Inhibitors of bruton's tyrosine kinase
View Patent ↗Disclosed herein are compounds that form covalent bonds with Bruton's tyrosine kinase (Btk). Also described are irreversible inhibitors of Btk, such as those having the structure of Formula (B) Methods for the preparation of the compounds are disclosed. Also disclosed are pharmaceutical compositions that include the compounds. Methods of using the Btk inhibitors are disclosed, alone or in combination with other therapeutic agents, for the treatment of autoimmune diseases or conditions, heteroimmune diseases or conditions, cancer, including lymphoma, and inflammatory diseases or conditions.
1. A compound of Formula (B) having the structure:
wherein:
Y is alkylene or substituted alkylene, or 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), or -L a -(substituted or unsubstituted heteroaryl), 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 a pharmaceutically acceptable solvate, pharmaceutically acceptable hydrate, or pharmaceutically acceptable salt 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. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , and a pharmaceutically acceptable excipient.
16. The pharmaceutical composition of claim 15 that is formulated for a route of administration selected from oral administration, parenteral administration, buccal administration, nasal administration, topical administration, or rectal administration.