Treatment of B-cell malignancies by a combination JAK and PI3K inhibitors

1. A method of treating diffuse large B-cell lymphoma in a patient in need thereof, comprising administering to said patient: (a) an inhibitor of JAK1, selected from:

{1-{1-[3-Fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide;

((2R,5S)-5-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}tetrahydro-2H-pyran-2-yl)acetonitrile; and

4-[3-(cyanomethyl)-3-(3′,5′-dimethyl-1H,1′H-4,4′-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide;

or a pharmaceutically acceptable salt of any of the aforementioned; and

(b) an inhibitor of PI3Kδ, selected from:

7-(1-(9H-purin-6-ylamino)ethyl)-6-(3-fluorophenyl)-3-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;

4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}pyrrolidin-2-one;

and enantiomers and diastereomers thereof;

or a pharmaceutically acceptable salt of any of the aforementioned compounds, enantiomers, and diastereomers.

2. A method of treating diffuse large B-cell lymphoma in a patient in need thereof, comprising administering to said patient: (a) an inhibitor of JAK1; and (b) an inhibitor of PI3Kδ; wherein said inhibitor of JAK1 is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile, or pharmaceutically acceptable salt thereof; and said inhibitor of PI3Kδ is selected from 7-(1-(9H-purin-6-ylamino)ethyl)-6-(3-fluorophenyl)-3-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one and enantiomers and diastereomers thereof, or a pharmaceutically acceptable salt thereof.

3. The method of claim 2 , wherein said inhibitor of JAK1 is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile adipic acid salt.

4. The method of claim 1 , wherein said inhibitor of JAK1 is 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide, or a pharmaceutically acceptable salt thereof.

5. The method of claim 1 , wherein said inhibitor of PI3Kδ is selected from:

(S)-4-(3-((S)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one;

(R)-4-(3-((S)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one;

(S)-4-(3-((R)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one; and

(R)-4-(3-((R)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one;

and pharmaceutically acceptable salts of any of the aforementioned.

6. The method of claim 2 , wherein said inhibitor of PI3Kδ is (S)-7-(1-(9H-purin-6-ylamino)ethyl)-6-(3-fluorophenyl)-3-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one, or a pharmaceutically acceptable salt thereof.

7. The method of claim 1 , wherein said diffuse large B-cell lymphoma is activated B-cell like (ABC) diffuse large B-cell lymphoma.

8. The method of claim 2 , wherein said diffuse large B-cell lymphoma is activated B-cell like (ABC) diffuse large B cell lymphoma (ABC-DLBCL).

9. The method of claim 2 , wherein said inhibitor of JAK1 and said inhibitor of PI3Kδ are administered simultaneously.

10. The method of claim 2 , wherein said inhibitor of JAK1 and said inhibitor of PI3Kδ are administered sequentially.

11. A method of treating diffuse large B-cell lymphoma in a patient in need thereof, comprising administering to said patient {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile, or pharmaceutically acceptable salt thereof; and (S)-7-(1-(9H-purin-6-ylamino)ethyl)-6-(3-fluorophenyl)-3-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one, or a pharmaceutically acceptable salt thereof.

12. A method of treating diffuse large B-cell lymphoma in a patient in need thereof, comprising administering to said patient 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide, or pharmaceutically acceptable salt thereof; and 7-(1-(9H-purin-6-ylamino)ethyl)-6-(3-fluorophenyl)-3-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one, or a pharmaceutically acceptable salt thereof.

13. The method of claim 1 , wherein said inhibitor of JAK1 is ((2R,5S)-5-{2-[(1R)-1-hydroxyethyl]-1H-imidazo [4,5-d]thieno[3,2-b]pyridin-1-yl}tetrahydro-2H-pyran-2-yl)acetonitrile, or a pharmaceutically acceptable salt thereof.

14. The method of claim 1 , wherein said inhibitor of JAK1 is 4-[3-(cyanomethyl)-3-(3′,5′-dimethyl-1H, 1′H-4,4′-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide, or a pharmaceutically acceptable salt thereof.

