Discovery of a series of novel 5H-pyrrolo[2,3-b]pyrazine-2-phenyl ethers, as potent JAK3 kinase inhibitors.
We report the discovery of a novel series of ATP-competitive Janus kinase 3 (JAK3) inhibitors based on the 5H-pyrrolo[2,3-b]pyrazine scaffold. The initial leads in this series, compounds 1a and 1h, showed promising potencies, but a lack of selectivity against other isoforms in the JAK family. Computational and crystallographic analysis suggested that the phenyl ether moiety possessed a favorable vector to achieve selectivity. Exploration of this vector resulted in the identification of 12b and 12d, as potent JAK3 inhibitors, demonstrating improved JAK family and kinase selectivity.
T10 T11 T1 T2 T3 T4 T5 T6 T7 T8 T9
GENE-Y GENE-N CHEMICAL CHEMICAL CHEMICAL GENE-N GENE-Y GENE-N GENE-N GENE-Y GENE-Y
JAK3 kinase 5H-pyrrolo[2,3-b]pyrazine ATP 5H-pyrrolo[2,3-b]pyrazine-2-phenyl ethers JAK JAK3 JAK kinase Janus kinase 3 JAK3