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

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 crystalstructure of the lead compound 36 in complex with a gate-keeper variant of ITK enzyme. The lead com-pound showed good in vivo efficacy in preclinical RA models. 2011 Elsevier Ltd. All rights reserved. Bruton’s tyrosine kinase (BTK), a nonreceptor cytoplasmic tyro-sine kinase belonging to the Tec kinase family, has been shown tobe critical for B-cell proliferation, differentiation, and signaling. 1 In human, defects in the BTK gene lead to X-linked agammaglobu-linemia (XLA), which is characterized by a profound decrease in Bcell numbers and in serum immunoglobulin levels. BTK mutationin mice resulted in X-linked immunodeficiency (xid), a similarthough less severephenotypethan XLA. Since B cells play an essen-tial role in regulating immune response, inhibitors of BTK may beeffective in treating autoimmune diseases such as rheumatoidarthritis (RA) and systemic lupus erythematosus (SLE). The evi-dence that B cells play a central role in immune dysregulation inRA is substantiated by the observation of clinical improvementsin RA patients receiving B-cell depleting antibody therapies suchas Rituximab.Currently, there are no small moleculeBTK inhibitorsin clinical use for the treatment of autoimmune diseases. In thiscommunication, we will describe the discovery of a series of smallmolecule inhibitors of BTK having efficacy in in vivo preclinicalmodels of RA.Since the ATP binding site in kinases is highly conserved, it isoften difficultto find an ATP competitiveinhibitor having sufficientselectivity. In the present case, the ATP binding site of BTK shows aclose homology to that of other Src-family kinases, such aslymphocyte-specific protein tyrosine kinase (LCK) and LYN. A lackof selectivity of an inhibitor for BTK over these kinases couldpotentiallyhavenegativeconsequences.BTKisamemberofagroupofeleventyrosinekinases(theTecfamilykinases,EGFR,Jak3,ErbB2,ErbB4, and BLK) that contain a conserved cysteine residue adjacenttotheATP-bindingsite.