Discovery of C‑5 Pyrazole-Substituted Pyrrolopyridine Derivatives as Potent and Selective Inhibitors for Janus Kinase 1

Developing selective inhibitors for Janus kinase 1 (JAK1)
is a
significant focus for improving the efficacy and alleviating the adverse
effects in treating immune–inflammatory diseases. Herein, we
report the discovery of a series of C-5 pyrazole-modified pyrrolopyrimidine
derivatives as JAK1-selective inhibitors. The potential hydrogen bond
between the pyrazole group and E966 in JAK1 is the key point that
enhances JAK1 selectivity. These compounds exhibit 10- to 20-fold
JAK1 selectivity over JAK2 in enzyme assays. Compound 12b also exhibits excellent JAK1 selectivity in Ba/F3-TEL-JAK cellular
assays. Metabolism studies and the results of the hair growth model
in mice indicate that compound 12b may be a viable lead
compound for the development of highly JAK1-selective inhibitors for
immune and inflammatory diseases.