Combination therapy for treating cancer

1. A method for treating renal cancer in a patient in need thereof comprising administering a therapeutically effective amount of an EZH2 inhibitor and one or more tyrosine kinase inhibitors;

wherein the EZH2 inhibitor is GSK-126 having the following formula:

or a pharmaceutically acceptable salt thereof;

or

a compound of Formula (I):

or a pharmaceutically acceptable salt thereof;

wherein:

R 701 is H, F, OR 707 , NHR 707 , —(C≡C)—(CH 2 ) n7 —R 708 , phenyl, 5- or 6-membered heteroaryl, C 3-8 cycloalkyl, or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, wherein the phenyl, 5- or 6-membered heteroaryl, C 3-8 cycloalkyl or 4-7 membered heterocycloalkyl each independently is optionally substituted with one or more groups selected from halo, C 1-3 alkyl, OH, O—C 1-6 alkyl, NH—C 1-6 alkyl, and, C 1-3 alkyl substituted with C 3-8 cycloalkyl or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, wherein each of the O—C 1-6 alkyl and NH—C 1-6 alkyl is optionally substituted with hydroxyl, O—C 1-3 alkyl or NH—C 1-3 alkyl, each of the O—C 1-3 alkyl and NH—C 1-3 alkyl being optionally further substituted with O—C 1-3 alkyl or NH—C 1-3 alkyl;

each of R 702 and R 703 , independently is H, halo, C 1-4 alkyl, C 1-6 alkoxyl or C 6 -C 10 aryloxy, each optionally substituted with one or more halo;

each of R 704 and R 705 , independently is C 1-4 alkyl;

R 706 is cyclohexyl substituted by N(C 1-4 alkyl) 2 wherein one or both of the C 1-4 alkyl is substituted with C 1-6 alkoxy; or R 706 is tetrahydropyranyl;

R 707 is C 1-4 alkyl optionally substituted with one or more groups selected from hydroxyl, C 1-4 alkoxy, amino, mono- or di-C 1-4 alkylamino, C 3-8 cycloalkyl, and 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, wherein the C 3-8 cycloalkyl or 4-7 membered heterocycloalkyl each independently is further optionally substituted with C 1-3 alkyl;

R 708 is C 1-4 alkyl optionally substituted with one or more groups selected from OH, halo, and C 1-4 alkoxy, 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, or O—C 1-6 alkyl, wherein the 4-7 membered heterocycloalkyl can be optionally further substituted with OH or C 1-6 alkyl; and

n 7 is 0, 1 or 2.

2. The method of claim 1 , wherein the EZH2 inhibitor is of Formula (I).

3. The method of claim 1 , wherein the one or more tyrosine kinase inhibitors are VEGF/VEGFR inhibitors.

4. A method for treating renal cancer in a patient in need thereof comprising administering a therapeutically effective amount of an EZH2 inhibitor and one or more VEGF/VEGFR inhibitors;

wherein the EZH2 inhibitor is GSK-126 having the following formula:

or a pharmaceutically acceptable salt thereof;

or

a compound of Formula (I):

or a pharmaceutically acceptable salt thereof;

wherein:

R 701 is H, F, OR 707 , NHR 707 , —(C≡C)—(CH 2 ) n7 —R 708 , phenyl, 5- or 6-membered heteroaryl, C 3-8 cycloalkyl, or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, wherein the phenyl, 5- or 6-membered heteroaryl, C 3-8 cycloalkyl or 4-7 membered heterocycloalkyl each independently is optionally substituted with one or more groups selected from halo, C 1-3 alkyl, OH, O—C 1-6 alkyl, NH—C 1-6 alkyl, and, C 1-3 alkyl substituted with C 3-8 cycloalkyl or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, wherein each of the O—C 1-6 alkyl and NH—C 1-6 alkyl is optionally substituted with hydroxyl, O—C 1-3 alkyl or NH—C 1-3 alkyl, each of the O—C 1-3 alkyl and NH—C 1-3 alkyl being optionally further substituted with O—C 1-3 alkyl or NH—C 1-3 alkyl;

each of R 702 and R 703 , independently is H, halo, C 1-4 alkyl, C 1-6 alkoxyl or C 6 -C 10 aryloxy, each optionally substituted with one or more halo;

each of R 704 and R 705 , independently is C 1-4 alkyl;

