INHIBITORS OF BRUTON'S TYROSINE KINASE
Described herein are irreversible kinase inhibitor compounds, methods for synthesizing such irreversible inhibitors, and methods for using such irreversible inhibitors in the treatment of diseases. Further described herein are methods, assays and systems for determining an appropriate irreversible inhibitor of a protein, including a kinase.
1 .- 100 . (canceled)
101 . A kinase inhibitor having the structure of Formula (VII):
wherein:
is a moiety that binds to the active site of a kinase, including a tyrosine kinase;
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;
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, 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); and
pharmaceutically active metabolites, or pharmaceutically acceptable solvates, pharmaceutically acceptable salts, or pharmaceutically acceptable prodrugs thereof.
102 . The kinase inhibitor of claim 101 , wherein
is a substituted fused biaryl moiety selected from
103 . The kinase inhibitor of claim 101 , wherein:
Z is C(═O), NHC(═O), NCH 3 C(═O), or S(═O) 2 .
104 . The kinase inhibitor of claim 101 , wherein:
each of R 7 and R 8 is H; or
R 7 and R 8 taken together form a bond.
105 . The kinase inhibitor of claim 101 , wherein:
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, 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).
106 . The kinase inhibitor of claim 101 , wherein at least one of R 6 , R 7 , and R 8 is not H.
107 . The kinase inhibitor of claim 101 , wherein R 6 is H, R 7 is H, and R 8 is H.
108 . A kinase inhibitor having the structure of Formula (VII):
wherein:
is a moiety that binds to the active site of a kinase, including a tyrosine kinase;
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;
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, 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); and
pharmaceutically active metabolites, or pharmaceutically acceptable solvates, pharmaceutically acceptable salts, or pharmaceutically acceptable prodrugs thereof.
109 . The kinase inhibitor of claim 108 , wherein at least one of R 6 , R 7 , and R 8 is not H.
110 . The kinase inhibitor of claim 108 , wherein R 6 is H, R 7 is H, and R 8 is H.
111 . The kinase inhibitor of claim 101 or claim 108 that selectively and irreversibly binds to Btk.
112 . The kinase inhibitor of claim 101 , in which the plasma half life of the kinase inhibitor is less than about 4 hours.
113 . The kinase inhibitor of claim 101 , in which the plasma half life of the kinase inhibitor is less than about 3 hours.
114 . A pharmaceutical formulation comprising the kinase inhibitor of claim 101 and a pharmaceutically acceptable excipient.
115 . The pharmaceutical formulation of claim 114 formulated for a route of administration selected from oral administration, parenteral administration, buccal administration, nasal administration, topical administration, or rectal administration.
116 . The pharmaceutical formulation of claim 115 formulated for oral administration.