Fragment-Based Discovery of Pyrazolopyridones as JAK1 Inhibitors with Excellent Subtype Selectivity

Herein, we report
the discovery of a series of JAK1-selective kinase
inhibitors with high potency and excellent JAK family subtype selectivity.
A fragment screening hit 1 with a pyrazolopyridone core
and a JAK1 bias was selected as the starting point for our fragment-based
lead generation efforts. A two-stage strategy was chosen with the
dual aims of improving potency and JAK1 selectivity: Optimization
of the lipophilic ribose pocket-targeting substituent was followed
by the introduction of a variety of P-loop-targeting functional groups.
Combining the best moieties from both stages of the optimization afforded
compound 40, which showed excellent potency and selectivity.
Metabolism studies in vitro and in vivo together with an in vitro safety evaluation suggest
that 40 may be a viable lead compound for the development
of highly subtype-selective JAK1 inhibitors.