R 706 is cyclohexyl substituted by N(C 1-4 alkyl) 2 wherein one or both of the C 1-4 alkyl is substituted with C 1-6 alkoxy; or R 706 is tetrahydropyranyl;

R 707 is C 1-4 alkyl optionally substituted with one or more groups selected from hydroxyl, C 1-4 alkoxy, amino, mono- or di-C 1-4 alkylamino, C 3-8 cycloalkyl, and 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, wherein the C 3-8 cycloalkyl or 4-7 membered heterocycloalkyl each independently is further optionally substituted with C 1-3 alkyl;

R 708 is C 1-4 alkyl optionally substituted with one or more groups selected from OH, halo, and C 1-4 alkoxy, 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, or O—C 1-6 alkyl, wherein the 4-7 membered heterocycloalkyl can be optionally further substituted with OH or C 1-6 alkyl; and

n 7 is 0, 1 or 2.

5. The method of claim 1 , wherein the cancer is resistant to VEGF/VEGFR inhibitor treatment.

6. The method of claim 1 , wherein the EZH2 inhibitor is compound 44 having the following formula:

or pharmaceutically acceptable salt thereof.

7. The method of claim 1 , wherein the EZH2 inhibitor is:

or pharmaceutically acceptable salt thereof.

8. The method of claim 1 , wherein the EZH2 inhibitor is GSK-126.

9. The method of claim 1 , wherein the one or more tyrosine kinase inhibitors are selected from erlotinib (Tarceva); gefitinib (Iressa); imatinib (Gleevec); sorafenib (Nexavar); sunitinib (Sutent); trastuzumab (Herceptin); bevacizumab (Avastin); rituximab (Rituxan); lapatinib (Tykerb); cetuximab (Erbitux); panitumumab (Vectibix); everolimus (Afinitor); alemtuzumab (Campath); gemtuzumab (Mylotarg); temsirolimus (Torisel); pazopanib (Votrient); dasatinib (Sprycel); nilotinib (Tasigna); and vatalanib (Ptk787; ZK222584).

10. The method of claim 1 , wherein the one or more tyrosine kinase inhibitors includes sunitinib.

11. The method of claim 4 , wherein the one or more VEGF/VEGFR inhibitors are selected from bevacizumab (Avastin); sorafenib (Nexavar); sunitinib (Sutent); ranibizumab; pegaptanib; vandetinib; Vatalanib (Ptk787 or ZK222584); and motesanib diphosphate.

12. The method of claim 4 , wherein the one or more VEGF/VEGFR inhibitors include sunitinib.

13. The method of claim 1 , wherein the EZH2 inhibitor and the one or more tyrosine kinase inhibitors are administered simultaneously or sequentially.

14. The method of claim 1 , wherein the EZH2 inhibitor is administered prior to administration of the one or more tyrosine kinase inhibitors.

15. The method of claim 4 , wherein the EZH2 inhibitor and the one or more VEGF/VEGFR inhibitors are administered simultaneously or sequentially.

16. The method of claim 4 , wherein the EZH2 inhibitor is administered prior to administration of the one or more VEGF/VEGFR inhibitors.

17. The method of claim 1 , wherein the cancer is renal cell carcinoma.

18. The method of claim 4 , wherein the cancer is resistant to VEGF/VEGFR inhibitor treatment.

19. The method of claim 4 , wherein the EZH2 inhibitor is Compound 44 having the following formula:

or pharmaceutically acceptable salt thereof.

20. The method of claim 4 , wherein the cancer is renal cell carcinoma.