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Details for Patent: 8,940,750

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Details for Patent: 8,940,750

Title:Inhibitors of bruton's tyrosine kinase
Abstract: Described herein are irreversible kinase inhibitor compounds, 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 having the structure of Formula (A1) ##STR00001##
Inventor(s): Honigberg; Lee (San Francisco, CA), Verner; Erik J. (Belmont, CA), Buggy; Joseph J. (Mountain View, CA), Loury; David J. (San Jose, CA), Chen; Wei (Fremont, CA)
Assignee: Pharmacyclics, Inc. (Sunnyvale, CA)
Filing Date:Sep 07, 2012
Application Number:13/606,949
Claims:1. A method of treating a mast cell proliferative disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a compound that irreversibly inhibits an interleukin-2 inducible tyrosine kinase (ITK) having the structure of Formula (A1) ##STR00126## wherein: A is N; R.sub.1 is L.sub.2-(substituted or unsubstituted heteroaryl), or L.sub.2-(substituted or unsubstituted aryl), where L.sub.2 is a bond, O, S, --S(.dbd.O), --S(.dbd.O).sub.2, C(.dbd.O), -(substituted or unsubstituted C.sub.1-C.sub.6 alkylene), or -(substituted or unsubstituted C.sub.2-C.sub.6 alkenylene); R.sub.2 and R.sub.3 are independently selected from H or lower alkyl; R.sub.4 is L.sub.3-X-L.sub.4-G, wherein, L.sub.3 is optional, and when present is a bond, or an optionally substituted group selected from alkylene, heteroalkylene, arylene, heteroarylene, alkylarylene, alkylheteroarylene, and alkylheterocycloalkylene; 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--, heteroarylene, arylene, --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.11)--, 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 ##STR00127## wherein, R.sup.a is H, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl; R.sub.7 and R.sub.8 are H; and R.sub.6 is H, substituted or unsubstituted C.sub.1-C.sub.4alkyl, substituted or unsubstituted C.sub.1-C.sub.4heteroalkyl, C.sub.1-C.sub.8alkylaminoalkyl, C.sub.1-C.sub.8hydroxyalkylaminoalkyl, C.sub.1-C.sub.8alkoxyalkylaminoalkyl, substituted or unsubstituted C.sub.3-C.sub.6cycloalkyl, substituted or unsubstituted C.sub.1-C.sub.8alkylC.sub.3-C.sub.6cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted C.sub.2-C.sub.8heterocycloalkyl, substituted or unsubstituted heteroaryl, C.sub.1-C.sub.4alkyl(aryl), C.sub.1-C.sub.4alkyl(heteroaryl), C.sub.1-C.sub.8alkylether, C.sub.1-C.sub.8alkylamide, or C.sub.1-C.sub.4alkyl(C.sub.2-C.sub.8heterocycloalkyl); or R.sub.6 and R.sub.8 are H; and R.sub.7 is H, substituted or unsubstituted C.sub.1-C.sub.4alkyl, substituted or unsubstituted C.sub.1-C.sub.4heteroalkyl, C.sub.1-C.sub.8alkylaminoalkyl, C.sub.1-C.sub.8hydroxyalkylaminoalkyl, C.sub.1-C.sub.8alkoxyalkylaminoalkyl, substituted or unsubstituted C.sub.3-C.sub.6cycloalkyl, substituted or unsubstituted C.sub.1-C.sub.8alkylC.sub.3-C.sub.6cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted C.sub.2-C.sub.8heterocycloalkyl, substituted or unsubstituted heteroaryl, C.sub.1-C.sub.4alkyl(aryl), C.sub.1-C.sub.4alkyl(heteroaryl), C.sub.1-C.sub.8alkylether, C.sub.1-C.sub.8alkylamide, or C.sub.1-C.sub.4alkyl(C.sub.2-C.sub.8heterocycloalkyl); or R.sub.7 and R.sub.8 taken together form a bond; and R.sub.6 is H, substituted or unsubstituted C.sub.1-C.sub.4alkyl, substituted or unsubstituted C.sub.1-C.sub.4heteroalkyl, C.sub.i-C.sub.galkylaminoalkyl, C.sub.1-C.sub.8hydroxyalkylaminoalkyl, C.sub.i-C.sub.galkoxyalkylaminoalkyl, substituted or unsubstituted C.sub.3-C.sub.6cycloalkyl, substituted or unsubstituted C.sub.1-C.sub.8alkylC.sub.3-C.sub.6cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted C.sub.2-C.sub.8heterocycloalkyl, substituted or unsubstituted heteroaryl, C.sub.1-C.sub.4alkyl(aryl), C.sub.1-C.sub.4alkyl(heteroaryl), C.sub.1-C.sub.8alkylether, C.sub.1-C.sub.8alkylamide, or C.sub.1-C.sub.4alkyl(C.sub.2-C.sub.8heterocycloalkyl); 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, hydrate, or salt thereof.

2. The method of claim 1 wherein cells of the mast cell proliferative disorder express ITK.

3. The method of claim 1 wherein cells of the mast cell proliferative disorder express Bruton's tyrosine kinase (BTK).

4. The method of claim 1 wherein R.sub.2 and R.sub.3 are each independently H.

5. The method of claim 1 wherein R.sub.1 is a substituted phenyl.

6. The method of claim 1 wherein L.sub.3, X and L.sub.4 taken together form a nitrogen containing heterocyclic ring.

7. The method of claim 6 wherein G is or ##STR00128##

8. The method of claim 1 wherein R.sub.6, R.sub.7, and R.sub.8 are each independently H.

9. The method of claim 1 wherein the compound has the structure ##STR00129##

10. A method for treating a mast cell proliferative disorder comprising administering to a subject in need thereof an irreversible inhibitor of an interleukin-2 inducible tyrosine kinase (ITK), wherein the inhibitor is a compound having the structure of ##STR00130## or a pharmaceutically acceptable solvate, hydrate, or salt thereof.
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