INHIBITORS OF BRUTON'S TYROSINE KINASE

1 . A composition comprising rituximab and a compound of Formula (D) having the structure:

wherein:

L a is CH 2 , O, NH or S;

Ar is a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl;

Y is an optionally substituted group selected from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;

Z is C(═O), OC(═O), NHC(═O), C(═S), S(═O) x , OS(═O) x , or NHS(═O) x , where x is 1 or 2;

R 7 and R 8 are independently selected from the group consisting of H, unsubstituted C 1 -C 4 alkyl, substituted C 1 -C 4 alkyl, unsubstituted C 1 -C 4 heteroalkyl, substituted C 1 -C 4 heteroalkyl, unsubstituted C 3 -C 6 cycloalkyl, substituted C 3 -C 6 cycloalkyl, unsubstituted C 2 -C 6 heterocycloalkyl, and substituted C 2 -C 6 heterocycloalkyl; or

R 7 and R 8 taken together form a bond;

R 6 is selected from the group consisting of H, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 heteroalkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 8 alkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 2 -C 8 heterocycloalkyl, substituted or unsubstituted heteroaryl, C 1 -C 4 alkyl(aryl), C 1 -C 4 alkyl(heteroaryl), C 1 -C 4 alkyl(C 3 -C 8 cycloalkyl), and C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl);

or a pharmaceutically active metabolite, or a pharmaceutically acceptable solvate, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable prodrug thereof,

or a stereoisomer thereof.

2 . The composition of claim 1 , wherein L a is O.

3 . The composition of claim 2 , wherein Ar is phenyl.

4 . The composition of claim 3 , wherein:

Z is C(═O), NHC(═O), or S(═O) 2 .

5 . The composition of claim 4 , wherein:

each of R 7 and R 8 is H; or

R 7 and R 8 taken together form a bond.

6 . The composition of claim 5 , wherein:

R 6 is H, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 heteroalkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 8 alkylaminoalkyl, C 1 -C 4 alkyl(aryl), C 1 -C 4 alkyl(heteroaryl), C 1 -C 4 alkyl(C 3 -C 8 cycloalkyl), or C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl).

7 . The composition of claim 6 , wherein:

Y is a 4-, 5-, 6-, or 7-membered cycloalkyl ring; or

Y is a 4-, 5-, 6-, or 7-membered heterocycloalkyl ring.

8 . The composition of claim 1 , wherein the compound is selected from the group consisting of:

1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (Compound 4); (E)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)but-2-en-1-one (Compound 5); 1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)sulfonylethene (Compound 6); 1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-yn-1-one (Compound 8); 1-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (Compound 9); N-((1s,4s)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)acrylamide (Compound 10); 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one (Compound 11); 1-((S)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one (Compound 12); 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (Compound 13); 1-((S)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (Compound 14); and (E)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-4-(dimethylamino)but-2-en-1-one (Compound 15).

9 .- 17 . (canceled)

18 . A method for treating a cancer comprising administering to a subject in need thereof a composition containing a therapeutically effective amount of rituximab and a compound or a pharmaceutically acceptable solvate or salt thereof, wherein the compound is a compound of Formula (D), or a stereoisomer thereof, having the structure:

wherein:

L a is CH 2 , O, NH or S;

Ar is a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl;

Y is an optionally substituted group selected from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;

Z is C(═O), OC(═O), NHC(═O), C(═S), S(═O) x , OS(═O) x , NHS(═O) x , where x is 1 or 2;

R 7 and R 8 are independently selected from the group consisting of H, unsubstituted C 1 -C 4 alkyl, substituted C 1 -C 4 alkyl, unsubstituted C 1 -C 4 heteroalkyl, substituted C 1 -C 4 heteroalkyl, unsubstituted C 3 -C 6 cycloalkyl, substituted C 3 -C 6 cycloalkyl, unsubstituted C 2 -C 6 heterocycloalkyl, and substituted C 2 -C 6 heterocycloalkyl; or

R 7 and R 8 taken together form a bond;

R 6 is H, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 heteroalkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 4 alkyl-N(C 1 -C 4 alkyl) 2 , substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 2 -C 8 heterocycloalkyl, substituted or unsubstituted heteroaryl, C 1 -C 4 alkyl, C 1 -C 4 alkyl(heteroalkyl), C 1 -C 4 alkyl(C 3 -C 8 cycloalkyl), and C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl).

19 . The method of claim 18 , wherein the cancer is a B-cell proliferative disorder.

20 . The method of claim 19 , wherein the B-cell proliferative disorder is diffuse large B cell lymphoma, follicular lymphoma, follicular lymphoma, chronic lymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenström macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, burkitt lymphoma/leukemia, or lymphomatoid granulomatosis.

21 . The method of claim 18 , wherein the compound has the following structure: