Discovery and Evaluation of Pyrazolo3,4-dpyridazinone as a Potent and Orally Active Irreversible BTK Inhibitor

The identification and lead optimization of a series of pyrazolo3,4-dpyridazinone derivatives are described as a novel class of potent irreversible BTK inhibitors, resulting in the discovery of compound 8. Compound 8 exhibited high potency against BTK kinase and acceptable PK profile. Furthermore, compound 8 demonstrated significant in vivo efficacy in a mouse-collagen-induced arthritis (CIA) model.