Bruton's tyrosine kinase (Btk) is thought to play a pathogenic role in chronic 
immune diseases such as rheumatoid arthritis and lupus. While covalent, 
irreversible Btk inhibitors are approved for treatment of hematologic 
malignancies, they are not approved for autoimmune indications. In efforts to 
develop additional series of reversible Btk inhibitors for chronic immune 
diseases, we sought to differentiate from our clinical stage inhibitor 
fenebrutinib using cyclopropyl amide isosteres of the 2-aminopyridyl group to 
occupy the flat, lipophilic H2 pocket. While drug-like properties were 
retained-and in some cases improved-a safety liability in the form of hERG 
inhibition was observed. When a fluorocyclopropyl amide was incorporated, Btk 
and off-target activity was found to be stereodependent and a lead compound was 
identified in the form of the (R,R)- stereoisomer.