Imidazo[1,5-a]quinoxalines as irreversible BTK inhibitors for the treatment of rheumatoid arthritis

  • Bioorg Med Chem Lett. 2011 Nov 1;21(21):6258-63. doi: 10.1016/j.bmcl.2011.09.008.
Kyung-Hee Kim  1 ,  Andreas Maderna ,  Mark E Schnute ,  Martin Hegen ,  Shashi Mohan ,  Joy Miyashiro ,  Laura Lin ,  Evelyn Li ,  Sean Keegan ,  Jennifer Lussier ,  Christopher Wrocklage ,  Cheryl L Nickerson-Nutter ,  Arthur J Wittwer ,  Holly Soutter ,  Nicole Caspers ,  Seungil Han ,  Ravi Kurumbail ,  Kyri Dunussi-Joannopoulos ,  John Douhan 3rd ,  Allan Wissner
Affiliations
  • 1. Medicinal Chemistry, Pfizer, 200 Cambridge Park Drive, Cambridge, MA 02140, United States. [email protected]
PMID: 21958547 DOI: 10.1016/j.bmcl.2011.09.008
Abstract

Imidazo[1,5-a]quinoxalines were synthesized that function as irreversible Bruton's tyrosine kinase (Btk) inhibitors. The syntheses and SAR of this series of compounds are presented as well as the X-ray crystal structure of the lead compound 36 in complex with a gate-keeper variant of Itk enzyme. The lead compound showed good in vivo efficacy in preclinical RA models.