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|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 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)|
1. A compound of Formula (B) having the structure: ##STR00058## wherein: Y is alkylene or substituted alkylene, or a 4-, 5-, or 6-membered cycloalkyl ring; 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), -L.sub.a-(substituted or unsubstituted alkenyl), -L.sub.a-(substituted or unsubstituted heteroaryl), or -L.sub.a-(substituted or
unsubstituted aryl), 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; G is a Michael acceptor; R.sub.12 is H or lower alkyl; or Y and R.sub.12 taken together form a 4-, 5-, or
6-membered heterocyclic ring; or pharmaceutically acceptable salt thereof.
2. The compound of claim 1, having the structure: ##STR00059##
3. The compound of claim 2, wherein R.sub.a is -L.sub.a-(substituted or unsubstituted aryl).
4. The compound of claim 3, R.sub.a is --O-(substituted or unsubstituted phenyl).
5. The compound of claim 4, wherein Y and R.sub.12 taken together form a 4-, 5-, or 6-membered heterocyclic ring.
6. The compound of claim 5, wherein Y and R.sub.12 taken together form a pyrrolidine ring.
7. The compound of claim 5, wherein Y and R.sub.12 taken together form a piperidine ring.
8. The compound of claim 4, wherein Y is a 4-, 5-, or 6-membered cycloalkyl ring.
9. The compound of claim 8, wherein Y is a 6-membered cycloalkyl ring.
10. The compound of claim 4, wherein Y is substituted alkylene.
11. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1, and a pharmaceutically acceptable excipient.
12. The pharmaceutical composition of claim 11 that is formulated for a route of administration selected from oral administration, parenteral administration, buccal administration, nasal administration, topical administration, and rectal administration.
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