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 compound of Formula (B5) having the structure:
wherein:
Y and R 12 taken together form a 4-, 5-, or 6-membered heterocyclic ring;
each R a is independently H, halogen, CF 3 , CN, NO 2 , OH, NH 2 , -L a -(substituted or unsubstituted alkyl), -L a -(substituted or unsubstituted alkenyl), -L a -(substituted or unsubstituted heteroaryl), or -L a -(substituted or unsubstituted aryl), wherein L a is a bond, O, S, S(═O), S(═O) 2 , NH, C(O), CH 2 , NHC(O)O, NHC(O), or C(O)NH;
G is
wherein R 6 is selected from H, lower alkyl or substituted lower alkyl, lower heteroalkyl or substituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, and substituted or unsubstituted lower heterocycloalkyl;
or a pharmaceutically acceptable salt thereof.
102 . The compound of claim 101 , wherein R 6 is selected from lower alkyl or substituted lower alkyl, lower heteroalkyl or substituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, and substituted or unsubstituted lower heterocycloalkyl.
103 . The compound of claim 102 , wherein R 6 is lower alkyl.
104 . The compound of claim 103 , wherein R 6 is methyl.
105 . The compound of claim 101 , wherein Y and R 12 taken together form a 5-membered heterocyclic ring.
106 . The compound of claim 105 , wherein R 6 is selected from lower alkyl or substituted lower alkyl, lower heteroalkyl or substituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, and substituted or unsubstituted lower heterocycloalkyl.
107 . The compound of claim 106 , wherein R 6 is lower alkyl.
108 . The compound of claim 107 , wherein R 6 is methyl.
109 . A compound of Formula (B5) having the structure:
wherein:
Y and R 12 taken together form a 4-, 5-, or 6-membered heterocyclic ring;
R a at positions 2, 3, 5, and 6 are each H;
R a at position 4 is H, halogen, CF 3 , CN, NO 2 , OH, NH 2 , -L a -(substituted or unsubstituted alkyl), -L a -(substituted or unsubstituted alkenyl), -L a -(substituted or unsubstituted heteroaryl), or -L a -(substituted or unsubstituted aryl), wherein L a is a bond, O, S, S(═O), S(═O) 2 , NH, C(O), CH 2 , NHC(O)O, NHC(O), or C(O)NH;
G is
wherein R 6 is selected from H, lower alkyl or substituted lower alkyl, lower heteroalkyl or substituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, and substituted or unsubstituted lower heterocycloalkyl;
or a pharmaceutically acceptable salt thereof.
110 . The compound of claim 109 , wherein R a at position 4 is -L a -(substituted or unsubstituted heteroaryl).
111 . The compound of claim 110 , wherein L a is C(O)NH.
112 . The compound of claim 111 , wherein Y and R 12 taken together form a 5-membered heterocyclic ring.
113 . The compound of claim 112 , wherein R 6 is selected from lower alkyl or substituted lower alkyl, lower heteroalkyl or substituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, and substituted or unsubstituted lower heterocycloalkyl.
114 . The compound of claim 113 , wherein R 6 is lower alkyl.
115 . The compound of claim 114 , wherein R 6 is methyl.
116 . The compound of claim 109 , wherein Y and R 12 taken together form a 5-membered heterocyclic ring.
117 . The compound of claim 116 , wherein R 6 is selected from lower alkyl or substituted lower alkyl, lower heteroalkyl or substituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, and substituted or unsubstituted lower heterocycloalkyl.
118 . The compound of claim 117 , wherein R 6 is lower alkyl.
119 . The compound of claim 118 , wherein R 6 is methyl.
120 . A compound of Formula (B5) having the structure:
wherein:
Y and R 12 taken together form a 4-, 5-, or 6-membered heterocyclic ring;
each R a is independently H, halogen, CF 3 , CN, NO 2 , OH, NH 2 , -L a -(substituted or unsubstituted alkyl), -L a -(substituted or unsubstituted alkenyl), -L a -(substituted or unsubstituted heteroaryl), or -L a -(substituted or unsubstituted aryl), wherein L a is a bond, O, S, S(═O), S(═O) 2 , NH, C(O), CH 2 , NHC(O)O, NHC(O), or C(O)NH;
G is
wherein R 6 is selected from H, lower alkyl or substituted lower alkyl, lower heteroalkyl or substituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, and substituted or unsubstituted lower heterocycloalkyl.
121 . The compound of claim 120 , wherein R 6 is selected from lower alkyl or substituted lower alkyl, lower heteroalkyl or substituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, and substituted or unsubstituted lower heterocycloalkyl.
122 . The compound of claim 121 , wherein R 6 is lower alkyl.
123 . The compound of claim 122 , wherein R 6 is methyl.
124 . The compound of claim 120 , wherein Y and R 12 taken together form a 5-membered heterocyclic ring.
125 . The compound of claim 124 , wherein R 6 is selected from lower alkyl or substituted lower alkyl, lower heteroalkyl or substituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, and substituted or unsubstituted lower heterocycloalkyl.
126 . The compound of claim 125 , wherein R 6 is lower alkyl.
127 . The compound of claim 126 , wherein R 6 is methyl.