroethyl groups, respectively, exhibited considerably higher inhibition of IL-1β-stimulated IL-6 production in cellular assays than 2. Further, they also demonstrated improved selectivity for IL-1β signaling over tumor necrosis factor-α signaling compared with 2.