Inhibitors of Bruton'S tyrosine kinase
View Patent ↗Described herein are irreversible kinase inhibitor compounds exemplified by the following structure Formula (B2): methods for synthesizing such irreversible inhibitors, and methods for using such irreversible inhibitors in the treatment of a B cell proliferative disorder or a mast cell proliferative disorder.
1. A compound of Formula (B5) having the structure:
wherein:
Y is a 4-, 5-, 6-membered cycloalkylene 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
R 2 is selected from H, lower alkyl, and substituted lower alkyl;
R 6 , R 7 and R 8 are independently selected from among H, lower alkyl or substituted lower alkyl, lower heteroalkyl or substituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, and substituted or unsubstituted lower heterocycloalkyl;
R 12 is H or lower alkyl; or
Y and R 12 taken together form a 4-, 5-, or 6-membered heterocyclic ring; or pharmaceutically acceptable salts thereof.
2. The compound of claim 1 , wherein G is
3. The compound of claim 2 , wherein R 6 , R 7 , and R 8 are H.
4. The compound of claim 2 , wherein
R 7 and R 8 are H; and
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.
5. The compound of claim 4 , wherein R 6 is substituted lower alkyl.
6. The compound of claim 5 , wherein lower alkyl is substituted with a disubstituted amino group.
7. The compound of claim 2 , wherein
R 6 and R 8 are H; and
R 7 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.
8. The compound of claim 7 , wherein R 7 is substituted lower alkyl.
9. The compound of claim 8 , wherein lower alkyl is substituted with a disubstituted amino group.
10. The compound of claim 1 , wherein G is
11. The compound of claim 10 , wherein R 6 is H.
12. The compound of claim 10 , 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.
13. The compound of claim 12 , wherein R 6 is substituted lower alkyl.
14. The compound of claim 13 , wherein lower alkyl is substituted with a disubstituted amino group.
15. The compound of claim 1 , wherein Y and R 12 taken together form a 6-membered heterocyclic ring.
16. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , and a pharmaceutically acceptable excipient.
17. The pharmaceutical composition of claim 16 that is formulated for a route of administration selected from oral administration, parenteral administration, buccal administration, nasal administration, topical administration, or rectal administration.