Combination therapy for treatment of hematological diseases

1. A method of inhibiting or ameliorating a hematological disease selected from leukemia, lymphoma, and multiple myeloma in a patient in need thereof, comprising administering to the patient: (a) a therapeutically effective amount of a selective JAK1 inhibitor; (b) a therapeutically effective amount of an immunomodulatory agent, and (c) a therapeutically effective amount of a steroid; wherein:

(a) the JAK1 inhibitor is 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}-N-[4-fluoro-2-(trifluoromethyl)phenyl]piperidine-1-carboxamide;

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

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;

((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;

3-[1-(6-chloropyridin-2-yl)pyrrolidin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile;

3-(1-[1,3]oxazolo[5,4-b]pyridin-2-ylpyrrolidin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile;

4-[(4-{3-cyano-2-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}piperazin-1-yl)carbonyl]-3-fluorobenzonitrile;

4-[(4-{3-cyano-2-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]propyl}piperazin-1-yl)carbonyl]-3-fluorobenzonitrile;

[trans-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-(4-{[2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperazin-1-yl)cyclobutyl]acetonitrile;

{trans-3-(4-{[4-[(3-hydroxyazetidin-1-yl)methyl]-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{trans-3-(4-{[4-{[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl}-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{trans-3-(4-{[4-{[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl}-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

4-(4-{3-[(dimethylamino)methyl]-5-fluorophenoxy}piperidin-1-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile;

5-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-isopropylpyrazine-2-carboxamide;

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;

5-{3-(cyanomethyl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-isopropylpyrazine-2-carboxamide;

{1-(cis-4-{[6-(2-hydroxyethyl)-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(cis-4-{[4-[(ethylamino)methyl]-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(cis-4-{[4-(1-hydroxy-1-methylethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(cis-4-{[4-{[(3R)-3-hydroxypyrrolidin-1-yl]methyl}-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(cis-4-{[4-{[(3S)-3-hydroxypyrrolidin-1-yl]methyl}-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{trans-3-(4-{[4-({[(1S)-2-hydroxy-1-methylethyl]amino}methyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{trans-3-(4-{[4-({[(2R)-2-hydroxypropyl]amino)methyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{trans-3-(4-{[4-({[(2S)-2-hydroxypropyl]amino)methyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile; and

{trans-3-(4-{[4-(2-hydroxyethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

or a pharmaceutically acceptable salt of any of the aforementioned;

(b) the immunomodulatory agent is selected from thalidomide, lenalidomide, apremilast, linomide, and pomalidomide, or a pharmaceutically acceptable salt of any of the aforementioned; and

(c) the steroid is selected from prednisone, methylprednisolone, dexamethasone, hydroxycortisone, cortisone, desoxycorticosterone, fludrocortisone, betamethasone, prednisolone, methylprednisone, paramethasone, triamcinolone, flumethasone, fluocinolone, fluocinonide, fluprednisolone, halcinonide, flurandrenolide, meprednisone, and medrysone, or a pharmaceutically acceptable salt of any of the aforementioned.

2. The method of claim 1 , wherein the selective JAK1 inhibitor 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.

3. The method of claim 1 , wherein the selective JAK1 inhibitor 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 the immunomodulatory agent is thalidomide, or a pharmaceutically acceptable salt thereof.

5. The method of claim 1 , wherein the immunomodulatory agent is lenalidomide, or a pharmaceutically acceptable salt thereof.

6. The method of claim 1 , wherein the immunomodulatory agent is pomalidomide, or a pharmaceutically acceptable salt thereof.

7. The method of claim 1 , wherein the immunomodulatory agent is apremilast, or a pharmaceutically acceptable salt thereof.

8. The method of claim 1 , wherein the steroid is methylprednisolone, or a pharmaceutically acceptable salt thereof.

9. The method of claim 1 , wherein the steroid is dexamethasone, or a pharmaceutically acceptable salt thereof.

10. The method of claim 1 , wherein the steroid is prednisone, or a pharmaceutically acceptable salt thereof.

11. The method of claim 1 , wherein the hematological disease is chronic lymphocytic leukemia.

12. The method of claim 1 , wherein the hematological disease is non-Hodgkin's lymphoma.

13. The method of claim 12 , wherein the non-Hodgkin's lymphoma is B-cell related.

14. The method of claim 1 , wherein the hematological disease is multiple myeloma.

15. The method of claim 14 , wherein the multiple myeloma is relapsed, refractory, or relapsed and refractory multiple myeloma.

16. The method of claim 1 , wherein the hematological disease is multiple myeloma, the selective JAK1 inhibitor 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, the immunomodulatory agent is lenalidomide, or a pharmaceutically acceptable salt thereof; and the steroid is methylprednisolone or dexamethasone, or a pharmaceutically acceptable salt thereof.

17. The method of claim 1 , wherein the hematological disease is multiple myeloma, the selective JAK1 inhibitor 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, the immunomodulatory agent is lenalidomide, or a pharmaceutically acceptable salt thereof; and the steroid is dexamethasone, or a pharmaceutically acceptable salt thereof.

18. The method of claim 16 , wherein the multiple myeloma is relapsed, refractory, or relapsed and refractory multiple myeloma.

19. The method of claim 1 , wherein the selective JAK1 inhibitor is administered in a daily amount of from about 200 mg to about 1200 mg on a free base basis.

20. The method of claim 1 , wherein the immunomodulatory agent is administered in a daily amount of from about 2.5 mg to about 25 mg on a free base basis.

21. The method of claim 1 , wherein the steroid is administered in a daily amount of from about 20 mg to about 60 mg on a free base basis.

22. The method of claim 1 , wherein the method comprises cyclic administration of the selective JAK1 inhibitor, the immunomodulatory agent, and the steroid, or a pharmaceutically acceptable salt thereof.

23. The method of claim 1 , wherein the selective JAK1 inhibitor is administered in a daily amount of from about 200 mg to about 1200 mg on a free base basis on days 1-28 in a 28 day cycle.

24. The method of claim 1 , wherein the selective JAK1 inhibitor is administered as one or more sustained-release dosage forms.

25. The method of claim 1 , wherein the immunomodulatory agent is administered in a daily amount of from about 2.5 mg to about 25 mg on a free base basis on days 1-21 in a 28 day cycle.

26. The method of claim 1 , wherein the steroid is administered in an amount of from about 20 mg to about 60 mg on a free base basis every other day during days 1-28 in a 28 day cycle.

27. A method of inhibiting or ameliorating multiple myeloma in a patient in need thereof, comprising administering to the patient: (a) a daily amount of {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, of from about 200 to about 1200 mg on a free base basis on days 1-28 in a 28 day cycle; (b) a daily amount of lenalidomide, or a pharmaceutically acceptable salt thereof, of about 10 mg on a free base basis of on days 1-21 in the 28 day cycle; and (c) a daily amount of methylprednisolone, or a pharmaceutically acceptable salt thereof, of about 40 mg on a free base basis every other day during days 1-28 in the 28 day cycle.

28. A method of inhibiting or ameliorating multiple myeloma in a patient in need thereof, comprising administering to the patient: (a) a daily amount of {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, of from about 200 to about 1200 mg on a free base basis on days 1-28 in a 28 day cycle; (b) a daily amount of lenalidomide, or a pharmaceutically acceptable salt thereof, of about 10 mg on a free base basis on days 1-21 in the 28 day cycle; and (c) a daily amount of dexamethasone, or a pharmaceutically acceptable salt thereof, of from about 2 mg to about 20 mg on a free base basis on days 1-28 in the 28 day cycle.