Details for Patent: 8,748,439

Title:	Inhibitors of Bruton's tyrosine kinase
Abstract:	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: ##STR00001## 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.
Inventor(s):	Honigberg; Lee (San Francisco, CA), Verner; Erik (Belmont, CA), Pan; Zhengying (Austin, TX)
Assignee:	Pharmacyclics, Inc. (Sunnyvale, CA)
Filing Date:	Apr 18, 2012
Application Number:	13/450,158
Claims:	1. A compound having the structure: ##STR00058## wherein each R.sub.a is independently H, halogen, --CF.sub.3, --CN, --NO.sub.2, OH, NH.sub.2, -L.sub.a-(substituted or unsubstituted alkyl), or -L.sub.a-(substituted or unsubstituted alkenyl), wherein L.sub.a is a bond, O, S, --S(.dbd.O), --S(.dbd.O).sub.2, NH, C(O), CH.sub.2, --NHC(O)O, --NHC(O), or --C(O)NH; L.sub.3 is optional, and when present is a bond, optionally substituted or unsubstituted alkylene, optionally substituted or unsubstituted cycloalkylene, optionally substituted or unsubstituted alkenylene, or optionally substituted or unsubstituted alkynylene; X is optional, and when present is a bond, O, --C(.dbd.O), S, --S(.dbd.O), --S(.dbd.O).sub.2, --NH, --NR.sub.9, --NHC(O), --C(O)NH, --NR.sub.9C(O), --C(O)NR.sub.9, --S(.dbd.O).sub.2NH, --NHS(.dbd.O).sub.2, --S(.dbd.O).sub.2NR.sub.9--, --NR.sub.9S(.dbd.O).sub.2, --OC(O)NH--, --NHC(O)O--, --OC(O)NR.sub.9--, --NR.sub.9C(O)O--, --CH.dbd.NO--, --ON.dbd.CH--, --NR.sub.10C(O)NR.sub.10--, heteroaryl, aryl, --NR.sub.10C(.dbd.NR.sub.11)NR.sub.10--, --NR.sub.10C(.dbd.NR.sub.11)--, --C(.dbd.NR.sub.11)NR.sub.10--, --OC(.dbd.NR.sub.ii)--, or --C(.dbd.NR.sub.11)O--; L.sub.4 is optional, and when present is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted heterocyclene; or L.sub.3, X and L.sub.4 taken together form a nitrogen containing heterocyclic ring; G is ##STR00059## wherein, R.sub.6, R.sub.7 and R.sub.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.sub.9 is selected from among H, substituted or unsubstituted lower alkyl, and substituted or unsubstituted lower cycloalkyl; each R.sub.10 is independently H, substituted or unsubstituted lower alkyl, or substituted or unsubstituted lower cycloalkyl; or two R.sub.10 groups can together form a 5-, 6-, 7-, or 8-membered heterocyclic ring; or R.sub.10 and R.sub.11 can together form a 5-, 6-, 7-, or 8-membered heterocyclic ring; or R.sub.11 is selected from H, --S(.dbd.O).sub.2R.sub.8, --S(.dbd.O).sub.2NH.sub.2, --C(O)R.sub.8, --CN, --NO.sub.2, heteroaryl, or heteroalkyl; or a pharmaceutically acceptable solvate, pharmaceutically acceptable hydrate, or pharmaceutically acceptable salt thereof. 2. The compound of claim 1, wherein L.sub.3, X and L.sub.4 taken together form a nitrogen containing heterocyclic ring. 3. The compound of claim 2, wherein G is ##STR00060## 4. The compound of claim 3, wherein R.sub.6, R.sub.7, and R.sub.8 are H. 5. The compound of claim 3, wherein R.sub.7 and R.sub.8 are H; and R.sub.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. 6. The compound of claim 5, wherein R.sub.6 is substituted lower alkyl. 7. The compound of claim 6, wherein lower alkyl is substituted with a disubstituted amino group. 8. The compound of claim 3, wherein R.sub.6 and R.sub.8 are H; and R.sub.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. 9. The compound of claim 8, wherein R.sub.7 is substituted lower alkyl. 10. The compound of claim 9, wherein lower alkyl is substituted with a disubstituted amino group. 11. The compound of claim 2, wherein G is ##STR00061## 12. The compound of claim 11, wherein R.sub.6 is H. 13. The compound of claim 11, wherein R.sub.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. 14. The compound of claim 13, wherein R.sub.6 is substituted lower alkyl. 15. The compound of claim 14, wherein lower alkyl is substituted with a disubstituted amino group. 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.