Discovery of a series of novel 5H-pyrrolo[2,3-b]pyrazine-2-phenyl ethers, as potent JAK3 kinase inhibitors

  • Bioorg Med Chem Lett. 2013 May 1;23(9):2522-6. doi: 10.1016/j.bmcl.2013.03.015.
Saul Jaime-Figueroa  1 ,  Javier De Vicente ,  Johannes Hermann ,  Alam Jahangir ,  Sue Jin ,  Andreas Kuglstatter ,  Stephen M Lynch ,  John Menke ,  Linghao Niu ,  Vaishali Patel ,  Ada Shao ,  Michael Soth ,  Minh Diem Vu ,  Calvin Yee
Affiliations
  • 1. Hoffmann-La Roche Inc., pRED, Pharma Research & Early Development, Small Molecule Research, Discovery Chemistry, 340 Kingsland Street, Nutley, NJ 07110-1199, USA. [email protected]
PMID: 23541670 DOI: 10.1016/j.bmcl.2013.03.015
Abstract

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.