Patent ID: 8883435

Claim:
A method of identifying an irreversible inhibitor of a Bruton's tyrosine kinase (Btk) comprising: (1) contacting Btk with a compound of Formula VII; (2) contacting at least one non-kinase molecule having at least one accessible SH group including glutathione and/or hemoglobin with the compound of Formula VII; and (3) determining the covalent binding of the compound of Formula VII with Btk and the at least one non-kinase molecule; and repeating steps (1), (2), and (3) for at least one other compound of Formula VII, wherein the compound of Formula (VII) has the structure: wherein: is a moiety that binds to the active site of a Btk kinase; Y is an optionally substituted group selected from among alkylene, heteroalkylene, arylene, heteroarylene, heterocycloalkylene, cycloalkylene, alkylenearylene, alkyleneheteroarylene, alkylenecycloalkylene, and alkyleneheterocycloalkylene; Z is C(═O), OC(═O), NHC(═O), NCH 3 C(═O), C(═S), S(═O) x , OS(═O) x , NHS(═O) x , where x is 1 or 2; R 7 and R 8 are independently selected from among H, unsubstituted C 1 -C 4 alkyl, substituted C 1 -C 4 alkyl, unsubstituted C 1 -C 4 heteroalkyl, substituted C 1 -C 4 heteroalkyl, unsubstituted C 3 -C 6 cycloalkyl, substituted C 3 -C 6 cycloalkyl, unsubstituted C 2 -C 6 heterocycloalkyl, and substituted C 2 -C 6 heterocycloalkyl; or R 7 and R 8 taken together form a bond; and R 6 is H, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 heteroalkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 8 alkylaminoalkyl, C 1 -C 8 hydroxyalkylaminoalkyl, C 1 -C 8 alkoxyalkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 2 -C 8 heterocycloalkyl, substituted or unsubstituted heteroaryl, C 1 -C 4 alkyl(aryl), C 1 -C 4 alkyl(heteroaryl), C 1 -C 4 alkyl(C 3 -C 8 cycloalkyl), or C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl); wherein a desired irreversible inhibitor is selective for Btk relative to glutathione and hemoglobin.