The Janus kinase (JAK) family of tyrosine kinases plays a central role in the cytokine-dependent regulation of proliferation and function of cells involved in immune response. It consists of four closely related proteins (JAK1, JAK2, JAK3 and TYK2) that transduce signaling from cytokine receptors by phosphorylation and subsequent activation of signal transducers and activators of transcription (STAT). Recently, subtype-selective JAK1 inhibitors have attracted attention as possible therapeutic agents for atopic dermatitis, and the most advanced compounds are now in phase III clinical trials for this indication. High selectivity over JAK2 may reduce the side-effect burden of the first-generation JAK inhibitors, e.g. tofacitinib (Xeljanz®). Herein, we report the discovery of a series of JAK1-selective kinase inhibitors with high potency, excellent JAK family subtype selectivity and promising in vitro and in vivo pharmacokinetic properties. A fragment screening hit (1) was selected as the starting point. X-ray crystallography was unsuccessful for this compound, but initial SAR indicated that the kinase hinge region interacts with at least one of the NH donors of the scaffold. Thus, analogs with aromatic and aliphatic rings appended to the 4-position of the scaffold were targeted. This lead to a large increase in potency, and importantly allowed us to obtain an X-ray crystal structure. With the binding mode known, we proceeded to optimize the substituent in the 4-position. A selection of mono- and bicyclic aliphatic ring systems were investigated, and a trend towards higher potency with increasing steric bulk was observed. In particular, the norbornane scaffold was selected for further exploration due to its balance of good potency without excessive lipophilicity. Norbornane acetonitrile 2 showed excellent potency and selectivity, and we profiled this compound further in in vitro and in vivo metabolism studies. The results of these studies indicate that 2 may be a viable lead compound for the development of highly subtype-selective JAK1 inhibitors.

Fragment-based discovery of pyrazolopyridones as JAK1 inhibitors with excellent subtype selectivity

256th National Meeting (2018)

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