Tpl2 (cot/MAP3K8) is an upstream kinase of MEK in the ERK pathway. It plays an 
important role in Tumor Necrosis Factor-alpha (TNF-alpha) production and 
signaling. We have discovered that 
8-halo-4-(3-chloro-4-fluoro-phenylamino)-6-[(1H-[1,2,3]triazol-4-ylmethyl)-amino]-quinoline-3-carbonitriles 
(4) are potent inhibitors of this enzyme. In order to improve the inhibition of 
TNF-alpha production in LPS-stimulated human blood, a series of analogs with a 
variety of substitutions around the triazole moiety were studied. We found that 
a cyclic amine group appended to the triazole ring could considerably enhance 
potency, aqueous solubility, and cell membrane permeability. Optimization of 
these cyclic amine groups led to the identification of 
8-chloro-4-(3-chloro-4-fluorophenylamino)-6-((1-(1-ethylpiperidin-4-yl)-1H-1,2,3-triazol-4-yl)methylamino)quinoline-3-carbonitrile 
(34). In a LPS-stimulated rat inflammation model, compound 34 showed good 
efficacy in inhibiting TNF-alpha production.