15. The method of claim 1 , wherein said inhibitor of PI3Kδ is (S)-4-(3-((S)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one, or a pharmaceutically acceptable salt thereof.

16. The method of claim 1 , wherein said inhibitor of PI3Kδ is (R)-4-(3-((S)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one, or a pharmaceutically acceptable salt thereof.

17. The method of claim 1 , wherein said inhibitor of PI3Kδ is (S)-4-(3-((R)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one, or a pharmaceutically acceptable salt thereof.

18. The method of claim 1 , wherein said inhibitor of PI3Kδ is (R)-4-(3-((R)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one, or a pharmaceutically acceptable salt thereof.

19. The method of claim 1 , wherein said inhibitor of JAK1 is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile, or pharmaceutically acceptable salt thereof; and said PI3Kδ is selected from:

(S)-4-(3-((S)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one;

(R)-4-(3-((S)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one;

(S)-4-(3-((R)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one; and

(R)-4-(3-((R)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one;

and pharmaceutically acceptable salts of any of the aforementioned.

20. The method of claim 1 , wherein said diffuse large B-cell lymphoma is germinal center B cell (GCB) diffuse large B cell lymphoma (GCB-DLBCL).

21. The method of claim 2 , wherein said diffuse large B-cell lymphoma is germinal center B cell (GCB) diffuse large B cell lymphoma (GCB-DLBCL).

22. The method of claim 11 , wherein said diffuse large B-cell lymphoma is activated B-cell like (ABC) diffuse large B-cell lymphoma.

23. The method of claim 11 , wherein said diffuse large B-cell lymphoma is germinal center B cell (GCB) diffuse large B cell lymphoma (GCB-DLBCL).

24. The method of claim 12 , wherein said diffuse large B-cell lymphoma is activated B-cell like (ABC) diffuse large B-cell lymphoma.

25. The method of claim 12 , wherein said diffuse large B-cell lymphoma is germinal center B cell (GCB) diffuse large B cell lymphoma (GCB-DLBCL).

26. A method of treating diffuse large B-cell lymphoma in a patient in need thereof, comprising administering to said patient: (a) an inhibitor of JAK1, selected from:

4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide;

((2R,5S)-5-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}tetrahydro-2H-pyran-2-yl)acetonitrile; and

4-[3-(cyanomethyl)-3-(3′,5′-dimethyl-1H, 1′H-4,4′-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide;

and pharmaceutically acceptable salts of any of the aforementioned; and

(b) an inhibitor of PI3Kδ, selected from:

7-(1-(9H-purin-6-ylamino)ethyl)-6-(3-fluorophenyl)-3-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one; and

4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}pyrrolidin-2-one;

and enantiomers and diastereomers thereof;

or a pharmaceutically acceptable salt of any of the aforementioned compounds, enantiomers, and diastereomers.

27. The method of claim 26 , wherein said diffuse large B-cell lymphoma is activated B-cell like (ABC) diffuse large B-cell lymphoma.

28. The method of claim 26 , wherein said diffuse large B-cell lymphoma is germinal center B cell (GCB) diffuse large B cell lymphoma (GCB-DLBCL).

29. A method of treating diffuse large B-cell lymphoma in a patient in need thereof, comprising administering to said patient: (a) an inhibitor of JAK1, which is {1-{1-[3-Fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl acetonitrile, or a pharmaceutically acceptable salt thereof; and

(b) an inhibitor of PI3Kδ, selected from:

7-(1-(9H-purin-6-ylamino)ethyl)-6-(3-fluorophenyl)-3-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one; and

4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}pyrrolidin-2-one;

and enantiomers and diastereomers thereof;

or a pharmaceutically acceptable salt of any of the aforementioned compounds, enantiomers, and diastereomers.

30. The method of claim 29 , wherein said diffuse large B-cell lymphoma is activated B-cell like (ABC) diffuse large B-cell lymphoma.

31. The method of claim 29 , wherein said diffuse large B-cell lymphoma is germinal center B cell (GCB) diffuse large B cell lymphoma (GCB-DLBCL).