Potent and Selective Amidopyrazole Inhibitors of IRAK4 That Are Efficacious in a Rodent Model of Inflammation

IRAK4 is a critical upstream kinase in the IL-1R/TLR signaling pathway. Inhibition of IRAK4 is hypothesized to be beneficial in the treatment of autoimmune related disorders. A screening campaign identified a pyrazole class of IRAK4 inhibitors that were determined by X-ray crystallography to exhibit an unusual binding mode. SAR efforts focused on the identification of a potent and selective inhibitor with good aqueous solubility and rodent pharmacokinetics. Pyrazole C-3 piperidines were well tolerated, with <i>N</i>-sulfonyl analogues generally having good rodent oral exposure but poor solubility. <i>N</i>-Alkyl piperidines exhibited excellent solubility and reduced exposure. Pyrazoles possessing N-1 pyridine and fluorophenyl substituents were among the most active. Piperazine <b>32</b> was a potent enzyme inhibitor with good cellular activity. Compound <b>32</b> reduced the <i>in vivo</i> production of proinflammatory cytokines and was orally efficacious in a mouse antibody induced arthritis disease model of inflammation